Polycystic Ovarian Syndrome

Background

Polycystic ovary syndrome (PCOS) is a complex, endocrine and metabolic disorder characterized by ovulatory dysfunction and hyperandrogenism. But it’s challenging to define. In fact, its diagnostic criteria (see below) differs in adolescents in comparison with adults!

PCOS frequently manifests during adolescence, and is primarily characterized by ovulatory dysfunction and hyperandrogenism. It is heterogeneous both clinically and biochemically, encompassing a spectrum of clinical features:

  • Cutaneous signs of hyperandrogenism (e.g., hirsutism, moderate-severe acne)
  • Menstrual irregularity (e.g., oligo- or amenorrhea, or irregular bleeding)
  • Polycystic ovaries (one or both)
  • Obesity and insulin resistance

Because of this clinical heterogeneity, most cases will not have all of these features, so it is sometimes challenging to diagnose PCOS.

The prevalence of PCOS varies between 6-12% of women in their reproductive years in the US, based on the diagnostic criteria used.

Multiple conditions are associated with PCOS:

  • Infertility
  • Obesity
  • DM (all types)
  • History of premature adrenarche

The exact pathophysiology is unknown. There is a strong association with insulin resistance, which is commonly seen in obesity. Specifically, there is an increase in peripheral estrogen synthesis from adipose tissue and decrease in peripheral sensitivity to insulin.

  • Hyperinsulinemia stimulates androgen production in ovarian theca interna cells. Levels of free androgens are further increased by reduced sex hormone-binding globulin (SHBG) production in the liver.
  • Hyperandrogenemia stimulates LH release from the anterior pituitary gland, resulting in a disruption of LH/FSH balance and, consequently, impaired follicle maturation.
  • LH/FSH balance is further impaired by increased GnRH pulsatility in the hypothalamus and the conversion of androgens to estrogen in adipose tissue.

Peripheral insulin resistance leads to hyperinsulinemia, resulting in acanthosis nigricans, hyperandrogenism, anovulation/oligoovulation (often manifesting as infertility), and an increased risk of endometrial carcinoma.

Diagnosis

Adults

The most commonly used diagnostic criteria in adults is the Rotterdam Criteria, for which two out of three of the following criteria are required to make the diagnosis of PCOS:

  • Oligoovulation and/or anovulation
  • Clinical and/or biochemical signs of hyperandrogenism
  • Polycystic ovaries (by US)

Specifically, the above criteria notes that signs of hyperandrogenism may be clinical or biochemical. Clinical evidence includes hirsutism (most common), acne (moderate/severe), and alopecia (most often diffuse). Biochemical evidence includes elevated free testosterone or the free testosterone index. US findings include enlarged ovaries (volume ≥10 mL) and/or the presence of multiple cystic follicles measuring 2-9 mm (string of pearls appearance) in one or both ovaries (i.e., one ovary fitting this definition is sufficient to meet US criteria).

Key point: Patients can have normal ovaries on US or no obesity and still have PCOS if they have irregular periods and hyperandrogenism.

A note on hirsutism: Midline terminal hair, which has a darker and coarser appearance, is more likely related to androgen excess (e.g., midline chest / lower abdomen). Hair on the upper arms or upper back also suggests hyperandrogenism. In contrast, facial hair or hair around the nipples can be normal and often genetically inherited.

These criteria generate four phenotypes, as shown in the following figure, in order of decreasing clinical severity (severity of hyperandrogenism, insulin resistance, obesity, and LH excess), which corresponds to decreasing specificity of the milder phenotypes:

Source: UpToDate

Adolescents

The above diagnostic criteria are problematic when applied to adolescents for several reasons:

  • Anovulatory cycles and associated menstrual irregularity are frequent in normal adolescents.
  • Hirsutism may occur in a developmental phase
  • Acne vulgaris is common in adolescents
  • The measurement of testosterone concentrations in adolescents is problematic because serum concentrations rise during anovulatory cycles, there is a paucity of reliable norms for androgen levels in adolescent females, and the extent to which adolescent hyperandrogenism predicts adult hyperandrogenism is unclear
  • Polycystic ovary morphology by adult standards is common in normal adolescents. In fact, the 2015 Pediatric Endocrine Society consensus does not endorse the use of US in adolescents to evaluate PCOS.

