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Fertility Treatment for the PCOS Patient

By Kathryn Calhoun, M.D.

Chronic anovulation is a hallmark of Polycystic Ovary Syndrome (PCOS), so the vast majority of women with PCOS will require fertility treatment to conceive.

In a young PCOS patient with no obvious barriers to conception (other than anovulation), it is reasonable to start ovulation induction medicines before evaluating her uterus/tubes or her partner’s semen analysis. If the woman/ couple has not conceived after three successful ovulations, then a hysterosalpingogram (HSG) and semen analysis should be performed.

In contrast, an older woman (> 35 years) or a couple with risk factors for pelvic disease or sperm problems should have an HSG and a semen analysis before proceeding with ovulation induction therapy. Examples of risk factors for pelvic disease include a prior history of infections, surgery, pain, broids, endometriosis or pregnancy loss. Examples of risk factors for an abnormal semen analysis include changes in strength/libido, erectile dysfunction, obesity, sleep apnea, diabetes or cardiovascular disease.

Until recently, the first-line medication for ovulation induction in women with PCOS was clomiphene citrate (Clomid). Clomid is a selective estrogen receptor modulator (SERM) that blocks estrogen feedback on receptors throughout the body. At the brain (hypothalamic-pituitary) level, this perceived low estrogen state results in altered hormone (FSH/LH) signaling to the ovaries.

In 80 percent of PCOS women, this change in FSH/LH levels will result in ovulation.1 Side effects of Clomid are due to this reduced estrogen signaling and include headaches, hot ashes, mood changes, decreased cervical mucus, vaginal dryness and a temporary thinning of the uterine lining. Rarely, women may experience changes in vision, and this is a reason to discontinue Clomid use. The risk of twins is ~8 percent per cycle, the risk of triplets is < 1 percent. No causal relationship has been established between ovulation induction medicines and birth defects, miscarriage or ovarian cancer.1

A recent study followed women with PCOS for up to five treatment cycles and reported better rates of ovulation (61.7 percent vs 48.3 percent) and live birth (27.5 percent vs 19.1 percent) with Letrozole (Femara) rather than Clomid.2 Thus, Femara is now the first choice for ovulation induction in PCOS patients. Femara is an aromatase inhibitor that blocks the conversion of androgens to estrogens, thereby actually lowering estrogen levels in the body. The effect on the brain is similar to Clomid, though the side effects (hot ashes, headaches, thinning of uterine lining) are often less. Though it was underpowered to detect a significant difference, the risk of twins in this study was lower with Femara (3.9 percent) than Clomid (6.9 percent).2

Both Femara and Clomid are taken daily for 5 days at the start of a menstrual cycle. Progesterone may be used to induce a menstrual period, if necessary. Ovulation most often occurs 5-12 days after the last pill, and the patient should begin ovulation predictor kits (“OPKs”) and regular intercourse (if possible) during this interval.1 An ultrasound is performed to check ovarian response, to evaluate the uterine lining and to help the couple plan further intercourse and/or intrauterine insemination (IUI). If the ovaries are not responding, dosing can be immediately adjusted at this visit.

If Femara is unsuccessful at inducing ovulation, the dose can be increased, the duration may be extended or the patient can then try Clomid. Adjunct medications are sometimes used, such as low-dose Dexamethasone or Metformin, though these may yield minimal additional benefit.

Using Metformin alone has demonstrated lower rates of ovulation, live birth and twin pregnancy than Clomid.3 If the patient demonstrates continued resistance to oral medications, the importance of lifestyle modification (weight loss, if applicable) is reinforced and ovarian drilling (surgery to reduce the androgen-producing stromal portion of the ovary) may be considered. After six months of therapy, the chance of pregnancy drops significantly despite ovulation.1

If oral medications are unsuccessful, the next step may be injectable gonadotropins (FSH/LH.) Women with PCOS have a very high follicular/egg count, so these medicines may be risky if combined with intercourse or IUI. The chance of over-response, ovarian hyperstimulation syndrome (OHSS) or higher-order multiple gestations (triplets+) can lead to canceled cycles, treatment delays and disappointment.

For PCOS patients who do not succeed with lesser therapies, in vitro fertilization (IVF) represents a safe and effective next step. For the youngest PCOS patients, per cycle pregnancy rates can approach 70 percent. In an IVF cycle, a woman administers injectable gonadotropins (FSH/LH) for 9-12 days in order to mature a high percentage of her monthly egg group. The eggs are then retrieved with a short outpatient surgical procedure, then fertilization and early embryo development occur in the laboratory. An embryo is replaced in the uterus to begin the pregnancy.

Women with PCOS require special IVF care due to their robust egg count. The focus of treatment is to safely recruit a moderate-size group of eggs without significant OHSS. OHSS causes fluid shifts and third-spacing that can lead to symptomatic ascites and intravascular depletion. In addition to illness, OHSS can also result in lower-quality eggs/embryos. PCOS IVF protocols should employ lower doses and different combinations of medicines, as well as adjunctive therapies (i.e Metformin), to ensure an optimal and safe response.4 Even with appropriate treatment, at the end of the stimulation, most PCOS patients will have hormone levels that are too high for ideal implantation. To ensure the highest pregnancy rates, and a safe and healthy pregnancy overall, embryos are often frozen and transferred in the next cycle as a frozen embryo transfer (FET).

The good news is that most PCOS patients will conceive and enjoy a low-risk pregnancy. This is especially true for those patients with singleton gestations and no other comorbidities (i.e. obesity, insulin resistance/diabetes, hypertension). It is possible that the observed increased risks of pregnancy loss and late pregnancy complications in PCOS are most common in women with those additional risk factors.


REFERENCES
1. Fritz, Marc A.; Speroff, Leon. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; c2010.

2. Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, Christman GM, Coutifaris C, Taylor HS, Eisenberg E, Santoro N, Zhang H; NICHD Reproductive Medicine Network. The Pregnancy in Polycystic Ovary Syndrome II (PP- COS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials. 2012 May;33(3):470-81. doi: 10.1016/j.cct.2011.12.005. Epub 2012 Jan 13.

3. Legro RS, Barnhart KH, Schlaff WD, etc al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007; 356: 551-566.

4. Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016; 106: 1634-1647.

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