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Home > News/Events > Newsletter
Newsletter
Volume 11-2
PCOS and Infertility... The Tip of the Iceberg
By Christo Zouves, MD
Polycystic ovarian syndrome (PCOS) is one of the leading causes of infertility in women. In fact after tubal disease it is the
most common female fertility factor that takes a patient to a fertility specialist. PCOS occurs in 8% to 10% of women of
childbearing age and is both underdiagnosed and undertreated. No two women with PCOS are alike, some are obese and others are
thin and some women may ovulate regularly and others not at all. The picture is further complicated by the fact that all physicians
do not even agree on the exact definition of who should be included in the spectrum of PCOS.Fifteen years ago, the First International Conference on PCOS was held under the auspices of the NIH. At that time, the consensus opinion was that, after the exclusion of conditions like congenital adrenal hyperplasia, androgen secreting tumors and Cushing’s syndrome, the diagnosis of PCOS required the presence of:
- Chronic anovulation
- Androgen excess (clinical or biochemical)
- Ultrasound evidence of polycystic ovaries
- Classical PCOS (increased androgens/anovulation and increased BMI)
- Ovulatory PCOS
- Normoandrogenic polycystic ovaries on ultrasound
The insulin resistance seen in PCOS patients occurs in both obese and lean women. Metabolic syndrome (MS) is present in 50% of PCOS patients, independent of body weight.
Metformin, or glucophage, has emerged as a first line of treatment for PCOS and infertility. A recent Cochrane review reported an odds ratio of 3.88 for restoration of ovulation with Metformin. A recent randomized trial of Metformin vs. clomiphene citrate showed a cumulative pregnancy rate of 69.8% with Metformin which was significantly better than the 34% (P<0.01) rate achieved with clomiphene. In addition, than in the clomiphene group (37.5%). Even when Metformin does not result in ovulation, it appears to facilitate clomiphene and gonadotropin stimulation and may also improve egg quality during in vitro fertilization (IVF).
Metformin is the oldest and most used insulin sensitizer, controlling glucose metabolism by decreasing glucose production in the liver, increasing the uptake of glucose by skeletal muscle and by decreasing the intestinal absorption of glucose. It does not work by increasing blood insulin and therefore seldom causes hypoglycemia. Fasting insulin levels are not good predictors of who will benefit from this therapy, although Metformin usage in PCOS patients is associated with a decrease in hyperinsulinaemia. In PCOS patients, Metformin usage is also associated with a decrease in androgens and gonadotropins and improvement in other metabolic abnormalities including altered lipid profiles and the prothrombotic effects of plasminogen-activator inhibitor type I (PAI-I). Metformin therapy may decrease hirsutism, acne and hypertension while improving ovulation and fertility. Tapering up to the effective dose of Metformin 1500-2500 mg daily helps patients avoid or reduce the initial gastrointestinal side effects. The other cornerstone in treating classical PCOS is weight loss and one needs to loose at least 5% of body weight in order to increase the number of ovulatory cycles.
We may therefore be seeing only the tip of the iceberg that is PCOS as it pertains to infertility. This is especially true when ovulatory women who are not overweight but have polycystic ovaries on ultrasound, are included. Weight loss and treatment with Metformin should be the first line treatment and will often result in pregnancy in patients who have been unresponsive to conventional ovulation induction and may also result in pregnancies without having to resort to IVF. The issues of an increased risk of type II diabetes, cardiovascular disease and endometrial cancer should not be ignored especially in classical PCOS.
New Improved 12 Chromosome Panel for PGD
By Frank Barnes, Ph.D.
Pre-Implantation Genetic Diagnosis or PGD is a relatively new
procedure in which embryos can be tested for chromosomal abnormalities
such as single gene defects, translocations, and aneuploidies prior to
being replaced in the womb. The use of PGD in
conjunction with IVF may allow for increases in pregnancy rates
by decreasing the number of abnormal embryos transferred to a
patient and improving our ability to select healthy embryos.
The purpose of PGD is to select and replace only those embryos
that appear to be chromosomally normal so that a patient may
increase the chance of conceiving while reducing the probability
of losing the pregnancy or carrying a chromosomally abnormal
baby to term.Women aged 35 years or older can benefit from PGD by testing for age-related chromosomal disorders such as aneuploidy. Aneuploidy refers to an error occurring during cell division that results in the creation of an embryo with too few or too many chromosomes. Younger women with repeated unexplained miscarriages can also benefit from this test. PGD for aneuploidy can determine the presence or absence of a certain number of chromosomal disorders, but cannot detect genetic disease nor predict congenital malformation. ZFC has offered PGD since 2001. In the course of the last 6 years new probes have come available leading to a new and enhanced screening panel. This aneuploidy screening panel now includes chromosomes X, Y, 8, 13, 14, 15, 16, 17, 18, 20, 21 & 22.
