Overview
This lecture covers menopause and perimenopause: the loss of ovarian function and its neuroendocrine and endocrine basis, the resulting systemic effects of oestrogen deficiency (bone, cardiometabolic, cardiovascular, cognitive), diagnosis and classification by age of onset, primary ovarian insufficiency (POI), and management, moving from lifestyle and non-hormonal options through to menopausal hormone therapy (MHT) (history, the WHI study, risks/benefits, contraindications and prescribing), genital syndrome of menopause, and the structure of a menopause consultation.
Definitions and Loss of Ovarian Function
- Menopause: a point in time 12 months after the final period.
- Perimenopause: the time from onset of menopausal symptoms to 12 months after the final period.
Ovarian lifespan and mechanism of loss:
- Oocyte number falls from ~700,000 at birth to ~300,000 at puberty.
- Apoptosis of oocytes and loss occurs over 400-500 cycles of follicular recruitment.
- Genetic factors: risk of early menopause increases 6-12x if the mother had early menopause.
- Neuroendocrine events: age-related desynchronisation of GnRH secretion causes impaired timing of the LH surge.
- Endocrine changes: loss of inhibin B raises FSH release, causing an “overshoot” of oestrogen production; over time follicles become less sensitive to FSH/LH, producing anovulatory cycles and luteal phase defects.
Pathway (genetic factors, environment, lifestyle, systemic disease feed into the brain/hypothalamus/pituitary axis and into the ovary):
- Hypothalamic ageing: desynchronised GnRH secretion -> impaired timing of the LH surge -> FSH increase.
- Functional ovarian ageing: decline in inhibin B and AMH -> oestradiol fluctuation and decline; decrease in ovarian follicle mass and function.
- Both pathways converge on anovulatory cycles and eventual loss of menstrual cycles.
Menstrual Cycle Recap and Feedback Mechanisms
Normal cycle:
- Gonadotropins: LH shows a sharp mid-cycle peak (ovulation); FSH shows a smaller mid-cycle rise.
- Ovarian events: egg -> developing follicle -> ovulation -> corpus luteum.
- Ovarian hormones: oestrogen rises to a peak before ovulation, dips, then rises again in the luteal phase; progesterone rises after ovulation, peaking in the luteal phase then falling.
- Uterine lining: menses (days ~1-5) -> follicular/proliferative phase (thickens) -> luteal phase (thickest, days ~15-28), then sheds.
Feedback: Hypothalamus -(GnRH)-> Pituitary -(LH/FSH)-> Ovary -> oestrogen/progesterone -> acts on uterus.
- Positive feedback (green): days 12-14, oestrogen/progesterone act back on hypothalamus and pituitary to drive the LH surge.
- Negative feedback (red): over most of the cycle, oestrogen/progesterone suppress hypothalamus and pituitary.
Effect of follicle demise on this feedback:
- Follicles fail to develop, so oestradiol and progesterone fall.
- Loss of ovarian hormone output breaks both loops: the negative feedback loop breaks at the ovary and at the oestrogen/progesterone-to-uterus link; the positive feedback loop breaks between oestrogen/progesterone and the ovary.
- With the loops broken, FSH and LH rise unchecked.
Hormone changes across life stages:
- Premenopause: regular cyclical oestrogen/progesterone oscillations with corresponding FSH/LH cycling.
- Perimenopause: oscillations become irregular and erratic, oestrogen spikes of variable amplitude, FSH/LH begin to rise.
- Postmenopause: oestrogen and progesterone flatten to low, stable levels; FSH and LH rise to and remain at sustained high levels.
Effects of Oestrogen Deficiency
Osteoporosis
- Oestrogen normally couples bone resorption and formation.
- Deficiency uncouples remodelling via cytokines (RANKL up, OPG down) -> excess resorption.
- Also reduces intestinal calcium absorption and skeletal muscle stimulation (reduced activity/loss of muscle mass) -> decreased bone formation.
- Net effect: reduced bone strength and increased fractures.
