IVF Resources

Backed by the expertise of our fertility specialists, we guide you through the medication options available. We understand that each individual's path to parenthood is different, and our goal is to provide clarity and support every step of the way.

Learn information covering every aspect of the IVF process, from initial consultations to embryo transfer. Our resources provide insights into fertility medications, embryo development, and the various stages of IVF treatment.

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IVF Resources

Acupuncture and IVF
Acupuncture and IVF
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Clinical Trials & Research
Clinical Trials & Research
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Embryo Development
Embryo Development
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Embryo Freezing
Embryo Freezing
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Failed Fertility Treatments and Health Risks
Failed Fertility Treatments and Health Risks
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First Time IVF Success
First Time IVF Success
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Frozen Embryo Transfer
Frozen Embryo Transfer
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Frozen Embryo Transfer Problems
Frozen Embryo Transfer Problems
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Frozen Embryo Transfer Success
Frozen Embryo Transfer Success
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In Vitro Maturation (IVM)
In Vitro Maturation (IVM)
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IVF and Birth Defects
IVF and Birth Defects
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IVF Answers From Start to Finish
IVF Answers From Start to Finish
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IVF Pregnancy Screening
IVF Pregnancy Screening
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Pesticides & Success Rates
Pesticides & Success Rates
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Risks of Multiple Pregnancy
Risks of Multiple Pregnancy
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Single Embryo Transfer
Single Embryo Transfer
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Acupuncture and Infertility

Acupuncture and Infertility

Acupuncture is the insertion of thin metallic needles into anatomically defined locations on the body to affect bodily function. Acupuncture needles are regulated by the FDA just like other medical devices such as surgical scalpels and hypodermic needles. This helps ensure that the needles meet standards for quality and sterility. In Illinois, practicing acupuncturists must show proof of adequate training by an approved acupuncture program and be licensed.

The general theory of acupuncture is based on the premise that there are patterns of energy flow (Qi) through the body, which are essential for health. Disruption of this flow is believed to be responsible for disease. Acupuncture can correct imbalances of flow at identifiable points close to the skin. These acupuncture points correspond to specific areas on the surface of the body. Attempts to study these areas have found that they do have unique identifiable properties such as temperature and electrical conductance.

Acupuncture Treatment

Some studies have shown that acupuncture has an effect on brain chemicals called endorphins. Endorphins, in turn can affect the levels of the pituitary hormones which control the function of the ovaries. It is possible, therefore, that acupuncture may be used to influence ovulation and fertility.

Several studies have shown that acupuncture apparently affected the levels of these hormones in the blood as well as the levels of estrogen and progesterone from the ovaries. A small series of women who had problems with ovulation found that that about half of them responded to acupuncture treatment.

A larger group of patients was studied by a German group. These women had various types of ovulation problems. They were divided into two groups. One group received medical fertility treatments and the other group had acupuncture. Although the investigators concluded that the acupuncture group had better results, the actual data is not that clear.

For example, seven pregnancies in the acupuncture group were actually achieved with hormone treatment 6 months after acupuncture was stopped. Another study used electro-acupuncture in PCOS patients in attempt to induce ovulation. Before treatment about 15% of menstrual cycles were associated with ovulation. After treatment, about 66% of the cycles were ovulatory.

Acupuncture and IVF – How might it work?

There are several mechanisms by which acupuncture could influence the results of In vitro Fertilization – IVF. Acupuncture has been shown in some studies to affect the levels of pituitary and ovarian hormones. Electro-acupuncture may help improve blood flow in the uterine arteries of infertile women.

The most immediate possible effect is that acupuncture served to “relax” the uterus around the time of the transfer. Several studies have shown that the uterus has contractions and that these contractions could cause expulsion of the transferred IVF embryos. If the contractions were reduced by acupuncture then that could be a mechanism for an improvement in IVF pregnancy rate.

However, researchers performing a study on 164 IVF patients found that acupuncture did not reduce uterine contractions. Furthermore, implantation of the embryos into the uterine lining does not occur for two to five days after embryo transfer depending upon when the embryos were transferred. It is unknown whether the effect of acupuncture performed on the day embryo transfer would last until the day of embryo implantation or longer.

Many patients have been told that they should use acupuncture for IVF because they will respond better to medication, get more eggs, get healthier eggs, or get higher pregnancy rates. Many women with specific problems such as high FSH levels or miscarriages have been promised that acupuncture will cure all these problems. To date, however, there is no objective data that backs up these claims.

As of early 2018, there have now been several studies looking at whether acupuncture influences the outcome of IVF cycles. I have reviewed some of the major studies below.

Acupuncture and IVF – Study Number 1

Published in the Journal of the American Medical Association (JAMA) in May 2018. This study is hailed as the most definitive evidence yet that acupuncture has no benefit in terms of increasing the chance for a live birth with IVF.

Acupuncture IVF Patient Groups- Study Number 1

The study was performed in 16 IVF programs in Australia and New Zealand, the randomized clinical trial involved 848 women aged 18 to 42 undergoing an IVF cycle using fresh embryos. Treatments occurred between 2011 and 2015. Participants were given either acupuncture or a sham acupuncture control (a non-insertive needle placed away from the true acupuncture points).

Acupuncture and IVF Treatment – Study Number 1

Women were recruited at the time of the decision to undergo an IVF or ICSI cycle, and randomization occurred prior to starting medication. Following randomization, women made an appointment with the study acupuncturist onsite at the IVF centers or nearby. The first treatment was administered between days 6 and 8 of ovarian stimulation, and 2 treatments were given on the day of embryo transfer.

The acupuncturists had a minimum of 2 years clinical experience, held membership with a national professional association, and in Australia, were registered with the national Australian Health Practitioner Regulation Agency.

Acupuncture and IVF Pregnancy Rates and Results – Study Number 1

The frequency of live births did not differ between groups: 74 of 405 women (18.3%) randomized to acupuncture had a live birth compared with 72 of 404 (17.8%) in the sham acupuncture group. The likelihood of a live birth was not different between the 2 groups after adjusting for age, number of previous IVF cycles, and participating IVF center. there was also no difference in the rate of miscarriage.

Conclusions from Study Number 1

These findings do not support the use of acupuncture to improve the rate of live births among women undergoing IVF.

Acupuncture and IVF – Study Number 2

The first published study, which received a great deal of attention, was conducted by Paulus and colleagues. Although this study was well designed, it looked at a very specific group of patients. The results may not be applicable to other patient groups.

Acupuncture IVF Patient Groups- Study Number 2

The study looked at 160 women aged 21 to 43. Over half the couples were being treated for IVF because of male factor. One fourth had blocked tubes. This is an important consideration since three fourths of the patients would not be expected to have any hormonal abnormalities or uterine issues.

Another requirement for entry into the study was that only couples “with good embryo quality” were eligible. This is an extremely important point. Based on the results of this study, we do not have any idea whether acupuncture would work for couples who do not have good embryo quality.

Acupuncture and IVF Treatment – Study Number 2

In this study, IVF patients received acupuncture 25 minutes before and 25 minutes after the embryo transfer. No patients received acupuncture before or during treatment with fertility medications. Thus, we do not know if acupuncture would have had any effect on improving the number of eggs or any influence in the preparation of the uterine lining.

The acupuncture points chosen for the study were supposed to result in:

  • Better blood perfusion and “energy” in the uterus
  • Sedation of the patient
  • “Stabilization” of the endocrine system

Acupuncture and IVF Pregnancy Rates and Results – Study Number 2

In this study, IVF patients who had acupuncture had a 42% pregnancy rate. IVF patients who did not have acupuncture had a 26% rate.

There was no difference between the two groups in the thickness of the uterine lining or indexes of blood flow through the uterine arteries either before or after the embryo transfer. Hormone levels were not measured during this study.

One of the criticisms of this study is that the results could be due to the placebo effect. To counter these criticisms, one year after publishing the original study, the authors presented a placebo-controlled study at the annual meeting of the European Society for Human Reproduction and Embryology. Two hundred patients with good embryo quality were randomized to receive either real or sham acupuncture for 25 minutes before and after ET. There were clinical pregnancies in 43% of the real and 37% of the sham acupuncture patients. Statistical analysis of the results determined there was no significant difference between the groups. In other words, in this study, conducted by the same investigators and performed in the same way as the original study, acupuncture was not found to improve pregnancy rates.

Conclusions from Study Number 2

When the first and second parts of this study conducted by these investigators are taken into account, it would appear that performing acupuncture immediately before and after the embryos transfer may not result in a higher chance for pregnancy.

Acupuncture and IVF – Study Number 3

Prior to beginning their study, the doctors who conducted acupuncture study number 2 performed a “power analysis”. This means they used some of the data from the Paulus study above as well as the pregnancy rate results from their own clinic to calculate, ahead of time, the number of patients they would need to study in order to prove that acupuncture either works or doesn’t work. They determined that to find a difference in the clinical pregnancy rate of 11% between no acupuncture (the control group) and acupuncture (the treatment group) they would require approximately 100 patients in a control group and 200 patients in the acupuncture groups.

Acupuncture and IVF Treatment Protocol- Study Number 3

The study was conducted over a period of 16 months. During that time, about 1000 couples underwent in vitro fertilization at their center. Of these, 300 couples agreed to participate in the study and were randomized to one of three groups on the day of egg retrieval. After randomization, 27 patients were excluded for various reasons. Of the remaining 273 patients, 87 were allocated to no acupuncture (control group), 95 to acupuncture on the day of embryo transfer, and 91 to receive acupuncture on the day of ET and again 2 days later.

Acupuncture IVF Pregnancy Rates and Results – Study Number 3

There was no difference between the three groups in the number of eggs retrieved or the number of embryos available to transfer to the uterus.

The ongoing pregnancy rate was higher in both of the acupuncture groups compared to the control group. The ongoing pregnancy rate in the group which received acupuncture once was 36%, in the group that received acupuncture twice, the rate was 33% and in the group that did not receive acupuncture at all it was 22%. Statistical analysis was performed to determine whether these results might have been due to random chance. The analysis determined that the improvement in pregnancy rates in the single acupuncture group was unlikely to be due to chance but that the improvement in the double acupuncture group may have been due to chance.

Interestingly, the miscarriage rate in the group that received acupuncture twice was 33%. This is higher than the miscarriage rate in the group that had acupuncture once 21% or the control group — 15%. Statistical analysis showed that these results might have occurred by random chance however.

The results of this study are somewhat confusing. If acupuncture was beneficial in increasing pregnancy rates, then why weren’t two acupuncture sessions better than one? What was the reason for the seemingly higher miscarriage rate in the group that received acupuncture twice?

Acupuncture and IVF – Study Number 4

In this third acupuncture study, a total of 225 infertile patients were included: 116 women were randomized into group I (the study group), and 109 women were randomized into group II (the control group). The physician who performed the embryo transfer was not aware of which couples were in which group. On the day of embryo transfer, the patients in the study group received acupuncture according to the principles of traditional Chinese medicine. At the same time, a special Chinese medical drug (the seed of Caryophyllaceae) was placed on the patient’s ear. The seeds remained in place for 2 days and were pressed twice daily for 10 minutes. Three days after the embryo transfer, the patients received a second acupuncture treatment. In addition, the same ear points were pressed at the opposite ear twice daily. The seeds were removed after 2 days.

The control group received placebo or phony acupuncture. As in the treatment group, patients received phony acupuncture treatment for 30 minutes. The phony acupuncture treatment was repeated three days after the embryo transfer. Equal numbers of needles were applied to the study and control groups. The placebo acupuncture treatment was designed not to influence fertility.

Acupuncture and IVF Pregnancy Rates and Results – Study Number 4

Both groups were similar in terms of age, weight, duration of infertility, cause of infertility, and number of previous IVF attempts. No differences were found in the specifics of the ovarian stimulation, the number of eggs retrieved, the fertilization rate, or the number of embryos transferred.

The success rates were looked at in a few ways. The implantation rate is the number of pregnancies produced divided by the number of embryos transferred. The real acupuncture group had an implantation rate of 14.2% whereas the phony acupuncture group’s implantation rate was only 5.9%. The ongoing pregnancy rate was 28.4% in the real acupuncture group compared to 13.8% in the phone group.

Acupuncture and IVF – Conclusions from Study Number 4

This study introduced a number of variables that make it difficult to interpret the results. First, a Chinese medicine was administered in addition to the acupuncture. There is no way to determine, therefore, whether the results were the result of the acupuncture or the medicine.

The “control group” had acupuncture performed at sites that were not thought to improve fertility. It is possible however, that these sites actually had a negative effect. The way the study was designed, there is no way to determine which is correct.

Acupuncture and IVF – Study Number 5

This next acupuncture and in vitro fertilization study subjected the patients to three acupuncture treatment sessions. The first took place before the egg retrieval on the 9th day of ovarian stimulation with fertility drugs, and the second and third acupuncture treatments were performed immediately before and after the embryo transfer. Women were randomly allocated to receive treatment with acupuncture or with noninvasive “sham” (placebo or phony) acupuncture.

Acupuncture IVF Patient Groups- Study Number 5

Subjects were randomly allocated to a study group by selection of sealed envelopes. Women were allocated to receive treatment with acupuncture or with noninvasive sham acupuncture.

Acupuncture and IVF Treatment Pregnancy Rates – Study Number 5

Of the 228 subjects randomized, 15% were unable to complete the treatment protocol because their IVF cycle was cancelled prior to the embryo transfer. No difference in the grading of embryos was found between groups. The pregnancy rate, defined as fetal heart rate on ultrasound scan, was 31% in the acupuncture group and 23% in the control group. Statistical analysis demonstrated that the difference seen was likely the result of chance and not the acupuncture itself.

The pregnancy rate was also not found to differ between groups if the women studies were under age 35.

No difference was found between groups for other study endpoints: number of eggs retrieved, fertilization rate or number of embryos transferred.

To examine whether the attempts to conceal from the patients the treatments they were receiving was successful, subjects were asked which group they thought they had been allocated to. Twenty-six subjects (11%) correctly guessed which group they were in. 16 subjects were in the treatment group and 10 were in the control group.

Acupuncture and IVF — Conclusions from Study Number 5

This study, which appeared to have a valid control group, could not demonstrate a benefit in terms of better pregnancy rates when acupuncture was used.

Acupuncture in infertility

We have several acupuncturists that work with our patients. If you are interested in having acupuncture performed as part of your IVF treatment then contact the office for a list of names.

IVF1 Clinical Trials & Research

Although we have many effective treatments for couples with infertility, there are still many unanswered questions. At IVF1, we conduct research studies to help answer some of these questions. Our clinical trials involve the use of actual treatments on patients with a variety of different problems. Currently we are conducting studies involving patients with infertility, recurrent miscarriage and those who have failed other treatments such as IVF or frozen embryo transfer.  Click the links below to learn about current studies.

Fertility Preservation and the Role of AMH (Anti-Mullerian hormone)

Recurrent miscarriage in IVF Patients

Thin uterine lining during FET (frozen embryo transfer)

IVF Recurrent Implantation Failure

Treatment of poor ovarian reserve

Primary investigator: Hillary Klonoff-Cohen, Ph.D.

Co-investigator: Randy Morris M.D.

NAME OF RESEARCH STUDY: Fertility Preservation and the Role of  AMH

Summary: The purpose of this study is to measure Anti-Mullerian Hormone (AMH) in your blood, which is often used to check a women’s ovarian function and fertility. As a newly diagnosed breast cancer patient, you have the option of undergoing in-vitro fertilization to store your eggs or embryos prior to beginning cancer treatment. Measuring AMH could provide an accurate measure of your future ability to become pregnant after completion of your cancer treatment.

Eligible patients:

  1. Reproductive age females (18-45)
  2. Newly diagnosed with breast cancer who have not yet undergone chemotherapy, radiation, or surgery,
  3. Planning to store oocytes or embryos for fertility preservation.

Exclusions:

  1. Patients with other chronic medical conditions such as hypertension or diabetes which is not adequately controlled

Primary Investigator:  Randy Morris M.D.

Status: Recruiting eligible patients

Protocol ID: IVF-03

NAME OF RESEARCH STUDY: A prospective, longitudinal cohort study to investigate the effects of intrauterine infusion of platelet rich plasma (PRP) in women with recurrent pregnancy loss during IVF.

Summary: This study is looking at the effects of effects of intrauterine infusion of platelet rich plasma (PRP) in infertile women with recurrent miscarriage who are attempting pregnancy using IVF. We are trying to determine whether injecting PRP into the uterine cavity (where it will come in contact with the uterine lining) will improve the likelihood of an embryo to continue to develop after implantation.

Eligible patients

In order to participate in this study, you must

  1. Have had at least two unexplained, first trimester miscarriages
  2. Have completed an evaluation on both male and female partners without any causes for recurrent miscarriage being found
  3. Have embryos frozen at the blastocyst stage that are available for transfer
  4. Embryos must be frozen using vitrification
  5. Embryos must be considered high quality as judged by Naperville Fertility Center embryologists
  6. The embryos must be in storage at the Naperville Fertility Center before study enrollment
  7. Embryos may not have been thawed previously
  8. Embryos must have have undergone biopsy and testing for chromosome abnormalities (PGS or preimplantation genetic screening)
  9. Prior to study enrollment, demonstrate a normal uterine cavity and absence of hydrosalpinx by hysterosalpingogram, hysteroscopy or laparoscopy with chromopertubation.
  10. Have a BMI of less than 30 in order to enroll and must maintain a BMI of less than 30 when estrogen supplementation begins
  11. Have normal thyroid function as evidenced by a TSH level in the normal range within two months prior to enrollment.

Exclusions

You may not participate in this study if

  1. You have any contraindication to the use of estrogen or progesterone supplementation
  2. You have an uncorrected uterine abnormality
  3. You have an uncorrected hydrosalpinx
  4. You or your partner have other causes for recurrent miscarriage
  5. Either you or your partner who produced the embryos have tested positive for either syphilis, hepatitis B, hepatitis C, or HIV AIDS
  6. You have taken any non-prescription supplements within one month of enrolling in the study
  7. You have uncontrolled diabetes (HbA1c > 6)
  8. You have uncontrolled high blood pressure (140/90 despite use of medication)

Primary Investigator:  Randy Morris M.D.

Status: Recruiting eligible patients

Protocol ID: IVF-01

NAME OF RESEARCH STUDY: A prospective, longitudinal cohort study to investigate the effects of intrauterine infusion of platelet rich plasma (PRP) in infertile women with thin endometrial linings during preparation for frozen embryo transfer (FET)

Summary: This study is looking at the effects of intrauterine infusion of platelet rich plasma (PRP) in infertile women with thin endometrial linings during preparation for frozen embryo transfer (FET). We are trying to determine whether injecting PRP into the uterine cavity (where it will come in contact with the uterine lining) will improve the thickness of the lining in women who have previously had problems developing a thick lining.

Eligible patients

In order to participate in this study, you must

  1. Have had at least one previous FET attempt using a standard estrogen and progesterone protocol that was cancelled because of a thin uterine lining (< 6 mm) as measured by transvaginal ultrasound
  2. Have embryos frozen at the blastocyst stage that are available for transfer
  3. Embryos must be frozen using vitrification
  4. Embryos must be considered high quality as judged by Naperville Fertility Center embryologists
  5. The embryos must be in storage at the Naperville Fertility Center before study enrollment
  6. Embryos may not have been thawed previously
  7. Priority will be given to patients whose embryos have undergone biopsy and testing for chromosome abnormalities (PGS or preimplantation genetic screening)
  8. Prior to study enrollment, demonstrate a normal uterine cavity by either saline ultrasound, hysterosalpingogram, or hysteroscopy. A “normal” cavity at the end of an operative hysteroscopy must have follow-up with a subsequent evaluation at a separate time.
  9. Have a BMI of less than 30 in order to enroll and must maintain a BMI of less than 30 when estrogen supplementation begins
  10. Have normal thyroid function as evidenced by a TSH level in the normal range within two months prior to enrollment.

Exclusions

You may not participate in this study if

  1. You have any contraindication to the use of estrogen or progesterone supplementation
  2. You have an uncorrected uterine abnormality
  3. Either of the partners who produced the embryos have tested positive for either syphilis, hepatitis B, hepatitis C, or HIV AIDS
  4. You have taken any non-prescription supplements within one month of enrolling in the study
  5. You have uncontrolled diabetes (HbA1c > 6)
  6. You have uncontrolled high blood pressure (140/90 despite use of medication)

Clinical Trial: IVF Implantation FailurePrimary Investigator:  Randy Morris M.D.

Status: Recruiting eligible patients

PROTOCOL ID: IVF1-02

NAME OF RESEARCH STUDY: A prospective, longitudinal cohort study to investigate the effects of intrauterine infusion of platelet rich plasma (PRP) in infertile women with recurrent implantation failure.

Summary: This study is looking at the effects of intrauterine infusion of platelet rich plasma (PRP) in infertile women with recurrent implantation failure. We are trying to determine whether injecting PRP into the uterine cavity (where it will come in contact with the uterine lining) will improve the likelihood of an embryo to implant.

Eligible patients

In order to participate in this study, you must

  1. Have failed to achieve pregnancy after transfer of
  2. At least two expanded blastocysts that have undergone comprehensive chromosome screening
  3. At least four expanded blastocysts that have not had comprehensive chromosome screening
  4. Have embryos frozen at the blastocyst stage that are available for transfer
  5. Embryos must be frozen using vitrification
  6. Embryos must be considered high quality as judged by Naperville Fertility Center embryologists
  7. The embryos must be in storage at the Naperville Fertility Center before study enrollment
  8. Embryos may not have been thawed previously
  9. Priority will be given to patients whose embryos have undergone biopsy and testing for chromosome abnormalities (PGS or preimplantation genetic screening)
  10. Prior to study enrollment, demonstrate a normal uterine cavity and absence of hydrosalpinx by hysterosalpingogram, or laparoscopy with chromopertubation.
  11. Have a BMI of less than 30 in order to enroll and must maintain a BMI of less than 30 when estrogen supplementation begins
  12. Have normal thyroid function as evidenced by a TSH level in the normal range within two months prior to enrollment.

