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Menopause

  • Strictly = last menstrual period
  • Diagnosed retrospectively after 12 months of amenorrhea.
  • Termination of reproductive function in females.
  • Av age of menopause ~ 52 years.
    • Smoking makes it happen earlier
  • Perimenopause = time period preceding menopause when fertility declines and menstrual irregularity increases.
    • I.e. >7 days different from normal cycle (short or longer)
    • Ends 1 year after menopause because of definition of menopause
  • Precedes final menses by 2-8 years (mean 4 years)
  • Flags in diagram = period
  • Results from primary ovarian failure
    • effectively no primordial follicles
  • Loss of responsiveness to FSH and LH
  • Failure of production of estrogen and progesterone.
  • Loss of negative feedback on hypothalamic pituitary axis --> high levels of FSH and LH.
  • Note: LH and FSH are still released in pulses due to cyclic (pulsatile) release of GnRH
  • Graph shows follicles per ovary
  • Red squares = normal periods
  • Black squares = perimenopausal, irregular in last year
  • Triangles = not ovulating
  • Associated with decline in follicles, we get changes in the hormones
  • After menopause, cycle of oestrogen disappears, and magnitude of release goes down
  • Increase in gonadotrophins due to loss of feedback on HPA axis
  • Estradiol drops considerably after menopause
  • Estrone doesn't drop down anywhere near as much
  • Gonadotropins: biggest increase is in FSH rather than LH (not only feedback by E lost, but also lose inhibin, which inhibits FSH)

Levels of ovarian hormones in postmenopausal women

  • Estradiol <30 pg/ml
  • Progesterone <1 ng/ml
    • ie 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.
    • Hence not ovary-dependent
    • And effects of menopause aren't as marked in fat ladies (mainly skinny ones)

Three types of estrogen

  • Estrone = menopausal
  • Estradiol = normal women
  • Estriol = main estrogen in pregnancy
  • If estradiol potency is 100, then estriol is 10 and estrone is 1
    • So you need a lot of estrone to make up for it
  • Inhibin B is released by granulosa and theca cells and its level corresponds to size of antral follicle. It inhibits FSH
    • Its secretion decreases earlier because of drop in estradiol
    • As you drop inhibin B, you get higher FSH, stimulating more estrogen production (maintains it for a while)
    • Hence why perimenopausal women can get shorter cycles (follicular phase gets shorter, but luteal phase stays the same)
  • AMH is expressed in follicles that have undergone recruitment but haven't been selected for dominance. Hence it's an indicator of ovarian reserve. Sometimes used in people undergoing IVF, giving you an idea of the likelihood of a successful IVF cycle.
    • Reaches levels below detection about 5 years before menopause

Androgens

  • 10 year spans (15-24, etc etc, 65-75)
  • Most of the drop in the androgens occurs prior to menopause, mainly between late teens-early twenties and late thirties-early forties, not in the menopausal period
  • In 45-54, there isn't much change in androgen levels (they just drop with age, not specific to menopause)

Changes of the menopause

  • (Treatments: Topical estrogen = vagina; HRT = systemic problems)
  • Hot flashes can also occur in castrated men. It's hormone withdrawal e.g. doesn't occur in Turner's syndrome
  • Flashes occur due to serotonin and noradrenaline events in hypothalamus, sensitive to estrogen (causing LH and FSH surges, see diagram)

Genitourinary

  • Atrophy of the vaginal epithelial
  • Changes in vaginal pH
  • Decrease in vaginal secretions
  • Decrease in circulation to vagina and uterus
  • Pelvic relaxation
  • Loss of vaginal tone
  • Urinary tract infections
  • Decreased size of reproductive organs and breasts
  • Menopausal syndrome
  • Vasomotor instability
  • Hot flashes
    • sensation of warmth spreading from the trunk to the face
    • Occur in Occur in 75% of menopausal women ~75% of menopausal women
    • Also occur after bilateral ovariectomy and after castration in men.
    • Prevented by estrogen therapy
    • Cause unknown
    • Coincide with surges in LH secretion (but continue after removal of the pituitary)
    • ?so estrogen sensitive event in the hypothalamus triggers both the release of LH and the episode of flushing
    • Night sweats

