COMMENTARY

December 2004: The Year in Review -- Ob/Gyn & Women's Health

Ursula Snyder, PhD

Disclosures

January 24, 2005

Reproductive Endocrinology - Polycystic Ovary Syndrome, Infertility, and Assisted Reproduction

By Medscape Ob/Gyn & Women's Health board member
Peter Kovacs, MD, and Ursula Snyder, PhD

The first child following in vitro fertilization (IVF) was born in 1978. Initially, treatment cycles were performed during the woman's natural cycle. Since then, various medications have been incorporated into stimulation protocols, and the efficacy of the entire process has improved. Advances in the surgical and laboratory procedures have also occurred. There is a constant push to further increase the safety of the procedure, as well as to improve outcome.

When we talk about safety, we need to separate the safety of the mother undergoing ovulation stimulation, oocyte retrieval, and embryo transfer and the safety of the offspring. Certain women, for example those with polycystic ovary syndrome (PCOS), are at risk for hyperstimulation. A new set of diagnostic criteria has been proposed for PCOS. The new diagnostic criteria include irregular menstrual cycles, clinical or laboratory hyperandrogenism, and ultrasound findings.[69,70] (See Journal Scan review and Medscape Medical News CME story.)

The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.[69]

As the infertility management of women with PCOS can be quite challenging, it is not surprising that several investigators have targeted this group and tried to develop stimulation protocols that make ovulation induction safer and more effective for this population. We have thus learned about the beneficial effects of insulin-sensitizing agents for women with PCOS -- namely metformin, although troglitazone, rosiglitazone (see related Journal Scan review) pioglitazone, and D-chiro-inositol have also been studied.[71,72,73,74,75,76,77,78,79,80] For example, results of a trial published in 2004 have shown that metformin yields better reproductive outcomes than laparoscopic ovarian diathermy for women with PCOS and clomiphene citrate (CC) resistance.[79] (See related Journal Scan review and a Medscape Medical News CME story.)

Although metformin is superior to placebo for ovulation induction in the case of ovulatory infertility attributed to PCOS, whether the use of insulin-sensitizing medications is superior to CC in the same situation has not been established.[80] (See related Journal Scan review.)

Insulin-sensitizing agents may be useful for inducing ovulation in anovulatory women who do not have hyperandrogenism.[81] One of the authors remarked that more research is needed, however: "The mechanisms of action of metformin are complex and may involve direct effects on the ovary as well...I would not use [metformin] as first line in women who do not have traditional findings of PCOS at this point, although it may be helpful as an adjunct at some point."[82] Another study suggests that spironolactone, an aldosterone antagonist, may even be superior to metformin in restoring ovulation.[83] (See related Journal Scan review.)

In addition, one study published in 2004 did not find any benefit with metformin, which may be indicative of the heterogeneity of PCOS. Although the lack of positive findings may be explained by the relatively small sample size, it is also possible that not all types of PCOS patients will benefit from metformin administration during IVF, and we need to identify the subgroups that are likely to have a better outcome.[84] (See Journal Scan review.) Future studies should try to identify those subgroups that would benefit the most (eg, lean vs obese, high testosterone vs normal testosterone, high responder vs normal responder).

These agents restore monofollicular development; whether they may be safely and effectively continued during pregnancy to reduce the incidence of miscarriages, gestational diabetes, and potential hypertensive complications is under investigation. Norman and colleagues[85] suggest there is no evidence for increased risk of miscarriage solely due to PCOS and that there are insufficient data for promoting therapy with metformin. They also believe more research is required before metformin is used in mid-pregnancy to treat gestational diabetes.

Aromatase inhibitors have now also been used successfully for ovulation induction among women with PCOS.[86] During letrozole or anastrozole administration, the feedback mechanisms remain intact; therefore, monofollicular development is more likely than with CC or gonadotropins. Aromatase inhibitors alone or in combination with gonadotropins have been found to be effective for ovulation induction among regularly cycling women as well.[87] Just published are the results of a study showing that superovulation with letrozole and CC yielded similar pregnancy rates; the miscarriage rate was higher for CC.[88] (See Medscape Medical News CME story.)