Exclusions

You may not participate in this study if

  1. You have any contraindication to the use of estrogen or progesterone supplementation
  2. You have an uncorrected uterine abnormality
  3. You have an uncorrected hydrosalpinx
  4. Either you or your partner who produced the embryos have tested positive for either syphilis, hepatitis B, hepatitis C, or HIV AIDS
  5. You have taken any non-prescription supplements within one month of enrolling in the study
  6. You have uncontrolled diabetes (HbA1c > 6)
  7. You have uncontrolled high blood pressure (140/90 despite use of medication)

Clinical Trial: Treatment to Improve Ovarian ReservePROTOCOL NUMBER: IVF1-04

NAME OF RESEARCH STUDY: A prospective, longitudinal cohort study to investigate the effects of ovarian platelet rich plasma (PRP) injection in women with poor ovarian reserve

PRINCIPAL INVESTIGATOR:Randy  S Morris M.D.

Summary: This study is trying to determine whether injection of platelet rich plasma (PRP) into the ovaries of infertile women with decreased ovarian reserve will result in activation of ovarian stem cells and result in the production of healthy new eggs.

Eligible patients
In order to participate in this study, you must

  1. Be under the age of 40
  2. Have a history of infertility and be currently attempting pregnancy
  3. Be pre-menopausal as evidenced by still having menstrual cycles
  4. Have decreased ovarian reserve
  5. Low levels of AMH
  6. High levels of FSH on day 2 or 3 of the menstrual cycle
  7. Low antral follicle count on transvaginal ultrasound on day 2 or 3 of the menstrual cycle
  8. Have a BMI of less than 30
  9. Have normal thyroid function as evidenced by a TSH level in the normal range within two months prior to enrollment.

Exclusions

You may not participate in this study if you

  1. Are using any form of contraception
  2. Have previously had surgery on your ovaries
  3. Have undergone chemotherapy or radiation at any time in the past
  4. Have been diagnosed with Premature Ovarian Failure
  5. Have ovaries that are inaccessible by transvaginal ultrasound
  6. Have used any herbal or nutritional supplements other than prenatal vitamins in the previous 6 months
  7. Have any contraindications to anesthesia
  8. You have uncontrolled diabetes (HbA1c > 6)
  9. You have uncontrolled high blood pressure (140/90 despite use of medication)

Embryo Development

After fertilization has taken place, the embryos are transferred to a special growth fluid (media). The process of allowing embryos to develop in the IVF laboratory is called culturing. In order to enable the embryos to reach the blastocyst stage, the culture dishes containing the embryos and the media are maintained in an incubator where the atmosphere, humidity, and temperature are carefully monitored and controlled.

During this time in the incubator, it is hoped that the embryos will develop normally. Normal embryo development requires a process of cell division called mitosis. The single fertilized egg divides into two cells, then four and so on. Some embryos will not divide at all. Some embryos may divide at a very slow rate which is indicative of a poor potential for producing pregnancy. Some embryos may divide abnormally and start to fragment during their development. These embryos also have a poor potential for producing pregnancy. Normally, by the third day after the egg retrieval, healthy eggs will have divided into eight cell embryos.

Stages of Embryo Development

Embryos that have only divided into 2 or 4 cell embryos by the third day have a lower potential for producing a pregnancy. Sometimes, the embryos don’t divide equally giving rise to embryos with three, five or seven cells.

In addition to looking at the number of cells, embryologists will also grade the embryo by looking at its appearance under the microscope. Embryos that are dark in color or that have extensive fragmentation will also have a lower potential for producing pregnancy.

A “perfect” embryo would get a score of 1. A poor embryo might have a score of 3 or 4. We would like to see embryos that are 8 cells and grade 1. A patient may have a lot of good embryos or she may have none. Unfortunately, this scoring system isn’t perfect for predicting which embryos may produce a pregnancy. For this reason, some IVF programs may place more embryos into the uterus at this stage in order to increase the chances for a pregnancy. Unfortunately, this increases the risk for having a multiple pregnancy.

New technology allows for time lapse imaging of embryo development. Sophisticated software can take measurements of the exact timing of certain events. It is hoped that someday, as this technology improves, that it will enable selection of the best embryos for transfer. For now, however, time lapse imaging does not do better than an experienced embryologists.

Blastocyst Culture

Transferring embryos at the blastocyst stage will maintain the highest chance for pregnancy while keeping the risk for multiple pregnancy low. Blastocyst development requires culturing the embryos for two additional days in the laboratory. By this time (day 5 after the egg retrieval), healthy embryos will have reached the blastocyst stage.

Blastocyst Development

By definition, a blastocyst is an embryo that has divided into hundreds of cells and is composed of two parts. The outer sphere of the blastocyst is called the trophoblast. The inner portion of the blastocyst is filled with fluid. Inside the trophoblast, there is a clump of cells called the inner cell mass. The inner cell mass is the portion of the blastocyst that actually becomes the baby.

Blastocyst Transfer

Only a small percentage of embryos will reach the blastocyst stage. This self selection of the embryos allows the embryologist to pick the embryos that are most likely to produce a pregnancy. When transferring blastocysts, it is not necessary to transfer as many embryos to maintain a high pregnancy rate. This reduces the risk of multiple pregnancy and therefore increases the chances for a couple to have a live born healthy baby.

Many experts believe there is another reason for the higher pregnancy rates seen with blastocyst transfer. In a normal “in-vivo” (in the body) conception, the embryo does not reach the uterus until the blastocyst stage. If we were to place an embryo into the uterus at the 8-cell stage (after only three days of embryo culture, it is deviating from the normal body processes. That is, the 8 cell embryo does not belong in the uterus at that time. Transferring the embryos at the blastocyst stage is more “physiologic”.

Studies now demonstrate conclusively that the chance for pregnancy and the risk for multiple pregnancy are reduced with the use of blastocyst transfer. This is true for all age groups.

Embryo Freezing

Very often in IVF cycles, the number of embryos produced exceeds the amount that will be transferred. There are several options for what to “do” with extra embryos. One option is to freeze the extra embryos for a couple to use at a later time. In this way, if a couple fails to achieve pregnancy on an IVF attempt, they can try again using the embryos that were frozen. This is less costly and less invasive than a fresh IVF cycle. Alternatively, if a couple does achieve pregnancy and delivers a healthy live born baby, they can use their frozen embryos to have additional children later on.

As simple as it may sound, embryo freezing is a complex process. There are many techniques in use today for embryo freezing. There are slow methods for freezing and fast methods. Embryos can be frozen immediately after fertilization (pronuclear stage freezing), while the embryos is in the early stages of development (cleavage stage freezing) or in the later stages of development (blastocyst stage freezing). It is unclear if any one method is better than another.

Embryo freezing

Slow Embryo Freezing Method

The traditional method of freezing embryos is the slow freeze method. These techniques lower the temperature of the embryos gradually. One of the dangers of embryo freezing is the formation of ice crystals. If ice crystals are present when thawing the embryos, they can lead to damage of the embryo and the embryo may not survive the thawing process. In order to reduce the chance for ice crystal formation, before the embryo is frozen, it is soaked in a solution known as “cryoprotectant”.

Cryoprotectant is a solution used to protect biological tissues from freezing damage. The slow freeze method of freezing embryos relies on low initial concentrations of cryoprotectant. This low concentration of cryoprotectant is introduced when the embryo is still at a relatively warm temperature and is still experiencing the normal functions of living cells. The cryoprotectant will permeate and fill the embryo, replacing most of the water in the embryo.

The embryo is then inserted into a small plastic container and placed into a cooling chamber. By injecting tiny amounts of liquid nitrogen into the cooling chamber, the temperature is then lowered slowly to around –6°C. A computer controls the cooling process. The temperature is further lowered to around –32°C. By now, the metabolic rate of the embryo is quite slow. The embryo container is then plunged into liquid nitrogen, causing the temperature to drop even further which completes the freezing of the embryo.

Thawing of these embryos requires a fast approach. The embryos are rapidly warmed to room temperature to prevent ice crystal damage.

Rapid Embryo Freezing Method (Vitrification)

A newer method of freezing embryos is the rapid freeze method. The technical term is vitrification. To prepare an embryo for rapid freezing, the concentration of the cryoprotectant is much higher than that used for slow freezing. Again, this is accomplished while the cells of the embryo are at room temperature. The embryo cannot stay at this temperature for long and is immediately plunged directly into the liquid nitrogen which will immediately drop the temperature by a large amount.

An extremely rapid rate of thawing is used once again to prevent ice-crystal damage.

Vitrification is a newer method for freezing embryos. The possible advantages of vitrification are a lower chance for ice crystal formation and therefore a higher chance for survival of the embryo when it is thawed. Some studies have even suggested the possibility that embryos could be frozen and thawed repeatedly without being damaged.

Do Frozen Embryos Work As Well As Fresh Embryos?

This is a question that is often misunderstood even by doctors who are supposed to be experts in fertility. At IVF1, there is little if any difference in the chance for pregnancy whether fresh or frozen embryos are used. Why, then, do other programs say the opposite?

One of the main factors in determining the chance for pregnancy in IVF is the number of embryos transferred. If there are less embryos transferred, this can lower the chance for pregnancy. Let’s take the example of a couple that has four high quality blastocysts produced in a fresh IVF cycle. Two embryos are transferred and two are frozen. Let’s say the couple delivers a baby from the fresh IVF cycle and then returns to use the frozen embryos a few years later. Upon thawing, however, only one of the embryos survives and it is transferred.

In this case, the chance for pregnancy on the frozen cycle would be lower than the fresh cycle. Not because the embryos were frozen but because only one embryo was available on the frozen attempt instead of the two which were used on the fresh attempt.

Second, there are some programs that will freeze any extra embryos, regardless of the embryo quality. Of course, when these embryos are thawed, there is a lower chance for pregnancy not because they were frozen but because they were lower quality to start with.

Finally, of course, some programs simply have difficulty with embryo freezing and have lower success rates across the board.

There have been several studies in which the rate of pregnancy between fresh and frozen embryos has been compared. In some of these studies, when the number and quality of the embryos is taken into account, it has been found that there was no difference in the pregnancy rates.

Follow this link to learn more about the process of using frozen embryos to attempt pregnancy which is called a frozen embryo transfer or FET cycle.

Does Failure of Fertility Treatment Predict Future Health Risk?

An important question to answer in any field of medicine is whether treatment will increase the chance for health problems in our patients. In the infertility field, there are three questions:

  1. Are infertility patients at greater risk for health problems?
  2. Do fertility treatments increase the risk for health problems?
  3. Is there a difference in the risk for health problems depending on whether the treatment is successful?

A recent study from a Canadian medical journal has tried to answer some of these questions.

Infertile Study

The INFERTILE study (Investigation of Notable Failed Endeavours at Reproductive Treatment and Ischemic Long-term Events looked at whether fertility therapy failure is associated with subsequent adverse cardiovascular events. Cardiovascular events are things like strokes, heart attacks and blood clots. This study followed over 28,000 women who received fertility treatment in Ontario Canada between 1993 and 2011.

What Did the Study Show?

The study found that women who took injections of fertility medications and failed to deliver a baby had a higher rate of cardiovascular events over the next several years compared to women who took injections and did not deliver a baby. Overall, the annual rate of cardiovascular events was 19% higher among women who did not give birth after fertility therapy than among those who did.

Risk of cardiovascular events
Failure of fertility therapy and subsequent adverse cardiovascular events. Jacob A. Udell MD MPH, Hong Lu PhD, Donald A. Redelmeier MD MSHSR CMAJ 2017 March 13;189:E391-7. doi: 10.1503/cmaj.160744

Does This Mean That Fertility Treatments Caused These Problems?

Probably not. The study did not include infertile women who did not take fertility medications. That is a group you would need to study in order to determine whether the medication treatment itself was responsible. What this study showed is that women who did not deliver a baby had a greater risk than those who did.

The reasons for this are not clear but it may be that failure to achieve pregnancy is a way to identify women who were already at higher risk of developing these problems. We know, for example, that men who have chest pain or EKG changes when running on a treadmill are more likely to have cardiovascular events. This is known as a “stress test”. In this case, failure to become pregnant after fertility treatment might be a stress test that predicts women who will be more likely to develop cardiovascular problems.

Some evidence to support this interpretation comes from looking at some of the characteristics of these women BEFORE they started fertility treatment. The women who failed to deliver a baby were more likely to be obese, smoke cigarettes and have high cholesterol. All of these are known risk factors for cardiovascular disease.

What Should I Do?

All women should be aware of the risk factors for cardiovascular disease. If you have risk factors, you should work with your primary physician to try to modify or reduce those risk factors.

Reference

Failure of fertility therapy and subsequent adverse cardiovascular events. Jacob A. Udell MD MPH, Hong Lu PhD, Donald A. Redelmeier MD MSHSR CMAJ 2017 March 13;189:E391-7. doi: 10.1503/cmaj.160744

First Time IVF Success

If there is one question that we hear more than any other, its “What can we do to maximize the chance for 1st Time IVF Success?” Although nobody can guarantee that you will be successful after IVF treatment, there are several options that can help sway the odds in your favor. If you prefer to watch videos instead… check out our YouTube Playlist

First Time IVF Success

Does ICSI improve First Time IVF Success

There are two methods that have been used to fertilize eggs during IVF. The older method, known as “standard insemination” involved placing sperm near to but outside of the egg. The newer method, ICSI, involves injecting sperm directly into the egg.

Standard insemination is easier and less expensive, but has a higher chance for fertilization failure. In other words, sperm is added but doe not result in an embryo being formed. Numerous studies have shown that with standard insemination, the chance for fertilization failure is around 5-15%. Couples who have more severe problems such as low sperm counts or movement will have an even higher rate of fertilization failure.

Therefore, at IVF1, our recommendation to increase the chance for 1st time IVF success is to use ICSI for fertilization EVEN IF there are no known sperm problems.

Does Blastocyst Transfer Improve The Chances For First Time IVF Success?

Once fertilized, not all embryos will grow and develop. some embryos will degenerate, some embryos will develop for a few days and then stop. In IVF, there are different choices that can be made about how long to observe an embryo before deciding to transfer it. Commonly, IVF programs will choose embryos based on 3 days of development (cleavage stage) or 5-7 days (blastocyst transfer.

Watching the embryo for a longer period of time will help identify the embryos which are the healthiest and therefore the ones that are most likely to result in pregnancy. The rule of thumb here is “watching longer is better”. Nothing is more frustrating than placing a Day 3 embryo in the uterus and then wondering whether it continued to develop normally or not. Embryos that don’t become blastocysts in the lab would not have become blastocysts in your body. Identify the best embryos BEFORE transfer.

Does PGS (Embryo Testing) Increase The Odds For First Time IVF Success?

Some embryos may grow normally and reach the blastocyst stage but still not be good, healthy embryos that are capable of producing a viable pregnancy. Many embryos have chromosome abnormalities. The most common type of chromosome abnormalities are called aneuploidies. This is when an embryo has too many or too few chromosomes.

The older a woman gets when she creates an embryo, the higher chance for the embryos to have chromosome abnormalities. Since the early 1990s, we have had technology to identify embryos with chromosome abnormalities. Over the years since, the technology has improved. Today, using techniques such as Next Generation Sequencing, embryos testing has become very accurate and very helpful.

Therefore, if you are an woman who is 37 year or older, we would strongly recommend embryo testing. Many studies have proven that this will improved your chances for 1st time IVF success.

Optimize The Stimulation Of The Ovaries

To get the best egg quality, the ovaries need to be stimulated with two different hormones – FSH and LH. FSH is the hormone found in medications like Follistim and Gonal F. Either of these medications will work great for your IVF protocol.

IVF protocols that combine FSH and hCG may work better than FSH and LH. So ask your doctor for the low dose hCG protocol. Oh, and one other advantage, hCG is a lot cheaper so you can save a few thousand dollars in medication costs.

Use The Right Kind Of Progesterone

You already know from our last video on first time IVF success that you should be doing a frozen transfer instead of a fresh transfer. To do a frozen embryo transfer, you first prepare the uterus with two medications – estrogen (to get the lining thicker) and progesterone to make the lining receptive to an embryo. It does not seem to matter what kind of estrogen is used. It can be oral estrogen, vaginal estrogen, estrogen patches or even estrogen injections. Doesn’t matter.

The type of progesterone does matter however. This last year, a study was presented involving about 1000 women who were doing a frozen embryo transfer. They were split into three groups. Group 1 took vaginal progesterone only. Group two used vaginal progesterone and a daily injection of progesterone. The third group used vaginal progesterone and a progesterone injection every three days.

What they found is that the group using vaginal progesterone only had lower pregnancy rates. So much so that they stopped adding patients to that group even before the study was over. There was no difference detected in whether injections of progesterone were added every day or every three days.

So for this tip make sure you are taking both types of progesterone. Vaginal progesterone every day and injections of progesterone every 3 days.

Timing The Embryo Transfer

It turns out that not only does it not matter what type of estrogen you use, it also doesn’t matter how long you take the estrogen. The amount of time for progesterone however is very improvement. Progesterone changes the uterine lining to make it receptive to an embryo. For most women, the optimal time to place a blastocyst stage embryo into the uterus is on the 6th day of progesterone.

Where To Go For More Information

Check out this YouTube Playlist about First Time IVF Success if you prefer to watch videos. If you prefer reading articles, here is the previous article on First Time IVF Success

Frozen Embryo Transfer

Frozen embryos is a term used to refer to those embryos that are not transferred during in vitro fertilization cycles and are subsequently cryopreserved. A frozen embryo transfer can be used to produce a viable pregnancy by first thawing the frozen embryo, and transferring it into an appropriately prepared uterus. Other names for this process such as embryo freezing or embryo cryopreservation have been commonly used. The treatment to establish a pregnancy using frozen embryos has been called a thaw cycle or a frozen embryo transfer cycle or simply an FET cycle.

Pretesting For A Frozen Embryo Transfer

In order to maximize the chances for success using frozen embryos, a woman should have a normal uterine cavity. There are three tests that can be used to assess the uterine cavity:

  • Hysterosonogram – In which saline is injected into the uterus and the cavity is viewed with ultrasound
  • HSG in which x-ray dye is injected into the uterus and the cavity is viewed with x-rays.
  • Hysteroscopy – In which a fiberoptic telescope is introduced into the uterus and the cavity is viewed directly.

If abnormalities of the uterine cavity are discovered, they should be corrected surgically before proceeding with a frozen embryo transfer.

Hormone preparation for FET

Using hormones to prepare the uterus is the most common way in which a frozen embryo transfer is performed. In some cases, the physician may decide to suppress the pituitary gland. This can be done to reduce the chances of ovulation occurring unexpectedly. , Lupron can be used for pituitary suppression. For most women, this will require approximately two weeks of daily Lupron injections. Another medication can also be used to suppress the pituitary gland is called Ganirelix. Ganirelix does not need to be given ahead of time as it works immediately.

The second step in a frozen embryo transfer cycle is to use hormones to duplicate the changes that normally occur in the uterus during a regular menstrual cycle. This requires the use of two hormone medications: estrogen and progesterone.

Estrogen preparation for FET

During a normal menstrual cycle, estrogen is produced by the developing follicle. This estrogen acts on the uterus to thicken and mature the uterine lining. Estrogen is given in a FET cycle for the same reason. There are many different ways that estrogen can be given in a frozen embryo transfer cycle:

  • Estrogen pills – Estrace, Premarin
  • Estrogen patches – Estraderm, Climera
  • Estrogen injections – Delestrogen (estradiol valerate), Depogen (estradiol cypionate)
  • Vaginal estrogen – Vagifem, Femring

There is no data that any one method works better than another and a method is usually chosen based on physician preference. We like to use estrogen pills since it is easy to do, inexpensive and very well tolerated.

During the time when estrogen is given, the woman will come to the office periodically to be monitored. A transvaginal ultrasound is performed to determine the thickness of the uterine lining and a blood test is performed to look at the level of estrogen in the blood. On occasion, if the lining is not thickening as it should, the dose or type of estrogen must be increased or prolonged. The length of time the estrogen can be given is very flexible. During this phase, for example, the duration of estrogen may be prolonged to delay the day of embryo transfer to accommodate the patient’s schedule. The monitoring in a thaw cycle is very flexible. Unlike a fresh IVF cycle during which the required days for monitoring are determined by the growth of the follicles in the ovary, in an FET cycle, the days can be adjusted at any time. Thus, a frozen embryo transfer cycle is much less stressful on the patient.

Progesterone in an FET cycle

Once the uterine lining has been thickened sufficiently, progesterone is added. Once the progesterone is added, the Lupron may be stopped. Progesterone matures the uterine lining and makes it receptive to an embryo to implant. Once the progesterone is begun, there is a certain “window of implantation” during which the embryo must be transferred. The stage of the embryo must match the stage of development of the uterus. Therefore, the only factor that locks the patient into performing the transfer on a certain day is starting the progesterone. Once the progesterone is begun, if the embryo transfer is not performed on a certain day, the cycle must be cancelled and a new preparation with hormones must be begun after allowing a period to occur. There are many different types of progesterone that can be used in a frozen embryo transfer cycle. Some of the more common methods include:

  • Progesterone pills – Prometrium
  • Progesterone injections
  • Progesterone vaginal suppositories
  • Progesterone vaginal gels – Crinone, Procheive

There is considerable uncertainty in the medical literature concerning which type of progesterone is the best for FET cycles. Again, the choice of progesterone for an FET cycle is up to the discretion of the physician. A few things, however, most experts would agree on. Progesterone given by mouth is unreliable due to variable absorption and subsequent metabolism in the liver. In our practice, we give progesterone as intramuscular injections and with a vaginal gel. In this way, we can ensure that we have used whatever method of progesterone is ultimately determined to be the best.

Once the uterine lining is adequately thickened with estrogen, the progesterone is usually started on a particular day to allow for scheduling of the embryo thaw and embryo transfer for a time that is convenient for the in vitro fertilization laboratory staff. In our practice, we commonly freeze embryos at the blastocyst stage. This is an embryo that has developed for five days in the laboratory. It must be placed into a uterus that has been exposed to progesterone for five days. Our protocol is to start progesterone so that the thaw and transfer occur Tuesday though Thursday, in the afternoon. This allows my laboratory staff to be able to prepare ahead of time for all of the frozen embryo transfer cycles on one day. The afternoon transfer allows them to thaw the embryos in the morning, assess for viability during the day, thaw additional embryos if necessary and still have the transfer the same day.

FET During A Natural Cycle

If a woman has regular, ovulatory menstrual cycles, a frozen embryo transfer can be performed without the use of hormone preparation. Several studies have shown that the pregnancy rates in natural FET cycles are equivalent to that of hormone prepared cycles. In practice however, these cycles are much more difficult logistically to perform.

