Menopause

Amenorrhoea for 12 months after final menses.
The permanent cessation of the primary functions of the human ovariesj by definition, begins 12 months after the final menses.
Characterized by a continuation of vasomotor symptoms and by urogenital symptoms such as vaginal dryness and dyspareunia.

Climacteric- the period of this transition to the early postmenopausal phase of a woman's reproductive life cycle.
Perimenopause refers to the time before menopause when vasomotor symptoms and irregular menses often commence. Perimenopause can start 5-10 years or more before menopause.

Epidemiology


Mean age of menopause: 51 years (has not changed since antiquity)
Length of time spent in menopause has increased: up to one third of life, as expected age is around 79

Risk factors (factors that lower the age of physiologic menopause) include
  • smoking,
  • hysterectomy,
  • Fragile X carrier,
  • autoimmune disorders,
  • living at high altitude,
  • history of certain chemotherapy medications and/or radiation treatment.


Pathophysiology


Sequence leading to menopause:
  • From the age of 40 (+ 5), a woman's ovaries becoem less receptive to the effects of follicle-stimulating homrone and luteinizing hormone. Either because the number of receptor-binding sites on each follicle is decreasing, or because increasing numbers of follicles are disappearing.
  • The negative feedback to the hypothalamus and pituitary gland is less effective, with the result that FSH levels begins to rise. The release of FSH levels is also increased by the falling levels of inhibin secreted by the ovarian follicles.
  • Oestrogen secretion declines and fluctuates- the fluctuations are a major factor in causing the menstrual disturbances that occur in soem women in tye years preceding the menopause.
  • Anovulation becomes more frequent.
  • Gonadotrophins persist from immediate post-menopause

Menopause results from:
  • Follicular decline and dysfunction (ie shortened follicular phase in which less recruitment of oocytes occurs, constant luteal phase), directly related to external image Menopause.gif
  • Loss of ovarian sensitivity to gonadotropin stimulation, causing increased circulating levels of FSH and LH (FSH level rise more than the LH level because of the reduced renal clearance of FSH compared with LH), leading to
  • Stromal stimulation of the ovary, with resultant increase in estrone levels and decrease in estradiol levels. Dramatic decrease in circulating ESTROGEN levels. Without a follicular source, the larger
    proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation. This extragonadal production of oestrogen is unopposed by progesterone production by corpus luteum. Thus some perimenopausal women are exposed to unopposed estrogen for long periods, which can lead to endometrial hyperplasia, a precursor for endometrial cancer.
  • Dropped inhibin levels due to negative feedback of elevated FSH levels.


Perimenopause:
  • Variable menstrual cycle length, can be due to anovulation or to irregular maturation of follicles.
  • Irregular bleeding, due to hormonal fluctuation and also pelvic pathologies, which are more prevalent during this time (e.g. uterine fibroids, tuerine polyps, endometrial hyperplasia, endometrial cancer)
  • Shorter menstrual cycle length (for women WITHOUT pelvic pathology and continue to be ovulatory) due to shortened follicular phase.

Signs and Symptoms


Climateric syndrome- several symptoms that are collecively termed the climbateric syndrome.
It is the Irregular Ovarian Function and considerable Estrogen Level Fluctuation (NOT deficiency of estrogen) cause climateric symptoms during menopause.
external image menopause.gif

Climateric changes
  • hot flushes (75% women), insomnia, weight gain and bloating, irregular menses, mastodynia, and headache.
The vasomotor flush is described as a feeling of warmth or heat that begins from the umbilical area and moves
upward toward the head, followed by sweating of the head and upper body. May be associated with major sleep
disturbances, cognitive or affective disorders from sleep deprivation. Other cardiovasulcar or neurologic symptoms
include palpitations, dizziness, light-headedness and vertigo.
  • vaginal dryness, often with 'burning' sensations.

Duration of symptoms is widely variable; symptoms may begin during perimenopause and continue for 5-10 years
after menopause.