Triggers/Provocation techniques

IRL

  • Hot weather
  • Exercise
  • Anxiety
  • Caffeine
  • Alcohol
  • Spicy food
  • Close physical contact
  • Dreams

Note: all these things trigger Stress (common cause)


Lab

  • Water pads at 42C on torso.
  • Yohimbine (an a2 adrenergic antagonist)

Notes:

  • Dreams might explain night sweats
  • Sometimes use clonidine to treat hot flashes (a2 agonist)
  • Bottom panel = sternal skin conductance (shows you vasodilation of skin)
    • Associated with hot flash, there is an increase in skin conductance. And before the hot flash, there is a rise in core temperature, just prior to the experience
  • In women who get hot flashes, their sweating threshold is reduced. As your body temperature rises, you eventually get to a point where you trigger sweating - don't need to get as hot before triggering sweating, and there is also an increase in shivering threshold.
  • Changes in threshold relate to brain noradrenaline

Mechanism of hot flashes (diagram)

  • Less estrogen --> less serotonin --> increase in serotonin receptors
  • Stimulus (stress) --> releases 5-HT moduline --> antagnises 5HT-1b receptors (which inhibit serotonin release) --> increased release of 5-HT
  • Hence more serotonin acts on upregulated receptors in hypothalamus --> change in setpoint --> autonomic reactions to cool the body down --> hot flash
  • Estrogen withdrawal also reduces endorphins and catecholestrogen, which normally tonically inhibit noradrenaline
  • Therefore we get more noradrenaline, which is important in set point regulation
  • Noradrenaline also stimulates GnRH, increasing LH release
  • Takes a few weeks from E withdrawal for flashes to start, and a while for treatment to work (due to the slow upregulation of receptors)

Other menopausal symptoms

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

(Lose E --> lose protective effects). Note: once you've started forming atheroma, then increasing E after that can be detrimental (due to prothrombotic effects of E).

Bone

  • Cortical bone = dense
  • Cancellous = spongey
  • Osteocyte = sits inside compact bone
  • Osteoblast = makes ground substance of bone
  • Osteoclasts = break down bone
  • Bone is continuously made and remodelled
  • Osteoclast uses acids and protelytic enzymes to break down bone

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) 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).
    • Trabecular bone appears more holy when it has osteoporosis
  • Commonest cause of osteoporosis is involutional. (I.e. getting old --> osteoporosis)
    • Phase 2 - unique to women, lose bone mass rapidly
    • Males: steady drop, slower, and trabecular bone isn't as targeted

Role of estrogens in bone

  • Stimulates osteoblasts.
  • Inhibit secretion of cytokines such as IL-1, IL-6 and TNF-a from osteoblasts.
  • These cytokines foster the development of osteoclasts.
  • Stimulates the production of TGF-β
    • Increases the apoptosis of osteoclasts.
  • Note: Two subtypes of E receptor a (important in bone) and and β.
  • ERa knock out mice have a modest reduction in bone mass.
  • Mutation of ERβ has less effect on bone

?role of FSH

  • NOTE: recent suggestion that increasing FSH may contribute to perimenopausal bone loss.
    • Increased FSH predictive of bone loss
    • Bone has FSH receptors (on osteoclasts: high FSH --> more osteoclast activity)
    • Studies in FSHR null mice

X-ray

  • Vertebral crush fracture: one vertebra looks like a wedge - bone density gets low and you get a crush fracture. Several of those end up in a widow's hump

HRT

  • Last 10 cycles before menopause: 38% of cycles are ovulatory and 62% are anovulatory
  • 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. (The testes don't stop producing sperm)
  • 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
  • Although in males there is a 30% decrease in T production, but there is a 50% decrease in bioavailable T due to SHBG increase
  • Postmenopausal women have lower oestrogen levels than 80 year old male

Females vs males

? Testosterone treatment

  • “Physiological replacement” in older men decreases body fat mass and increases lean mass.
  • Concern regarding
    • cardiovascular risk
    • prostate carcinoma