- Pathway: ageing (vitamin D deficiency, reduced intestinal calcium absorption, impaired renal synthesis of 1,25(OH)2 vitamin D3; reduced physical activity, sarcopenia) -> loss of mechanical stimulation of osteocytes -> decreased bone formation -> secondary hyperparathyroidism -> increased bone resorption. Separately, menopausal oestrogen decline -> osteoblasts -> increased RANKL/decreased OPG -> pre-osteoclasts -> osteoclasts -> increased bone resorption. Both arms converge on low bone mass/architecture -> low-trauma fracture.
Cardiometabolic changes
- Age-related weight gain plus menopause-related body fat redistribution to visceral abdominal fat -> increased waist size and altered body shape.
- This is a cause of cardiovascular disease via increased insulin resistance and increased diabetes risk.
- Blood lipid profiles become atherogenic within 1 year of the final menstrual period (FMP).
- Pathway: reduced satiety/increased food intake and sleep deprivation (circadian desynchronisation), plus reduced physical activity (reduced MC4R and ER-alpha signalling) and direct adverse vascular effects (impaired endothelial function) -> fatty liver, visceral adipose tissue accumulation, and muscle insulin resistance (loss of oestrogen-mediated insulin sensitivity via ER-alpha; reduced mitochondrial DNA replication, impaired muscle oxidative metabolism) -> converge on insulin resistance (decreased HDL, increased LDL, increased triglycerides, increased inflammation, impaired arterial function).
Cardiovascular disease
- Oestrogen normally promotes vascular remodelling/elasticity and regulates reactive dilation and local anti-inflammatory activity.
- Deficiency activates the renin-angiotensin system and increases endothelin (vasoconstriction) while decreasing vasodilation.
- Consequences: increased BP and subclinical CVD (early); ischaemic heart disease clinically about 10 years later than in men; stroke risk doubles in the 10 years after menopause.
- Pathway: menopause/ageing -> physical inactivity, mood instability, sarcopenia (indirect) -> visceral adiposity, dyslipidaemia, raised triglycerides, insulin resistance, raised BP, chronic inflammation -> obesity. Separately, oestrogen decline -> direct vascular effects (renin-angiotensin activation, raised angiotensin II and endothelin-1, reduced NO synthase) -> oxidative stress, vascular proliferation, wall inflammation, arterial stiffness, endothelial dysfunction. Both converge on atherosclerosis -> ischaemic heart disease and stroke.
Cognition
- Oestrogen acts in CNS areas controlling learning, memory registration/retrieval, judgement, evaluation and language, and increases cell proteins that promote neuronal growth/survival, neural transmission and synaptogenesis.
- Deficiency affects verbal memory and fluency (delayed processing speed and recall), potentially limited to the perimenopausal stage.
- Surgical menopause is associated with increased risk of dementia later in life.
- More severe vasomotor symptoms are associated with more complaints of poor cognitive function.
Overview of symptoms by system
- CNS: vasomotor symptoms, sleep disruption, depression/anxiety, cognitive changes, migraine.
- Skin/mucosa/hair: reduced skin thickness, elasticity and hydration, increased wrinkling, hair loss.
- Weight/metabolic: weight gain, increased visceral adiposity, increased waist circumference.
- Sexual function: decreased desire, dyspareunia.
- Urogenital: vaginal dryness, vulvar itching/burning, dysuria, urinary frequency/urgency, recurrent UTIs.
- Musculoskeletal: joint pain, sarcopenia.
Diagnosis: Menopause Categories and Perimenopause
By age of onset:
- <40 years - Premature menopause: primary ovarian insufficiency (1%) or surgery/chemo/radiotherapy (6% of women <40); a pathological condition; increased osteoporosis/fracture/cardiovascular disease risk. Diagnosis: FSH >25 IU/L on 2 occasions 4-6 weeks apart. MHT indicated until age 50 (or longer) for symptom management and to preserve bone density and improve cardiovascular health.
- 40-45 years - Early menopause: same diagnostic criteria and MHT indication as premature menopause.
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45 years - Menopause (average age 51): a retrospective diagnosis. MHT indicated if within 10 years of menopause, for symptom management.
