MCC of anovulation

| Clinical features | • Androgen excess (eg, acne, male pattern baldness, hirsutism) • Oligoovulation or anovulation (eg, menstrual irregularities) • Obesity • Polycystic ovaries on ultrasound • Insulin resistance (acanthosis nigricans) | | --- | --- | | Pathophysiology | • ↑ Testosterone levels • ↑ Estrogen levels • LH/FSH imbalance (elevated **LH:FSH ratio* ≥ 2:1)* | | Comorbidities | • Metabolic syndrome (eg, diabetes, hypertension) • Obstructive sleep apnea • Nonalcoholic steatohepatitis • Endometrial hyperplasia/cancer | | Treatment options | • Weight loss (first-line) • No wish to concieve • Oral contraceptives for menstrual regulation (1st line) • Metformin (2nd line) • Wish to concieve • Letrozole for ovulation induction |

<aside> 💡 Although patients with PCOS can have elevated serum testosterone or LH levels, serum concentrations can also be normal with symptoms due to a relative imbalance in hormone levels (ie, LH/FSH ratio) rather than absolute values.

biochemical evidence of hyperandrogenism with elevated serum levels of total testosterone, these laboratory values may be normal in some due to decreased levels of sex hormone-binding globulin, with elevated free testosterone levels instead.

Therefore, the diagnosis requires either clinical or biochemical evidence of hyperandrogenism.

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Acanthosis nigricans velvety hyperpigmentation of intertriginous areas (eg, neck, axillae). Although it is often seen concurrently with hirsutism in patients with PCOS, acanthosis nigricans is due to insulin resistance (eg, diabetes mellitus), rather than hyperandrogenism.

Acanthosis nigricans velvety hyperpigmentation of intertriginous areas (eg, neck, axillae). Although it is often seen concurrently with hirsutism in patients with PCOS, acanthosis nigricans is due to insulin resistance (eg, diabetes mellitus), rather than hyperandrogenism.

<aside> 💡 Polycystic ovaries can also be incidental findings in some patients without hyperandrogenism or menstrual irregularities (eg, no PCOS).

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Hyperandrogenism, resulting from ovarian steroid overproduction, can be diagnosed clinically (eg, hirsutism, acne, alopecia) or biochemically with elevated serum testosterone levels.

Hperandrogenism, and the subsequent hyperestrogenism (due to peripheral androgen conversion), results in chronic anovulation. Anovulatory cycles cause irregular menses, decreased progesterone secretion, and uncontrolled endometrial proliferation from unopposed estrogen.  When menstrual periods do occur, they are often associated with heavy bleeding that may result in anemia.

persistently elevated estrone levels due to peripheral androgen conversion in adipose tissue and decreased levels of sex-hormone–binding globulin.  Such high estrone levels affect gonadotropin-releasing hormone (GnRH) pulses at the level of the hypothalamus, resulting in high frequency, short interval GnRH pulses.  The high frequency GnRH pulses preferentially produce LH, resulting in an imbalance in LH and FSH release from the anterior pituitary.  The LH/FSH imbalance results in a lack of LH surge.  In the ovary, this results in the failure of follicle maturation and oocyte release (eg, anovulation).

Therefore, weight loss is the first-line treatment to reestablish ovulation by decreasing the peripheral estrogen conversion. If weight loss is unsuccessful, ovulation can be induced with letrozole, an aromatase inhibitor, which inhibits the conversion of androgens to estrogens The resultant decreased estradiol secretion causes a positive feedback mechanism to the pituitary gland, thereby increasing and normalizing LH and FSH levels. This creates an LH surge that results in ovulation.

In patients with PCOS who are pursuing pregnancy, weight loss is the first-line treatment as it restores ovulatory cycles; if unsuccessful, ovulation induction agents (eg, letrozole, clomiphene citrate) may be used.

Metformin is used in patients with PCOS and decreased insulin sensitivity to improve menstrual irregularities, metabolic outcomes, and weight loss. However, metformin monotherapy is only used in PCOS as a second-line treatment for menstrual irregularities in patients with contraindications for the first-line options, which this patient does not have. Finally, metformin may be used as an adjunct to first-line pharmacotherapy, which this patient has not yet received, to address metabolic comorbidities.

Women with PCOS typically have decreased progesterone secretion due to chronic anovulatory cycles.  Therefore, these patients usually have a constant and unbalanced proliferation of the endometrium by estrogens.  This unopposed estrogen stimulation places patients at increased risk for endometrial hyperplasia and cancer.  Treatment with cyclic progesterone, estrogen/progestin oral contraceptives, or progesterone-releasing intrauterine devices protects the endometrium from hyperplasia and reduces cancer risk.

<aside> 💡 Letrozole is the first-line ovulation induction agent in patients with PCOS to treat infertility due to higher live birth rates compared with clomiphene citrate.

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As part of work up PCOS patients should be screened for metabolic syndrome, eventhough there is increased risk for NAFLD there is no consus to screen them for it.

Spironolactone, an androgen receptor antagonist, is indicated for treatment of hirsutism; it does not regulate menstrual cycles.

The first-line therapy for menstrual regulation is a combination of weight loss and combined estrogen/progestin oral contraceptives.  Combined oral contraceptives contain progesterone to stimulate endometrial differentiation (ie, limit continued proliferation) and estrogen to stabilize the uterine lining, which restores normal cycles.  In addition, combined oral contraceptives reduce hirsutism by blocking adrenal androgen secretion and increasing production of sex hormone-binding globulin, which binds and decreases free testosterone.

Cyclic progesterone may be administered for endometrial protection against uncontrolled endometrial proliferation due to elevated estrogen levels in patients with PCOS.  However, progesterone does not facilitate ovulation and is not used to treat infertility.

Patients with PCOS are at increased risk for multiple comorbidities, including dyslipidemia, hypertension, and type 2 diabetes mellitus (eg, metabolic syndrome) and should undergo screening for these conditions. Due to obesity and metabolic syndrome, patients are at risk for developing obstructive sleep apnea, nonalcoholic fatty liver disease, and endometrial cancer.