In the section above, it was stated that there is a precise window of implantation for transferring frozen embryos. This must be maintained in a natural FET cycle as well. This requires precise determination of the time of ovulation. This can be done by using a home ovulation predictor kit. However, as anyone who has ever used these kits knows, it is sometimes difficult to read them accurately. Although the instructions accompanying the ovulation kits usually recommended that women test the urine once each morning, for FET cycles we recommend testing in the morning and evening. It is also possible to monitor natural cycles using blood tests and ultrasounds just as we do for a hormone prepared frozen embryo cycle. Unfortunately, during a natural cycle, we cannot control the day of ovulation. If the day of embryo thaw and transfer falls regularly on a Sunday or holiday, the transfer will be cancelled.

Stage of Cryopreservation For Frozen Embryos Transfer

After an egg is fertilized, it can be grown in the laboratory for up to seven days. Cryopreservation of the embryos has been accomplished at all stages of embryo development. There is no universal agreement as to which stage of embryo development is the best for cryopreservation.

If an embryo is frozen immediately after it has been fertilized (pronuclear stage), the survival of the embryo after thawing appears to be high. However, since the embryo was not cultured in the laboratory first, its potential viability is unknown. Therefore, after the embryo is thawed, it must then be cultured in the laboratory in the same way it would have been if it had not been frozen. It is impossible to predict how many of the thawed embryos will reach the stage of development desired by the physician for transfer. Therefore, a higher number of embryos must be thawed.

If a large number of embryos does reach that stage of development, then there is a dilemma. Either a larger number of embryos must be transferred (which increases the risk of multiple pregnancy) or the extra embryos must be discarded or refrozen. There is very little data about the safety or success of refreezing embryos so it is not recommended.

An embryo can also be frozen after two to three days of embryo development. This is called the cleavage stage. Cleavage stage cryopreservation allows for some limited assessment of the development of the embryos. Some embryos, for example, will not have developed or look abnormal and thus would not be frozen. On the downside, the survival of cleavage stage embryos is lower. As with the case of embryos frozen at the pronuclear stage, cleavage stage embryos can also be cultured after thawing to further help determine the best embryos for transfer.

We freeze embryos at the blastocyst stage. Since the embryos have been cultured for five to six days, this enables the best assessment for viability and thus fewer non-viable embryos will be frozen at this stage. In the past, survival of the embryo after thawing has not been very good. In recent years, however, techniques for freezing blastocysts have improved and in selected centers the survival rate is very good. Blastocyst cryopreservation allows for the thaw and transfer of embryos on the same day.

Pregnancy Rates Using Frozen Embryos

There is much confusion about the ability of frozen embryos to produce pregnancy. On initial inspection, the chance for pregnancy using frozen embryos appears to be lower than the transfer of fresh embryos. On closer analysis, however, this may not be true. Find out more about frozen embryo transfer success rates on the follow up page. How long can frozen embryos remain viable ?   In 2006, researchers from New Jersey compared the pregnancy rates obtained when embryos were frozen for different lengths of time. The data showed that no difference in the chance for pregnancy was evident even when embryos were frozen for more than ten years.   Is embryo freezing safe for the baby?

Frozen Embryo Transfer Problems

Frozen embryo transfer or FET is a highly effective method for conceiving a pregnancy. In fact, recent studies show that the chances for pregnancy are higher when embryos are frozen and placed into the uterus at a time after the stimulation of the ovaries.

Frozen embryo transfers are most commonly performed by preparing the uterine lining with hormones. Estrogen is used first to thicken the lining and progesterone is used next to produce the changes necessary for an embryo to implant.

So what can go wrong with a frozen embryo transfer?

A Thin Uterine Lining

Many studies have demonstrated that not as many women get pregnant if their uterine lining, as measured on ultrasound, does not thicken enough. In most women, it isn’t clear why this happens and there isn’t a sure fire treatment that will always get the lining thicker. Fertility experts will try a number of different approaches such as increasing the dose of estrogen or changing how the estrogen is given. In other cases, supplemental medications can be tried. In some women, however, the problem will persist.

What Is Done If The Problem Persists?

One approach is to cancel the embryo transfer and try again at a later time, perhaps with a different treatment method. A second option is to go ahead with the transfer. A thin lining does not necessarily mean that it is impossible to get pregnant but the efficiency may be reduced. One other option is to use the opportunity to do additional testing to assess the “receptivity” or ability of the uterus to allow embryos to implant.

Unexpected Ovulation

In order for embryos to implant into the uterus, they must be placed at precisely the correct time. This is known as the window of implantation. The timing is based on the length of time since progesterone reaches the uterine lining.

When your doctor has you start taking progesterone supplements, he or she knows the correct time to place the embryos. However, if you were to ovulate – you would start producing progesterone earlier than expected and this would shift the window of implantation. Since it is nearly impossible to identify the exact time of ovulation, this will introduce some uncertainty into the timing.

For this reason, many doctors will use medications to try to prevent unexpected ovulation. The medications most commonly used for this are called GnRH antagonists. In the USA, two brands of GnRH-a medications are Ganirelix and Cetrotide

Inappropriate Timing For The Embryo Transfer

This problem is related to the early ovulation problem. However, in some cases, the window of implantation is shifted even then the timing of the transfer is accurate. Previously, doctors believed that the timing of the window of implantation was the same in all women. Studies using molecular markers to identify the correct “window of implantation” have shown that a small percentage of women may have a window of implantation that is earlier or later than usual.

Tests such as the Endometrial Receptivity Array were performed for many years in the hopes that it could help identify patients that has a shift in their window of receptivity and therefore allow the doctor t make adjustments. Unfortunately, several studies in the last few years have failed to show a benefit in making these adjustments Therefore, the ERA is no longer recommended.

Fluid In The Uterine Cavity

Fluid in the uterine cavity
Fluid in the uterine cavity

The cells of the uterine lining are constantly producing fluid. Some of this fluid is reabsorbed by cells in the uterine lining, some of the fluid leaks out of the uterus through the cervix into the vagina and some leaks out thought the fallopian tubes into the abdomen. In some cases, however, extra fluid may accumulate in the cavity and this can be seen on ultrasound. Doctors do not want to transfer embryos into a uterine cavity that is filled with fluid as this will lessen the chances that the embryos will implant.

In some patients, fluid accumulation in the uterine cavity may be a sign that the ends of the fallopian tubes are blocked causing the tubes to fill with fluid. This is called a hydrosalpinx. Women who have a hydrosalpinx have much lower pregnancy rates with IVF or FET cycles. The treatment to fix this cause for fluid is to perform surgery and remove the fallopian tubes. This is known as a salpingectomy. This is a well-studied treatment that is found to double the chances for pregnancy.

In the absence of a hydrosalpinx, getting rid of fluid in the uterine cavity is more challenging. If the fluid is present during the time that estrogen is being taken, then starting progesterone will often cause the excess fluid to be reabsorbed and an embryo transfer can proceed normally.

Some doctors will put a catheter inside the uterus and try to aspirate the fluid. There is little evidence that this is an effective treatment.

Finally, it may be prudent to cancel the FET cycle, induce a period and try again on a different month.

Unknown Factors

The uterine lining and the embryo have many complex interactions that are poorly understood. Even when none of the problems described in this article are present, embryos may still fail to implant. With continued research, new problems and new therapies will hopefully be discovered. IVF1 is currently conducting clinical research studies of a new treatment that we hope may help some women with recurrent implantation failure achieve a pregnancy.

Frozen embryo transfer is an effective means for achieving pregnancy. Problems can occur while preparing a woman for an FET. These problems include a failure to adequately thicken the uterine lining, premature ovulation, fluid accumulation in the uterine cavity and incorrect timing of a transfer. There may be other problems that scientists have not yet discovered.

Frozen Embryo Transfer Success

There is much confusion about the ability of frozen embryos to produce pregnancy. Frozen embryo transfer success has improved dramatically over the last several years. In the past, the chance for pregnancy using frozen embryos seemed to be lower than the transfer of fresh embryos. More recent data, however, suggests that this is no longer true.

Reasons Why Frozen Embryo Transfer Success Was Lower In The Past

Typically, when a frozen embryos transfer was performed, the embryos that were frozen were those that were not chosen for the initial fresh embryo transfer. Why not? Often, the embryologist chose the “best” embryos for the initial transfer. The embryos that remained were frozen. Some programs are very strict about the quality of the embryos they will freeze, other programs will freeze any and all remaining embryos. As in the case of fresh embryo transfer, embryo quality has a profound effect on the chance for pregnancy. If poor quality embryos were frozen, the survival rate after thawing as well as the pregnancy rate would be expected to be lower.

A second important factor is the number of embryos that were transferred. Take the example of a couple who produce four good quality embryos. Two are transferred in the fresh in vitro fertilization cycle and two are frozen. A pregnancy results and the couple delivers a baby. Later, the couple decides to attempt pregnancy again using the frozen embryos. Upon thawing, however, only one embryo survives. The frozen transfer is of a single embryo. Frozen embryo transfer success of a single embryo is going to be lower than that seen with a multiple embryo transfer.

Finally, the method to freeze embryos underwent a big change several years ago. In the past, embryos were frozen by a slow method. More recently, embryos are frozen by a fast method known as vitrification. The survival rates when the embryos are thawed is much better and the pregnancy rates when those embryos are transferred is also now much better.

Studies Show High Success Rates

Studies have been performed in women who had a very vigorous stimulation of their ovaries and were considered to be at high risk for ovarian hyperstimulation syndrome (OHSS). Their physicians decided to skip the embryo transfer and instead freeze all of the embryos for later use. This significantly decreases the risk of serious or complicated OHSS. In other cases, the physicians decided to go ahead with a fresh embryo transfer anyway, despite the risk of OHSS. In this experiment, the couples in both groups have a large number of embryos and the selection of embryos for transfer was for the best embryos in each case. These studies show no difference in the pregnancy rates between fresh or frozen embryos or higher pregnancy rates with frozen embryos.

We can conclude that cryopreservation does not by itself decrease the chances for pregnancy, rather it is the number of quality of embryos available that is the determining factor.

In 2006, researchers from New Jersey compared the pregnancy rates obtained when embryos were frozen for different lengths of time. The data showed that no difference in the chance for pregnancy was evident even when embryos were frozen for more than ten years.

In Vitro Maturation (IVM)

In vitro fertilization has helped hundreds of thousands of couples to achieve pregnancy and live births. Although initial efforts at in vitro fertilization in the 1960s attempted to mature eggs in the laboratory, these techniques were largely unsuccessful. The first live birth from in vitro fertilization obtained a single egg that was matured inside the ovary. No fertility medications were used. This “natural cycle” in vitro fertilization was gradually replaced by “stimulated” in vitro fertilization using various fertility medications since it was shown that when a larger number of eggs were retrieved, a larger number of embryos could be created. This allowed for selection of the best embryos for transfer into the uterus and as a result – pregnancy rates improved.

However, the use of fertility medications for ovarian stimulation has become extremely expensive. In addition, some women are extremely sensitive to the effects of these medications and, as a result, can develop a potentially life-threatening condition known as ovarian hyperstimulation syndrome (OHSS). Finally, there are some women who have cancers that are hormonally responsive and therefore must avoid the high hormone levels that result from ovarian stimulation.

Clearly, there is a great need to develop better techniques to perform in vitro fertilization without the use of fertility medications. In 1991, physicians in Korea reported the first pregnancy from eggs that were obtained from an ovary at the time of a cesarean section and then matured in the laboratory. In 1994, another pregnancy was established in Australia using immature eggs that were obtained from women with polycystic ovary syndrome.

Recent improvements in culture conditions and techniques have led to a great improvement in the likelihood for in vitro matured eggs to produce viable embryos.

In Vitro Maturation Candidates

The best candidates for IVM (in vitro maturation) are young women with large numbers of egg containing follicles or women who have attempted stimulated in-vitro fertilization and had production of a large number of eggs.   Ideally, women under the age of 30 or 35 would be expected to have the greatest likelihood for having many eggs.   There are two tests that are used to identify women with a large number of eggs. Using vaginal ultrasound, the ovaries can be seen and the egg containing follicles can be counted for each ovary. An excellent number of follicles to be a great IVM candidate would be more than 15 follicles in each ovary.

A blood test can also tell about the number of eggs in the ovaries. A hormone called AMH (anti-mullerian hormone) is produced by follicles in the ovary. A higher AMH level indicates a larger number of eggs in the ovaries. AMH levels will vary by age. As women get older and the number of eggs in their ovaries decrease, the AMH levels will start to decrease. For IVM, a woman should have an AMH level in the upper half for her age group.   Women who are obese are not good candidates for IVM. The ovaries are very small when they are not first stimulated by fertility medications. This makes them more difficult to see on ultrasound. Obesity also makes it more difficult to see the ovaries on ultrasound and therefore makes it more difficult and more risky to try to remove the eggs from the ovaries.   Women who have taken injectable fertility drugs previously and who had a very vigorous response or had a treatment that was cancelled for fear of hyperstimulation syndrome, may be very good candidates for IVM.

In Vitro maturation Techniques

The technique involved for in vitro maturation begins with a woman having a transvaginal ultrasound performed between day 3 and 5 of her menstrual cycle. If she does not have evidence for regular menstrual cycles and natural ovulation, she would be a candidate for in vitro maturation alone. If she has regular ovulatory cycles, then she is a candidate for natural cycle in vitro fertilization combined with in vitro maturation.

An injection of hCG is given and the eggs are retrieved 36 hours later. The immature eggs are placed in a petri dish containing specialized media to help the eggs mature. Once the eggs are matured, they are injected with sperm – this is a fertilization technique known as ICSI . The injected eggs are now cultured for several additional days to allow the embryos to develop. This is the same technique that is used in standard in vitro fertilization.

During this time, the female is given hormones to prepare the uterine lining. Both estrogen and progesterone are given after the eggs have been retrieved.  A few embryos are then selected and an embryo transfer is performed.

In Vitro Maturation Results

A recent series from a fertility group in Canada followed the treatments of 63 women without ovulatory cycles. The average age of the women was 31. An average of 16 immature eggs were collected. Of these, about 65% could be matured in the laboratory. 79% of the eggs which matured were able to be normally fertilized by injection of a single sperm into each egg (ICSI). 90% of the fertilized eggs began to divide. If a patient had viable embryos for transfer, approximately 30% had a live birth. This is significantly lower than the pregnancy rate that can be achieved with stimulated in vitro fertilization, however, it is similar to what is seen using injectable fertility medications and intrauterine insemination.

Women who had ovulatory cycles are first monitored until they are though to be at a point just before ovulation. This enables the physician to potentially obtain one or two mature eggs in addition to the immature eggs. Using this technique, a similar live birth rate was obtained by the same Canadian group.

As with all fertility treatment, success rates are lower for older women. Using in vitro maturation, the pregnancy rates for women above age 35 were very low. Thus these women are not good candidates for this technique.

IVF1 was the first fertility center in the United States to achieve pregnancy using IVM.

IVF and Birth Defects

The risk of birth defects in the general population is usually cited at 1-3% of all births. The risk is higher with multiple pregnancies. Babies born from in vitro fertilization – IVF may also have birth defects. This may be due in part to the higher rate of multiple births seen in IVF cycles. There have also been studies that suggest that the risk of birth defects may be higher in babies born from IVF even when controlling for the rate of multiple births.

Another confounding factor is that couples who have infertility seem to have a higher rate of birth defects than the general population even if no fertility treatments are used. Thus, any study attempting to look at the birth defect rate in IVF babies must use a carefully chosen comparison or control group. Studies that use birth defect rates from the general population as a comparison to IVF, therefore, are probably overestimating the risk from IVF.

Nonetheless, a recent study from Finland found an increased risk of birth defects in babies conceived from IVF. There were two comparison groups: naturally conceived babies from the general population and babies who were conceived with non-IVF fertility treatments. The rate of birth defects in the IVF babies was 4.3%. The non-IVF fertility treatment rate was 3.7% and the general population rate was 2.9%.

The increased risk due to multiple pregnancies was again confirmed in this study. Even when conceived naturally, the rate of birth defects amongst multiple pregnancy babies was almost twice that of singleton babies (526 birth defects per 10,000 births versus 285 per 10,000).

Statistical analysis showed that the risk was mostly due to singleton boys conceived from IVF. On the other hand, the risk of birth defects in girls from multiple pregnancies was actually decreased.

Another recent study from the University of Iowa also found an increased risk of about 30% in the incidence of birth defects in babies from IVF . This study looked at the birth defect rate in three different groups: IVF babies, babies born after intrauterine insemination, and spontaneously conceived babies from the general population delivering at the University of Iowa.

A higher rate of birth defects was seen in IVF babies compared to the general population but not when compared to babies from insemination. Furthermore, there was no correlation between the invasiveness or complexity of a procedure and the rate of birth defects. For example, embryos that were kept in the laboratory for a longer number of days might be expected to produce babies with a higher rate of birth defect but this did not hold true. Likewise, when fertilization of an egg by ICSI, a more invasive method, was compared to fertilization by placing the sperm and egg together only, there was no difference in the rate of birth defects. Finally, when embryos were frozen and then thawed before transfer were compared to fresh embryos, there was still no difference in the birth defect rate.

In this study, males had a birth defect rate that was double that of females (8.03% vs 4.26%). Further analysis suggested that the increase in birth defects in males was primarily due to an abnormality known as hypospadias. Other studies however, have not shown an increase in the hypospadias incidence in IVF boy babies.

If there is truly a 30% greater chance of birth defects with IVF babies, then the overall rate of birth defects amongst all IVF babies would be from 1.3% to 3.9% of IVF births.

One further study worthy of mention was recently presented at a scientific meeting but has not yet been published. Canadian researchers looked at 2005 birth data from an Ontario database. They identified 870 births including 320 who used fertility medications, 180 who underwent intrauterine insemination and 370 who underwent in vitro fertilization.

The babies born after fertility treatment were compared to deliveries that were not the result of assisted reproductive techniques (ART). The overall incidence of birth defects in the ART population was 2.62% compared with 1.87% in the non-ART population.

When analyzed by the type of treatment, the incidence of birth defects in the IVF group was 2.97% compared to 2.66% for the intrauterine insemination group and 2.19% for ovulation induction with fertility medications.

Gastrointestinal defects were most common followed by cardiovascular defects and then musculoskeletal defects.

Due to the fact that the comparison group was women without infertility, the researchers acknowledged that further studies are needed to clarify the contribution of infertility itself.

On the other hand, a multi-center study funded by the National Institutes of Health was performed in 2005. 36,000 pregnancies were analyzed. 95% were spontaneously conceived, 1222 (3.4%) conceived with ovulation inducing drugs and 554 (1.5%) used IVF. This study found no association between either fertility treatment and the incidence of birth defects.

IVF and Chromosomal Abnormalities

Normal human beings have 23 pairs of chromosomes. Embryos commonly have an abnormal number of chromosomes. These are called aneuploidies. As a woman gets older, she produces an increasing number of embryos with chromosome abnormalities.

In 2002, a study published in the New England Journal of Medicine suggested that the rate of chromosome abnormalities in babies may be higher than that seen in the general population. However, a 2005 study in the United States was unable to find an increase in the risk for chromosome abnormalities from IVF.

The use of intracytoplasmic sperm injection (ICSI) to fertilize eggs has been linked with a higher incidence of sex chromosome abnormalities in male offspring. Currently, this is thought to be due to transmission of chromosome abnormalities from the father rather than an effect of the ICSI per se.

Some studies have found that couples with certain types of problems may have a higher rate of chromosome abnormalities than expected. For example, one recent study showed that couples with recurrent miscarriage produce a higher rate of chromosome abnormalities.

IVF and Gene Imprinting Disorders

Genes are the functional part of chromosomes – they are responsible for specific functions in the body. Genes come in pairs with one member of the pair being inherited from the mother and one member from the father. Normally, the genes from both the mother and father function equally. With imprinted genes, however, only one member of the gene pair is functional and this is determined by the parent of origin. For example, maternal imprinting means that for a particular gene only, the copy received from the mother functions.

Imprinted genes have evolved over time in mammals to help fine-tune the growth of a fetus. Paternally expressed genes generally enhance growth, whereas maternally expressed genes appear to suppress growth.

Disruptions in the normal pattern of imprinting may result in human diseases. Recent studies have suggested that babies born from IVF may have a higher rate of certain rare imprinting disorders. Since these disorders are very rare, it has been difficult to determine if there is an association with IVF. Investigators have used rare disease registries to help identify possible risk factors for imprinting disorders.

IVF and Beckwith-Wiedemann Syndrome

Some experts now believe that IVF is associated Beckwith-Wiedemann Syndrome (BWS). BWS is characterized by a triad of pre- and/or post-natal overgrowth, macroglossia (large tongue) and anterior abdominal wall defects. In addition, about 7% of BWS children develop a tumor, most commonly Wilms’ tumor. The incidence of BWS in the general population is estimated at 7.2 cases per 100,000 births. Some estimates suggest that IVF increases the risk 3-4 fold. If true, this would give an incidence of 21.6-28.8 cases per 10,000 births.

This data was based on upon physician’s investigation of patients in the BWS registry. They found that 4.6% of the children in the registry were conceived from IVF whereas, in the United States during that time period IVF made up 0.8% of all births.

Some experts have noted however, that parents who have undergone IVF are more connected to the medical system and are therefore more likely to have their children added to the registry. This may then account for the skewed results.

IVF and Other Imprinting Syndromes

There were a few isolated reports of babies born from IVF having a rare form of Angelman syndrome. However, a 2006 British study was unable to confirm an association. The British study was also unable to find a link to another imprinting disorder known as Prader-Willi Syndrome.

The Danish Study of IVF and Imprinting Syndromes

A 2005 study Danish study examined 442,349 singleton non-IVF and 6052 IVF children. The investigators were unable to find an increase in the incidence of any imprinting disorders.

07/17/2008 IVF Study fails to show any increase in the risk of developmental disorders in babies

IVF Answers From Start to Finish

On the first day of full flow bleeding of the menstrual cycle, the patient will call us. Yes, even if it is on a weekend or holiday. She will come to the office on the second or third day for a baseline blood test and ultrasound. If a group is due to begin at that time and everything looks o.k., she will start taking fertility medications that same night. If a group is not scheduled to start, then she will start taking birth control pills until a few days before the groups is scheduled to begin.