PGD is accomplished through three stages; embryo biopsy, cell processing or fixation, and cell analysis via FISH or PCR. Embryo biopsy is performed by creating a small opening in the embryo(s) outer shell, the zona pellucida, and extracting a blastomere with a micropipette. To facilitate this process the day-3 embryo is temporarily exposed to a calcium free/magnesium free culture medium which eliminates calcium dependent gap junctions between blastomeres. It is presumed that all cells of an embryo are identical; therefore it is customary to remove only a single cell for analysis, however certain circumstances may require removal of an additional cell.
Once the biopsied cell has been removed from the embryo, it is fixed to a glass slide in preparation for analysis or as in the case of single gene defects the cell is processed for PCR.
Analysis of the biopsied cell(s) for aneuploidy screening and translocations is performed via a technique called fluorescence in-situ hybridization or FISH. The cells are first glued to a glass slide, then heated and cooled, and finally the DNA from each is ‘labeled’ with colored fluorescent dyes called probes. Once the FISH procedure is complete, the technician counts the fluorescent signals. Normal cells are distinguished from abnormal cells by the presence of too few or too many colored signals. The information obtained is then related to the normalcy of the associated embryo being held in culture.
Analysis of biopsied cells for single gene defects such as cystic fibrosis are treated with a lysis buffer to prepare the cellular DNA for polymerase chain reaction (PCR) a process that includes thermal cycling of the DNA cocktail to produce multiple copies of the targeted gene. New probes are being developed for diseases every day as well as some for late life onset disease.
Ten Factors to Consider When Selecting a Gestational Surrogate
By Shelley Tarnoff, JD, LMFT
- Motivation. Most surrogates are motivated by a combination of financial compensation and altruism. They view surrogacy as a way to help others and help their family at the same time. "I love being pregnant, but don’t want to have any other children of my own. I am so grateful to have children to love and cherish and want to share this blessing with a couple who is unable to conceive. The surrogate fee will help pay off our car loan and establish a college savings account."
- Pregnancy history and post birth separation. Surrogate candidates must have previously given birth to at least one child. Did she enjoy the pregnancy? Any history of postpartum depression? Does she plan to have other children of her own? If so, does she understand that complications associated with childbirth and delivery may result in the loss of her reproductive capacity? How will the surrogate be able to cope emotionally with separation from the child post birth?
- History of psychiatric treatment, substance abuse, eating disorders, family mental illness. The physical and emotional demands of surrogacy require emotional stability, a strong sense of responsibility and a positive, yet realistic, outlook towards outcome. Psychological testing and interviewing can help assess the suitability of a surrogate candidate.
- Religious, ethical and moral beliefs. If your surrogate is affiliated with a formal religious practice, has she discussed the surrogacy with her clergy? Is the surrogacy consistent with her personal moral and ethical beliefs? Family, friends and community members may voice their opposition to the surrogacy, and the surrogate must have the strength and determination to deal with cruel comments and harsh judgments.
- Expectations regarding pre and post birth relationship. Are you hoping for a high level of involvement with your surrogate, including frequent updates and attendance at medical appointments and the birth of the child? Are you seeking a more "business-like" arrangement limited to the exchange of pertinent medical information? Some parties develop close ongoing relationships and become extended family. Others cease contact after the birth of the child. It is essential that Intended Parents and the surrogate share similar expectations regarding the pre and post birth relationship, communicate well and maintain an atmosphere of respect and goodwill.
- Ability to cope with medical procedures. The surrogate should be advised that the medical protocol involves months of injections, blood draws and other invasive procedures. Has she tolerated blood draws and injections well in the past? Is her spouse, partner or friend available to administer the injections and accompany her to the embryo transfer procedure?
- Compatible views regarding therapeutic abortion and multi-fetal reduction. Because of the U.S. Supreme Court case Roe v. Wade, the surrogate has the legal right to decide whether or not to undergo a therapeutic abortion or multi-fetal reduction procedure. However, if she does not comply with contract terms, she will be in breach and can be held liable for damages. As part of the surrogate matching process, confirm that she is in agreement with your views regarding pregnancy termination.
- Support network. The surrogacy process can be emotionally, as well as physically, challenging. It is important that your surrogate has a sufficient support network of friends and family members available to accompany her to medical procedures, assist with childcare and provide encouragement along the way.
