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GYN/MENO/RL/2021
CLIMACTERIC AND MENOPAUSE

I. Definitions
The climacteric (更年期) refers to the years of waning ovarian function, which marks
the transition from the reproductive to the non-reproductive state.

The menopause (絕經) is defined as the permanent cessation of menstruation that

results from loss of ovarian follicular activity, thus marking the end of a woman’s
reproductive life. It is a specific event (the last menstrual period) that occurs during the
climacteric.

The perimenopause refers to the period beginning with the first clinical, biological and
endocrinological features of the approaching menopause and ends 12 months after the
final menstrual period.

Clinical types of menopause

1. Natural menopause - clinically diagnosed in retrospect following spontaneous
amenorrhoea for 12 months without other obvious pathological or physiological
cause. The median age at menopause is 51 years.
2. Artificial menopause – loss of ovarian function due to surgical castration,
irradiation or chemotherapy (e.g. alkylating agents)
3. Premature menopause - spontaneous onset of menopause before the age of 40.

II. Endocrine Changes at the Menopause

a) There is progressive loss of ovarian follicles and declining ovarian
responsiveness to gonadotrophin, leading to cessation of follicular development
and ovulation. Oestradiol production declines, and oestrone becomes the main
circulating oestrogen due to peripheral conversion of androstenedione.
b) There is rise in circulating FSH and LH due to decreased negative feedback of
oestrogen. FSH rises earlier and to a greater extent than LH.
c) Cessation of menstruation: In some women the periods stop abruptly, whereas
in others it may become light and infrequent before it finally ends.

III. Climacteric Symptoms

Symptomatology in the climacteric varies widely among individuals and between
different ethnicities. Symptoms can be so negligible as to pass unnoticed by the woman,
or they can be mild or severe and disabling.

A. Vasomotor symptoms
The most characteristic vasomotor symptoms are the hot flushes and night sweats due
to vasomotor instability. Other vasomotor symptoms include palpitation and dizziness.
Duration and severity of symptoms varies. The mechanism of this vasomotor
instability is uncertain, although oestrogen deficiency is probably responsible.

B. Psychological symptoms
e.g. loss of energy and drive, loss of concentration, irritability, anxiety, depression,
fluctuation in mood, sleep disturbance, etc.
These symptoms can be multifactorial and may be related to the woman’s socio-cultural
background. Vasomotor symptoms may be the cause of irritability and sleep
disturbance. There may also be other reasons causing irritability; she may be
experiencing new crisis and events in life e.g. sickness and death of significant others,
children leaving home, challenges and changes at career, economic problems, etc.,
which may aggravate the symptoms.

C. Sexual dysfunction
Dysparaeunia and decreased libido are common. Dysparaeuia may be due to atrophic
vaginal changes leading to reduced lubrication. The cause can be multifactorial.

D. Urogenital atrophy
The lower urinary and genital tracts share the same embryological origin. Oestrogen
deficiency results in vaginal atrophy; loss of rugae and petechial haemorrhage may be
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evident on examination. There is reduced vaginal and cervical secretions leading to

dryness, dysparaeunia, itchiness and burning. Uterovaginal prolapse may arise due to
atrophy and laxity of the uterine supports. Atrophic changes in the urinary tract
predisposes to irritative urinary symptoms and recurrent urinary tract infection.

IV. Longer term conditions affecting posmenopausal health

A. Cardiovascular disease
Before menopause, cardiovascular disease is less common in women compared to men,
but the incidence of ischaemic heart disease and stroke increases after the menopausal
age. Increased incidence of coronary heart disease can be due to loss of the protective
effect of oestrogen through its influence on the vasculature and lipid profile.

B. Postmenopausal osteoporosis
Oestrogen is antiparathyroid and anticatabolic in bones. Peak bone mass is reached in
Chinese women at around 30-39 years. Bone loss occurs with aging and this loss is
exaggerated after the menopause due to the deprivation of oestrogen, which, through
many mechanisms, can reduce bone resorption and maintains bone mineral density.

Osteoporosis is a skeletal disorder characterised by compromised bone strength

predisposing to an increased risk of fracture. Bone strength primarily reflects the
integration of bone density and bone quality. There are multiple factors, including
genetic, body mass index, age at menopause, environmental, drugs and medical
diseases, which can predispose a woman to the risk of osteoporosis. The most
important clinical consequence is fractures, which has tremendous impact on quality of
life and mortality in the elderly. The FRAX tool can be used to evaluate an individual’s
fracture risk and serves as a guide to clinical management.

C. Musculoskeletal
There is substantial decrease in collagen, resulting in increased laxity of ligaments and
reduced muscular strength. The woman may complain of backache and joint pains.

D. Dementia and cognitive decline

The effect of oestrogen deprivation on dementia and cognition is controversial.