Medications and monitoring

The first medications taken are the injections of gonadotropins medications

Fertility Treatment Success

containing FSH (Follistim or Gonal F). She will do this for four or five nights. By the fifth or sixth day of stimulation, she will return to the office for another blood test and ultrasound. By looking at her hormone levels and follicle development on ultrasound, we will decide which medications she should take, their dose and when she will come again for monitoring. This process will continue until the eggs have matured and the patient is ready for egg retrieval.

By about the fifth or sixth of stimulation, a second medication, the GnRH antagonist (Cetrotide or Ganirelix) is added to the FSH to prevent premature ovulation.

By the seventh or eighth day, on average, the dose of FSH will be decreased and replaced with low dose hCG.

The Trigger Injections

Most women will be ready to receive the trigger injections by the ninth or tenth day. For some, it may be as early as the seventh day and for others, as long as 16 days. The type of trigger injections given will be determined by what type of IVF cycle is being performed. If the patient is having a fresh embryo transfer, she will receive a high dose of Follistim and a high dose of hCG. If she is not having a fresh transfer, then she will take a low dose of hCG and Lupron for the trigger.

Patients who will not have a fresh transfer include women who are

  • at risk for OHSS (ovarian hyperstimulation syndrome)
  • freezing embryos for PGS or PGD
  • freezing embryos for a deferred transfer
  • egg donors
  • using a gestational carrier

The egg retrieval is performed two days after the trigger injection day. During this time, antibiotic pills are given to reduce the risk of infection

Egg Retrieval and Embryo Transfer

After the egg retrieval, the woman will take one more antibiotic pill. If she is having a fresh embryo transfer, then she will also start taking progesterone. Typically, vaginal progesterone is used  but in some circumstances progesterone may also be given by intramuscular injection along with supplements of oral estrogen.

If a fresh transfer is planned, it will occur on the fifth day after egg retrieval. After the embryo transfer, the progesterone is continued. A pregnancy test is performed eight days later.

Misconceptions about IVF

Recently, I have been seeing an increasing number of couples with unrealistic expectations about in vitro fertilization and cryopreservation. I have listed some of these and explained the problems in the context of an explanation of the realities of in vitro fertilization.

#1 The Ultrasonographer Told Me She Saw 20 Eggs During My Ultrasound!

Monitoring during an in vitro fertilization cycle includes blood tests for hormone levels and ultrasounds of the ovaries. The eggs, themselves, are too small to be seen on ultrasound. So what are the black circular areas that are seen on the ultrasound? These are the follicles. Follicles are small ovarian cysts that contain the developing eggs and fluid. As the eggs grow and mature, the follicle produces more fluid and thus the follicle gets larger. Only the follicles are seen on ultrasound, not the eggs.

#2 I Counted 20 Follicles On The Ultrasound, I Should Expect 20 Eggs From The Egg Retrieval.

During an egg retrieval, a needle is placed into the follicle and the fluid is aspirated. On the ultrasound, the doctor can see the follicle collapse around the needle. At this point, however, it is unknown whether an egg has been obtained. An embryologist inspects the fluid under the microscope to determine whether an egg has been obtained.

As an average, we are only able to get an egg out of the follicle about 70% of the time. In other words, if a patient has ten follicles aspirated, we would typically expect to get seven eggs. This is an average. Sometimes we get more, sometimes we get less. Women who commonly have lower retrieval rates include those who :

  • Are older women
  • Have poor ovarian reserve (high FSH levels, low AMH levels or low antral follicle counts)
  • Demonstrate a poor response to fertility medications
  • Have a high percentage of small follicles
  • Anatomically have one or both ovaries that are difficult to reach during the retrieval
  • Are obese

Occasionally, however, women who have none of the above problems may get a low yield of eggs from the retrieval.

#3 The Doctor Retrieved 20 Eggs, That Means I’ll Have 20 Embryos!

Initially, the eggs obtained are difficult to assess. They are covered with a large number of cells from the follicle. These cells are called cumulus cells. In order to assess the eggs clearly, these cells are stripped off the egg. Now the egg can be clearly assessed. The embryologist may find several characteristics about the eggs. The eggs can be classified as:

  • Immature
  • Mature
  • Normal, healthy appearing
  • Abnormal appearing
  • Degenerated
  • Fractured

Only the healthy appearing, mature eggs will have sperm injected into them. The range of healthy mature eggs can extend from 0-100% with an average around 60%.

Once a sperm has been injected into each healthy mature egg, they are placed into an incubator overnight. The next day, the injected eggs are inspected again under the microscope. The possible things the embryologist may see include:

  • An unfertilized egg
  • A normally fertilized embryo
  • An abnormally fertilized embryo
  • Unable to determine

As an average, about 70% of the eggs that are injected will become normally fertilized. Only those eggs that are normally fertilized will be placed back into the incubator and cultured in the laboratory. The remainder will of the eggs will be discarded.

#4 I Have 10 Embryos, That Means I Will Have Two For Transfer And 8 To Freeze!

The fact is that most of the embryos created through in vitro fertilization have poor reproductive potential. The purpose behind producing a large number of embryos to enhance the ability to select the best embryos for transfer.

We inspect the embryos at two time points only. The fertilization check (1 days after the sperm was injected) and four days after the fertilization check (5 days after the sperm was injected).

Several things may be seen during the inspection of the embryos:

  • An embryo may not have shown any development at all. This is known as cleavage failure.
  • The embryo may be dividing, but at a rate that is slow. This is indicative of a poor quality embryo.
  • The embryo may have been dividing initially, but then stopped dividing at some stage. This is known as embryonic arrest.
  • The embryos may have become fragmented as they divided. This is indicative of a poor quality embryo.
  • The embryos may have divided at a normal rate but appear to be of poor quality under the microscope.
  • The embryo has divided at a normal rate and appears to be of normal quality under the microscope

Remember that our ability to assess an embryo strictly by looking under the microscope is very limited. There are potentially many different types of embryo abnormalities that could interfere with the embryo’s ability to produce a live born baby that will not be seen by simply looking at it under the microscope. One type of abnormality occurs when an embryo has too many or too few chromosomes. This is why chromosome testing of embryos is so valuable. However, there are other types of abnormalities that we do not have the ability to test.

However, until we have newer and better tools to help assess an embryo’s potential, the microscope remains one of the best tools to help us find embryos to transfer. We are going to transfer the most normal looking, best appearing embryos even if the rate of development or the “quality” is not as good as we would like. We will not transfer embryos that, in our opinion, are not viable.

Transferring embryos at the blastocyst stage enhances our ability to assess embryos. This is based on the fact that that only about 30% of embryos, on average, will reach the blastocyst stage. This self selection process enables us to narrow down those embryos with the best viability. This means that if a patient has 10 embryos, on average, we would expect to have two for immediate transfer and ONE embryo to freeze.

We are very selective when picking embryos for cryopreservation. Only well developed, good quality embryos will be cryopreserved. In our experience, choosing lower quality embryos results in poor survival and pregnancy rates.

In the majority of the in vitro fertilization cases that we do, couples will not have any embryos frozen. Those who do have embryos frozen, may only have one or two. It is very rare, in our program, to have a large number of embryos frozen.

IVF Pregnancy Screening

Many women who seek fertility treatment are older and are therefore at greater risk for fetal chromosomal abnormalities. Consequently, many of these women will have 1st and 2nd trimester screening tests performed to try to identify abnormal fetuses. However, IVF treatment may cause these levels to differ from spontaneous pregnancies and therefore they should be interpreted with caution. In fact, one study has demonstrated that the rate of falsely abnormal results is twice as high in In vitro pregnancies.

Overview — screening for chromosome abnormalities

Any test that is performed on a pregnant woman to find an abnormal fetus has a chance for making the correct diagnosis and a certain chance for making an incorrect diagnosis. One type of error could be the result of the test not finding an affected fetus. This is called a false negative. A test which is very good at finding an abnormality is said to have a high detection rate. The higher the detection rate of a test, the lower the false negative rate will be. A second type type of error can result if the test indicates that a normal fetus "abnormal". This is called a false positive.

Ideally, we would like to have a test with a high detection rate and a low false positive rate. However, in practice, it usually doesn’t work like that. In fact, the higher the detection rate of a test, the greater the chance for a false positive.

If the results of a screening test is determined to be abnormal, then confirmation of a fetal chromosome abnormality is accomplished by checking the chromosomes directly through an amniocentesis or chorionic villous sampling (CVS). These tests are more invasive and carry a small risk for fetal loss. Thus, keeping the false positive rate as low as possible as a highly desirable idea. This would reduce the number of times an amniocentesis or CVS had to be performed. In that way, there would hopefully be very few fetuses lost from performing the amniocentesis.

Second Trimester Screening Tests

Hormone levels drawn from the blood a pregnant woman between the 15th and 20th week of pregnancy have been studied for their ability to predict a chromosomally abnormal pregnancy. Initially an association was found between low levels of maternal serum alpha-feto protein and fetal chromosomal abnormalities including Down’s Syndrome. Subsequently, an association also found with elevated hCG levels, and decreased unconjugated estriol level. These three blood tests formed the basis of the "Triple Screen". More recently, a fourth hormone, Inhibin-A was found in higher levels in affected pregnancies.

Comparisons
Test Detection Rate False Positive Rate
Triple Test – Study A 77% 9% 
Triple Test – Study B 69%  14%
Quadruple Test – Study A 83%  6%
Quadruple Test – Study B 81%  7%

This comparison tells us that using all four markers, raises the detection rate and lowers the chance for a false positive and thus is a better screening test than the triple screen.

First trimester screening tests

In the early 1990s, researchers discovered that measuring the thickness of the skin at the back of the neck of a fetus with ultrasound could predict fetal chromosomal abnormalities. Several years later, it was found that early in pregnancy, low levels of a hormone called pregnancy associated plasma protein A (PAPP-A) and high levels of hCG were associated with fetal chromosome abnormalities.

Comparisons
Detection Rate False Positive Rate
Study A 83% 6%
Study B 79% 9%
Study C 85% 5%

Studies looking at the effect of IVF on hormone marker levels

The data from study A (below) were obtained from analysis of 151 IVF pregnancies. This is considered a relatively small study. The data from study B was combined from multiple centers and included over 1500 pregnancies. This is considered a large study and the results would be considered to be more valid. Although the trends in Study B were similar to those seen in Study A, statistical analysis indicated that the results could have been due to chance. In fact, a third study did not find a difference in the markers between IVF pregnancies and spontaneous pregnancies.

Comparisons
Abnormal if.. Effect of IVF
Study A Study B
hCG Increased 9-14% higher 7% higher
Estriol Decreased 6% lower 12% lower
AFP Decreased No difference 6% lower

Pesticides & Success Rates

Impact of pesticides on fertility

Fruits and vegetables are supposed to be good for you, right? It’s true. They are. However when you eat fruits and vegetables you are eating more than just the fruit or vegetable. In order to keep insects from destroying these crops, we use pesticides.

More than 90% of the US population has detectable concentrations of pesticides or their metabolites in their bodies. While pesticide exposure occurs through a variety of routes, the primary route in most people is through diet – especially from eating fruits and vegetables.

Women exposed to pesticides through their jobs and women living in or near agricultural areas seem to have a higher risk of infertility and adverse pregnancy outcomes such as miscarriage. Until now, however, there hasn’t been any studies to show whether women who are exposed to pesticides from eating a regular diet containing fruits and vegetables have the same risks or not.

A new study suggests looked at over 300 women with infertility who were going to be treated with IVF.

The total amount of fruits and vegetables that women ate did not have an impact on their chance for having a pregnancy or live birth from IVF. However, the researchers divided the fruits and vegetables into those that had a low or high amount of pesticide residue on them. They then determined whether women ate a larger or smaller amount of these fruits and vegetables. Here is what they found:

Compared with women who had less than one serving a day of the high pesticide fruits and vegetables, women who ate more than 2-3 servings a day had an 18% lower chance for pregnancy and a 26% lower chance for a live birth. On the other hand, eating the low pesticide fruits and vegetables did not have an impact on pregnancy or live birth.

The researchers then looked at the possibility of miscarriage. They found that the more high pesticide fruits and vegetables that a woman ate, the greater the likelihood that she would have a miscarriage – with the highest group miscarrying 34% of the time.

What Should You Do?

One interesting analysis that these researchers did was to look at the impact of swapping out a high pesticide fruit or vegetable with a low pesticide type. By doing this, women showed an 80% Improvement in the chance for pregnancy and an 88% increase chance for a live birth.

Since this is the first study of its kind, these conclusions should not be considered final or absolute. We also do not know if the same impact occurs and women who are trying to get pregnant without IVF or who do not have infertility. However, it seems reasonable to try to limit the amount of pesticide exposure in your fruits and vegetables. This may have a benefit on your ability to have a baby during IVF.

Dietary Tips

  1. When eating fruits or vegetables try to choose those with lower pesticide residue over those with higher amounts (see listing below)
  2. When possible, choose organic fruits and vegetables which have lower amounts of pesticide residue
  3. Be sure to clean your fruits and vegetables thoroughly to try to remove as much pesticide residue as possible. Simple Tricks to Remove Pesticides From Fruits and Vegetables

Low Pesticide Residue

  • Peas or lima beans
  • Dried plums or prunes
  • Onions
  • Beans or lentils
  • Avocado
  • Corn, fresh or frozen
  • Cabbage or cole slaw
  • Orange juice,
  • Tomato sauce  / Tomato paste
  • Apple juice or cider
  • Cauliflower
  • Grapefruit

Intermediate Pesticide Residue

  • Cantaloupe
  • Tofu Soybeans
  • Bananas
  • Eggplant, summer squash, zucchini
  • Yam or sweet potatoes
  • Oranges
  • Broccoli
  • Carrots
  • Head lettuce, leaf lettuce
  • Celery

High Pesticide Residue

  • Tomatoes
  • Apple sauce
  • Blueberry, fresh or frozen
  • Kale, mustard, chard greens
  • Winter squash
  • Fresh apple or pear
  • String beans Green beans
  • Grape or raisin
  • Potatoes
  • Spinach
  • Peach or plum
  • Strawberries
  • Green/yellow/red peppers

Risks of Multiple Pregnancy

The greatest risk to undergoing fertility treatment is multiple pregnancy. Most fertility treatments will increase your risk for multiple pregnancy. Complications increase with each additional fetus in a multiple pregnancy and include severe nausea and vomiting, Cesarean section, or forceps delivery. You should be aware of these and other potential problems you might experience.

Premature Birth

Premature labor and delivery pose the greatest risk to a multiple pregnancy. Feasibility of a vaginal delivery depends on the size, position, and health of the infants, as well as the size and shape of the pelvic bones. Cesarean section is often needed for twin pregnancies and is expected for delivery of triplets. Although only 1% of all deliveries are twins, they account for 10% of all premature deliveries. Compared to singletons, of which eight per 1,000 die in the first month of life, twins are seven times more likely to die (56 deaths per 1,000), and triplets are 20 times more likely to die (160 deaths per 1,000).

Since premature labor and delivery present such a serious risk, a woman contemplating fertility treatment must understand the risks associated with prematurity that occur with multiple pregnancies.

Placental Problems

The placenta is attached to the wall of the uterus, and the fetus is attached to the placenta by the umbilical cord. The placenta provides blood, oxygen, and nutrition to the fetus through the umbilical cord. Placental function is likely to be abnormal in a multiple pregnancy. The placenta ages prematurely and may slow fetal growth, especially late in the third trimester. If the placenta is unable to provide adequate oxygen or nutrients to the fetus, the fetus cannot grow properly. This is known as intrauterine growth restriction or IUGR.

IUGR occurs when a fetus has a weight is below the 10th percentile for its gestational age and whose abdominal circumference is below the 2.5th percentile. For a full term delivery, the cutoff birth weight for IUGR is 2,500 g (5 lb, 8 oz). Infants who weigh less than 2,500 g (5 lb, 8 oz) at term have a perinatal mortality rate that is five to 30 times greater than that of infants whose birth weights are at the 50th percentile. The mortality rate is 70 to 100 times higher in infants who weigh less than 1,500 g (3 lb, 5 oz). Low birth weight of less than 5 and a half pounds (2,500 grams) occurs in 50% of twins. The average birth weight is approximately 4 pounds (1,800 grams).

Another placental problem is twin-twin transfusion, a life threatening condition in identical twins. This transfusion occurs when blood flows from one fetus to the other. Poor growth occurs in the “donor” twin, and excessive blood passes to the “recipient” twin. Therapeutic amniocentesis and laser coagulation of blood vessels may reduce complications of twin-twin transfusion.

Preeclampsia

Preeclampsia, also known as toxemia, occurs three to five times more often in multiple pregnancies. Preeclampsia is diagnosed when the mother’s blood pressure becomes elevated and protein is detected in the urine. The condition may progress and threaten the health of the mother and the pregnancy. When severe, the mother may have seizures or even a stroke.

Diabetes

Women with multiple pregnancies are more likely to develop gestational diabetes which is diabetes (elevated blood sugar) occurring during pregnancy. Mild gestational diabetes can cause problems for the baby including macrosomia (excess growth which causes the baby to be at increased risk for birth injuries or cesarean section). Babies at are greater risk for respiratory distress after birth, diabetes, obesity and developmental problems later in life. Women with gestational diabetes are also more prone to diabetes after pregnancy.

Fetal and Newborn Complications

Premature delivery places an infant at increased risk for severe complications or early death. A baby’s lungs, brain, circulatory system, intestinal system, and eyes may be too immature. These severe problems will often require that the babies stay in an intensive care unit specially designed for very ill babies. This is known as the neonatal intensive care unit or NICU. Survivors of premature birth may have lifelong handicaps.

Of the premature babies who die, 50% succumb to respiratory distress syndrome, the inability to circulate oxygen from the lungs throughout the body. Brain damage is responsible for almost 10% of premature newborn deaths. Birth defects and stillbirths account for about 30% of the deaths in twins and multiple pregnancies.

Cerebral palsy

Cerebral palsy is condition, sometimes thought of as a group of disorders that can involve brain and nervous system functions such as movement, learning, hearing, seeing, and thinking. Cerebral palsy is more common in twins than singletons. Among twins, if one twin suffers a fetal death or dies in infancy, the prevalence of cerebral palsy in the surviving co-twin is considerably increased, and those that are the same sex are particularly at high risk.

Single embryo transfer in IVF

During in vitro fertilization, the largest risk that a couple faces is that of multiple pregnancy. Doctors can increase the chance for pregnancy by increasing the number of embryos transferred in an IVF cycle. Doing this however, increases the chances for a multiple pregnancy.

A multiple pregnancy, even if it is only a twin pregnancy, is associated with a large number of problems for both mother and babies. The incidence of

IVF success

pregnancy complications is higher compared to singleton pregnancies. Problems such as gestational diabetes, pre-eclampsia, preterm labor and cesarean section occur more commonly with twin pregnancies. These complications result in a rate of fetal death before delivery that is five times higher in twins than singletons. Preterm delivery leads to significant problems for babies such as respiratory distress and low birth weight. Prematurity is one of the primary reasons that seven times more twin babies die in the first month of life than singleton babies and why they have almost double the rate of severe handicaps. Babies that are born as multiples also experience a higher rate of birth defects and have a four times greater rate of cerebral palsy compared to singletons.

In sum, avoiding multiple pregnancy in in-vitro fertilization is a very desirable goal. The problem is how to accomplish this goal without reducing the chance for pregnancy overall.

Several IVF studies have looked at transfer of a single embryo to the uterus compared to two embryos. These studies have compared the overall pregnancy rate and the multiple pregnancy rates. In most cases, these studies looked at a very select group of women who were thought to have a very good chance for pregnancy. They were young, had a large number of high quality embryos (as assessed under the microscope), and usually were on their first in vitro fertilization attempt. As a whole, these studies showed a lowering of the risk of multiple pregnancies but also a lowering of the overall IVF pregnancy rate.

One recent study looked at an unselected in vitro fertilization population and found the same to be true but to a larger extent. There was a greater difference in pregnancy rates between those women that had two embryos transferred compared to those that had one embryo transferred.

Some programs persist on transferring embryos after only two or three days in the laboratory. These are known as cleavage stage embryo transfers. Studies comparing single embryo transfer to double embryo transfer at the cleavage stage have uniformly shown a lower pregnancy rate for the single embryo transfer. Although many studies using blastocyst transfer have not shown a difference in pregnancy rates, more studies are needed before definite conclusions can be drawn. It also has yet to be seen whether greater use of such methods as preimplantation genetic diagnosis can narrow or eliminate the difference in pregnancy rates and make single embryo transfer a more widely used practice.

Patients undergoing IVF have an interesting perspective on IVF risks. Most studies assessing the preferences of IVF patients have concluded that they would actually prefer to have twin pregnancies than singletons. A survey of 81 Scottish couples found that the majority of couples would prefer dealing with twin related complications than risk treatment failure and childlessness. A study of British couples found that even if these patients were given extra information and counseling about the risks of multiple pregnancy, only 25-30% would accept a single embryo transfer if they thought there was even a slight chance of a lower IVF pregnancy rate.

Vagifem® (estradiol vaginal tablets)

What is Vagifem? (estradiol vaginal tablets)?

Occasionally, during infertility treatments, we may tell you that the uterine lining is thin based on ultrasound measurements. There is some evidence, though it is far from conclusive, that a thin lining may be associated with a lower chance for pregnancy in that month. We may, therefore, recommend using estrogen supplementation to improve the thickness. Since vaginal medications have a much better effect than those administered elsewhere, we use VAGIFEM? (estradiol vaginal tablets) for this purpose. Estradiol, is the bio-identical hormone to that that produced by the ovaries during development of the egg.

How Do I Use Vagifem? (estradiol vaginal tablets)?

Tear off a single applicator.

Separate the plastic wrap and remove the applicator from the plastic wrap.

First select the best position for vaginal insertion of VAGIFEM? (estradiol vaginal tablets) that is most comfortable for you.

One method is to recline on your back

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Another option is stand.

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The applicator should be held so that the finger of one hand can press the applicator plunger. The other hand should be used to guide the applicator gently and comfortably through the vaginal opening.If the tablet has come out of the applicator prior to insertion, do not attempt to replace it. Use a fresh tablet-filled applicator.

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The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less.

Once the tablet-filled applicator has been inserted, gently press the plunger until a click is heard and the plunger is fully depressed. This will eject the tablet inside your vagina where it will dissolve slowly over several hours.