As such, diagnostic criteria based on international consensus is preferred for diagnosing PCOS in adolescents, defined as the otherwise unexplained combination of:

  1. Abnormal menstrual pattern as evidence of ovulatory dysfunction
    a. Abnormal for age or gynecologic age, and
    b. Persistent symptoms for 1 to 2 years
  2. Clinical and/or biochemical evidence of hyperandrogenism
    a. Hirsutism, especially if moderate to severe, is clinical evidence of hyperandrogenism
    b. Elevation of serum total or free testosterone by a specialty reference assay is biochemical evidence of hyperandrogenism

Defining an abnormal menstrual pattern is also tricky, but guidance does exist:

Source: UpToDate (adapted from Rosenfield RL. J Clin Endocrinol Metab 2013)

Hyperandrogenism: DDx & Work-up

  • PCOS (most common, constituting 75-80% of cases)
  • CAH
  • Cushing disease
  • Hypothyroidism
  • Hyperprolactinemia
  • Androgen-secreting tumor (e.g., Sertoli-Leydig cell tumor)
  • Acromegaly
  • Ovarian hyperthecosis
  • Placental aromatase deficiency
  • Drug-induced (e.g., exogenous steroids/androgens)

Given the above DDx, initial diagnostic work-up for hyperandrogenism typically includes

  • Pregnancy test
  • TSH
  • Prolactin
  • 17-hydroxyprogesterone
  • Free testosterone, DHEA-S

For US imaging, the transvaginal approach is preferred for best visualization of ovarian follicles whereas the transabdominal approach focuses on measuring ovarian volume.

We should also consider evaluating for comorbidities associated with PCOS:

  • Metabolic screening and monitoring:
    • BMI
    • Lipids
    • OSA symptoms
    • Regular BP monitoring
    • A1C
  • Mental health and quality of life:
    • Screening for anxiety, depression, psychosexual dysfunction
  • Endometrial cancer evaluation (if there is a high index of suspicion):
    • Transvaginal US, endometrial biopsy

Treatment

General recommendations:

  • Exercise
  • Healthy eating
  • Maintaining BMI <25
  • Comorbidities screening with targeted treatment
  • Frequent mental health assessment and referral, if indicated

Next, we should tailor therapeutic interventions based on reproductive goals, comorbidities, and individual risk factors.

For patients NOT planning to conceive:

  • Combined oral contraceptives (COCs)
    • First-line treatment for hyperandrogenism and/or irregular menses
  • Metformin
    • Second-line treatment for menstrual irregularity in patients unable to tolerates COCs
    • Add-on to COCs to improve metabolic outcomes
  • Antiandrogens
    • Spironolactone, finasteride, flutamide
    • Treatment of hirsutism and androgen related alopecia in patients unable to tolerate COCs

For patients planning to conceive:

  • First-line therapies for ovulation induction:
    • Letrozole (off-label)
      • Aromatase inhibitor
      • Improves pregnancy and live birth rates
    • Clomiphene citrate (alternative)
      • May be preferred over metformin monotherapy in obese women
      • Systematic review showed improve rates of live births, pregnancy, and ovulation when used in women with BMI >30
  • Second- and third-line therapies for ovulation induction:
    • Low-dose exogenous gonadotropins
      • Exogenous FSH
      • Human menopausal gonadotropin
    • Metformin
    • Laparoscopic ovarian drilling
      • Reduces ovarian tissue volume with a laser beam or surgical needle, thereby decreasing androgen production
      • Associated with lower risk of ovarian hyperstimulation syndrome and multifetal gestation
    • IVF

Take-Home Points!

  • There are different diagnostic criteria when diagnosing PCOS in adults and adolescents, owing to the overlap between symptoms and normal pubertal changes
  • Screen and treat comorbid conditions associated with PCOS
  • The treatment of symptoms, acne, hirsutism, or menstrual irregularities is based on patients’ desired clinical outcomes

Blog post based on Med-Peds Forum talk by Nora Jean-Baptiste, PGY1

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