Physiology of Menopause

Key concepts addressed

1. Terminology of menopause
2. Physiology underlying menopause and key hormonal changes
3. Clinical features of menopause – symptoms and signs; late changes and health risks
4. Current understanding of hot flushes
5. Osteoporosis and the role of estrogen in bone
6. Hormonal changes in males with ageing – “andropause”

Terminology
- Strictly menopause = last menstrual period
- Diagnosed retrospectively after 12 months of amenorrhea.
- Termination of reproductive function in women.
- Av age of menopause ~ 52 years. (Smokers tend to have menopause 2 years earlier)
- Perimenopause = time period preceding menopause when fertility declines and menstrual
irregularity increases (menopausal transition) until 1 yr after.
- Menopausal transition precedes final menses by 2-8 years (mean 4 years).

Perimenopause = menopausal transition + 1 year

Why does menopause occur?

- Results from primary ovarian failure (Although it is still released by the anterior pituitary
gland)
- Loss of responsiveness of ovary to LH and FSH
- Failure of production of estrogen and progesterone (and testosterone)
- Loss of negative feedback on hypothalamic pituitary axis  high levels of LH and FSH
(Much higher than that in ovulatory phase)
- Note: LH and FSH are still released in pulses due to cyclic release of GnRH.
The number of primordial follicles in women decreases drastically in 50s (age of
menopause) and is greatest after birth

Estrogen level excreted in urine gradually increases after puberty in a cyclical fashion. Then,
it decreases gradually in the mid-life and further decreases after menopause
Total urinary gonadotropins in female is slightly higher than male after piberty. After
menopause in female, the level increase drastically (from 40-60 yo) and then decreases
gradually while that of male is quite stable throughout life

The order of hormones (descending order)

Before menopause: Estradiol, Estrone, FSH, LH
After menopause: FSH, LH, Estrone, Estradiol

Levels of ovarian hormones in postmenopausal women

- Estradiol <30 pg/ml and Progesterone <1 ng/ml (both lower than lowest level of the
menstrual cycle in younger women)
- Inhibin levels decreased.
- Main estrogen produced is estrone (Formed in peripheral tissues, especially fat, by
aromatization of androstenedione produced by the adrenal cortex)

Three types of estrogen: Estrone (E1), 17B-Estradiol (E2), Estriol (E3)

Inhibin B and FSH

Inhibin can be a marker for small antral follicles

Less inhibin, more FSH, therefore having more frequent follicular phase

Inhibin B decreases 4 years prior to FMP

Androgens
- Total testosterone, free testosterone, DHEAS, androstenedione are not so related to
menopause

Changes of the Menopause

- Genitourinary
 Atrophy of the vaginal epithelial
 Changes in vaginal pH (more alkaline)
 Decrease in vaginal secretions
 Decrease in circulation to vagina and uterus
 Pelvic relaxation (due to less collagen)
 Loss of vaginal tone
 Urinary tract infections
 Decreased size of reproductive organs and breasts

Menopausal syndrome
- Vasomotor instability
- Hot flushes (Hot flashes)
- sensation of warmth spreading from the trunk to the face
- Occur in ~75% of menopausal women
- Also occur after bilateral ovariectomy and after castration in men.
- Prevented by estrogen therapy
- Exact cause unclear.
- Likely central mechanism rather than peripheral. - Involves ? noradrenaline ?
serotonin ? Neurokinin B
- Flushes coincide with surges in LH secretion (but continue after removal of the
pituitary)
- ?some estrogen sensitive event in the hypothalamus triggers both the release of LH
and the episode of flushing
- Night sweats
- Hot flushes more common in African American, Hispanic and White population

Triggers/Provocation techniques
- Stress
- Hot weather
- Exercise
- Anxiety
- Caffeine
- Alcohol
- Spicy food
- Close physical contact
- Dreams
- Water pads at 42C on torso.
- Yohimbine (an 2 adrenergic antagonist)

There is an increase of core temperature prior to the hot flushes

There is a narrower thermoregulatory zone
CBT = core body temperature

Recent researches
- Neurokinin B administration may induce hot flushes in women
- CGRP is critical for hot flushes in ovariectomized mice (Hot flush initiated by hypothalamus
but mediated by CGRP)