After depressing the plunger, gently remove the applicator and dispose of it the same way you
would a plastic tampon applicator. The applicator is of no further use and should be discarded properly.

In most cases, our patients will be using vagifem twice daily. Insertion should be done upon waking in the morning and again in the evening before bed.

Treatment of Insulin Resistance in PCOS

Metformin

Metformin for the treatment of PCOS

Metformin is the generic name for a medication which reduces insulin resistance. It is also known as Glucophage, Riomet or Fortamet. Metformin is used as a fertility treatment to cause ovulation in women with insulin resistance or PCOS.

Read more…

Byetta is used to treat insulin resistance in PCOS patients
Byetta is used to treat insulin resistance in PCOS patients

Alternatives to metformin for treating insulin resistance in PCOS

Medications such as Byetta and Acarbose and minerals such as chromium have been studied in PCOS patients. Some may have benefit for patients with insulin resistance who do not ovulate.

Avandia treatment of insulin resistance
Avandia treatment of insulin resistance

Actos and Avandia for treating insulin resistance in PCOS

A class of medications called TZDs have been used in the past to induce ovulation in PCOS patient and others with insulin resistance. due to potential risks, this medication is rarely if ever used for this purpose any more.

Alternative PCOS treatments for insulin resistance

Table Of Contents

  • Alternatives to glucophage for treating insulin resistance in PCOS
  • Sitagliptin (Januvia)
  • Byetta (Exenatide for injection)
  • Glycosidase Inhibitors for PCOS Treatment
  • Precose (Acarbose)
  • Miglitol (Glyset)
  • Chromium treatment for PCOS
  • Exercise and PCOS
  • Green Teas for PCOS
  • Herbal Drugs and Chemicals
  • Cinnamon for PCOS
  • Vitex for PCOS

Alternatives to glucophage for treating insulin resistance in PCOS

For women with polycystic ovary syndrome – PCOS, insulin resistance is a common finding. In addition, many of these women do not respond to Clomid (Clomiphene Serophene) (Clomid resistance). For these reasons, many women are now treated with a diabetes medication known as glucophage (metformin) which works, in part, to reduce insulin resistance and improves the chances for ovulating spontaneously or with Clomid. However, many women will have side effects from glucophage such as bloating, cramping, diarrhea, flatulence and nausea. The most serious complication of glucophage is lactic acidosis which is a rare but potentially life threatening condition.

Sitagliptin (Januvia)

Incretins are naturally occurring hormones secreted from the intestines in response to food intake. In the pancreas, incretin hormones act to increase insulin secretion in response to rising sugar levels in the blood. This helps to ensure an appropriate insulin response following ingestion of a meal.

Sitagliptin prolongs the action of incretin hormones by prohibiting their degradation through inhibition of the dipeptidyl peptidase-4 enzyme (DPP4).

A 12 week study of obese women with PCOS who were unable to tolerate metformin were treated with sitagliptin. Sitagliptin was found to improve insulin resistance. another study found that the chance for ovulation was similar to metformin. sitagliptin, however, was tolerated much better than metformin was.

Sitagliptin has been rated by the FDA as belonging to pregnancy category B. Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 12 time the maximum recommended human dose did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) did not produce birth defects at approximately 30- and 20-times the maximum recommended human dose. Higher doses increased the incidence of rib malformations in offspring at approximately 100 times human exposure at the MRHD.

Byetta (Exenatide for injection)

Byetta belongs to a class of medications known as incretin mimetics. The incretin hormone which scientists have studied the most is called glucagon-like peptide-1 (GLP-1). Byetta works by mimicking the effects of GLP-1. Studies show it increases insulin sensitivity.

Byetta is approved by the FDA for the treatment of diabetes – not PCOS yet. Two advantages of Byetta that have been shown in clinical studies include better control of blood sugar levels in diabetics and weight loss. Since Byetta improves insulin resistance, some scientists feel that PCOS patients may benefit from taking Byetta.

In a study of 60 overweight women with PCOS, Byetta improved the likelihood of women having regular menstrual cycles. The combination of Byetta with metformin was found to be better than either metformin or Byetta alone. Byetta alone showed improvement in several parameters such as weight, BMI, insulin resistance and androgen levels. Byetta in combination with metformin improved these parameters to a greater extent then Byetta alone.

It is clear, therefore, that Byetta exerts a positive impact on PCOS patients and that combining Byetta with metformin works better than either medication alone.

Byetta has been rated by the FDA as belonging to pregnancy category C. Byetta has been shown to cause reduced fetal and neonatal growth and skeletal effects in mice.  Byetta has also been shown to cause skeletal effects in rabbits. There are no adequate and well-controlled studies in pregnant women. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The most common adverse events associated with Byetta were nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia. In October of 2007, the FDA reported that it had received 30 reports of patients taking Byetta developing a serious condition known as pancreatitis. Five patients developed serious complications from the pancreatitis such as kidney failure. Although most patients improved after they stopped taking Byetta, eight out of the thirty patients did not improve.

Since those initial reports, there have been several studies trying to determine if there is a relationship between Byetta and pancreatitis. The results have been mixed, some studies showed an increased risk, some did not. Complicating the matter is the fact that type 2 diabetics have a higher rate of pancreatitis even without the use of Byetta. As of late 2011, there were no reports of PCOS patients taking Byetta developing pancreatitis.

At this time, Byetta cannot be recommended as a first-line treatment for PCOS. It may be considered as an alternative, however, with proper counseling.

Glycosidase Inhibitors for PCOS Treatment

Precose (Acarbose)

50-100 mg and are taken with meals

Miglitol (Glyset)

50-100 mg and are taken with meals

Acarbose is another medication used to treat diabetes. Acarbose is an alpha-Glycosidase inhibitor. It works by reducing the absorption of monosaccharides (simple sugars) through intestines and minimize the increase in blood sugar and insulin seen after meals. Serious side-effects of acarbose are rare and although it shares many of the gastrointestinal side effects as glucophage (abdominal distension, diarrhea and flatulence), lactic acidosis is not a problem with this drug. side effects may lessen over time.

Some studies have demonstrated that these medications are capable of lowering the androgen levels in women with PCOS.

In a recent study, researchers looked at 30 women with polycystic ovary syndrome – PCOS who did not previously respond to Clomid . The women were divided into two groups. One group received acarbose and Clomid. The other group received glucophage and clomid.

By the end of three months, the women taking acarbose lost more weight than the glucophage group. Both groups showed a similar improvement in the number of women who ovulated. There were 15 women in each in group and they were studies for three months so there was a possibility of 45 ovulatory cycles (15 x 3). The acarbose group had 20 ovulations and the glucophage group had 24 ovulations. The incidence of side effects was the same in both groups and there were no serious adverse effects in either group.

In summary, it seems that acarbose could provide a reasonable alternative to glucophage for treating insulin resistance in polycystic ovary syndrome – PCOS patients, though the expected benefits are minimal. This was a small study so there isn’t nearly as much data showing a positive effect as exists for glucophage at the moment. Acarbose did not have a better ovulation rate than glucophage so the main benefit comes down to a lower risk of lactic acidosis which is a very rare complication anyway.

I would think of acarbose as a second line drug for the time being. If first line drugs like glucophage were not tolerated or ineffective than trying something like acarbose might be reasonable.

Chromium treatment for PCOS

Chromium is a mineral required in small quantities by the body. It enables insulin to function normally and helps the body process (metabolize) carbohydrates and fats. Good sources of chromium include carrots, potatoes, broccoli, whole-grain products, and molasses. Picolinate, a by-product of the amino acid tryptophan, is paired with chromium in supplements because it is claimed to help the body absorb chromium more efficiently. Chromium deficiency is very rare in developed countries. Nonetheless, it has become a popular supplement.  Chromium picolinate has been suggested to promote weight loss, build muscle, reduce body fat, and enhance the function of insulin. It may lower levels of cholesterol and triglycerides.

Chromium picolinate is of possible interest in the treatment of PCOS patients due to its possible effects in improving insulin resistance. A few small studies have been performed in which women with PCOS were given chromium.

One such study, in women with polycystic ovary syndrome, found that chromium picolinate (200 μg/d) improved glucose tolerance compared with placebo but it did not improve ovulatory frequency or the abnormal hormonal parameters commonly found in women with PCOS. The authors of this study concluded that future studies in the polycystic ovary syndrome population should examine higher dosages or longer duration of treatment.

Another study examined the effects of chromium picolinate at a dose of 1000 ug per day. PCOS patients were given chromium but were instructed not to change their diet or exercise level. These PCOS patients experienced a  38% mean improvement in a measure of insulin resistance. These authors concluded that chromium picolinate, an over-the-counter dietary product, may be useful as an insulin sensitizer in the treatment of polycystic ovary syndrome.

Exercise and PCOS

Exercise may be the single most important lifestyle factor for both preventing and reversing insulin resistance. Exercise training results in a preferential loss of abdominal body fat and reverses the loss of muscle mass associated with insulin resistance, providing the single-most important intervention for changes in body composition.

Exercise improves insulin sensitivity in skeletal muscles and fat tissue, reducing both fasting blood sugar and insulin levels. Findings demonstrate that consistent exercise training, even without accompanying improvements in body composition, improve peripheral insulin activity in subjects with impaired glucose tolerance.

Even an exercise routine as simple as incorporating brisk walking four times weekly dramatically improves endurance fitness, decreases body fat stores, tends to reduce food consumption, and decreases insulin resistance.

To date, only a few controlled studies have examined the direct effects of physical exercise in PCOS women. In the first study, a 6-month exercise program significantly decreased plasma total homocysteine concentrations and waist-to-hip ratio, but had no effect on fasting insulin or androgen levels in young overweight and obese women with PCOS.

More recently, a 2005 study showed that insulin resistance was improved by up to 25% in sedentary women with PCOS and insulin resistance following a 5-month moderate-intensity exercise program without weight loss. In 2007, investigators determined that any improvements seen with exercise in PCOS patients were lost within 12 weeks if they stopped their exercise program.

Green Teas for PCOS

Many varieties of green tea have been created in China and other countries. these teas can differ substantially due to variable growing conditions, processing and harvesting time. Although many health benefits are supposed to result from drinking green teas, few if any of these claims have been proven in rigorously performed studies.

Herbal Drugs and Chemicals

Unfortunately, the internet has resulted in a huge increase in the use of herbal drugs and elixirs. In addition to being exempt from U.S. Food and Drug oversight, there is little evidence to support the use of these powerful chemical compounds. There are reported cases of adverse complications occurring in women taking these things to try to promote their fertility.

Cinnamon for PCOS

Cinnamon is a spice that comes from the bark of a small evergreen tree native to Sri Lanka and South India. The bark is widely used as a spice due to its distinct odor. In India it is also known as “Daalchini”.

Cinnamon is prepared by roughly pounding the bark, soaking it in sea-water, and then quickly distilling the result. Cinnamon contains a large amount of active chemicals including cinnamic aldehyde, ethyl cinnamate, eugenol, cinnamaldehyde, beta-caryophyllene, linalool and methyl chavicol.

Like other herbal remedies, there are many varieties of cinnamon which have distinct chemical components and may differ from each other substantially. It is therefore difficult to perform accurate scientific comparisons and draw valid conclusions.

In the summer of 2007, a very small pilot study was performed to determine whether cinnamon had any beneficial effects on women with PCOS. Fifteen women with polycystic ovary syndrome were randomized to daily oral cinnamon and placebo for 8 weeks. The results indicated a reduction in insulin resistance in the cinnamon group but not in the placebo group. Because the number of women studied was so small, a larger trial is needed to confirm the findings of this pilot study.

Vitex for PCOS

Vitex agnus-castus  (commonly called just Vitex, but also called Chaste Tree, Chasteberry, or Monk’s Pepper — is a plant which grows in the Mediterranean region. The leaves, stem, flowers and ripening seeds, have been used for medicinal purposes.

The berries have been used as an herbal drug for both the male and female reproductive systems. The leaves are believed to have the same effect but to a lesser degree. This plant is commonly called monk’s pepper because it was originally used as anti-libido medicine by monks to aid their attempts to remain celibate. It is believed to decrease sexual interest, hence the name chaste tree.

There is little if any clinical evidence of a benefit of Vitex for infertility or women with PCOS. Like other herbal drugs, many varieties of the plant are grown in various areas. The chemical composition is quite complex and varied from variety to variety.

One study has found that treatment with one variety of Chinese Vitex caused a slight reduction of a pituitary hormone known as prolactin in mice. There are no studies in human beings. There are no studies which have looked at the effects of Vitex in women with PCOS.

Actos and Avandia for PCOS

Background on Actos and Avandia

Actos (pioglitazone) and Avandia (rosiglitazone) belong to a class of medications known as thiazolidinidiones or TZDs. A third medication known as Rezulin (troglitazone) is no longer available in the United States. All three of these medications have been approved by the Food and Drug Administration for the treatment of diabetes. The use of Actos and Avandia for PCOS is considered an off label indication.

Because of the risks, TZDs such as Actos and Avandia are no longer recommended for the treatment of PCOS

Why diabetes drugs for PCOS?

There are many reasons why a woman may not ovulate regularly. It appears that some women are resistant to the hormone insulin. Insulin is normally thought of as a hormone that helps regulate blood sugar. Insulin is produced by cells that are located adjacent to the pancreas called the Islets of Langerhans. While this is true, insulin also has many other effects in the body. The ovary has receptors for insulin and thus insulin is capable of modifying hormone production from the ovaries.

The are several conditions that may result in a woman becoming resistant to the effects of insulin. Among these are PCOS (Polycystic Ovary Syndrome), genetics and obesity. When insulin resistance occurs, the body needs a higher level of insulin to accomplish the same tasks. High insulin levels are frequently seen in women with insulin resistance.

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return.

In fact some studies in women with PCOS demonstrated that thiazolidinidiones could be an effective treatment.

Rezulin in PCOS

Rezulin was the first TZD studied. Studies with Rezulin in PCOS patients demonstrated an improvement in some of the hormone abnormalities seen in PCOS.

In 2 other studies, Rezulin either alone or combined with clomiphene citrate induced ovulation in insulin and/or clomiphene-resistant patients with PCOS. Ovulation and pregnancy rate were 83% and 39% in 18 Clomid resistant patients, and in most of the patients, ovulation was achieved with Rezulin alone or in combination with low doses of CC.

Actos in PCOS

More recently, a well designed study using Actos in PCOS patients was published. The Actos study was a randomized, double-blind, controlled trial was to investigate whether Actos was capable of decreasing insulin resistance and the elevated levels of male hormones (androgens) that are common in women with PCOS. The Actos study also sought to determine whether the ovulation rate would improve in women with PCOS.

Forty pre-menopausal women with PCOS were assigned to treatment with either Actos (30 mg/d) or a placebo for three months. The results were very encouraging. The group which took Actos showed a decline in both fasting serum insulin levels and insulin response after giving them a high load of sugar.

This represented an increase in insulin sensitivity. In addition, Actos increased the levels of a protein called SHBG. SHBG binds up the male hormones in the circulation resulting in less “free” male hormones (androgens).

Treatment with Actos was also associated with higher ovulation rates.

Avandia in PCOS

A similar study using Avandia was published in March of 2005. The stated goal of this randomized, controlled, double-blind trial was to learn whether Avandia would improve the ovulation rate and androgen levels in non-obese women with polycystic ovary syndrome (PCOS). An interesting aspect of this study is that women were chosen based on the fact that all laboratory testing for insulin resistance was normal.

100 women with PCOS were enrolled in the study. The women received either 850 mg of Glucophage, 4 mg Avandia, a combination of both treatments, or a placebo twice a day for 6 months.

The results of this Avandia study are interesting. Women given Avandia gained an average of 1 kg (about 2.2 pounds). However, all treatment groups except the placebo group had a significant decline in their waist-to-hip ratio which implies a reduction in insulin resistance. Likewise, systolic blood pressure fell in all actively treated groups but not in those who received placebo.

Avandia and Glucophage treatment resulted in an increase in the number of times the PCOS patients ovulated. The highest rates of ovulation were found in the combined Avandia and Glucophage group and in the Glucophage only group.

The male hormone testosterone decreased significantly with active treatment.

Avandia dose for PCOS

Avandia 4 or 8 mg tablets. Maximum 8 mg daily

Actos dose for PCOS

Actos 15, 30 or 45 mg tablets. Maximum dose 45 mg daily.

Actos and Avandia side effects

Rezulin which is no longer available in the U.S. has been found to cause liver injury, jaundice and very rare cases of liver failure, liver transplants, and death. In early studies, Rezulin was noted to increase the levels of certain blood markers of liver injury (liver enzymes, AST, ALT). The other members of this class have not been found to cause similar problems. In fact, it is when Actos and Avandia were approved by the FDA that Rezulin was removed from the U.S. market. However, due to the close structural similarity of all these medications, it is strongly recommended that all patients undergo regular assessment of liver enzymes.

The incidence of other reported side effects in clinical trials of Actos and Avandia did not differ from that of placebo (sugar pills).

In a small percentage of people, Actos or Avandia may cause fluid retention. Others may notice swelling in the lower extremities during use.

Because of the possible risks, you should not take Actos or Avandia if:

1. You have known liver problems
2. You drink alcohol excessively
3. Heart disease

Patients who develop nausea, vomiting, abdominal pain, fatigue, loss of appetite, dark urine, light colored stools, or yellowing of the whites of the eyes should immediately report these symptoms to us.

Newly reported possible risks of Actos and Avandia

Takeda pharmaceuticals recently performed an analysis of its clinical trial database of Actos with a special focus on fractures, comparing patients treated with Actos or a comparator (either placebo or a different medication). The results suggest that Actos users are at higher risk for fractures. In the analysis, the maximum duration of Actos treatment was up to 3.5 years. There were more than 81 00 patients in the Actos-treated groups and over 7400 patients in the comparator-treated groups. The majority of fractures observed in female patients who received Actos were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia).

Based on their calculations, if 1000 women took Actos for one year, 19 fractures would be expected compared to 11 expected fractures in the comparison group. There was no increased risk of fracture identified in men.

Avandia was shown in a separate study published in the New England Journal of Medicine in May 2007 to possibly be associated with an increase in the risk for myocardial infarction (heart attack) and cardiovascular death. However, the study did not separate diabetics from PCOS patients and incldued both men and women. It is not clear at this time whether PCOS patients have a similar increase in risk.

Actos and Avandia: Effects on pregnancy

Rezulin and Avandia are considered pregnancy category B.

Animal studies in rats and rabbits at very high doses did not result in a higher than expected incidence of birth defects. At extremely high doses, body weights of fetuses were decreased. Postnatal development, attributed to decreased weight was delayed.

Actos is pregnancy category C. Delayed parturition and postnatal development and embryo toxicity (as evidenced by increased post-implantation losses, delayed development and reduced fetal weights) were observed in rats and/or rabbits when given very high doses.

There are no good, well-controlled studies in women. It is recommended that Actos or Avandia be stopped immediately upon the diagnosis of pregnancy.

Progesterone vaginal suppositories

Progesterone vaginal suppositories

Progesterone suppositories are relatively simple to use. Progesterone suppositories are compounded by the pharmacist and consist of natural progesterone suspended in a base similar to cocoa butter.

The suppositories will feel soft and "squishy" to the touch. Usually they are oblong or bullet shaped. Someitmes the suppositories will come with an applicator but an applicator is not necessary to use them.

The suppositories are intended to be used vaginally. First, the suppository must be removed form the wrapping or covering material. The suppository is then fitted onto the end of the applicator into the "cup". The applicator is inserted into the vagina. Once resistance is felt, stop advancing the applicator.

Press the plunger on the end of the applicator to release the suppository and then remove the applicator.

Alternatively, the suppository can be grasped between the fingers and inserted without an applicator.

Progesterone injections

What is Progesterone?


Progesterone, one of the reproductive hormones normally produced by the ovary after ovulation. It is needed to prepare the endometrium for implantation of an embryo and is used as part of an assisted reproductive technology (ART), ovulation induction or sometimes to induce a period in a woman who hasn’t ovulated.

Here are step-by-step instructions for administering Progesterone Injection injections:


Wash your hands thoroughly and make sure that the surface you work on is clean.

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Use an alcohol swab to cleanse the rubber stopper of the progesterone medication.

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Using the 3cc syringe with a 1.5 inch needle, pull back on the plunger to the 1cc mark.

Pierce the rubber stopper of the progesterone vial. Inject 1cc of air into the vial.

Turn the vial upside down, making sure the tip of the needle is below the fluid level. Withdraw the dosage ordered. Progesterone is an oil. It will pull into the syringe more slowly than sterile water does as when you use your other fertility medications.


Pull out the needle and replace the cap. Pull back on the plunger to clear the needle of any medication. Remove the needle from the syringe and replace with a new 1½ inch needle.

Flick the syringe with your finger

With the needle pointing toward the ceiling, flick the side of the syringe to disperse the air bubbles and the air pocket at the top of the syringe

Press the plunger on the syringe


Then gently push the plunger to eliminate any air until you expel one or two drops of liquid from the tip of the needle.

You are now ready to administer the progesterone by intramuscular injection.

Click here to learn how to give a intramuscular injection

IVF Progesterone supplementation

Progesterone is made from the ovaries after ovulation. During IVF cycles, progesterone is produced after the hCG trigger injection is taken. Using medications to prevent premature ovulation and performing an egg retrieval may cause the progesterone production to be inadequate. For this reason, we will supplement progesterone in women being treated with IVF.

Vaginal or IM Progesterone?

The most reliable way to get progesterone to the uterus is to administer it vaginally. Several studies have been performed comparing vaginal progesterone to intra-muscular injections. In the past, some studies have shown that vaginal progesterone is best whereas some studies showed that  intra-muscular progesterone is best. Today, it is almost universally agreed that there is no difference in the chance for pregnancy between the two.

Most women prefer to use vaginal progesterone. This is due to the fact that administration of intramuscular progesterone is painful and can result in welts at the injection site. some women also have allergic reaction to the oil base in the progesterone injections.

A few women seem to prefer progesterone injections because they do not like the vaginal discharge that can sometimes occur with the use of vaginal progesterone.

We like to use vaginal progesterone in the evening (either a natural progesterone cream called Crinone or a vaginal progesterone dissolving tablet called Endometrin ). Crinone comes in an applicator like medications that are used to treat yeast infections. One applicator of Crinone is given each morning and night starting on the night of the egg retrieval. Endometrin is used three times daily.

