Pathophysiology

Pathophysiology

I-25. Disorders of female hormonal regulation

女性ホルモン調節の異常

Female Sex Hormone Regulation

  • GnRH → FSH + LH (pituitary) → ovary:
    • FSH: stimulates granulosa cells → estrogens; produces inhibin (negative feedback).
    • LH: stimulates theca cells → progestins + androgens (androstenedione → granulosa cell → estradiol via aromatase).

Amenorrhea

(= absence of menstrual cycle; not classified by site of damage)

Primary amenorrhea

  • Causes: gonadal dysgenesis (Turner 45,X0), androgen insensitivity (abnormal Müllerian development), PCOS, absent GnRH (±anosmia / Kallmann).
  • Symptoms: absent/delayed puberty; delayed/blocked external sexual characteristics.

Secondary amenorrhea / oligomenorrhea

  • Previously established cycle ceases; external organs developed (may be atrophied).
  • Causes: functional hypothalamic amenorrhea, PCOS, hyperprolactinemia (±hypothyroidism), drug-induced (opioids, glucocorticoids), menopause.
  • Symptoms: infertility, ↓libido, vaginal atrophy, hot flashes, ↓breast size, osteoporosis (menopause-like); pituitary tumor → visual field loss + hypopituitarism; hyperprolactinemia → galactorrhea.

Functional Hypothalamic Amenorrhea

  • Normal GnRH regulation: opioid neurons inhibit; leptin stimulates (via kisspeptin/neurokinin B).
  • Pathology:
    • Malnutrition/dieting → ↓leptin → ↓GnRH (and loss of leptin’s opioid inhibition → opioids further suppress GnRH).
    • Strong physical stress → ↑CRH → inhibits hypothalamus/pituitary → ↓GnRH.
  • Consequences: ↑ACTH/cortisol; ↓FSH/LH/estradiol; ↓TSH/T3.

Polycystic Ovary Syndrome (PCOS)

Affects 5–20% of women.

Pathomechanism

  • Neuroendocrine: altered pulsatile GnRH → ↑LH, ↓FSH (≥2× LH) → theca cells → ↑androstenedione/testosterone (→ metabolic disorders + follicular arrest); granulosa converts to estradiol → endometrial hyperplasia (→ cancer) + further ↓FSH.
  • Metabolic (hyperandrogenism): ↓lipolysis → ↑visceral fat; ↓adiponectin → insulin resistance → hyperglycemia → ↑insulin + hepatic steatosis.
  • Hyperinsulinemia: ↑free IGF (↓IGFBP), ↓SHBG → ↑free testosterone → ↑AMH → blocks FSH → follicular arrest → polycystic ovary.

Diagnosis (Rotterdam — 2 of 3)

  1. Oligo-/anovulation.
  2. Clinical/lab androgen excess.
  3. Polycystic ovarian morphology (ultrasound). (Exclude other causes.)

Symptoms & consequences

  • Short-term: hirsutism, androgenic hair loss, acne, impaired fertility, miscarriage/premature birth.
  • Long-term: T2DM, dyslipidemia, endometrial cancer.

PCOS vs. Functional Hypothalamic Amenorrhea

  • PCOS: high androgens, high LH/FSH ratio, obesity/insulin resistance common.
  • FHA: low/normal androgens, low LH/FSH ratio, linked to dieting/low energy availability.

一問一答

▶How is female reproductive hormone secretion regulated?

GnRH → FSH + LH. FSH stimulates granulosa cells → estrogens + inhibin; LH stimulates theca cells → progestins/androgens, with androstenedione converted to estradiol in granulosa cells via aromatase.

▶How is GnRH normally modulated by opioids and leptin?

Opioid neurons inhibit GnRH, while leptin stimulates it (via kisspeptin/neurokinin B).

▶What are common causes of secondary amenorrhea?

Functional hypothalamic amenorrhea, PCOS, hyperprolactinemia (± hypothyroidism), drugs (opioids, glucocorticoids), and menopause.

▶What is the difference between primary and secondary amenorrhea?

Primary: menstruation never established (absent/delayed puberty). Secondary: a previously established cycle ceases (external organs already developed).

▶What are common causes of primary amenorrhea?

Gonadal dysgenesis (Turner 45,X0), androgen insensitivity (abnormal Müllerian development), PCOS, and absent GnRH (± anosmia / Kallmann).

▶How does malnutrition/dieting cause functional hypothalamic amenorrhea?

↓Leptin lowers GnRH, and loss of leptin's restraint on opioids lets opioids further suppress GnRH → ↓FSH/LH/estradiol.

▶How does severe physical stress cause functional hypothalamic amenorrhea?

Stress raises CRH, which inhibits the hypothalamus/pituitary → ↓GnRH → ↓FSH/LH/estradiol (with ↑ACTH/cortisol and ↓TSH/T3).

▶How common is PCOS and what is its core neuroendocrine abnormality?

It affects 5–20% of women; altered pulsatile GnRH → ↑LH with ↓FSH (LH ≥ 2× FSH) → theca cells overproduce androstenedione/testosterone with follicular arrest.

▶How does hyperinsulinemia worsen PCOS?

Insulin raises free IGF (↓IGFBP) and lowers SHBG → ↑free testosterone → ↑AMH → blocks FSH → follicular arrest (polycystic ovary).

▶What are the Rotterdam diagnostic criteria for PCOS?

Two of three: (1) oligo-/anovulation, (2) clinical/biochemical androgen excess, (3) polycystic ovarian morphology on ultrasound — after excluding other causes.

▶What are the short- and long-term consequences of PCOS?

Short-term: hirsutism, androgenic hair loss, acne, impaired fertility, miscarriage/preterm birth. Long-term: type 2 DM, dyslipidemia, and endometrial cancer.

▶How do PCOS and functional hypothalamic amenorrhea differ?

PCOS: high androgens, high LH/FSH ratio, obesity/insulin resistance. FHA: low/normal androgens, low LH/FSH ratio, linked to dieting/low energy availability.

▶Why does PCOS predispose to endometrial hyperplasia/cancer?

Granulosa-derived estradiol (unopposed by progesterone due to anovulation) causes endometrial proliferation/hyperplasia, which can progress to cancer.

▶What metabolic disturbance underlies hyperandrogenism in PCOS?

↓Lipolysis → ↑visceral fat and ↓adiponectin → insulin resistance → hyperglycemia/hyperinsulinemia and hepatic steatosis.

▶What hormonal changes occur in functional hypothalamic amenorrhea?

↑ACTH/cortisol; ↓FSH/LH/estradiol; and ↓TSH/T3.

▶What symptoms occur with secondary amenorrhea from estrogen deficiency?

Infertility, ↓libido, vaginal atrophy, hot flashes, ↓breast size, and osteoporosis (menopause-like).

▶What is Turner syndrome's relevance to amenorrhea?

Turner syndrome (45,X0) causes gonadal dysgenesis → primary amenorrhea with absent/delayed puberty.

▶What are the respective roles of FSH and LH in the ovary?

FSH stimulates granulosa cells (estrogen + inhibin production); LH stimulates theca cells (progestins/androgens) and triggers ovulation.

▶How can a pituitary tumor present alongside amenorrhea?

With visual field loss (chiasm compression) and hypopituitarism; if it raises prolactin, also galactorrhea.

▶Why does PCOS feature elevated AMH?

Excess small antral follicles and hyperandrogenism/hyperinsulinemia increase AMH, which blocks FSH action and causes follicular arrest.