- Lifestyle. The surrogate should maintain a healthy lifestyle throughout the pregnancy including a nutritious diet and moderate exercise. Will she refrain from alcohol consumption and dangerous sports and activities during the pregnancy? Does her occupation necessitate exposure to toxic chemicals? You will want to choose a surrogate who can provide a healthy in utero environment for your child.
- Outside stressors. In some cases, an otherwise excellent surrogate candidate is deemed unsuitable because of her present life circumstances. This may include the recent loss or serious illness of a family member, breakup of a relationship, inflexible work schedule, financial difficulties, lack of available childcare or recent deployment of a spouse or partner.
The Importance of Genetic Counseling and Family History Risk Assessment for Ovum Donors
by Amy Vance, MS, CGC
What is genetic counseling?Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates:
- Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
- Education about inheritance, testing, management, prevention, resources and research.
- Counseling to promote informed choices and adaptation to the risk or condition.
Ovum donors are typically screened through the use of a family history questionnaire as part of their profile, usually focusing only on first degree relatives and grandparents. The majority of questionnaires that I have seen omit _ siblings, nieces, nephews, aunts, uncles, and cousins.
Most gamete donor programs do not utilize genetic counseling services for family history risk assessment and do not obtain a three generation pedigree. If a donor has a positive genetic test result, many donor agencies do not refer for genetic counseling and do not adequately address the implications for the donor and her family.
At ZFC, a genetics consult is required for all donors in the program. The written consult is then sent to the intended parent for approval and discussion of any concerns with the genetic counselor.
The benefits to intended parents
Having a thorough review and interpretation of the family medical history helps ensure that intended parents have not only complete information but also interpretation of potential risks to their offspring.
A copy of the family tree, or "pedigree", is provided to the intended parents for their records. For a couple using an anonymous gamete donor, this may be the most detailed information they receive about the medical history of their offspring’s family.
Sometimes there is new information which comes up during the genetics consult that was not elicited by the profile, or there is a genetic test result on the donor which is positive. These are difficult circumstances that on occasion lead to the intended parent deciding not to go forward with the donor. Knowing this information prior to a pregnancy and having the opportunity to make decisions accordingly is important.
Risk assessment includes
- Donor’s pregnancy history
- Donor’s health history
- Family history of mental retardation or birth defects
- Personal or family history of stillbirth/miscarriage/neonatal death
In almost every population or ethnic group, certain genetic conditions occur more frequently than in the general population. Once a genetic mutation occurs in an individual or population, it is conserved from generation to generation over many years as people mate and marry with partners from the same geographic region or racial background as themselves.
Specific conditions occur more commonly in different ethnic groups. All are inherited in an autosomal recessive fashion, meaning that both parents have to be carriers for the same condition in order to have an affected child. While the carrier rate is highest in the below mentioned groups, a person of any ethnic group can be a carrier for any disease. The only way to know if someone is a carrier for a recessive disorder is to have carrier screening. Donors are offered ethnicity based carrier screening as indicated below:
- CF screening offered to all Caucasian/Hispanic donors (optional for other ethnic groups)
- Tay Sachs/Canavan/Familial Dysautonomia/Gaucher/Cystic Fibrosis offered to all Ashkenazi Jewish donors
- Tay Sachs – French Canadian and Cajun ancestry
- MCV (screening for thalassemia) for all donors; follow up hemoglobin electrophoresis for MCV<80 or for donors in which the recipient has a hemoglobin trait.
We studied the number and types of risk factors identified in ovum donors at ZFC. A total of 214 consecutive donor family histories were reviewed. The outcomes are reported below.
Specifically, 6 donors were carriers for cystic fibrosis, 1 was a carrier for Tay Sachs, 1 had an unusual hemoglobin variant; 12 had a family history of mental retardation, Down syndrome, or autism. Type I diabetes in a first degree relative was present in 2, family history of early heart attack or stroke in 5. An increased risk for mental illness was seen in 8. An increased risk for cancer was identified in 12. Previous child with a limb defect was seen in 1, 3 had a family history of a genetic disorder, and 1 had a positive genetic test for fragile X syndrome.
Many of these outcomes above require providing specific detailed information to the agency, donor, and recipient and making further testing recommendations. Discussion of the risks associated with the family history allows the intended parents to determine whether they wish to proceed with the donor.
Summary
In summary, family history risk assessment for ovum donors by a genetic counselor using a three generation pedigree provides enhanced information to the ovum donor program to allow them to better screen their donors. It allows recipient couples make informed decisions about potential genetic risks prior to donor selection and pregnancy and allows them to take advantage of technology such as PGD. It enhances the quality of service that is provided to the intended parent.
©2008, Zouves Fertility Center
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