Síndrome do Ovário Poliquístico

Epidemiologia e Fisiopatologia

Epidemiologia

• Prevalence: 5%–10% of reproductive-age women in the United States
• One of the most common causes of:
  • Oligomenorrhea 
  • Secondary amenorrhea 
  • Infertility
  • Hirsutism (abnormal facial and body hair growth)
• 50%–65% of patients are obese.

Fisiopatologia

Os mecanismos exatos são desconhecidos, mas considerados complexos e incluem fatores genéticos e ambientais. A síndrome metabólica e a obesidade estão frequentemente, mas nem sempre, presentes e provavelmente contribuem para a fisiopatologia em alguns indivíduos.

• Polycystic ovarian syndrome (PCOS) includes:
  • ↑ Androgens
  • Chronic anovulation
  • Polycystic-appearing ovaries
  • Metabolic dysfunction (commonly known as metabolic syndrome):
    • Insulin resistance
    • Dyslipidemia
    • Hypertension
    • Associated with obesity
    • ↑ Risk for diabetes and cardiovascular disease
• Dysfunction in the hypothalamic-pituitary-ovarian axis:
  • ↑ Luteinizing hormone (LH) level:
    • Stimulates testosterone production in ovarian theca cells
    • LH receptors tend to be over-expressed in polycystic ovaries.
    • Cause of ↑ LH: ↑ Estrogen from adipocytes and chronically anovulatory ovarian follicles → alters gonadotropin-releasing hormone (GnRH) pulse → ↑ LH secretion
  • Follicle-stimulating hormone (FSH):
    • FSH stimulation is insufficient for ovulation → abnormal follicle development
    • Evidence of FSH resistance at the follicular level
  • Chronic unopposed estrogen:
    • No ovulation → ↓ progesterone 
    • Results in endometrial proliferation without menses
    • ↑ Risk for endometrial hyperplasia or carcinoma
• Hyperandrogenism:
  • ↑ LH → ↑ testosterone:
    • ↑ Insulin → sensitizes the ovary to LH
    • Theca cells overexpress steroidogenic enzymes → ↑ testosterone
  • Likely involves a genetic predisposition
  • Androgens secreted primarily from the ovaries and adrenal glands
• Insulin resistance and obesity:
  • ↑ Insulin leads to:
    • ↑ Androgen production in ovarian theca cells
    • ↓ Hepatic production of sex hormone-binding globulin (SHBG) 
  • Obesity:
    • Adipocytes convert androgens → estrogens → ↓ FSH → worsening ovulatory dysfunction
    • ↑ Insulin resistance → ↑ free testosterone → ↑ hyperandrogenism
    • ↑ Prevalence of metabolic syndrome
    • Unclear whether obesity itself is causative in PCOS

Apresentação clínica

A síndrome do ovário policístico (SOP) deve ser suspeitada em qualquer mulher em idade reprodutiva com menstruação irregular e/ou sintomas de hiperandrogenismo, especialmente se obesa ou apresentando infertilidade.

Sintomas de hiperandrogenismo

• Hirsutism:
  • Excess terminal body hair
  • Male distribution:
    • Upper lip
    • Chin
    • Periareolar
    • Linea alba
• Acne vulgaris
• Male-pattern alopecia
• Early adrenarche (development of pubic hair, apocrine glands, and sebaceous glands)

Irregularidades do ciclo menstrual

• Oligomenorrhea (cycle length > 35 days) 
• Amenorrhea (cycles absent)
• Symptoms present for 3–6 months or 3 cycle lengths
• Due to chronic anovulation

Doenças associadas

• Metabolic syndrome:
  • Obesity (especially with ↑ waist:hip ratio)
  • Hypertension
  • Impaired glucose tolerance:
    • Type 2 diabetes mellitus
    • Acanthosis nigricans (marker of insulin resistance)
  • Dyslipidemia
• Infertility
• Cardiovascular disease
• Endometrial hyperplasia and carcinoma

Diagnóstico

A síndrome do ovário policístico (SOP) é um diagnóstico de exclusão, portanto, outras causas de oligo ou amenorreia e hiperandrogenismo devem ser descartadas. Os critérios de Rotterdam são comumente usados para fazer o diagnóstico, uma vez que outras causas são excluídas.

Critérios de Roterdã

O diagnóstico requer 2 dos 3 critérios a seguir:

• Clinical and/or biochemical signs of hyperandrogenism
• Oligo- or anovulation
• Polycystic ovaries on ultrasound

Exame objetivo

• Hirsutism:
  • Male-pattern facial and body hair growth
  • Ferriman-Gallwey score:
    • An objective evaluation of hirsutism
    • Often not helpful as some women remove unwanted hair
  • Consider normal ethnic variations in hair: Mediterranean, Middle Eastern, and South Asian (most hair) > Caucasian and Black > East Asian and Native American (least hair)
• Pelvic exam:
  • Mild ovarian enlargement
  • Rule out structural causes of abnormal bleeding.
• Signs of Cushing’s syndrome (alternate diagnosis):
  • Moon face
  • Buffalo hump
  • Abdominal striae