V. Diagnosis
Menopause is a clinical diagnosis. No adequate biological marker exists. Serum
hormonal measurement (raised FSH and low E2) can be supplementary for diagnosing
menopause when it occurs prematurely, in post-hysterectomy women or in women
using hormonal contraception, but a raised FSH per se should not be taken as diagnostic
as it can be observed many years before menopause.

VI. Management
As a result of the increase in the female lifespan, more than 1/3 of a woman’s life is now
postmenopausal. Any measure that will improve her health during this postmenopausal
period warrants very serious consideration. Such therapy will not only improve the well
being of the woman during the climacteric, but it will also reduce considerably the
health care costs of the community, since a large percentage of the female population is
in the postmenopausal age group. To make this period happy and fulfilling, the
distressing symptoms during and after this change of life should be properly managed.

A. Treatment of menopausal symptoms

 It is logical to treat symptoms and health sequelae of the menopause by oestrogen
replacement. However, in view of the potential risks associated with long-term use of
hormone replacement therapy (HRT), it should NOT be used as a universal panacea for
all postmenopausal women.
 HRT is indicated for treatment of severe climacteric symptoms (vasomotor symptoms
and atrophic symptoms) which significantly affect the quality of life for women without
contraindications. Some of the mood symptoms and musculoskeletal symptoms may
also be improved with HRT.
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 For psychological symptoms, it is important also to explore if there are other life events
which may also aggravate the menopausal symptoms, forming a vicious cycle which
may not be dealt with by HRT alone.
 Urogenital atrophic symptoms may be better treated by topical oestrogen which is more
effective and has less systemic effects.
 For vaginal dryness and dysparaeunia, use of lubricants / topical oestrogen may help.

B. Prevention of chronic health conditions in the postmenopause

 Oestrogen has a role in the prevention and treatment of osteoporosis. HRT can prevent
or delay the rate of bone loss. There is evidence from RCT that HRT reduces both
vertebral and non-vertebral fractures.
 There had been some controversies on the association between oestrogen therapy and
cardiovascular disease. Although the Women’s Health Initiative (WHI, 2002) study
suggested an increase in coronary events in users of combined HRT, the subjects
recruited in that study were of relatively older age (mean age 63) and the results may not
be generalizable to the typical use of HRT in the early postmenopausal age. Some
subsequent data showed a benefit of HRT in CHD prevention if administered to women
before 60 years of age and/or within 10 years of menopause (the
“window-of-opportunity” hypothesis).
 In view of the risks associated with long term use, it is now generally accepted that HRT
should NOT be prescribed for the sole purpose of prevention of osteoporosis or other
chronic diseases in the long term.

VI. Hormone Replacement Therapy

1. Types
Natural oestrogens are preferred for such purpose because of less metabolic impact, e.g.
conjugated equine oestrogen (Premarin®), 17ß-oestradiol (Estrofem®).

There are a wide variety of preparations including oral tablets, transdermal patch, gel,
implants and vaginal ring.

2. Hormone Replacement Regimens

a) Oestrogen alone preparations: Only patients with previous hysterectomy can be
given unopposed oestrogen.

b) Combined oestrogen and progestogen preparations: Women with a uterus must

have combined preparations to prevent endometrial stimulation by unopposed
oestrogen.
(i) Sequential (cyclical) regimen: progestogen is added for 12-14 days each
cycle; a scheduled bleeding usually occurs following P withdrawal;
(ii) Continuous combined regimen: continuous daily administration of both
oestrogen and progestogen results in atrophic endometrium and
produces no withdrawal bleeding. Breakthrough bleeding in the early
months may happen, especially in women shortly after menopause who
still have some residual ovarian activity. It is more suitable for women
after 2 years of menopause.

c) Tibolone: a synthetic steroid compound which on absorption is converted to

metabolites with oestrogenic, progestogenic and some androgenic actions. It
treats climacteric symptoms and reduces vertebral and non-vertebral fractures
(same as conventional HRT). Dosage: 2.5 mg daily.

d) Phytoestrogens: evidence is conflicting; little data on the role and safety

regarding long term postmenopausal health are available.

3. Dose: The dose used should be the lowest that can obviate the symptoms. It should be
tailored according to individual needs.
Minimum bone-sparing doses: 17ß-oestradiol (oral) 1-2 mg
17ß-oestradiol (patch) 25-50 mcg
17ß-oestradiol (gel) 1-5 g
Conjugated equine oestrogens 0.3 – 0.625 mg
Oestradiol implant 50 mg Q6 months
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4. Risks of HRT
a) Carcinoma of breast: Most evidence suggested an increased risk of breast
cancer; the risk appeared higher with combined HRT than unopposed oestrogen
b) Venous thromboembolism
Oral HRT is associated with increased risk of venous thromboembolism.
Limited evidence suggested that transdermal oestrogen may be safer in this
regard.
c) Stroke: There is a modest increase in risk of ischaemic stroke with standard
doses of HRT (not haemorrhagic stroke)
d) Gallbladder disease
Oestrogens affects protein and lipid metabolism by hepatocytes, leading to
supersaturation of cholesterol in bile and predispose to cholecystitis and gall
stone formation. Risk is smaller with transdermal HRT.