Post-menopausal changes
  • Atrophy of the ovaries, Fallopian tubes, uterus; atrophy of external genitals with labia major losing their fat, revealing the labia minora.
  • Pelvic organs On V/E,
    • Vaginal epithelium is redder due to thinning of the epithelial layer from loss of estrogen, and increased visibility of the small capillaries below the surface. Later, pale appearance on V/E as vaginal epithelium further atrophies and there is reduced number of capillaries.
    • Malodorous discharge (and/or pruritus) may result from decreased in urine pH, ie leading to change in bacterial flora
    • Rugation also diminishes, and vaginal wall becomes smooth. (May lead to insertional dyspareunia and eventually sexual abstinence if left untreated.)
    • Uterus becomes smaller. Ovaries should NOT be palpated- full evaluation is warranted for postmenopausal women with palpable ovaries.
    • General loss of pelvic tone may manifest as prolapse of reproductive or urinary tract organs. Vaginal pressure, lower back pressure, or bulging at hte vaginal introitus is common in women with prolapse. Cystocele, rectocele adn uterine prolapse may be evident O/E.
    • Permanent pain relief may be established with pelvic pain from endometriosis, adenomyosis. Fibroids, if present, also become less symptomatic.
  • Bone mineral denstiy (BMD) declines- Osteoporosis risks
  • Skin loses elasticity; dense breast tissue is replaced by adipose tissue (ie mammographic evaluation is easier)
  • IHD risks- Post-menopausal women are at greater risk of ischaemic heart disease

Investigations




FSH >40IU/L. Elevated FSH level is the clinical indication that menopause has occurred. If borderline in perimenopausal, measure again after 2-3 months.

Bone density by dual-energy x-ray absorptiometry (DXA)
Endometrial sampling to exclude pelvic pathology such as endometrial cancer
  • EMB (endometrial biopsy) or
  • D&C (dilatation and curettage)

Management


Aim is to stop hormone fluctuation, manage bone health and cardiovascular health, screen for endometrial and breast cancers.
Explain changes, recommend regular exercise/nutrition/diet, discuss HRT (oestrogen and progestogen) in earlier stages
  • Oral Contraceptive Pills (OCPs)
  • Hormone Therapy (HT)
    • Tibolone (synthetic steroid with weak oestrogenic, progestogenic, androgenic effects)
    • Selective oestrogen receptor modulators SERMs e.g. tamoxifen, raloxifene are used for chemotherapy for breast cancer.
  • Other therapies:
    • Raloxifene, a SERM (selective estrogen receptor modulator) which acts directly on estrogen receiptors in the bone to decrease resorption. Results in reduced vertebral fractures and increased BMD.
    • Calcitonin, a peptide hormone which acts by inhibiting osteoclasts. Results in decreased vertebral fractures, wtih small increased in BMD in older women. Must monitor serum calcium levels in patients taking this drug.
    • Bisphosphonates, work as antiresorptives. Beneficial effect on vertebral and hip fracture rates, cause a more significant increase in BMD than the two medications above. E.g. alendronate, risedronate for daily dosing. Ibandronate (newer bisphosphonate) is approved by monthly use. S/E: GORD. ie do not use in patients with significant GORD unless approved by gastroenterologist.
  • Calcium supplementation with 1000-1500mg of calcium per day. Mainstay of prevention therapy
  • Vitamin D supplementation
  • Weight-bearing exercise
  • Avoid excessive salt, animal protein, alcohol and caffeine.