Perimenopause:
- Time from onset of menopausal symptoms to 12 months after the final period; average duration 4-8 years.
- Can start while periods are still regular.
- Symptoms include hot flushes, night sweats, sleep disturbance.
- Most symptoms resolve within 2-5 years of menopause, but vaginal symptoms usually continue.
Primary Ovarian Insufficiency (POI)
Diagnostic features:
- Disordered menstrual cycle with amenorrhoea >4 months.
- FSH >25 IU/L on 2 occasions 4-6 weeks apart.
- If non-iatrogenic, investigate: chromosomal analysis, FMR1 premutation (fragile X gene), 21-hydroxylase antibodies, thyroid function tests (TFTs).
- Genetic counselling offered to female relatives.
Mechanism: in POI, oocytes/pre-granulosa cells undergo accelerated atresia, leading to a declining number of primordial follicles until exhaustion (contrasted with the normal folliculogenesis cycle: corpus luteum -> deterioration -> primordial -> primary -> pre-antral -> small antral -> large antral -> pre-ovulatory -> ruptured follicle -> corpus luteum again).
Consequences of POI:
- Menopausal symptoms: psycho-affective changes (mood lability, insomnia, irritability), vasomotor symptoms (hot flushes, night sweats), urogynaecological/sexual changes (amenorrhoea, vulvovaginal atrophy, low libido, dyspareunia).
- Long-term sequelae: accelerated cognitive impairment, accelerated cardiovascular disease, autoimmune disease (adrenal, thyroid), infertility, osteoporosis, premature mortality.
Treatment Options
- Hormonal: MHT is the most effective treatment for vasomotor symptoms, and is indicated for prevention of osteoporosis/cardiovascular disease in premature and early menopause.
- General advice for all peri- and postmenopausal women: healthy lifestyle, resistance exercise, adequate dietary protein and calcium.
- Lifestyle measures: exercise, reduce alcohol/coffee/spicy food, dress in layers.
- Non-medical/complementary: St John’s wort, maca, hypnosis, CBT, mindfulness.
- Non-hormonal medical treatment: SSRI/SNRI at low dose for flushes, mood changes and sleep (effective in ~60%); oxybutynin (low dose) for hot flushes; gabapentin/pregabalin; stellate ganglion blockade (used in Canterbury, ~80% effective).
Menopausal Hormone Therapy (MHT): History, Risks and Benefits
MHT is the most effective treatment for vasomotor symptoms of perimenopause and menopause.
Symptoms MHT helps with: vasomotor symptoms (hot flushes, night sweats), sleep disturbance, joint pain/stiffness, generalised aches/pains, loss of skin thickness/elasticity, vaginal dryness and recurrent UTIs, sexual dysfunction, and (late) reduced bone density.
Symptoms MHT might help with: weight/body shape changes, reduced muscle mass, changes in cognitive function.
History:
- 1960s: widespread use for hot flushes.
- 1970s: unopposed oestrogen found to increase endometrial cancer risk, leading to combined oestrogen + progestogen use.
- 1980s: FDA approved MHT for osteoporosis prevention.
- 1990s: the Women’s Health Initiative (WHI) study begins.
WHI study: RCT of 16,608 women aged 50-79. Regimens: E+P (if uterus intact) = oral CEE 0.625 mg + MPA 2.5 mg; E alone (no uterus) = oral CEE 0.625 mg.
- 2002: the E+P arm was stopped early due to increased coronary heart disease and increased breast cancer, with media release of results before publication causing public alarm.
Limitations of the WHI study that affect interpretation: average age at entry was 63 (average 12 years postmenopausal, much older than typical MHT initiators); used oral oestrogen only and only one type of oestrogen/progestogen; the media focused on relative risk; results from the oestrogen-only arm were largely ignored; and results were over-generalised to all people, delivery methods and doses.