Safety of progesterone in IVF

Many couples worry whether treatment with progesterone is safe for the baby. The short answer is yes.

Progesterone supplements come in different varieties. Only a few of these types are safe to use in pregnancy. Progesterone that is chemically identical to the “natural” progesterone made in the ovaries is safe to use in pregnancy. In fact, two brands, Crinone and Endometrin, are natural progesterones that are approved by the U.S. FDA for use in fertility treatments. Some pharmacies can also make natural progesterone vaginal suppositories. Progesterone intramuscular injections also contain natural progesterone and may be used during pregnancy.

There are progesterone supplements that are synthetically derived and not chemically identical to the progesterone made in the ovaries. For example, the progesterones that are contained in birth control pills like norethindrone, drospirenone (and others) should not be used in pregnancy. A very commonly used type of synthetic progesterone called Provera should also not be used in pregnant women.

How long do you need to continue progesterone?

As noted above, there is concern about the ovaries ability to produce progesterone because of the use of medications and because of the egg retrieval. At about the 7th week of pregnancy, progesterone production begins to shift from the ovaries to the placenta. By about the 11th week, the shift is complete and all progesterone is being produced by the placenta. At this posint, progesterone supplementation is no longer needed.

Lupron (Leuprolide acetate)

What is Lupron (Leuprolide acetate)?

Lupron® is a gonadotropin-releasing hormone agonist. It inhibits the pituitary gland’s ability to control the ovary and, therefore, has been used to reduce the likelihood of unintended ovulation during assisted reproduction treatment cycles. In women with endometriosis, Lupron® provides pain relief and reduction in the size of endometriosis lesions.

How do I use Lupron (Leuprolide acetate)?

Here are step-by-step instructions for taking Lupron® (leuprolide acetate) injections: Lupron® is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel;- and your upper, outer-thigh where the skin is loose.
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Lupron

Wash your hands thoroughly and make sure that the surface you work on is clean.

Use an alcohol swab to cleanse the rubber stopper of the vial.

Pull the plunger of the syringe back to the appropriate marking.

Pull off the cap of the needle, and pierce the rubber stopper of the Lupron® vial.

Push the plunger all the way in. Keeping the needle inside the bottle, turn the vial upside down. With the needle in the liquid, pull back the plunger, until the syringe fills to the proper mark. Remove the needle from the vial,

With the needle pointing toward the ceiling, flick the side of the syringe to disperse any air bubbles and the air pocket at the top of the syringe.

Gently push the plunger until one or two drops of liquid are expressed to make sure you have eliminated any air.

You are now ready to administer the lupron as a subcutaneous injection.
Click here to learn how to give a subcutaneous injection

Low Dose hCG

IMPORTANT: The low dose hCG should be premixed by the pharmacy. You should receive it on ice and it needs to be kept in the refrigerator. If you have not received your hCG in this way, please notify us immediately!

It is your responsibility to make sure you have received the correct medications. Do not wait until the last minute!

Do not attempt to use hCG for the trigger injection in place of low dose hCG!!!!

Why use Low Dose hCG?

hCG, or human chorionic gonadotropin, is very similar in structure to the pituitary hormone LH (luteinizing hormone). Many experts beleive that in order to optimally stimulate the ovaries for assisted reproduction technologies (ART), medications containing both FSH (follicle stimulating hormone) and LH are necessary.

Since most of the FSH medications used in ART are produced through recombinant DNA technology, they contain no LH activity. Supplementation with LH is problematic since LH is broken down very quickly in the body and therefore has very little effect.
hCG, however, lasts much longer and therefore has greater biologic activity. Very low dose hCG is used as a replacement for LH to help supplement the stimulation during ART cycles.

How do I use Low Dose hCG?

Here are step-by-step instructions for taking low dose hCG injections:
Low dose hCG is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

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You should receive your low dose hCG premixed and on ice. Place it in the refigerator until ready for use. If your medication is not mixed by the pharmacy, you will need to bring it into our office to have the nurses mix it for you.

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The first time you use the low dose hCG vial, it will have a foil wrapper covering the top. Grasp the foil tab and pull the foil off the the low dose hCG vial.

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Wipe the top of the vial with an alcohol swab.

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Remove the syringe from its wrapper. The needle is already attached to the syringe. Remove the cap from the needle.

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Draw the plunger back on the syringe to the mark that you have been instructed.

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With the vial of premixed low dose hCG on a flat surface, insert the needle straight down through the marked center circle of the rubber stopper. Slowly inject the air into the vial by depressing the syringe plunger.

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With the needle still in the vial, invert the vial. Keep the tip of the needle below the surface of the fluid hCG mixture.

Pull the plunger back to the mark you have been instructed. Make sure that you keep the tip of the needle under the surface of the fluid while withdrawing the hCG mixture.

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Remove the needle from the vial. The syringe is now ready for you to administer the lose dose hCG injection subcutaneously. Remember to place the hCG vial back into the refigerator until its next use.

Click here to learn how to administer the subcutaneous injection of low dose hCG

Lovenox (enoxaparin) Injection Instructions

What is Lovenox™ (enoxaprin sodium)?

Lovenox™ is a medication used to help reduce the chances for blood clots (a.k.a thrombosis) from forming. At IVF1, we use Lovenox™ to prevent Deep Vein Thrombosis (DVT) from occurring during or shortly after surgery. We also use  Lovenox™ in women with recurrent miscarriage due to increased blood clotting.

How do I use Lovenox™?

Here are step-by-step instructions for taking Lovenox™ (enoxaparin) injections:

Lovenox™ is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel.

Wash your hands thoroughly before beginning.

Lovenox

Lovenox™

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Remove the needle cap by pulling it straight off the syringe and discard it in a sharps collector. Do not twist the cap. Do not push on the plunger when pulling off the cap.

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Hold the syringe like a pencil in your writing hand.

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With your other hand, pinch an inch of skin that you have cleaned with alcohol to make a fold in the skin. Next, insert the full length of the needle straight down – at a 90˚ angle – into the fold of skin.

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Press the plunger with your thumb until the syringe is empty.

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Then pull the needle straight out and release the skin fold.

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Point the needle down and away from yourself and others, and then push down on the plunger to activate the safety shield.

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Place the used syringe in the sharps collector.

Click here to learn how to give a subcutaneous injection

Letrozole (Femara) for Infertility Treatment

Background information

Letrozole is being used commonly as an infertility treatment. Letrozole is a recent addition to the drugs being used for fertility treatment. Fertility drugs are used often in infertility treatments. There are two situations in which fertility drugs may be useful. First, these drugs can be used to induce an egg to develop and be released in women who are not ovulating on their own. This is known as ovulation induction. Fertility drugs can also be used to increase the chances of pregnancy in women who are already ovulating. This is known as superovulation.

Letrozole for infertility
Letrozole for infertility

In many fertility centers, clomiphene citrate (Clomid, Serophene) has been the drug of first choice for either ovulation induction or superovulation for many years. In general, it has been a relatively effective medication. However, clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining. Some groups of patients, such as women with PCOS – polycystic ovary syndrome, do not respond well to clomiphene citrate. The Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study found that over 6 months time, 1 in 4 PCOS patients never had a single documented ovulation. The cumulative live birth rate was only 23% over the 6 months. One reason theorized for the lower pregnancy rate with clomid is an adverse effect on the uterine lining.

Another group of fertility drugs which are administered as injections are called gonadotropins (Gonal F, Follistim). The gonadotropins are very efficient at inducing ovulation and have higher pregnancy rates than clomiphene citrate. However, gonadotropins are much more expensive than clomiphene citrate and the injectable route is uncomfortable for patients to administer and inconvenient. The risk for multiple pregnancies is also much higher with gonadotropins.

Letrozole as a Fertility Treatment

Letrozole is a medication that has been widely used in women with breast cancer. It is sold under the trade name Femara. Letrozole belongs to a class of medications known as aromatase inhibitors. Aromatase is an enzyme that is responsible for the production of estrogen in the body. Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks estrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries. These hormones, FSH and LH, can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in the ovaries of women who already ovulate. As a result, several studies have now been published using letrozole as a fertility drug.

One of the earliest studies using letrozole as a fertility drug looked at 12 women with inadequate response to clomiphene citrate. Ovulation on letrozole occurred in 9 of 12 cycles and 3 patients conceived. A later study by the same investigators compared the effects of letrozole to those of clomiphene citrate. This time 19 women were studied. Ten women received clomiphene citrate and nine women received letrozole. This study was unable to demonstrate any difference in the number of women who ovulated, the number of eggs that developed in each woman, or the thickness of the uterine lining during treatment. However, a more recent study by a different group of investigators found that compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate.

At the 2013 meeting of the American Society for Reproductive Medicine (ASRM), the results of the PPCOS II study were first presented. In this study, which has now been published, 750 PCOS women were randomized to receive either letrozole or Clomid for up to 5 treatment cycles.

  • The findings convincingly showed that for women with PCOS:
  • The ovulation rate was superior with letrozole (61.7%) than with Clomid (48.3%)
  • The cumulative live birth rate was higher with letrozole (27.5%) the with Clomid (19.5%)
  • The live birth benefit was higher in obese women (BMI ≥ 35)
  • letrozole was equal or superior to Clomid at all BMI groups

There was no difference in:

  • the risk for pregnancy loss (letrozole 31.8% vs Clomid 28.2%)
  • Multiple pregnancy rates (all twins) (letrozole 3.2% vs Clomid 7.4%)
  • The number of serious adverse events

Use of letrozole in women without PCOS

The majority of studies looking at the use of letrozole compared to Clomid in women who do not have PCOS have concluded either there is no difference between the two or that clomid is superior for this group of patients.

Letrozole and birth defects

A study presented at ASRM in 2005, in which researchers analyzed births that occurred after treatment with letrozole found seven serious birth defects in 150 babies, which is about 4.7%. This was compared to a database of 36,050 normal deliveries. The incidence of birth defects in the control babies was 1.8% This means that birth defects were 3 times more likely to occur with letrozole.

This prompted the manufacturer (Novartis) to review their safety database and found 13 reports of already pregnant women receiving the drug worldwide. Of those 13 women, two had children with birth defects (15.4%).Novartis sent a letter to fertility physicians stating: “Femara (letrozole) is contraindicated in women with premenopausal endocrine status, in pregnancy, and/or lactation due to the potential for maternal and fetal toxicity and fetal malformations”.

In response, 5 Canadian fertility centers reviewed their birth outcomes and incidence of birth defects in women who conceived with letrozole and compared them to Clomid. The Canadian study involved 911 newborns. The major birth defect rate in the letrozole group was 1.2% (6/514) and in the Clomid group was 3.0% (12/397).

In the United States, the labeling of letrozole already warned that it had been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and was clearly concerned about their liability if given in pregnancy.

Letrozole is a medication that is metabolized rapidly in the body. It is not thought to have significant levels in the blood or tissues for a prolonged period of time.

In the PPCOS II study, each baby born was closely studied for birth defects at the time of birth with additional screening within 1 month of birth by trained pediatric personnel. There was no difference in the rate of birth defects between letrozole and Clomid.

Letrozole side effects

Letrozole works based on its ability reduce estrogen levels. Low estrogen levels of any cause can cause a woman to have symptoms. The data on side effects comes from women who have been using letrozole for an extended period of time in order to treat breast cancer. The treatment duration for letrozole is only five days. In our experience, we have seen side effects that are similar to those seen with clomiphene citrate:

  • Hot flashes
  • Headaches
  • Breast tenderness

Letrozole and pregnancy

Studies conducted so far have shown either no increased risk of miscarriage or a decrease in miscarriage risk. Letrozole is considered pregnancy Category D. Letrozole should not be given to women who are already pregnant. Studies in rats and mice have shown that letrozole increases the risk of fetal death and malformations. Since there are no studies in human beings, it should be assumed that a similar effect is possible.

Letrozole Fertility Treatment Protocols

Monitoring with ovulation predictor kits and having intercourse only.

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole 2.5 mg tablet on days 5,6,7,8, and 9.
  4. Start testing urine on the morning of day 10 or 11.
  5. Look for the first definite color change. Do not continue to test after the color change.
  6. Have intercourse the same day you see the color change and the next day.
  7. Call the office when you see the color change. Schedule an appointment approximately one week later for a blood test to verify ovulation.

Monitoring with ovulation predictor kits and having an IUI – intrauterine insemination

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole 2.5 mg on days 5,6,7,8, and 9.
  4. Start testing urine on the morning of day 10 or 11.
  5. Look for the first definite color change. Do not continue to test after the color change.
  6. Call the office the same morning you see the color change. Have intercourse that night.
  7. Schedule the intrauterine insemination for the next day (The day after the color change)
  8. Schedule an appointment approximately one week later for a blood test to verify ovulation
  9. Schedule an appointment approximately two weeks later for a pregnancy test

Monitoring in the office with intrauterine insemination or intercourse

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole on days 5,6,7,8, and 9.
  4. Day 10 or 11 – Office visit – Blood test and ultrasound. You will receive instructions that afternoon when to return for the next visit.
  5. Only when instructed – Take the hCG trigger injection in the evening. Have intercourse that evening also.
  6. Schedule the insemination for 2 (two) days after the hCG trigger . If you are not doing intrauterine insemination, have intercourse again on this day
  7. 1 week after hCG trigger – Office visit – Blood test only (Progesterone level)
  8. 2 weeks after hCG trigger – Office visit – Blood test only (Pregnancy test)

hCG Trigger


What is the hCG Trigger?

The hCG trigger injection is a medication known as a human chorionic gonadotropin and is used after other fertility hormones, such as clomiphene citrate or menotropins, to induce ovulation (release of the egg from the ovary) or in women undergoing an assisted reproductive technology (ART), to induce final maturation of the eggs. The dose used for the trigger is dependent on the body mass index of the female.
There are several brand names for the hCG trigger and include:

Profasi

Pregnyl

Pregnyl

Novarel

Novarel

chorionic-gonadotropin.png

Generic hCGDirections for mixing and giving the hCG trigger — 10,000 I.U.
Wash your hands thoroughly and make sure that the surface you work on is clean.

Clean vial with alcohol

Use an alcohol swab to cleanse the rubber stoppers of both vials.

Pull the plunger back

Using the 3cc syringe with a 1.5 inch needle, draw back on the plunger to the 1cc mark.

Pierce the rubber stopper of the diluent vial. Inject 1cc of air into the vial.

Turn the needle upside down, making sure the tip of the needle is kept below the fluid level. Withdraw 1cc of the liquid.

Remove the needle and pierce the vial containing the powder. Slowly inject 1cc of diluent into the vial of powder. Gently swirl the solution until the powder is dissolved.

Turn the vial upside down and withdraw all of the medication, making sure that the tip of the needle is kept below the fluid level.
Remove the needle from the vial and carefully replace the cap. Pull back on the plunger to clear the needle of any medication. Remove the needle from the syringe and replace with a new 1.5 inch needle for intramuscular injection or a new 0.5 inch needle for subcutaneous injection.

Flick the syringe

With the needle pointing toward the ceiling, flick the side of the syringe to disperse the air bubbles and the air pocket at the top of the syringe, then

Gently push the plunger until one or two drops of liquid are expressed to ensure you have eliminated any air.

Changes if you are giving 15,000 I.U.

You will need two bottles of hCG powder. Each bottle contains 10,000 I.U. Inject 2 cc of fluid into the first powder bottle. Once dissolved, draw the 2 cc of dissolved powder back into the same syringe. Inject the dissolved powder from the syringe into the 2nd bottle of powder. Once the second bottle is dissolved, draw only 1.5 cc back into the syringe. There will be 0.5 cc of medication that remains in the bottle.

Changes if you are giving 20,000 I.U.

You will need two bottles of hCG powder. Each bottle contains 10,000 I.U. Inject 1 cc of fluid into the first powder bottle. Once dissolved, draw the 1 cc of dissolved powder back into the same syringe. Inject the dissolved powder from the syringe into the 2nd bottle of powder. Once the second bottle is dissolved, draw all of the medication back into the syringe.

The hCG Trigger injection can be given as an intramuscular or a subcutaneous injection. Either way will work. The intramuscular injection will cause more bruising. The subcutaneous injection will cause the injection area to be red, swollen and itchy. It may stay this way for a few days. This is normal.

Click here to learn how to give a intramuscular injection

Click here to learn how to give a subcutaneous injection

Gonal F 450 Multidose Vials

Gonal F 450 Multidose Vials

What is Gonal-F??

Gonal-F? is a follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Gonal-F? is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments(ART). This medication may also be used to induce ovulation in women for certain types of ovarian failure.

How Do I Use Gonal-F??

Here are step-by-step instructions for taking Gonal-F? (follitropin alfa) Multi-Dose injections:
Gonal-F? is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

GonalFflipofflid

Using your thumb, flip off the plastic cap of the Gonal-F? Multi-Dose 450 IU vial.

GonalFwipeofflid

Wipe the top of the vial with an alcohol swab.

GonalFtwistoffcap

Carefully twist and pull off the rubber cap from the prefilled syringe
of Bacteriostatic Water. Do not touch the needle or allow the needle to
touch any surface.

GonalFinsertneedle

Position the needle of the syringe of water in a straight, upright
position over the marked center circle of the rubber stopper on the
vial of Gonal-F Multi-Dose powder. Keep the needle in a straight,
upright position as you insert it through the center circle. Slowly
inject the water into the vial by depressing the syringe plunger.

GonalFInjectdiluent

After all of the water has been injected into the vial, remove your
finger from the plunger, allowing the plunger to rise to its original
position. Withdraw the needle safely and dispose of it in a sharp
container.
Swirl the mixture gently until it becomes clear. Do not shake.

GonalFwipevial

Wipe the top of the vial with an alcohol swab.

Removewrapper

Remove the wrapper from the custom dosing injection syringe. Carefully
loosen and pull the plastic cap from the needle and avoid touching the
needle.

GonalFPushplunger

With the vial of reconstituted Gonal-f on a flat surface, insert the
needle straight down through the marked center circle of the rubber
stopper.

Invertvial

Without removing the needle from the vial, turn it upside down so that the needle points upward.

Pullplungerback

Slowly pull the plunger back until the syringe fills to slightly more
than the unit marking that corresponds to your prescribed dose. Keeping
the needle in the vial, slowly push the plunger to your prescribed
dose. This will clear any air bubbles.

GonalFrecap

Carefully
remove the syringe from the vial and recap the needle. The custom
dosing syringe is now filled with the prescribed dose of Gonal-f and is
ready for administration.

Click here to learn how to administer the subcutaneous injection of Gonal F

Gonal F 1200 Multidose Vials

What is Gonal-F?

Gonal-F is a follicle stimulating hormone (FSH) ,

one of the hormones that stimulates the ovary to make mature eggs. Gonal-F is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments (ART). This medication may also be used to induce ovulation in women for certain types of ovarian failure.

How Do I Use Gonal-F?

Here are step-by-step instructions for taking Gonal-F (follitropin alfa) Multi-Dose injections:
Gonal-F is injected subcutaneously – or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

Using your thumb, flip off the plastic cap of the Gonal-F Multi-Dose vial.

Wipe the top of the vial with an alcohol swab.

Carefully twist the needle cap off the syringe labeled "Bacteriostatic Water for Injection USP." Do not touch the needle or allow the needle to touch any surface.

Position the needle of the syringe of water in a straight, uprightposition over the marked center circle of the rubber stopper on thevial of Gonal-F Multi-Dose powder. Keep the needle in a straight,upright position as you insert it through the center circle.

Slowly inject the water into the vial by depressing the syringeplunger. When all the water has been injected into the vial, withdrawthe needle.Swirl the mixture gently until it becomes clear. Do not shake.

Remove the cap from a new syringe. Invert the vial and insert the needle. Depress the plunger all the way.

Withdraw the recommended dose of medication

With the needle pointing toward the ceiling, flick the side of thesyringe to disperse any air bubbles and the air pocket at the top ofthe syringe.

Gently push the plunger until one or two drops ofliquid are expressed to make sure you have eliminatedany air.

Click here to learn how to administer the subcutaneous injection of Gonal F

Gonal-F RFF 75 IU Vials


What is Gonal-F RFF?

Gonal-F? RFF (Revised Formulation Female) is a follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Gonal-F? RFF is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments(ART). This medication may also be used to induce ovulation in women for certain types of ovulation problems.

How Do I Use Gonal-F RFF?

Here are step-by-step instructions for taking Gonal-F? RFF (follitropin alfa) injections:
Gonal-F? RFF is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

GonalFflipofflid

Using your thumb, flip off the plastic cap of the Gonal-F? RFF vial

GonalFwipeofflid

Wipe the top of the vial with an alcohol swab.

GonalFtwistoffcap

Hold the barrel of the prefilled syringe of sterile water in one hand. firmly hold the plastic cap between the thumb and forefinger of the other hand and with a back and forth motion, gently snap and pull off the cap. If the grey cap remains, simply remove it.

GonalFinsertneedle

Remove the safety seal cover of the 18 G 1 1/2″ needle. Push the needle on the prefilled syringe until it is tightened. Holding the hub, or base, of the needle, secure the needle on the tip of the prefilled syringe and remove the needle cap.

GonalFInjectdiluent

With the vial of Gonal F RFF powder on a flat surface, insert the needle of the prefilled syringe straight down through the marked center circle of the rubber stopper. Slowly inject the water into the vial by depressing the syringe plunger. Swirl the mixture gently until it becomes clear. DO NOT shake.

GonalFwipevial

Invert the vial and pull back the 18 G 1 1/2″ needle as far as needed and withdraw the entire contents of the vial. Remove the syringe from the vial.

Removewrapper

If your dose requires more than one vial of GOnal F RFF 75 IU, use the mixture in the syringe to reconstitute the next vial of powder. Use the same 18 G 1 1/2 needle and syringe to reconstitute additional vials.

GonalFPushplunger

Gently pull the plunger back to allow a small air space. Recap the needle. Twist and pull off the needle from the syringe and discard in your sharps container.

Invertvial

Remove the safety seal cover of the 27 G 1/2″ needle for injection. Push the needle on the prefilled syringe until it is tightened. Holding the hub, or base, of the needle, secure the needle on the tip of the prefilled syringe and remove the needle cap.

Pullplungerback

With the syringe pointing upward, gently tap on the syringe and slowly push the plunger until all air bubbles are gone and a drop of liquid appears on the tip of the needle.

GonalFrecap

Recap the needle. The administration syringe is now ready. Use immediately.

