I-26. Menopausal transition and menopause

更年期移行期と閉経

Definition & Life Stages

Menopause = end of ovarian reproductive function (oocyte maturation + hormone production). Defined as the final menstrual period (FMP) followed by 12 months of no bleeding (determined retrospectively).
Average age 51; <45 = early, <40 = premature.
Natural (primordial follicle depletion, follicular atresia) or iatrogenic (bilateral oophorectomy, radio-/chemotherapy).
Women spend ~25–30 years post-menopause.

Stages

Menopausal transition: starts 4–8 yrs before menopause, until menopause.
- Early: ≥7-day difference between consecutive cycles.
- Late: ≥60 days of amenorrhea (≥2 skipped periods).
Post-menopause: until end of life.
Perimenopause: transition + 1 year after.
Climacteric: transition + few years after (symptomatic period).

Hormonal Events

Driven by follicle depletion (atresia; ~400–500 oocytes ovulated over reproductive years).
Symptoms from ovarian dysfunction, extreme E2 fluctuations, then E2 decline.
Decline factors:
- Ovarian: ↓follicle number, ↓responsiveness to LH/FSH.
- Hypothalamic: imbalanced GnRH-regulating neurotransmitters, ↓estrogen sensitivity → inaccurate LH peak timing.
Sequence: earliest → ↓AMH, ↓inhibin B → ↑FSH (still maintains dominant follicle → normal/slightly ↑E2 → reduced fertility as only symptom). Later: further ↓inhibin B → ↑FSH/LH, E2 declines, AMH continues to fall.

Bleeding Disorders

From ↓inhibin B → ↑FSH:
- Normal cycle, altered length: ↑FSH → faster follicle maturation → shorter cycle (earliest sign); or weak FSH response → longer cycle.
- Abnormal/anovulatory: ↑FSH + inappropriate LH peak timing → anovulatory; weak response → delayed maturation → longer/shorter anovulatory cycle.
Bleeding from unopposed estrogen proliferating the endometrium, then irregular detachment (spotting or heavy bleeding); not progesterone withdrawal (no corpus luteum). High variability.

Symptoms of the Transition

Hypoestrogenism: endometrial hyperplasia (→ carcinoma), hypermenorrhea (→ anemia), spotty bleeding.
Short-term estrogen deficiency: vaginal dryness, emotional instability, sleep disturbance, hot flashes → ↓libido.

Hot flashes

Sudden heat/flushing of face, neck, upper limbs, trunk (sudden vasodilation), 1–5 min; with sweating, tachycardia, sometimes dizziness; often nocturnal (sleep disturbance); late transition + early post-menopause; spontaneously resolve after a few years.
Pathophysiology: ↓estradiol acts on hypothalamic thermoregulatory center (↑norepinephrine/serotonin) → narrowed thermoneutral zone → hot flashes, night sweats, sleep disturbance, depression, daytime fatigue.

一問一答

▶How is menopause defined?

The end of ovarian reproductive function, defined as the final menstrual period followed by 12 months without bleeding (determined retrospectively).

▶What is the average age of menopause, and what counts as early/premature?

Average age ~51; <45 is early and <40 is premature.

▶What distinguishes natural from iatrogenic menopause?

Natural: primordial follicle depletion/follicular atresia. Iatrogenic: bilateral oophorectomy or radio-/chemotherapy.

▶How are perimenopause and climacteric defined?

Perimenopause = the menopausal transition plus 1 year after menopause; climacteric = the transition plus the few symptomatic years after.

▶How are the early and late menopausal transition defined by cycle changes?

Early: a ≥7-day difference between consecutive cycles. Late: ≥60 days of amenorrhea (≥2 skipped periods).

▶What is the earliest hormonal change of the menopausal transition?

Falling AMH and inhibin B → rising FSH, which still maintains a dominant follicle (near-normal estradiol), so reduced fertility may be the only symptom.

▶What are the two main factors driving hormonal decline in menopause?

Ovarian (↓follicle number, ↓responsiveness to LH/FSH) and hypothalamic (imbalanced GnRH-regulating neurotransmitters, ↓estrogen sensitivity → mistimed LH peak).

▶Why do cycles shorten early in the menopausal transition?

↓Inhibin B raises FSH, which accelerates follicle maturation → shorter cycles (an early sign); weak FSH response can instead lengthen cycles.

▶Why is bleeding irregular during the transition rather than a normal progesterone withdrawal bleed?

Without ovulation there is no corpus luteum/progesterone; unopposed estrogen proliferates the endometrium, which then sheds irregularly (spotting or heavy bleeding).

▶What are the consequences of unopposed estrogen during the transition?

Endometrial hyperplasia (→ carcinoma), hypermenorrhea (→ anemia), and spotty bleeding.

▶What short-term symptoms arise from estrogen deficiency in the transition?

Vaginal dryness, emotional instability, sleep disturbance, hot flashes, and ↓libido.

▶What characterizes a hot flash clinically?

Sudden vasodilation and heat/flushing of the face, neck, upper limbs, and trunk lasting 1–5 min, with sweating, tachycardia, sometimes dizziness; often nocturnal and self-limited over a few years.

▶What is the pathophysiology of hot flashes?

↓Estradiol acts on the hypothalamic thermoregulatory center (↑norepinephrine/serotonin), narrowing the thermoneutral zone → hot flashes, night sweats, sleep disturbance, depression, and daytime fatigue.

▶What underlying process drives all the hormonal events of menopause?

Progressive follicle depletion through atresia (only ~400–500 oocytes are ovulated over the reproductive years).

▶What hormone changes occur in the late transition?

Further ↓inhibin B → ↑FSH/LH, declining estradiol, and continuing fall in AMH.

▶Why is menopause diagnosed retrospectively?

Because it is defined as the final menstrual period confirmed only after 12 consecutive months without bleeding.

▶Why can the menopausal transition cause anovulatory cycles?

↑FSH plus inappropriately timed LH peaks (from reduced hypothalamic estrogen sensitivity) lead to failed ovulation; weak follicular response further delays maturation.

▶When do hot flashes typically occur during the menopausal timeline?

Mainly in the late transition and early post-menopause, usually resolving spontaneously after a few years.

▶Why can hypermenorrhea during the transition cause anemia?

Unopposed estrogen thickens the endometrium, and heavy/prolonged shedding causes excessive blood (iron) loss → anemia.

▶Roughly how long do women live after menopause?

About 25–30 years, making management of long-term estrogen-deficiency consequences important.