WHI absolute risk data (cases per 10,000 person-years, EP vs placebo, and % change):
- Breast cancer: 38 vs 30 (26% increase)
- Coronary artery disease event: 37 vs 30 (29% increase)
- Stroke: 29 vs 21 (41% increase)
- Pulmonary emboli: 16 vs 8 (113% increase)
- Colorectal cancer: 10 vs 16 (37% decrease)
- Hip fracture: 10 vs 15 (34% decrease)
Risks/benefits in women <60 years or <10 years from menopause:
- Breast cancer: E+P increased risk (<1/1000/year); E alone had a neutral effect (non-significant decrease).
- Stroke: E+P increased risk (non-significant, ~0.5/1000/year); E alone had inconsistent results.
- VTE: increased risk with oral delivery for both regimens (minimal or neutral risk if transdermal).
- Fracture: decreased risk (both regimens).
- All-cause mortality: decreased risk (both regimens).
- Overall risk depends on type, dose, duration, age/time started, route, and whether a progestogen is used.
Breast cancer risk in context (per 1,000 women aged 50-59 over the next 5 years, UK data): 23 baseline cases; +4 cases with combined HRT; -4 cases with oestrogen-only HRT; +4 cases with combined hormonal contraceptives (the pill); +5 cases with drinking 2+ units of alcohol/day; +3 cases in current smokers; +24 cases if overweight/obese (BMI >=30); -7 cases with at least 2.5 hours moderate exercise/week.
Contraindications and Prescribing MHT
Absolute contraindications:
- Undiagnosed vaginal bleeding
- Previous breast cancer
- Previous VTE
- Previous MI/CVA
- High-risk cardiovascular disease
- Untreated hypertension
- Severe active liver disease
Prescribing principles:
- No uterus: oestrogen only, via patch, gel or oral.
- Intact uterus: oestrogen (patch/gel/oral) plus a progestogen (oral Utrogestan, medroxyprogesterone or norethisterone, or a Mirena IUS), or alternatively a combined oral preparation.
- If contraception is also needed: oestradiol patch/gel/oral plus a Mirena, or a combined oral contraceptive (until age 50).
Follow-up:
- Review every 2-3 months to check symptoms, bleeding and side effects.
- Review yearly for risks/benefits, treatment goals and screening.
- Consider stopping by age 60 or before 10 years from menopause.
Genital Syndrome of Menopause
- In perimenopause the vaginal epithelium thins; around 50% of postmenopausal women are symptomatic.
- Symptoms: dyspareunia, urinary urgency, recurrent UTI.
- Treatment: vaginal oestrogen (cream or pessary) if vaginal symptoms only, with MHT added if vasomotor symptoms also need treatment.
The Consultation
Key elements of a menopause consultation:
- Listen to the patient’s concerns and wishes.
- Establish whether they are peri- or postmenopausal.
- Establish whether they need contraception.
- Consider other causes of symptoms such as hot flushes: anxiety, depression, anaemia, thyroid disorders, unstable diabetes, medications; check FBC, ferritin, TSH.
- Ensure cervical and breast screening are up to date.
- Assess cardiovascular risk and check BMI, BP, lipids, HbA1c.
- Assess fracture risk.
- Give general advice: dress in layers, weight reduction, exercise, etc.
- Discuss hormonal and non-hormonal treatment options.
Self-test
- Define menopause and perimenopause.
- Describe the neuroendocrine and endocrine mechanisms that drive loss of ovarian function.
- Explain how loss of inhibin B and reduced follicle sensitivity to FSH/LH change hormone levels approaching menopause.
- Describe how follicle demise breaks the normal positive and negative feedback loops of the menstrual cycle, and the resulting effect on FSH and LH.
- Contrast the pattern of oestrogen, progesterone, FSH and LH across premenopause, perimenopause and postmenopause.
- Describe the mechanism by which oestrogen deficiency leads to osteoporosis.
- Explain the pathway by which oestrogen depletion contributes to cardiometabolic disease.
- Describe how oestrogen deficiency increases cardiovascular disease risk, including the approximate timeline versus men and the change in stroke risk.
- Describe the effects of oestrogen deficiency on cognition, including which population is most at risk of an associated dementia risk.
- List the symptom categories of menopause by body system, with an example symptom for each.