Hormone Replacement Therapy


Benefits of small doses of daily oestrogen:
2 Major:
  • Relieve the flushes and vaginal symptoms
  • Prevent bone loss and delay onset of osteoporosis
2 Minor:
  • Improve thickness of skin, reduce wrinkles, make the skin less dry
  • induce feeling of wellbeing
Risks:
  • Increased risk of breast cancer in long-term users of combined oestrogen and progestogen (ie use NO longer than 5 years; risk returned following cessation of therapy; oestrogen therapy alone carries less risk)
  • Increased risk of endometrial carcinoma (from 1 per 1000 to 3-4 per 1000)
C/I:
  • recent thromboembolism
  • acute or chronic liver disease
  • undiagnosed uterine bleeding
  • some diabetics (may require careful monitoring)

Treatment regime options:
  • daily oestrogen tablet / third daily oestrogen transdermal patch / oestrogenic vaginal ring / 6 monthly oestradiol implant (those with hysterectomy)
  • progestogen for women who have retained their uterus (take combined, as cessation of progestogen may cause 'withdrawal bleeding')
  • oestrogen pessaries ro cream for atrophic vaginitis
  • e.g. one treatment regimen is to comebine oestrogen, to decrease hot flushes, with a SERM to improve bone and protect against breast adn endometrial cancers.



external image Menstrual%20Cycle.jpg
external image Menstrual%20Cycle.jpg




Menstrual Changes

Differential Diagnosis



Menstrual Irregularity
  • PCOS
  • Vaginal and Uterus atrophy
  • Hormonal imbalance ie ovulation blocked by: hyper/hypothyroidism, high PRL
  • Medications e.g. psychiatric, seizure drugs, OCT
  • Eating disorders and severe exercise

Regular Heavy Menstrual Bleeding
  • Fibroids
  • Polyps
  • Cystic lesions
  • Endometrial hyperplasia
  • von Willabrand's disease

Lack of Menstrual Bleeding
  • Anovulation
  • Low E2
  • Uterus abnormalities e.g. Asherman's syndrome, prolactinoma



PMS



Defined as symptoms of concern occurring cyclical just before menses and resolves with the onset of menses.

Epidemiology
A symptom-free week after menses is an essential diagnostic feature.
95% of women of reproductive age exprerience some physiologycal symptoms premenstrually. 5% are affected.
Typical presentation at 30-40 years.

Pathophysiology
Rapidly declining levels of progesterone (or the progesterone/oestrogen ratio) in the luteal phase of the cycle.
Condition resolves after menopause

Signs and symptoms
Psychological:
affective liability (tearfulness, irritability, anger)
anxiety or tension
depression
loss of interest, difficulty, concentrating, lack of energy, sleep disturbance, appetite disturbance.

Physical:
breast tenderness
fluid retention and weight gain
headahces
aching joints

Treatment
  • Cognitive behavioural therapy (mapping graph of premenstrual symptoms)
  • SSRI, GnRH (medical oophorectomy, controversial)
  • other include evening primose oil which provides linoleic and gamolenic acids, precursors of prostaglandin E or progestrogens
COCP, cotinuous progesrogens, pyridoxine (vitamin B6), NSAIDs, calcium or magnesium
Specific treatment: spironolactone for fluid retention, bromocripting or evening primose oil for breast tenderness.

Dysmenorrhoea



Painful menstrual cramps of uterine origins

Epidemiology
Affects 50% of all women; secondary dysmenorrhoea is when there is identifiable pathology such as:
  • endometriosis, adenomyosis, pelvic congestion or pelvic adhesions,
  • mullerian abnormalities, cervical stenosis and gyanacological malignancies.

Primary
starts 2-3 years post-menarche; 15-25 years
pain begins 24 hours prior menstruation
last 24-36 hours; pain associated with Vasopressin

Secondary
usually after 30 years of age
pain beigns 48 hours prior menstruation
last until and peaks at late mensstruction
Ddx: PID, endometriosis

Management
Prostaglandin synthetase inhibitors
  • mefenamic acid
  • ibuprofen
  • diclofenac sodium
  • naproxen

Amenorrhoea


Secondary amenorrhoea may be physiological (thin, stress ie put on pill to assit with bones and increase appetite) or pathological

Causes
Brain- prolactinoma
Ovaries- PCOS, resistant ovary syndrome, premature menopause
Uterus- Asherman's syndrome