Keywords

A 37-year-old patient with PCOS wants to get pregnant. She is 5′ 4″ and weighs 210 lbs; her BMI is 36.0 kg/m2. Her menstrual cycles vary between 6 and 12 weeks. She has hair on her chin and neck which she waxes weekly. She also has mild acanthosis on her neck and axilla. Her laboratory results are as follows (Table 52.1).

Table 52.1 Laboratory test results of case 2
Full size table
FormalPara How the Diagnosis Was Made

The clinical presentation of oligomenorrhea and hirsutism fulfills the criteria for PCOS diagnosis. In addition, this patient is obese and has clinical finding of insulin resistance (acanthosis nigricans). Even though her total testosterone is normal, this is due to low levels of SHBG, indicating that the bound fraction of testosterone is low. Her bioavailable-T and free-T are high, accounting for the hirsutism. Anti-Mullerian hormone level is <5 ng/ml . This may be due to her age and is not an evidence against the diagnosis of PCOS. Elevated HgBA1 indicates prediabetes. Obesity, acanthosis nigricans, low SHBG, and high HgBA1 indicate presence of significant insulin resistance.

FormalPara Questions

She starts a low-carbohydrate diet and taking metformin. She cannot increase metformin more than 500 mg/day because of gastrointestinal side effects. She loses 12 lbs in 3 months. What is the next best step?

  1. 1.

    Switch metformin to metformin XR and try to increase the dose.

  2. 2.

    Reduce carbohydrates further and ask her to lose another 15 lbs.

  3. 3.

    Increase exercise.

  4. 4.

    Ovulation induction.

FormalPara Lessons Learned

  • Answer: The next best step is ovulation induction.

  • Even though she is obese and insulin-resistant and has prediabetes and weight loss, exercise and metformin are very appropriate for her health care; her priority is pregnancy. Follicular reserve and quality of the ovarian follicles decline with age. AMH concentration around 0.8 ng/ml is consistent with menopause, and after menopause AMH declines below 0.003 ng/ml. There is evidence that AMH >2.8 ng/ml is associated with higher rates of live birth after in vitro fertilization (IVF) in women older than 35 years [1]. Therefore, this patient has some urgency.

  • Both clomiphene and letrozole are used for ovulation induction. Letrozole is the preferred treatment because it leads to higher pregnancy and live birth rates [2].

  • Clomiphene blocks estrogen receptors and creates estrogen deficiency at the hypothalamus/pituitary. In response, FSH increases and stimulates the ovarian follicles and induces ovulation. Ovulation leads to higher estradiol levels, but since the estrogen receptors are blocked, the hypothalamus/pituitary cannot sense the feedback, and FSH secretion continues, leading to ovulation from multiple follicles. In addition, estrogen receptors in the endometrium are also blocked; hence, only half of the ovulatory cycles results in implantation and pregnancy. Letrozole treatment also creates estrogen deficiency by blocking aromatase and conversion of testosterone to estradiol in the granulosa cells. This leads to increased FSH secretion and stimulates ovulation, and estradiol levels rise. The big difference is that, since the estrogen receptors are not blocked, feedback at the hypothalamus/pituitary remains intact and FSH declines. This may cause fewer multiple pregnancies and higher endometrial implantation rates. The commonly used ovulation induction protocol involves administering 2.5 mg/day letrozole between the 3rd to 7th days of the menstrual bleed (natural or induced by progestin withdrawal). Ovulation occurs 5–8 days after the last letrozole pill. If ovulation does not occur, the dose is repeated and then increased to 5 mg/day and then 7.5 mg/day.

  • The next step would be specialized treatments such as IVF.