Click here to learn how to administer the subcutaneous injection of Gonal F

Glucophage

There are many reasons why a woman may not ovulate regularly. It appears that some women are resistant to the hormone insulin. Insulin is normally thought of as the hormone produced by the pancreas that helps regulate blood sugar. While this is true, insulin also has many other effects in the body. The ovary has receptors for insulin and thus insulin is capable of modifying hormone production from the ovaries.

The are several conditions that may result in a woman becoming resistant to the effects of insulin. Among these are  PCOS – Polycystic Ovary Syndrome – genetics and obesity. When insulin resistance occurs, the body needs a higher level of insulin to accomplish the same tasks. High insulin levels are frequently seen in this condition.

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return.

In fact some studies in overweight women with insulin resistance demonstrated that Metformin (Glucophage) was successful in getting ovulation to occur without any other additional medications. It also seemed to improve the response to a fertility medication called clomiphene citrate.

Results of the World’s Largest Metformin Study

Recently, a study was published comparing metformin to clomid in patients with PCOS. This study was conducted on over 600 patients and involved several academic centers. There were three groups of patients that were compared. Group 1 took metformin alone. Group 2 too clomid alone. Group 3 took a combination of metformin and clomid.

The outcome being measured in this study was the live birth rate. Patients were treated for 6 months or until an ongoing pregnancy occurred. The results were somewhat surprising. The total cumulative live birth rate in the metformin group after 6 months was only 7%. The clomid group had a live birth rate of about 25%. The live birth rate in the combination group was similar to the rate with clomid alone.

The results of this study indicate that while it is possible to ovulate and achieve pregnancies with metformin – this treatment is not nearly as efficient as clomid. Furthermore, combining clomid and metformin did not do any better than clomid alone. The main advantage of metformin therefore, is that the rate of multiple pregnancies was lower than in the clomid groups.

A secondary outcome looked at in this study was whether metformin was able to lower the miscarriage rate in women with PCOS. In fact, the results were just the opposite. The metformin groups had a higher rate of miscarriage although, when analyzed statistically, the results could have been due to chance.

Metformin (Glucophage) Instructions

Glucophage comes as either a short acting or extended release (Glucophage XR). I like to use the XR for a few reasons:

  • The tablets can all be taken together at the same time. It is not necessary to spread the dose out as was done with the short acting variety
  • The side effects seem to occur less frequently

Glucophage XR comes as 500 mg tablets. Most women will start with the 500 mg tablets. The starting dose is one tablet a day for one week. If this dose has been tolerated, then two tablets a day are taken during the second week. Finally, three tablets a day are taken during third week and continues thereafter. Some women will tolerate the medicine well and can increase their dose more quickly. Others may need to go more slowly.

Metformin also comes in a liquid preparation known as Riomet. There is also a long acting formulation that comes in a higher dose. Fortamet come in 1000 mg tablets. If a PCOS patient had demonstrated that she can tolerate the higher dose of metformin, switching to Fortamet can make pill taking a little easier since only two pills are required to reach the desired 2000 mg dose.

Metformin Side Effects

Gastrointestinal disturbance: Approximately 1/3 of the people who take glucophage will experience one or more of the following symptoms: nausea, diarrhea, vomiting bloating, or flatulence. Starting on a lower dose (1 tab / day) may reduce the likelihood of this problem. Taking glucophage with meals also may help. Symptoms do resolve with continued treatment.

Lactic acidosis: This is a rare but serious metabolic condition that results from accumulation of lactate in the blood. It can be seen in persons with diabetes, kidney problems and other problems. Glucophage may cause Lactic acidosis in 3 in 100,000 patients taking Glucophage over the course of a year. Lactic acidosis can be fatal when serious.

The symptoms of lactic acidosis are often subtle and non-specific. They include malaise, muscle aches (myalgia), difficulty breathing, increasing sleepiness (somnolence), and non-specific abdominal distress. IF YOU EXPERIENCE THESE SYMPTOMS, CONTACT THE OFFICE IMMEDIATELY.

Because of the risk of lactic acidosis, you should not take Glucophage if:

1. You have chronic kidney or liver problems
2. You drink alcohol excessively
3. You are scheduled to undergo a hysterosalpingogram or have surgery
4. You are pregnant

Metformin effects on pregnancy

A small series suggested that using metformin during pregnancy may have a benefit in terms of reducing the risk of miscarriage or gestational diabetes. Metformin is considered pregnancy category B. Animal studies in rats and rabbits at very high doses did not result in a higher than expected incidence of birth defects. There are no good, well-controlled trial in women. One study suggested that the use of metformin in pregnancy resulted in a higher incidence of some pregnancy complications. It is recommended that Metformin be stopped immediately upon the diagnosis of pregnancy. However, studies are currently ongoing to try to determine the safety and effectiveness of metformin in pregnancy.

A recent study has found pre-eclampsia, a complication of pregnancy involving high blood pressure, was over four times higher when metformin was used to treat gestational diabetes. You should read more about metformin risks here.

Follistim AQ Pen Injector

Follistim contains follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Follistim is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments (ART). This medication may also be used to induce ovulation in women for certain types of ovarian dysfunction.

How Do I Use Follistim?

Tear off a single applicator.

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Follistim?-AQ comes in 300 IU,  600 IU and 900 IU cartridges. Here are step-by-step instructions for taking Follistim? using the Follistim?-AQ cartridges:

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Wash your hands thoroughly and make sure that the surface you work on is clean.

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Pull the cap pen off. Unscrew the yellow section from the blue section. Clean the rubber end of the cartridge with an alcohol wipe.

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Insert the cartridge with the rubber end down into the yellow section.

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Screw the yellow and blue sections back together. Line up the blue triangle (on the yellow section) and the yellow rectangle (on the blue section).

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Screw the needle securely onto the end of the yellow section.

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Pull off the cap, and pull the inner sheath off. Hold the Follistim pen with the needle pointing upward. Tap the pen gently to help air bubbles rise to the top.

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Look for a droplet at the end of the needle. If you do not see a droplet, dial the dosage knob one notch on the dosage scale until you hear a click. With the needle pointing upward, push the orange injection button in all the way and look again for a droplet at the needle tip. Repeat until a droplet appears at the tip of the needle.

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To dial your dose turn the dial gently until the desired dose is in the clear section of the window. If you dial past your dose DO NOT turn it back. Turn it all the way forward until the dial is loose, push the injection button in all the way, and dial again.

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Wipe the injection site with alcohol. Let it dry.When the alcohol is dry, pinch a fold of skin. Holding the needle like a pencil, insert the needle.

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Inject the medication by pushing down on the dial. Once the dial is completely pushed down, hold the pen with the needle in place for 5 seconds. Pull the needle straight out.Gently press an alcohol pad on the injection site for five seconds.Check the pen dial. It should be at zero. If the dosage window does not read “0” it means there was not enough medication in the cartridge. The number in the window will give you the amount of medicine needed to complete your dose.

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Put the cap back on the needle.

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Unscrew it from the pen.

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And place it into a biohazard container such as a Sharps container – or in a sealable, unbreakable plastic container such as a laundry detergent bottle. Never Reuse Needles or Syringes!

Put the cap back on the pen. Save pen and cartridge for your next injection (if it still contains medication).

Please be aware that some of these instructions may vary slightly based upon your particular situation or preference.

Endometrin

Endometrin (progesterone vaginal insert) is a specially formulated vaginal tablet that contains the female hormone progesterone, which is one of the hormones essential for preparation of the uterus for implantation and maintenance of a pregnancy. Once the tablet is inserted into the vagina, it quickly dissolves and is available to be absorbed into the circulation to be taken to the uterus.

How Do I Use Endometrin

Each insert of Endometrin and each applicator comes individually wrapped within the Endometrin box. Here are step-by-step instructions for taking Endometrin:

Carefully unwrap the applicator and the Endometrin insert.

Put one Endometrin insert into the space provided at the end of the applicator. The insert should fit snugly and not fall out.

Choose a comfortable position for inserting the applicator. You may be sitting or laying on your back with your knees bent. You may stand

Gently slide the thin end of the applicator 2-3 inches into the vagina.

Push the bottom of the applicator upward to release the Endometrin insert. Remove the applicator and throw it away.

Side effects reported by women who used Endometrin in clinical studies reported the following side effect more than 2% of the time: uterine spasm (3-4%) vaginal bleeding (3%). Vaginal irritation, itching, burning, rash or swelling were reported less than 2% of the time.

Crinone 8%

Crinone (progesterone gel) is a specially formulated vaginal gel that contains the female hormone progesterone, which is one of the hormones essential for preparation of the uterus for implantation and maintenance of a pregnancy. The moisturizing gel of Crinone forms a coating on the walls of the vagina that allows for absorption of progesterone.

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How Do I Use Crinone 8%?

Here are step-by-step instructions for taking Crinone 8%:
Wash your hands thoroughly and make sure that the surface you work on is clean.

Crinone

Each prefilled applicator of Crinone comes individually wrapped within the Crinone box.

Crinone

Carefully remove the wrapper from the prefilled applicator.

crinone

Identify the thick end of the applicator. Grasp the applicator by the thick end but do not squeeze yet.

crinone

With your other hand, grasp and bend the tab located at the opposite end of the applicator. Bend and twist the tab until it breaks away from the applicator.

Choose a comfortable position for inserting the applicator. You may lay on your back or stand.

crinone
crinone

Insert the applicator into the vagina as far as it will comfortably go or when one half of the applicator has been inserted whichever is less.

crinone

Squeeze the bubble and the thick end completely. An amount of gel about the size of a dime will be dispensed into the vagina.

crinone

Remove the applicator. The gel will remain in the vagina. Dispose of the used applicator. Do not reuse the applicator.

Typically, the gel stays attached to the vaginal walls for a few days as the progesterone is absorbed. Do NOT be concerned is small, white globules appear as a discharge after serveral days of usage. It is common and not harmful, to have some gel residue build up.

If you wish, you may remove the residual gel by inserting your finger into the vagina and clearing the gel manually.

Cetrotide and Ganirelix (Antagon) in IVF

Cetrotide and Antagon in IVF

Cetrotide (cetrorelix) and ganirelix (Antagon) are examples of a type of medication that is used to prevent premature ovulation. This class of medications is referred to as GnRH antagonists or simply antagonists. Cetrotide and Antagon are newer medications than Lupron but have become tremendously popular as a result of their easy of use and high pregnancy rates.

Medications which work rapidly

Cetrotide and Ganirelix exert their action on the pituitary gland. The pituitary is responsible for producing the hormones which stimulate egg growth and development and for triggering ovulation of a mature egg. During an in vitro fertilization cycle, the physician needs to prevent ovulation from occurring so the eggs can be removed directly from the ovary.

In the early days of IVF, before medications to prevent ovulation were available, about 25% of IVF cycles would be cancelled for premature ovulation. Then a medication called Lupron was used to block the pituitary from causing premature ovulation. Lupron caused a few problems, however. When Lupron is first administered to a woman, it would stimulate her pituitary gland for several days before it would eventually suppress it. This is known as the stimulation or flare phase. The flare phase required that women start Lupron a few weeks before she could begin the fertility medications required for stimulation of the ovary. In some women, the flare effect can cause the development of cysts in the ovaries that could further delay the start of fertility medications.

A primary advantage of Cetrotide and Ganirelix is that they do not have a “flare phase”. Down regulation (suppression) of the pituitary occurs immediately. Therefore, it is not necessary to start these medications before the fertility medications begin (see picture). Cetrotide or Ganrelix would normally be started after 4-6 days after the start of the fertility medications. This shortens the number of days that a woman must take injections.

Protocol for using Cetrotide and Ganirelix

Fertility medications such as Follistim or Gonal F are the first injections which are administered in an antagonist cycle. The fertility medications may be started on the second or third day after the onset of a period or after a woman has been on birth control pills (oral contraceptives). A baseline assessment of hormones by blood test and the ovaries by ultrasound are performed at some point before the fertility medications are started.

Ganirelix Acetate Injection is available in disposable, pre-filled, ready to inject syringes containing 250 micrograms of ganirelix acetate. Mixing is not required. Ganarelix is designed to be self-injected using the supplied syringe for injection just under the skin (subcutaneous).

There are two protocols for beginning the Cetrotide or Ganirelix. One method, called the flexible start, utilizes the results of the blood and ultrasound monitoring of egg development. Once development of the eggs has started to occur, the Cetrotide or Ganirelix is started. A second method, called the fixed start, will begin the Cetrotide and Ganirelix after a certain number of days of fertility medication have been given regardless of the results of blood and ultrasound monitoring.

The GnRH antagonists are continued along with the fertility medication until the last day of fertility medication is given. Typically this means a woman will have 4-6 days of Cetrotide or Ganirelix before the egg retrieval.

Some experts believe that IVF cycles that use Lupron for pituitary suppression, may cause some women to become “over-suppressed” and therefore not respond as well to the fertility medications. Whether this occurs or not is subject to some debate. However, with the use of antagonists, there is no concern for this problem.

Cetrotide (cetrorelix acetate)

Cetrotide™ is a medication known as a gonadotropin-releasing hormone antagonist and is used to prevent premature ovulation in women undergoing fertility procedures.

How do I use Cetrotide™?

Here are step-by-step instructions for taking Cetrotide™ (cetrorelix) injections:

Cetrotide™ is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose.

Wash your hands thoroughly and make sure that the surface you work on is clean.

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Flip off the plastic cover of the vial and wipe the rubber stopper with an alcohol swab. Put the injection needle with the yellow mark (20 gauge) on the pre-filled syringe.

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Push the needle through the rubber stopper of the vial and slowly inject the solvent into the vial. Leaving the syringe in the vial, gently swirl the vial until the solution is clear. Avoid making bubbles. Do not shake.

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Invert the vial and pull back the needle as far as needed to withdraw all of the liquid in the vial. You might not be able to withdraw every drop.

Replace the needle with the yellow mark with the (27 gauge) inch syringe. Remove any air bubbles.

Click here to learn how to give a subcutaneous injection

Ganirelix (Antagon)

Ganirelix acetate (Formerly known as Antagon) is a medication known as a gonadotropin-releasing hormone antagonist and is used to prevent premature ovulation in women undergoing fertility procedures.

How do I use Ganirelix?

Here are step-by-step instructions for taking ganirelix injections:
Ganirelix is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose.

Wash your hands thoroughly and make sure that the surface you work on is clean. Uncap the needle of the pre-filled Ganirelix Acetate Injection syringe. Click here to learn how to give a subcutaneous injection

Cell phone use and male fertility

A recent study has suggested that cell phone use might be associated with infertility by causing abnormalities in the semen analysis.

Cell phones and male infertility – could there be a link?

Cell phones are commonly used by both males and females. It is estimated that there are over 700 million cell phone users in the world. Mobiles phones contain small transmitters that emit radio frequency electromagnetic waves (EMW). These phones operate at different frequencies in different countries and continents. Analog phones operate at 450–900 MHz, digital phones (Global System for Mobile Communications [GSM]) at 850–1900 MHz, and third-generation phones at approximately 2000 MHz. Higher frequency phones result in greater exposure to the body. Reports of potential adverse effects of radio frequency EMW from cell phones have appeared in the news in recent months.

The results of animal studies have yielded conflicting results. One study in mice, found that radio frequency EMW had harmful effects on the cells that produce sperm but another study found no harm. A study in rates did not find any adverse effect of cell phone exposure on sperm count, morphology, or the microscopic appearance of the testicles.

There have been two previous studies on this subject in human men. One recent study on 371 men undergoing infertility evaluations, found that increasing duration of possession and the daily transmission times of cell phones was associated with a lower proportion of sperm with rapid forward movement and an increase in the proportion of slow moving sperm.  The second study looked at only 13 men. They found that  using GSM phones for 6 hours per day for 5 days decreased the numbers of sperm with fast, forward movement.

New Study on Cell Phone Use and Sperm

The study examined 361 men who were being seen at an infertility clinic from September 2004 to October 2005. The average age of these men was 31-21. .Importantly, men who had a history of tobacco or alcohol  use were excluded.  Men with other medical problems that could affect their sperm were also excluded.

The men in the study collected a semen specimen after an abstinence period of 5 days. The information on cell phone usage was obtained and they were divided into 4 groups according to the daily duration of use.

  • Group A: no use (40 men)
  • Group B: Less than 2 hours per day (107 men)
  • Group C: 2–4 hours per day (100 men)
  • Group D: More than 4 hours per day (114 men)

The technicians analyzing the semen samples did not know the patients cell phone use.

Results: Cell phone use linked with sperm abnormalities

When analyzed, there was a correlation found with increasing duration of cell phone use and abnormalities in the semen analysis. Specifically, sperm count, percentage motility, viability, and normal morphology were worse in the groups that  reported higher cell phone use. But as the graph below shows, there was no difference found in the volume of ejaculate, the time it took sperm to liquefy, the pH or viscosity of the semen.    

Effects of cell phone use on sperm

Discussion

It is difficult to say how great a danger cell phones may cause toward male fertility. First, the study has several limitations that make it difficult to rely on the results. For example, the researchers did not actually verify the amount of cell phone use that the men reported. Very importantly, they did not take into account the occupations of the men and whether they might have had EMW exposure from other sources such as radio towers, PDAs, Bluetooth devices or computers. They also did not report whether the men predominantly used their cell phone by holding them to their ears or when attached to the waist using an ear phone. Theoretically, due to the closer proximity, a cell phone attached to the waist during use might result in increased EMW exposure to the testicles.

Furthermore, although the use of cell phones may cause a decrease in some sperm parameters, this does not necessarily correlate with infertility. For example,  the average sperm count in the group that reported no cell phone use was 85 million sperm per mL. The concentration in the group that reported more than four hours per day of use was about 50 million per mL. This is still well above the level that is considered normal which is 20 million sperm per mL.

More studies on this subject are clearly needed. Until we have better data, it seems reasonable to recommend to men who are trying to conceive that they should try to limit their cell phone use. Alternatively, keeping the cell phone away from the testicles may also offer some protection.

Obstructive Azoospermia

Azoospermia, defined as complete absence of sperm from the ejaculate, is present in less than 1% of all men and in 10-15% of infertile men. There are many causes of azoospermia

  1. Failure of hormones to adequately stimulate the testicles to produce sperm (also known as Pre-testicular)
  2. Primary testicular failure in which the sperm producing cells in the testicles are either missing or damaged
  3. Obstruction of the sperm delivery system (also known as Post-testicular)

Obstruction is responsible for approximately 40% of cases of azoospermia. Obstructive azoospermia may result from blockage in any of the tubes leading from the testicle to the opening in the tip of the penis. These tubes are

  1. Epididymis
  2. Vas Deferens
  3. Ejaculatory duct

Causes of Sperm Obstruction

Vasectomy is the most common cause of obstruction in the vas deferens. Severe genital or urinary infections, injury during scrotal or inguinal surgery and birth defects are other common causes of obstructive azoospermia.

Treatments For Sperm Obstruction

Men with obstructive azoospermia may father children by

  1. Surgical correction of the obstruction,
  2. Retrieval of sperm from the male reproductive system for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).

Microsurgical Vasectomy Reversal

In the United States, estimates are that 500,000 to 750,000 vasectomies are performed annually; as many as 4%to 10% of these men later request reversal. A very important factor influencing the likelihood of sperm returning to the semen and of pregnancy after vasectomy reversal is the number of years between vasectomy and attempted reconstruction. Other factors influencing the success of vasectomy reversal include the:

  1. presence or absence of sperm seen during the surgery
  2. appearance of the vas fluid as seen during the surgery
  3. quality of the sperm in the vas fluid
  4. length of the vas segment between the epididymis and the vasectomy site
  5. presence or absence of a sperm granuloma (a lump of hardened, old sperm sometimes seen after vasectomy)
  6. age of the female partner.
 Vasal fluid Patency ratePregnancy rate
 Motile sperm 94%63%
 Nonmotile sperm 90%54%
 Sperm heads only 75%44%
 No sperm 60% 31%

There are two microsurgical procedures used for vasectomy reversal:  vasovasostomy  and vasoepididymostomy. Vasectomy reversal is usually performed with the patient under general anesthesia. Alternatively, the procedure can be performed with a local anesthetic (with or without sedation) or with a spinal or epidural anesthetic.

Vasovasostomy

This method of microsurgery removes an obstruction and connects one part of the vas deferens to another part.  In addition to vasectomy reversal , this type of microsurgery is also  performed for blockage caused by injury during a hernia repair.

In a report by the Vasovasostomy Study Group, overall patency rate and pregnancy rate for more than 1200 vasovasostomy procedures were 86% and 52%, respectively. The patency rate and pregnancy rate fell from 97% and 76% at less than 3 years after vasectomy to 71% and 30% at 15 years or longer after vasectomy.

 Obstructive interval Patency ratePregnancy rate
 < 3 years 97%76%
 3-8 years 88%53%
 9-14 years 79%44%
 >15 years 71% 30%

Vasoepididymostomy

This method of microsurgery removes an obstruction and connects the vas deferens to the epididymis. Vasoepididymostomy is considered one of the most challenging microsurgical procedures, requiring significant microsurgical experience. In addition to vasectomy reversal, it can also be performed for the following types of obstructions:

  1. congenital (present at birth)
  2. scarring from infections
  3. Unexplained blockage of the epididymis

Following this type of microsurgery, the patency rate and pregnancy rate range, respectively, from 67% to 85% and from 27% to 49%.

Repeat Vasectomy Reversals

A history of a previous vasectomy reversal attempt does not preclude a new attempt. Patency and pregnancy rates of 79% and 31%, respectively, have been reported for repeated reversals.

Transurethral Resection of the Ejaculatory Ducts (TURED)

This method is used to treat blockage in the ejaculatory duct. This condition is uncommon. Ejaculatory duct obstructions (EDO)can be congenital, (due to abnormal development as a fetus) or acquired. Acquired obstructions may be secondary to trauma or infection/inflammation. Obstructed ejaculatory ducts are usually diagnosed by transrectal ultrasound imaging or by special radiographic tests called vasograms.

Transurethral resection of the ejaculatory duct results in the appearance of sperm in the ejaculate in 50-75% of cases. The pregnancy rate achieved by this surgery is about 25%.