- Distinguish premature menopause, early menopause and menopause by age of onset and diagnostic criteria.
- Describe the diagnostic criteria for primary ovarian insufficiency (POI) and the further investigations required if non-iatrogenic.
- List the long-term consequences of POI.
- A 38-year-old woman presents with amenorrhoea for 5 months. What diagnostic test would you order, and if confirmed, until what age would MHT typically be indicated and why?
- List the non-hormonal treatment options for menopausal symptoms with their approximate efficacy where given.
- Describe the design of the WHI study and the reasons it was stopped early.
- Explain why the WHI results have been considered difficult to generalise to current MHT prescribing.
- Distinguish the risks of combined (E+P) versus oestrogen-only MHT in women under 60 or within 10 years of menopause, for breast cancer, stroke and VTE.
- List the absolute contraindications to MHT.
- Describe how MHT is prescribed differently depending on whether the patient has a uterus, and how the choice changes if contraception is also required.
- Describe the follow-up schedule recommended once a patient starts MHT.
- Define genital syndrome of menopause and describe its treatment.
- Outline the key components of a menopause consultation, including how other causes of vasomotor-type symptoms should be excluded.
Answers
Reveal answers
- Menopause is a point in time 12 months after the final period. Perimenopause is the time from onset of menopausal symptoms to 12 months after the final period.
- Genetically, risk of early menopause rises 6-12x if the mother had early menopause. Neuroendocrine: age-related desynchronisation of GnRH secretion impairs the timing of the LH surge. Endocrine: loss of inhibin B raises FSH, causing an oestrogen “overshoot,” while follicles become progressively less sensitive to FSH/LH, producing anovulatory cycles and luteal phase defects, alongside ongoing oocyte apoptosis over 400-500 cycles of follicular recruitment.
- Loss of inhibin B removes negative feedback on FSH, so FSH rises; reduced follicle sensitivity to FSH/LH means ovulation and normal cyclical hormone production become impaired, giving anovulatory cycles and luteal phase defects.
- As follicles fail to develop, oestradiol and progesterone fall. This breaks the negative feedback loop (at the ovary and at the oestrogen/progesterone-uterus link) and the positive feedback loop (between oestrogen/progesterone and the ovary), so FSH and LH are no longer suppressed and rise.
- Premenopause: regular cyclical oestrogen/progesterone oscillations with matching FSH/LH cycling. Perimenopause: irregular, erratic oestrogen spikes of variable amplitude, with FSH/LH beginning to rise. Postmenopause: oestrogen and progesterone flatten to low stable levels, while FSH and LH rise to and remain at sustained high levels.
- Oestrogen deficiency uncouples bone resorption and formation via cytokines (increased RANKL, decreased OPG), causing excess resorption; it also reduces intestinal calcium absorption and skeletal muscle stimulation, decreasing bone formation. The combined effect is reduced bone strength and increased fractures.
- Central effects (reduced satiety/increased intake, sleep deprivation from circadian desynchronisation) and reduced physical activity plus direct vascular effects (impaired endothelial function) lead to fatty liver, visceral fat accumulation and muscle insulin resistance (loss of oestrogen-mediated insulin sensitivity via ER-alpha), which converge on insulin resistance with reduced HDL, raised LDL, raised triglycerides, increased inflammation and impaired arterial function.
- Oestrogen deficiency activates the renin-angiotensin system and raises endothelin while reducing vasodilation, raising BP and causing subclinical CVD early; clinically, ischaemic heart disease appears about 10 years later than in men, and stroke risk doubles in the 10 years after menopause.
- Oestrogen deficiency affects verbal memory and fluency (delayed processing speed and recall), an effect potentially limited to the perimenopausal stage. Surgical menopause is associated with increased dementia risk later in life, and more severe vasomotor symptoms correlate with more cognitive complaints.
- CNS (vasomotor symptoms, sleep disruption, depression/anxiety, cognitive changes, migraine); skin/mucosa/hair (reduced thickness/elasticity/hydration, wrinkling, hair loss); weight/metabolic (weight gain, visceral adiposity, increased waist circumference); sexual function (decreased desire, dyspareunia); urogenital (vaginal dryness, itching/burning, dysuria, urinary frequency/urgency, recurrent UTIs); musculoskeletal (joint pain, sarcopenia).