Others
- Mood changes
- Short-term memory loss
- Poor concentration
- Sleep disturbances
- Headaches
- Loss of libido
Late changes
- Cardiovascular disease
- Osteoporosis

Estrogen and cardiovascular function

- Vascular protective effects (Protection against CVD: Before menopause, the risk of CVD in
women is lower than men. After menopause, vice versa.)
-  nitric oxide (NO) (Dilators and inhibit platelets)
-  prostacyclin (PGI2) (dilators)
-  endothelin-1 (ET-1) (vasoconstrictor)
-  angiotensin (1-7) ( ACE2 activity and expression) (vasodilator)
- Improves circulating lipoprotein profiles
-  clearance of LDL by liver
-  circulating HDL (good cholesterol)
- Promotes thrombosis
- Timing hypothesis (Timing for HRT is really crucial)
- If you are giving HRT at the time of menopause -> cardioprotective
- If it is given after menopause, the build-up of plaques with HRT is not helpful
(thrombosis will build up in the plaques)

Osteoporosis
- A condition in which there is a reduction of bone mass (or density) and the incidence of
fractures is increased.
- Caused by a relative excess of osteoclast function.
- Fractures are especially common in the
- distal forearm (Colles’ fracture)
- vertebral bodies ( kyphosis; widow’s hump)
- hip
- These sites have a high content of trabecular bone (more metabolically active and bone is
lost more rapidly).

Commonest cause of osteoporosis is involutional.

Total body calcium as an index of bone mass

The drop is higher in the cancellous bone

Women (39.7%) has a higher risk of hip fracture, forearm fracture, vertebral fracture than
men (13.1%)

Measuring bone density

- Dual energy x-ray absorptiometry (DXA).
- Usually measured in lumbar spine and hip.
- Problem of using DXA
- Two x-ray energies are used to estimate the area of mineralized tissue, and the
mineral content is divided by the area to correct for body size.
- Only partial correction – small people tend to have lower than average BMD.
- Bone spurs (frequent in osteoarthritis) falsely increase bone density. (Falsely representing
a better bone mineral density)
- Absolute values vary with different machines  normalization with T and Z scores.

Role of estrogen in bone

- Suppresses bone turnover
- Decreases osteoclasts
- Inhibits secretion of cytokines such as IL-1, IL-6 and TNF- which foster the
development of osteoclasts.
- Stimulates the production of TGF-β which increases the apoptosis of osteoclasts.
- Inhibits osteoblast/bone lining cell expression of RANK ligand (and may stimulate
osteoprotegerin)
- Antagonises glucocorticoid induced osteoblast apoptosis
- Note: Two subtypes of E receptor  and β.
- ER knock out mice have a modest reduction in bone
mass.
- Mutation of ERβ has less effect on bone.
Potential role of FSH in bone
- Increasing FSH may contribute to perimenopausal bone loss.
- Increased FSH predictive of bone loss - Bone has FSH receptors
- Studies in FSHR null mice

HRT
- Most changes are due to reduced estrogen levels – hence Hormone Replacement Therapy
helps.
- Only small doses of estrogen are required as
don’t need to suppress the hypothalamic pituitary
axis
- Not contraceptive
- Progestagins are given because unopposed estrogen increases the risk of endometrial
neoplasia.

Changes in males with ageing

- Although testicular function declines with age, strictly, “andropause” is a misnomer.
- Decrease in T with ageing is due to
- Decrease in Leydig cell number and secretory
capacity.
- Age related decrease in episodic and stimulated gonadotrophin secretion.
Testosterone treatment
- “Physiological replacement” in older men decreases body fat mass and increases lean
mass.
- Concern regarding
- cardiovascular risk
- prostate carcinoma.
- Catalyst episode (25/10/16 – Testosterone)
“Adrenopause”

- DHEAS levels are 5X higher at 30y than 85y.

- Note: cortisol levels are maintained.
- Selective decrease in the functional zona reticularis cells in the adrenal cortex.

- ? DHEA = “fountain of youth”

- Functional parameters of daily living in males > 90 years were lowest in those with the
lowest DHEAS.
- Replacement may have beneficial effects on cardiovascular and immunological processes.
- Insufficient trials on the safety of exogenous DHEA.