Sperm Retrieval Techniques and IVF/ICSI

ICSI or intracytoplasmic sperm injection is a method to fertilize eggs during IVF in which a single sperm is injected into a single mature egg. ICSI must be used in all cases in which sperm are retrieved from the testes or epididymis. This is necessary for two reasons:

  1. The amount of sperm obtained is usually very small
  2. Sperm from the testicles and most of the epididymis have not developed the capability to fertilize an egg without help

ICSI provides fertilization rates of 45-75% per injected oocyte when surgically retrieved epididymal or testicular spermatozoa are used.

Sperm Retrieval for ICSI

There are different methods employed for retrieving sperm for ICSI

  1. MESA – Microsurgical Epididymal Sperm Aspiration
  2. PESA – Percutaneous Epididymal Sperm Aspiration
  3. TESE – TEsticular Sperm Extraction
  4. TESA -Percutaneous Testicular Sperm Aspiration
  5. VASA – VAsal Sperm Aspiration
  6. SESA – SEminal vesicle Sperm Aspiration

Microsurgical methods utilize an incision and surgery tiny instruments with the assistance of large, high powered surgical microscopes.

Percutaneous methods do not make an incision but rather, use a tiny needle directed in the appropriate place to aspirate sperm. This is sometimes aided by transrectal ultrasound. The choice of sperm retrieval method in men with obstructive azoospermia depends primarily on the experience and preference of both the urologist.

There are not enough data to conclude that either the technique of sperm retrieval (microsurgical or percutaneous) or the source of sperm (testicular, epididymal, vasal or seminal vesicular) significantly affects pregnancy rates. Each technique and sperm source usually provides a sufficient number of sperm for ICSI and may provide enough viable sperm for cryopreservation (freezing).

Sperm retrieval may be performed prior to or simultaneously with the female’s egg retrieval. Sperm retrieval is most commonly performed before the female starts fertility medication injections for IVF.

Microsurgical Reconstruction Versus Sperm Retrieval with IVF/ICSI

In good prognosis cases, microsurgical reconstruction may be more cost-effective than sperm retrieval with IVF/ICSI, and allows couples to have subsequent children without additional medical treatment.

Many couples will opt for IVF/ICSI however. In couples with good prognosis, a higher percentage of couples will achieve pregnancy more quickly with IVF/ICSI. Also, the presence of female infertility factors may reduce the chance for pregnancy after microsurgical reconstruction.

Medications That Interfere With Male Fertility

Male fertility can be adversely affected through any of 5 basic mechanisms:

  1. Direct toxic effects on the testicles,
  2. Disruption of the pituitary gland and its stimulation of the testicles,
  3. Direct effects on ejaculation and/or erectile function,
  4. Decrease in libido (sex drive)
  5. Blocking the sperm’s ability to fertilize an egg

Medications that have a direct toxic effect on the testicles can damage the cells which produce sperm. This can result in lower sperm counts or in severe cases – cause a complete absence of sperm. Damage to the sperm producing cells can be temporary or permanent.

Normally, the pituitary gland, which is located just beneath the brain, will produce hormones that will stimulate the cells in the testicles. These cells will, in turn, produce sperm and produce hormones such as testosterone. The testosterone that is produced, along with some other hormones from the testicles, will regulate the level of stimulation to the testicles.

In some cases, medications may disrupt the connection between the pituitary gland and the testicles and result in inadequate stimulation to the testicles. This can result in lowered sperm counts and abnormal hormone levels.

In order for sperm to be delivered into the female reproductive tract, the male must be able to achieve an erection and subsequently, he must ejaculate. The coordination of these events is very complex and can be disrupted in a number of different ways.

Some medications may act to decrease male sexual interest in intercourse, or libido. Other medications may interfere with the ability of a man to get an erection or ejaculate.

Finally, some medications may affect the sperm directly. For example, a group of medications which are commonly used to treat high blood pressure called calcium channel blockers have been shown in some studies to block the ability of the sperm to fertilize an egg.

Listed below are several categories of medications and their effect on the five areas influencing male fertility. Men should not stop any prescription medication before discussing it first with his prescribing physician.

Recreational drugs

Medication Directly toxicAffects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Alcohol ++++
 Cigarettes + –+
 Marijuana + + –
Opiates – + +
Cocaine + – +

Blood pressure medication

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Thiazide diuretics+
Spironolactone+++
Beta-blockers++
Calcium channel blockers+
Alpha blockers+

Hormone medications

Medication
Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Testosterone++
Androgen blockers –++
Progesterone derivatives –+++
Estrogens+++
Anabolic steroids –++

Psychiatric medications

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Anti-psychotics – + + + –
 Tricyclic anti-depressants – + + + –
 MAO Inhibitors – – – + –
 Phenothiazines – + – – –
 Lithium – – + + –

Antibiotics

Medication Directly toxic Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Nitrofurantoin ++
 Erythromycin +
 Tetracycline –+
 Gentamycin +

Miscellaneous

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Cimetidine+
Cyclosporine –+
Colchicine –+
Allopurinol –+
Sulfasalazine ++
      

Male fertility and Y chromosome Microdeletions

Normal human beings have 23 pairs of chromosomes. One pair of these are called the sex chromosomes. Women have two X chromosomes and men have one X chromosome and one Y chromosome. Most, if not all of the genes that are responsible for sperm production in men are found on the Y chromosome. Abnormalities involving the sex chromosomes can result in sperm production problems and infertility. For example, men who have an extra X chromosome (XXY) are often lacking in sperm and are infertile. Men who have portions of the Y chromosome are missing (deletions) or redundant (duplications) can also show sperm production problems and infertility.

Microdeletions occur when very small pieces of the Y chromosome are missing. These problems cannot be detected through a routine chromosome analysis (karyotype). Microdeletions of the Y chromosome have been found in:

  • 2% or men with normal fertility
  • 7% of infertile men
  • 16% in men with azoospermia (no sperm in their ejaculate) or severe oligozoospermia (less than 1 million sperm)

To identify these microdeletions, special testing must be performed using a technology known as the polymerase chain reaction.

All chromosomes, including the Y chromosome, are divided into a “short arm” and a “long arm”.  Most deletions causing azoospermia or oligozoospermia occur in regions of the long arm known as the azoospermia factor (AZF) regions.  The AZF regions are further divided into

  • AZFa (proximal)
  • AZFb (central)
  • AZFc (distal)
Y chromosome

It appears that these regions, and possibly other regions of the Y chromosome, contain multiple genes necessary for normal sperm production. The specific location of the deletion along the Y chromosome and its size influences its effect on spermatogenesis.

AZFc Microdeletions

Men with microdeletions in the AZFc region have sperm production but they will commonly have very low sperm concentration while other men will not have any sperm visible in their ejaculate. However, areas of sperm production can still be found with a testicular biopsy. If testicular sperm are found, they can be used during IVF to fertilize eggs and produce pregnancies.

AZFa and AZFb Microdeletion

Men who have deletions involving the entire A2Fb region will rarely, if ever, have sperm in the ejaculate and doctors will rarely be able to find sperm with a testicular biopsy. The same may be true for men having deletions involving the entire A2Fa region of the Y chromosome.

What Is The Impact of The Father’s Y Chromosome Microdeletion On His Children?

Since daughters do not inherit a Y chromosome from their fathers, they will not have any fertility or health problems themselves. The sons, however, will inherit the abnormality and, therefore, may also have the same type of fertility problems as their fathers. What about other health issues? Unfortunately, there haven’t been a lot of studies on the children born to men with these microdeletions.  A study from 2011 found that some men with Y chromosome microdeletions also had abnormalities of another part of the Y chromosome (the pseudoautosomal regions or PARs). Abnormalities in one of the genes in this region, called the SHOX gene,  has been associated with short stature, mental retardation, and arm and wrist deformities. More work needs to be done in this area

Which Men Should Have Microdeletion Testing?

Men who have no sperm in their ejaculate which is not due to a known obstruction, should have Y chromosome microdeletion testing. In addition, men who have otherwise unexplained low sperm concentration (less than 1 million) should also be tested unless they have fathered children in the past without any fertility treatments.

Varicocele and Male Fertility and Infertility

Varicocele is the presence of enlarged or dilated veins in the blood vessels of the scrotum. Normally the scrotal veins have valves that regulate the blood flow. However, in some cases, the valves are absent or defective and the blood does not circulate out of the testicles efficiently. This results in swelling of the veins above and behind the testicles. 85% of varicoceles develop in the left testicle.

Varicocele

Varicocele and Infertility

It is estimated that varicoceles are present in about 20% of the normal fertile male population and up to 40% of an infertile population. It is clear, then, that the finding of a varicocele is not necessarily abnormal. At the present time, there is no way to determine whether a varicocele in an individual is the cause of infertility problems.

Scientists believe that at least some varicoceles are associated with infertility because they are found more commonly in infertile men. It is uncertain how varicoceles may cause infertility. Some evidence points to the increased temperature of the blood raising the temperature of the testes, which then damages the sperm. Heat can damage or destroy sperm. The increased temperature may also impede production of new, healthy sperm. Another theory is that in men with varicoceles, the testicular fluid which carries sperm has an increased concentration of chemicals which can damage sperm. The chemicals are called reactive oxygen species or ROS.

Varicocele Diagnosis

A varicocele may be detected on a physical exam. It is describes as looking or feeling like a “bag of worms”. It is more obviously seen or felt when a man is standing then when he is lying down. Sometimes, a varicocele may become more apparent when a man “bears down” to try to increase the intra-abdominal pressure.

The American Urological Association states that only varicoceles that can be felt have been documented to be associated with infertility. Not everyone agrees with that position. Scrotal ultrasound can be used to diagnose a smaller, less obvious varicocele. Echo color Doppler is a type of ultrasound that can measure blood flow in the veins of the scrotum.

Varicocele Treatment

Surgery

Most varicoceles can be corrected through a surgical procedure called varicocelectomy ( surgically “tying off” the affected veins). The following methods are used.

Surgical ligation

This procedure is performed under general anesthesia (the patient is asleep). In this procedure, a 2 to 3 inch incision is made in the groin or lower abdomen, the affected veins are identified and the surgeon cuts the veins and ties them off. This surgery can usually be performed on an outpatient basis. Full recovery takes about 6 weeks.

Laparoscopy

Laparoscopy is a technique in which a fiber optic telescope is inserted through the belly button into the abdominal cavity through a small incision. The surgeon can view what is happening by connecting a video camera to the laparoscope and watching a monitor. Once the varicocele has been located, the surgeon will introduce special instruments through small incisions near the pubic hair line to tie off the dilated veins. Most men can resume normal activities in a few two days.

Non-Surgical Methods

An alternative to tying off the veins is blocking the blood flow to the veins.

Embolization

Since embolization is a non-surgical procedure, it does not require general anesthesia but often the patient will be sedated. A small catheter is inserted into the veins just beneath the varicocele. A special dye is used to highlight the varicocele on x-ray and to visually guide the catheter. This is known as venography. Tiny coils are then advanced through the catheter to block the blood flow to the dilated veins. Most men can resume normal activities in a few two days.

Varicocele treatment with embolization coil

There is no evidence to suggest that any of these procedures work better than any other. However, the risks and recovery times are different.

There are two endpoints that are discussed after a varicocele repair: improvement in sperm counts and pregnancy. Unfortunately, many of the studies looking at varicocele repair have been poorly done. Consequently, there are mixed results as to whether more couples achieve pregnancy. There have been two well designed and well performed studies looking at varicocele repair. One study showed an improvement in pregnancy rates and one study did not.

Varicocele and In Vitro Fertilization – IVF and Intracytoplasmic Sperm Injection -ICSI

For couples in whom the men who have mild to moderately low numbers of moving sperm , intrauterine insemination (placing the sperm in the uterus) at the time of ovulation can be performed with reasonable success. For couples with any severity of sperm problems, in vitro Fertilization – IVF with intracytoplasmic sperm injection -ICSI is a highly effective method to achieve fertilization. Pregnancy rates are no longer dependent on the number of sperm but rather on female factors such as her age and response to fertility drugs.

Effects of male age on reproduction

In 1993, fathers aged <35 years accounted for 74% of live births within marriage, while only 25% of such births were to fathers aged 35–54 years. Ten years later, these percentages were 60% and 40%.  When the reproductive potential of older men is discussed, several celebrities who became fathers at advanced age such as Rod Stewart, Pablo Picasso, Charlie Chaplin, Warren Beatty, Tony Randall and Anthony Quinn are often cited as examples.

While the public regards these cases with a mixture of admiration and skepticism, birth statistics show that there are quite a number of children born to fathers aged >50 years in the general population and this is true of Eastern and Western cultures alike. However, it is well known that practically no children are born to mothers aged >50 years and it is common to all older fathers that they have younger partners.    

The effect of aging on the sperm

Semen is studied under the microscope. A typical semen analysis will evaluate a specimen for the total volume of the ejaculate, the number of sperm (concentration), the percentage of moving sperm (motility) and the percentage of sperm with a normal appearance (morphology). Studies have tried to determine if any of these semen parameters decrease over time. These are difficult studies to perform since many variables are present. The majority of studies seem to indicate that the volume of the ejaculate decreases with age as well as the percentage of moving sperm. There is no definite conclusion about whether the concentration of sperm or the microscopic appearance of the sperm (morphology) changes or not.

Age-dependent alterations of semen parameters may have several causes. In addition to age per se, factors such as infections, vascular diseases or an accumulation of toxic substances may be responsible for a deterioration in semen parameters. In a study of almost 4000 infertile men, researchers showed an infection rate in some of the reproductive  glands in 6.1% in patients aged <25 years but in 13.6% of patients >40 years. More importantly, total sperm counts were significantly lower in men with infections compared to those without.

Fertility of older men

Fertility has been documented scientifically in men up to an age of 94 years. If fertility in men decreases with age, it may in part be due to erectile dysfunction. In a large survey of Italian men, the frequency of erectile dysfunction rose from 4.6% in men <25 years to 37.6% in men >74 years. A history of cigarette smoking essentially doubled the risk of erectile dysfunction as men aged.

Several studies have been performed that tried to control for these and other variables in male fertility. For example, a study of birth rates in married couples in Ireland before the widespread use of contraception found that the probability of birth decreased for men starting from 42–43 years of age. Another study found that men >45 years old are 4.6-fold more likely to take over 1 year to get their partners pregnant relative to men aged < 25 years old.

With the use of fertility treatments , age related sperm problems may be bypassed. In fact, the more invasive the treatment, the less important male age appears to be. For example, several studies looking a the success rates of intrauterine insemination where sperm is injected directly into the uterus of a woman on the day of ovulation,  found an adverse impact of increased male age. On the other hand, several studies looking at the use of ICSI in which sperm is injected directly into an egg, did not find an effect of male age.  However, recently a group of researchers analyzed data from a German IVF registry from 1998 to 2002. They found a significantly reduced pregnancy rate in couples with male age >50 years and female age between 31 and 40 years, compared to couples with a male age <50 years. They suggest that this effect may have escaped the notice in previous studies because of a lower number of couples in this male age category.

There may also be an increase in the risk of miscarriage in older men. A recent study of over 5000 pregnant women in California concluded that the risk of miscarriage increased with increasing paternal age, and found that the association was stronger for miscarriages that happened in the first trimester. A study completed in 2002 found that the risk of miscarriage increased in older men but only when the women were also older.

Miscarriage risk according to father's age

This study suggests that for women under age 30, the age of the father does not increase the risk of miscarriage. Women who are aged 30 to 34 are at increased risk for miscarriage if the male is over age 40. Women who are over age 35 are at particularly high risk if their partners are over age 40. In this group, the risk for miscarriage was 6 times higher.

The causes for the increase in miscarriages with male aging is unknown. It is well known that the risk for chromosomal abnormalities in fetuses increases as women age and that these chromosomal abnormalities are responsible for the increase in miscarriage risk. No studies have ever found an increase in the rate of chromosomal abnormalities in fetuses with increasing male age however.

Risks to babies with older fathers

Women have all of the eggs they are ever going to have in their lives before they are born. The cells in the ovary which are destined to become eggs will go through several cell divisions and then stop. The eggs will then remain in this “off position” for the entire duration of a woman’s life until the egg is ovulated. It is this process that is thought to be responsible for the increased risk of chromosome abnormalities in eggs and embryos as women age. Men, on the other hand, produce sperm continuously all through their lives. The cells that produce sperm are constantly dividing during a man’s life. Every time a cell divides, the DNA must be exactly copied so that each “daughter cell” is identical to the “parent cell”. However, the more times a cell divides, the greater the chances for an error to be made when the DNA is being copied. These errors in DNA are called mutations.

It is possible, therefore, that older men may be at greater risk for having sperm with small errors (mutations) in the DNA and that these errors could cause certain diseases in the children of older men.

Risk of chromosome abnormalities

Two studies have found that older men have a greater risk for producing children with Down’s Syndrome (Trisomy 21).  In one study, men over age 40 were compared to men under age 25. The other study compared men 50 and older to men aged 25 to 29. Both studies found the risk for producing Down’s syndrome was higher.

Risk of genetic mutations

In August 2012, a study found that dads pass on an average of 25 new mutations at age 20, increasing to 65 mutations at age 40.   In the last several years, studies have focused on diseases caused be genetic mutations in the DNA and whether their is a relationship to the age of the father. Genetic diseases which are strongly thought to be related to the age of the father include:

  • Achondroplasia
  • Crouzon’s syndrome
  • Pfeiffer’s syndrome
  • Apert’s syndrome
  • Thanatophoric dysplasia
  • Osteogenesis imperfecta
  • Neurofibromatosis
  • Retinoblastoma

A Danish population based study of 1920 affected births of 1.5 million live births concluded that paternal age is associated with cleft lip and cleft palate, independently of maternal age. Single gene mutations are the suggested mechanism. Other diseases may have both a genetic and an environmental component and are referred to as complex or multi-factorial diseases. Some of these diseases have been identified as possibly occurring more commonly in older father.

  • Acute lymphoblastic leukemia
  • Congenital heart disease
  • Ventricular septal defect
  • Atrial septal defect
  • Alzheimer’s disease
  • Schizophrenia

A population based study of childhood brain cancers reported to the Swedish Cancer Registry between 1960 and 1994 concluded that there is a paternal age affect, estimated to confer about 25% excess risk in fathers >35 years of age.

Advanced paternal age has also been associated with increased risk of breast cancer and prostate cancer in their children.

Risk of Autism From Older Fathers

The cause of autism and related disorders (ASDs) is unknown; however, results from twin and family studies provide evidence for a strong genetic contribution. Environmental influences may also be important. The reported prevalence of ASDs has increased significantly during the past few decades. In this same period, the average age of men and women at the time of conception has also increased.  

The results of several large, well performed studies on the effects of parental age have yielded conflicting results. In an Australian population, one study found that increased female age, but not male age, was associated with autism. In a Danish population, a study found that the risk of autism was associated with increasing male age but not female age. A second Danish study reported no association between risk of autism and either male or female age. In April, 2007, the results of a large American study were published. This study concluded that both male and female age were associated with an increased risk of autism and related disorders even after adjusting for other factors. The older the parent, the greater the increase in risk.   In August, 2012, a study of families with an autistic child concluded that a father’s age could account for 15% to 30% of cases of autism due to the occurrence of new mutations the occur as men age.

Conclusion

Increasing male age may cause a decrease in fertility if the female is also older. The chance for miscarriage also seems to increase but the mechanism is not due to the most common reason for miscarriage which is numerical chromosome abnormalities. The overall impact of male age is far less than the impact of female age. Several diseases caused by gene mutations as well as several with multiple genetic and environmental causes are related to increasing paternal age. Despite these increased risks, the absolute risk of the diseases remains small.

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Amazing staff. They made us feel like family. They cried when I called to tell them the birth of our daughter. Starting round two next month. Simply the best. They care!

BT Warner

Dr. Morris and staff were very friendly. Dr. Morris was very informative and patient with answering all questions I had. We were uncertain on the options and next steps to take and Dr. Morris explained all the details and options we have. Excellent staff and a great doc.

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I don't even know where to start...THANK YOU! Thank you for giving us our son. We went through a year of IVF. Although there may have been things I didn't want to hear (chances of pregnancy, factors out of our control, etc.) it was important to hear the truth and know what our chances were. The staff was always great with us and they were very patient. They really have everything figured out and what the best options out for outcomes. I never felt pressured to make certain decisions and always felt well informed. Again, I can't thank Dr. Morris and all his staff for everything!!!

Lauren Throm

The staff is amazing here. I’m in the middle of IVF and had an issue with a medication and they went above and beyond to make sure everything was done to continue our journey (on the weekend no less); truly above and beyond. The staff are very caring and professional. Definitely recommend Dr. Morris and this amazing practice.

Megan Buetikofer

I honestly can’t praise this company enough. Dr. Randy Morris bedside manner is absolutely amazing, his staff professionalism and customer service is also amazing. Your experience with this company will be nothing but perfect. From the initial call to the receptionist. To speaking with the nursing staff, billing, etc. everyone wants to help you with family planning. No matter what my outcome is, I know I’m with a co that will make sure I have the best chances. Thank you to Dr Randy Morris and Staff a bunch!

Misty Johnson

Dr. Morris is by far the best fertility doctor! When I transferred to IVF1 from my previous fertility doctor, he read all my medical records in depth. Never once did I feel stressed or unsure of what was happening. The entire staff there is so nice and make you feel so comfortable. It was so easy to schedule appointments, get medications, or ask a nurse a question. My calls were always returned within 20 minutes. I highly recommend IVF1! Dr. Morris made it possible for us to get pregnant!

Lisa

I’m so grateful to have been referred to Dr. Morris and his team! I’ve spent the last month or so working with the team and they’ve made what is naturally a hard process both mentally and physically as comforting and easy as possible. Dr. Morris’s success rates speak for themselves, but what I want to let everyone know is that he is equally comforting. A special thank you to Jocelyne, Pam and Barbie, these three women on his staff from front desks to RNs really have made the experience an extremely positive one. PS. My cousin who referred me to Dr. Morris has a smart, healthy and beautiful baby boy who he helped bring into this world!

Alex Villa

He is a very professional and good doctor. the whole clinic is very nice. all the staff are amazing. The doctor operated on me for endometriosis and I got pregnant during the second IVF. we have a wonderful 1 year old son. thank you doctor we still have an embryo, I think I will definitely come back to you in a year or two.

Ziva Ru

Thanks to Dr.Morris I am holding today my little dream girl. I don't have enough words to express how thankful I am to him and everyone working in IVF1 Naperville. Highly recomend Dr.Morris and his clinic to everyone looking for real professional help and attitude!

Petya Vasilev
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