- Premature menopause: <40 years, due to POI (1%) or surgery/chemo/radiotherapy (6% of women <40); associated with increased osteoporosis/fracture/CVS disease risk. Early menopause: 40-45 years. Menopause: >45 years, average age 51, a retrospective diagnosis. Premature and early menopause share the diagnostic criterion of FSH >25 IU/L on 2 occasions 4-6 weeks apart.
- POI is diagnosed by disordered menstrual cycle with amenorrhoea >4 months and FSH >25 IU/L on 2 occasions 4-6 weeks apart. If non-iatrogenic, further tests include chromosomal analysis, FMR1 premutation (fragile X gene), 21-hydroxylase antibodies and TFTs, plus genetic counselling of female relatives.
- Accelerated cognitive impairment, accelerated cardiovascular disease, autoimmune disease (adrenal, thyroid), infertility, osteoporosis, and premature mortality.
- Order FSH, repeated on 2 occasions 4-6 weeks apart (looking for >25 IU/L). If confirmed as premature menopause, MHT is indicated until age 50 (or longer), for symptom management and to preserve bone density and improve cardiovascular health.
- SSRI/SNRI at low dose for flushes, mood changes and sleep (~60% effective); oxybutynin (low dose) for hot flushes; gabapentin/pregabalin; stellate ganglion blockade (~80% effective, used in Canterbury).
- The WHI was an RCT of 16,608 women aged 50-79, comparing oral CEE 0.625 mg + MPA 2.5 mg (E+P, if uterus intact) against oral CEE 0.625 mg alone (no uterus). The E+P arm was stopped early in 2002 due to increased coronary heart disease and increased breast cancer.
- The study population was older on average (63 years, 12 years postmenopausal) than typical MHT initiators, used only oral oestrogen and only one oestrogen/progestogen type, results were released to media before publication and framed around relative risk, the oestrogen-only arm’s (more favourable) results were largely ignored, and findings were over-generalised across all populations, delivery methods and doses.
- Breast cancer: E+P increases risk (<1/1000/year), E alone has a neutral or non-significantly decreased effect. Stroke: E+P has a non-significant increased risk (~0.5/1000/year), E alone gives inconsistent results. VTE: both increase risk with oral delivery, with minimal/neutral risk if given transdermally.
- Undiagnosed vaginal bleeding, previous breast cancer, previous VTE, previous MI/CVA, high-risk cardiovascular disease, untreated hypertension, severe active liver disease.
- Women without a uterus receive oestrogen only (patch, gel or oral). Women with an intact uterus need oestrogen plus a progestogen (oral Utrogestan, medroxyprogesterone or norethisterone, or a Mirena IUS) or a combined oral preparation, because unopposed oestrogen increases endometrial cancer risk. If contraception is also needed, options are an oestradiol patch/gel/oral plus a Mirena, or a combined oral contraceptive (until age 50).
- Review every 2-3 months to check symptoms, bleeding and side effects; review yearly for risks/benefits, treatment goals and screening; consider stopping by age 60 or before 10 years from menopause.
- Genital syndrome of menopause is thinning of the vaginal epithelium in perimenopause, symptomatic in about 50% of postmenopausal women, causing dyspareunia, urinary urgency and recurrent UTI. Treatment is vaginal oestrogen (cream or pessary) if vaginal symptoms alone, with MHT added if vasomotor symptoms also require treatment.
- Listen to the patient’s concerns/wishes; determine peri- vs postmenopausal status; assess contraceptive need; exclude other causes of vasomotor-type symptoms (anxiety, depression, anaemia, thyroid disorders, unstable diabetes, medications) via FBC, ferritin and TSH; confirm cervical/breast screening is current; assess cardiovascular risk (BMI, BP, lipids, HbA1c) and fracture risk; give general lifestyle advice; and discuss hormonal versus non-hormonal treatment options.