5. Contraindications to oestrogen replacement therapy

a) Severe liver disease
b) Cerebral vascular disease
c) Deep vein thrombosis and embolism
d) Oestrogen-dependent tumours e.g. breast, uterus
e) Undiagnosed uterine bleeding

6. Starting treatment
The indication for HRT is mainly based on symptoms. Amenorrhoea needs NOT be
awaited before starting HRT. The choice of regimen should depend on the presence of
uterus and time since menopause.

7. Follow-up of women on hormonal therapy

A woman on HRT has to be monitored by the doctor at least once every year.
a) Well women check-up as usual.
b) Measurements will be made on body weight and blood pressure.
c) Side effects: breast tenderness, fluid retention, bloating, nausea, headache,
irregular bleeding. These are usually transient.
d) Bleeding pattern, if any. For breakthrough bleeding: check compliance, GI
upsets and concurrent drug interactions; that occurring in the first 6 months of
treatment should require no immediate intervention.
e) Duration of HRT: There is no universal rule for optimal duration. The general
advice is that the lowest dose should be used for the shortest possible duration
for symptom relief. Can taper off after adequate symptom control, although no
good evidence that it is superior to stopping abruptly. Some symptom
recurrence may occur when HRT is stopped.

VII. Non-hormonal Treatments

A. Menopasual symtoms:
1. Vasomotor symptoms: progestogens, clonidine, antidepressants (e.g. serotonin and
noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors), gabapentin;
relaxation techniques, lifestyle modifications

2. Mood symptoms: psychological counselling and therapy; anti-depressants

3. Vaginal atrophy: lubricants, moisturizers

B. Prevention and treatment of osteoporosis:

1. Lifestyle modifications: adequate calcium intake and vitamin D intake (sun exposure);
weight bearing exercise; avoid smoking, excessive alcohol and caffeine

2. Selective estrogen receptor modulator (SERM) - e.g. raloxifene

Raloxifene has targeted agonist activity in bones; it reduces vertebral but not
non-vertebral fracture. Minor side effects: vasomotor flushes and leg cramps. Not
suitable for symptomatic women. Same risk of venous thromboembolism as HRT.
Reduced risk of breast cancer.
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3. Bisphosphonate: e.g. alendronate, risedronate, etidronate, ibandronate

Inhibits bone resorption, hence effective treatment of osteoporosis; reduces fracture at
vertebral and non-vertebral (not ibandronate) sites.
Main side effect: upper GI tract irritation
Rare but potentially serious concerns: atypical fractures, osteonecrosis of jaw
Must be taken with empty stomach and remain upright for at least 30 minutes.

4. Others: e.g. denosumab

C. Cardiovascular health:
Healthy lifestyle: diet, exercise, avoid smoking
Control of predisposing factors, e.g. hypertension, DM, hyperlipidaemia, obesity

VIII. Premature Ovarian Insufficiency

A. Definition: Premature ovarian insufficiency (POI) refers to the loss of ovarian activity
before the age of 40. It is characterised by menstrual disturbance (amenorrhoea or
oligomenorrhoea) with raised gonadotropins and low oestradiol. Menopause occurring
before the age of 40 is termed “premature”, while that occurring between 40 and 45
years is termed “early menpause”.

B. Aetiology:
 idiopathic
 chromosomal abnormalities e.g. Turner’s syndrome
 autoimmune
 FSH receptor gene polymorphism and inhibin B gene mutations
 Galactosaemia
 Iatrogenic: surgery, chemotherapy, radiotherapy

C. Work-up:
 FSH measurement >25 IU/L x 2 (at least 4 weeks apart)
 Anti-thyroid and anti-adrenal antibodies, anti-nuclear factor
 Chromosomal analysis, Fragile X premutation
 DXA scan

D. Management:
 HRT till age 51. This does NOT increase the risk of breast cancer than general
population. No evidence for the efficacy of SERM or bisphosphonate in this
scenario.
 Fertility: oocyte / embryo donation, adoption
 Contraception if not desiring fertility – sporadic ovulation (resistant ovary
syndrome) can happen

References:
1. Hillard, T, Abernethy K, Hamoda H, Shaw I, Everett M, Ayres J, Currie H. Management
of the menopause, 6th edition. British Menopause Society, 2017.
2. Baber RJ, Panay N, Fenton A; the IMS Writing Group. 2016 IMS Recommendations on
women’s midlife health and menopause hormone therapy. Climacteric 2016; 19(2):
109-150,
3. Stuenkel CA et al. Treatment of Symptoms of the Menopause: An Endocrine Society
Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100: 3975–4011.
4. Menopause: diagnosis and management. NICE guideline 2015.
5. POI Guideline Development Group. Management of women with premature ovarian
Insufficiency. Guideline of the European Society of Human Reproduction and
Embryology, 2015.

Dr. R. Li
April 2021