Avaliação laboratorial e de imagem

• Urine human chorionic gonadotropin (HCG): rule out pregnancy
• Assess other potential causes of abnormal bleeding:
  • Thyroid-stimulating hormone (TSH)
    • ↑ → hypothyroid
    • ↓ → hyperthyroid
  • ↑ Prolactin → hyperprolactinemia
• Assess for biochemical hyperandrogenism (and other potential causes of hirsutism):
  • Free testosterone: ↑ in PCOS
  • Dehydroepiandrosterone sulfate (DHEA-S): ↑ in certain androgen-secreting adrenal tumors
  • 17-hydroxyprogesterone: ↑ in non-classic congenital adrenal hyperplasia (NCCAH)
• Assess for metabolic syndrome:
  • 2-hour glucose tolerance test 
  • Fasting lipid panel:
    • ↑ Triglycerides and low-density lipoproteins (LDLs)
    • ↓ High-density lipoproteins (HDLs)
• Other laboratory tests to consider:
  • Cycle day 3 LH:FSH ratio → often > 2 in PCOS (normal is < 1)
  • 24-hour urinary free cortisol → screen for Cushing’s syndrome
• Transvaginal ultrasonography:
  • “Pearls on a string” (also known as the pearl necklace sign): multiple antral follicles at the periphery of the ovary
  • ↑ Ovarian volume
  • Not required if a woman already meets the Rotterdam criteria

Tratamento

Tratamento Geral

• Weight loss:
  • Goal of 5%–10% weight reduction
  • ↓ Estrogen production in adipocytes → ↓ FSH inhibition by estrogen → resumption of normal ovulation
  • ↓ Risk of metabolic syndrome
• Regular screening and treatment for:
  • Diabetes
  • Dyslipidemia
  • Hypertension
  • Cardiovascular disease
• Endometrial protection:
  • Goal is to ↓ risk of endometrial hyperplasia or cancer.
  • Combined oral contraceptive pills (OCPs) → allows regular withdrawal bleeding.
  • Levonorgestrel-containing intrauterine device (IUD) → endometrial suppression
  • Intermittent or continuous progestin therapy

Manejo do hirsutismo

• Mechanical hair removal (e.g., waxing, laser hair removal)
• Combined OCPs:
  • ↓ LH → ↓ testosterone production in the ovary
  • ↑ SHGB → ↑ binding of testosterone → ↓ free testosterone
  • ↓ DHEA-S in the adrenals
  • ↓ 5-α-reductase activity in the skin
• Antiandrogens:
  • Spironolactone
  • Finasteride
• Metformin:
  • No longer 1st line treatment for any PCOS indication
  • Still considered 1st line in patients with type 2 diabetes mellitus
  • Insulin sensitizing agent: ↓ hepatic glucose production → ↓ insulin → ↓ testosterone 
  • Despite ↓ testosterone, there is limited reduction in hirsutism.

Gerenciamento de infertilidade

• Letrozole:
  • Aromatase inhibitor
  • More effective at ovulation induction and safer than clomiphene citrate in PCOS
  • Not approved by the Food and Drug Administration (FDA) for fertility indications, though considered 1st line by many experts
  • ↓ Estrogen → ↓ inhibition of FSH → ↑ FSH → ↑ follicular development → ovulation
• Clomiphene citrate:
  • A selective estrogen receptor modulator (SERM) 
  • FDA approved to treat infertility
  • Inhibits effects of estrogen at the pituitary → ↑ FSH → ↑ follicular development → ovulation
• In vitro fertilization

Diagnóstico diferencial

• Non-classical congenital adrenal hyperplasia (NCCAH): a less severe form of an inherited enzyme deficiency (usually 21-hydroxylase) resulting in decreased production of aldosterone and cortisol. Instead, precursors are shunted down the sex steroid pathways, leading to increased androgens. Patients will develop hirsutism, oligomenorrhea, and infertility. Elevated 17-hydroxyprogesterone is diagnostic for congenital adrenal hyperplasia (CAH), but will be normal in PCOS. Management involves antiandrogens and glucocorticoids. 
• Cushing’s syndrome: elevated cortisol due to excess adrenocorticotropic hormone (ACTH) secretion, adrenal tumors, or exogenous steroids. Presentation is similar to PCOS with menstrual irregularities and hirsutism, as well as abdominal purple striae, truncal obesity, and moon face. Patients can be screened with a 24-hour urine free cortisol test or a dexamethasone suppression test. Management depends on the cause and includes withdrawal of exogenous steroids, adrenal inhibitors, or surgery for tumors. 
• Exogenous testosterone exposure: occurs when a man’s testosterone cream is transmitted to a woman through contact exposure. Patients may develop hirsutism; diagnosis is based on history and elevated testosterone levels.
• Ovarian tumors: sex-cord stromal tumors arising from the theca or granulosa cells within the ovary secreting androgens or estrogens, respectively. Patients may have signs of virilization, irregular menstrual cycles, or abnormal uterine bleeding. Androgen and estrogen levels tend to be more elevated than typically seen in PCOS. Initial treatment is surgical and based on the stage of malignancy.
• Hypothyroidism: a thyroid hormone deficiency resulting in either oligo- or amenorrhea, which may negatively impact fertility. Effects are likely due to structural similarities between TSH, FSH, and LH, as well as associated decreases in SHBG. Other symptoms include thinning of the hair, dry skin, brittle nails, periorbital edema, constipation, and fatigue. Thyroid-stimulating hormone (TSH) is increased due to low thyroxine. Hypothyroidism is treated with levothyroxine. 
• Pregnancy: results in amenorrhea, though typically not causing hirsutism symptoms. Pregnancy should be ruled out with a urine pregnancy test when evaluating amenorrhea. Treatment is obstetric care.