Several studies published this year have investigated the connection between PCOS and CVD.[89,90,91,92,93] (See also Journal Scan review and Medscape Medical News story.) Hypertension, dyslipidemia, insulin resistance, diabetes, and obesity are all diagnosed more often among women with PCOS. Lifestyle changes should be recommended to all young women with these risk factors. Prolonged use of insulin-sensitizing agents might decrease their long-term risk, and further investigation in large, prospective trials is warranted. Once the infertility issue is addressed, it is equally important to counsel young women with PCOS about possible heath risks and preventive measures.

Several studies and systematic reviews were published in 2004 about the safety of infertility drugs.[94,95,96,97,98] These studies generally observed no significant increased risk of breast (see Journal Scan review), ovarian, or uterine cancer as a result of drug treatment. Some of these cancers are more frequent among infertile or nulliparous women. Although as Ayhan and colleagues[99] point out, "It should also be kept in mind that cancers are overdiagnosed in infertile women ...because of the close medical surveillance, which may also contribute to the early detection of cancers." Whether drug therapy used in assisted reproduction further increases in this risk is not established definitively, and monitoring for long-term risks needs to continue. One study found a nonsignificant increase in ovarian cancer in women exposed to CC or gonadotropins.[96] The authors also noted that there was a slightly higher risk associated with CC use among women who remained nulligravid. Another found an increased risk of ovarian cancer among nulliparous women with a history of infertility, especially when infertility manifested relatively late in reproductive life, but the increased risk was not associated with any of the drug therapies.[97] The results of one meta-analysis even suggest that treated infertile patients may have a lower incidence of ovarian cancer than untreated infertile patients.[98] (See Journal Scan review.)

Brinton and colleagues[100] further evaluated the risk of ovarian cancer in relation to underlying causes of infertility. Women who had both endometriosis and primary infertility had a significantly higher rate of ovarian cancer than the general female population. (See Journal Scan review.) Finally, a small study found ovarian cysts are a common finding in women seeking CC therapy; nearly 1 in 5 had a baseline ovarian cyst >10 mm.[101]

It is equally important to point out that childhood cancer rates among children born following IVF are comparable to rates in the general population.[102] However, the question as to whether children born through assisted reproduction are at increased risk for adverse health outcomes is one that requires a great deal of further research.[103]

Over the past decades, there has been a dramatic increase in the number of multiple gestations. Assisted reproductive technology is responsible for the majority of the excess multifetal gestations. Studies have shown that even a singleton gestation following IVF poses a greater risk to the fetus.[104] (See Journal Scan review.) Preterm labor, low birth weight, and malformations are all more frequent. The case is even worse with a multiple gestation. Several groups have considered whether the outcome of IVF cycles should be expressed as singleton birth per initiated cycle.[105,106,107] Twins should be considered an adverse outcome.[108] (See Journal Scan review.)

We now have tools to better identify those embryos that are likely to implant. Morphologic characteristics could be used to differentiate between embryos, and extended embryo culture will allow a natural selection process to take place. Preimplantation genetic diagnosis will enable us to identify the genetically intact embryos. The number of embryos transferred should be limited as well. In several European countries the number of embryos to be transferred is limited; in certain patient groups it is limited to one! If we better understand those factors that play a role in implantation, we could further improve our results without putting the patient at risk.

In the near future, more patient-friendly and milder stimulation protocols will be developed that are tailored to the patients' needs. Further improvement in laboratory technology will allow us to transfer 1 or 2 embryos in high-risk groups. It is hoped that within the next couple of years, single embryo transfer will become the routine. As Land and Evers[109] suggest:

[P]regnancy rates tend to be low in countries in which many embryos are transferred, and the highest pregnancy rates occur where the number of embryos per transfer is low. Only top-level clinics (where treatment efficacy is guaranteed) are able to decrease the number of embryos transferred without compromising their pregnancy rate, and to vouch for safety in this way. Elective single embryo transfer (eSET) can never be mandatory in all patients, but the percentage of eSETs performed by a particular assisted reproduction treatment centre does reflect its quality: the ultimate outcome measure of efficacy and safety.

Two of the interesting breakthroughs that occurred this year were the successful restoration of fertility and endocrine function in a 30-year-old breast cancer patient after heterotopic transplantation of cryopreserved ovarian tissue[110] (see Medscape Medical News Story) and then the first case of a human live birth after successful orthotopic autotransplantation of cryopreserved ovarian tissue.[111] (See Medscape Medical Newsmaker Interview.)

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