Discussion

of ovulation induction with clomiphene citrate or gonadotropins. It has been reported to be associated with pregnancy loss and late pregnancy complications such as gestational diabetes and preeclampsia. However, many of these issues resolve completely after weight loss and bariatric surgery [5].

The differential diagnosis of this condition, which have to be ruled out, include other causes of ovulatory dysfunction and hirsutism such as androgen-producing tumors, congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, thyroid dysfunction, hypothalamic dysfunction (hypothalamic amenorrhea), hyperinsulinemia, and the HAIR-AN syndrome (Hyperandrogenism, insulin resistance, and acanthosis nigricans).

One of the most important steps in the evaluation of this patient is obtaining a full history of the onset, progression, and duration of symptoms, as well as obtaining a careful menstrual history, medication intake, and the use of exogenous androgens.

Physical examination should include blood pressure measurement, weight, and BMI. A BMI between 25 and 30 is categorized as being overweight, while >30 is de ned as obesity. General body inspection should follow to diagnose the presence of hirsutism, acne, alopecia, clitoromegaly, or acanthosis nigricans, a skin condition characterized by velvety, hyper-pigmented areas in the skin of the back of the neck, axillae, and underneath the breasts. The presence of acanthosis nigricans is usually considered as a marker for insulin resistance and signals the need for further evaluation. Waist circumference ≥35 in. is one of the components of metabolic syndrome. Pelvic examination may occasionally reveal bilaterally enlarged ovaries and should be con rmed by transvaginal ultrasound. A typical appearance of polycystic ovaries entails ≥12 follicles measuring 2–9 mm in diameter in each ovary, or an increase in ovarian volume (>10 cm3). Moreover, ultrasound examination should include a thorough evaluation of the endometrium as the initial step to rule out the possible presence of endometrial hyperplasia or other endometrial abnormalities.

Laboratory testing should encompass the evaluation of hyperandrogenemia by obtaining total and free testosterone levels along with sex hormone binding globulin (SHBG). DHEA-S levels will help rule out adrenal causes of hyperandrogenemia, and elevated levels may point to an adrenal source. Other causes of ovulatory dysfunction and hirsutism should also be ruled out by measuring a morning level of 17-hydroxyprogesterone, with the purpose of excluding non-classical congenital adrenal hyperplasia due to 21 hydroxylase de ciency, especially in patients from populations at risk of the disease such as Ashkenazy Jews. An elevated basal level should prompt a follow-up with an ACTH stimulation test. FSH and LH levels should also be obtained since up to 60% of women with PCOS have a high LH/FSH ratio. Prolactin and TSH levels should also be evaluated since hyperprolactinemia is a known etiologic factor in oligo-amenorrhea, and hypothyroidism may be associated with hirsutism since abnormal thyroid function may in turn affect testosterone levels by altering circulating SHBG levels. Screening for Cushing syndrome should be performed only if there are any clinical features such as moon facies or abdominal striae. Evaluation of metabolic abnormalities should include an evaluation of hemoglobin A1C or a 2-h glucose tolerance test after the administration of a 75 g glucose load. Measurements of glucose and insulin will aid in the diagnosis of

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letrozole (Femara®) have been used off label and recommended as primary or secondary treatment for anovulatory women with PCOS. This drug reduces circulating estrogen inhibiting the negative feedback at the hypothalamic-pituitary axis; this results in increased FSH secretion with resulting follicular development. Ovulation rates have been reported to be between 60% and 84%, with conception rates between 10% and 40% cumulatively. A meta-analysis has shown comparative pregnancy rates between women treated with clomiphene citrate and those treated with letrozole. More recently, however, a randomized controlled trial reported higher ovulation and live birth rates with letrozole. In patients that fail to ovulate with oral ovulation induction agents, injectable gonadotropins can be utilized [8]. Careful dosing is mandatory since the use of these agents is associated with development of a higher number of follicles, and therefore risks of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) have to be watched carefully. The latter is an iatrogenic condition associated with increased vascular permeability, third spacing with resultant ascites and hydrothorax with pulmonary edema, thromboembolic events, and kidney failure. It can be life-threatening in the most extreme cases. The regimen, when gonadotropins are used to induce ovulation in PCOS patients, is the so-called step-up protocol designed to reach a threshold serum concentration of FSH to achieve mono-follicular development. Gonadotropins are usually started on cycle day 2 of a spontaneous or an induced menses with doses as low as 37.5 IU daily. It is gradually increased depending upon the ovarian response determined by frequent ovarian ultrasound and estrogen level measurement. Despite a low-dose approach and careful monitoring, higher than expected response can still be encountered. If there is multi-follicular development (>3 dominant follicles) and/or estrogen levels >1000 pg/mL, the patient should be counseled regarding risks of OHSS and multiple pregnancy. Such cycle should be canceled, and the patient is advised against attempting to conceive during that cycle. An alternative to cancelation is to convert the treatment to in vitro fertilization (IVF). However, the latter approach may not be most desirable because the patient is not mentally prepared for IVF and cost may present as an issue. Moreover, while the number of follicles is too many for timed intercourse or intrauterine insemination (IUI), it may be low for IVF.

IVF should be considered in PCOS patients when oral agents or a low-dose gonadotropin approach either fails to induce ovulation or achieve a conception with timed intercourse or IUI, or the response is too high for pregnancy to occur safely as described above. The advantage of IVF compared to ovulation induction is that regardless of the number of follicles recruited or eggs retrieved, a single embryo will be transferred back to the patient, much reducing the risk of multiple pregnancies. Rest of the viable embryos can be frozen for future use. Moreover, in IVF, gonadotropins will be used together with a GnRH antagonist which, on one hand, is employed to prevent ovulation from occurring before the intended oocyte retrieval and, on the other hand, allows the utilization of a GnRH agonist, instead of hCG, to trigger ovulation which will signi cantly reduce the risk of OHSS. If risks of OHSS are still considered high, all embryos should be frozen to avoid pregnancy in that cycle. Patients can return for a frozen embryo transfer in a later cycle when OHSS risk is not present. A recent

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