Menopause and premature ovarian failure

Published on 09/03/2015 by admin

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Chapter 12 Menopause and premature ovarian failure

Michael Flynn

Definitions. Natural menopause is the permanent ceasing of menstruation resulting from the loss of ovarian follicular activity. Menopause is by definition only after 12 months of amenorrhoea with no other pathological cause. Menopause is the final period diagnosed only in retrospect. Perimenopause is the time immediately premenopause, as characterised by endocrinological and clinical features, and continuing until the year postmenopause. Premature menopause occurs at an age <2 standard deviations from the community mean. In practice, this is menopause prior to the age of 40. The average age of menopause is 50–51 years.

Aetiology

Menopause is due to the exhaustion of primordial follicles, causing a fall in oestrogen and progesterone levels.

Endocrinology in the climacteric and menopause

Three phases of endocrine changes

• hypothalamic–pituitary hyperactivity occurring years before and continuing after menopause
• ovulatory failure
• ovarian follicular failure

Initial changes in ovarian function are due to a failure in ovulation and a deficient luteal phase. Following this is a reduction in serum oestradiol and a rise in follicle-stimulating hormone (FSH) due to the negative hormonal feedback. Rises in luteinising hormone (LH) occur later, but these are not as marked as the rise in FSH. Follicular development and menstrual cycles then become irregular. At menopause, insufficient ovarian follicular development results in insufficient oestrogen to cause endometrial growth. In the postmenopausal state, oestradiol decreases with a normal or slightly raised level of oestrone.

Gonadotrophins after the menopause

• Maximal rises in FSH and LH occur in the first 2–3 years.
• After 20 years, FSH and LH may return to reproductive life levels.

Oestrogens

• Postmenopausal oestrogen sources are derived from the peripheral conversion of androstenedione (produced by the adrenals and ovaries) to oestrone.
• Aromatisation of androstenedione occurs at peripheral sites.

Androgens

• Ovaries continue to secrete androgens: androstenedione and testosterone.

Progesterone

• Levels are lower than premenopausal levels.

Others

• Prolactin levels decrease.
• Inhibin has a specific negative feedback control on FSH and levels are reduced.

Clinical features of menopause

Generally, clinical features are the best guide to menopause: 10%–20% have no symptoms; 60% have mild to moderate symptoms; and 10%–20% have severe symptoms. While vasomotor symptoms predominate, they are not necessary and symptoms are variable. Symptoms are relieved by oestrogen.

Vasomotor symptoms

• A hot flush lasts between 1 and 4 minutes and is associated with a rise in temperature, peripheral vasodilatation and a slight rise in pulse rate.
• There is a possible association with rising and falling oestrogen levels.
• Hot flushes are synchronous with, but are not caused by, LH pulses.
• Up to 50%–80% of women suffer from vasomotor effects at the menopause and climacteric, and 20%–25% of these women continue to have symptoms after 5 years.
• Symptoms include intense heat, flushing and sweating.

Genital and urinary tract symptoms

• Urogenital atrophy results in reduced glycogen and lactobacilli, causing a rise in vaginal pH, dryness and increased risk of infection.
• Vaginal dryness and dyspareunia due to atrophy respond to oestrogen.
• Oestrogen also reduces irritative urinary symptoms and urinary tract infections.
• There is decreased libido.

Psychological changes

• Anxiety, depression, insomnia and irritability may be reduced with oestrogen.

Skin, bone and joint changes

• Formication (or sensation of crawling under the skin) may be present.
• In the long term, there may be osteoporosis and associated complications.
• There may be joint and muscle aches.

Concentration and memory

• Perimenopausal changes in short-term memory are reported.

Premature ovarian failure

Incidence. Incidence is 1%. It is associated with primary amenorrhoea in 10%–30% of cases.

Embryology

Development of oocytes

• Primordial follicles/ovary develop from the gonadal ridge and germ cells migrate there from the primitive endoderm of the yolk sac during the fifth week of embryonic life.
• The 8-week-old embryo has 60,000 germ cells; the 20-week fetus has 6–7 million follicles. At menarche there are 300,000–400,000 follicles.
• Two X chromosomes are needed for definitive ovaries to develop.

Oocyte

• The oocyte commences meiosis, but arrests in the diplotene phase of prophase.
• The primary oocytes, which are surrounded by granulosa cells, are the primordial follicles.
• The first meiotic division is completed at the time of ovulation with the extrusion of the first polar body.

Causes of premature ovarian failure

Genetic

Chromosomal

• Turner’s syndrome 45XO; 45XO/XX
• pure gonadal dysgenesis 46XX, 46XY
• trisomy: 13 and 18, 47XXX
• deletions/inversions
• familial

Metabolic

• 17-hydroxylase deficiency, galactosaemia, myotonic dystrophy

Autoimmune

• thyroid disease: Hashimoto’s disease, Graves’ disease, hypothyroidism, thyroiditis, silent thyrotoxicosis
• Addison’s disease
• others: myasthenia gravis, hypoparathyroidism, autoimmune haemolytic anaemia/thrombocytopenia, pernicious anaemia

Infectious

• mumps (the commonest)
• tuberculosis

Environmental

• smoking (there is a dose-related effect of smoking on age of menopause)
• increasing parity
• poor health and nutrition

Iatrogenic

• irradiation, chemotherapy (methotrexate, actinomycin)
• posthysterectomy (ovarian failure may be advanced by 6 years)

Idiopathic

Pathophysiology

• Ovarian biopsy shows a reduced number of preantral follicles. The lack of gonadotrophin receptors may be the underlying cause of premature ovarian failure, because follicles require gonadotrophins and gonadotrophic receptors to develop beyond the preantral stage.
• Resistant ovary syndrome may be an early stage of premature ovarian failure. It implies decreased sensitivity of gonadotrophin receptors or a defect in the adenyl cyclase system.

Diagnosis of premature ovarian failure

Diagnosis is based on a triad of amenorrhoea, raised gonadotrophins and signs/symptoms of oestrogen deficiency.

• age <40 years
• primary or secondary amenorrhoea
• FSH levels of >15 IU/L indicating perimenopausal levels
• hot flush and genital atrophy present in 50% of cases

Examination and investigations

Examination

• stigmata of Turner’s syndrome
• secondary sexual characteristics
• body mass index, blood pressure, thyroid
• signs of hypo-oestrogenism

Investigations

• to exclude pregnancy as a cause of amenorrhoea
• gonadotrophin levels
• FSH of >40 IU/L diagnostic
• repeat if results borderline (e.g. three assays at 2–4-week intervals)
• karyotype (required for all patients with primary amenorrhoea and early-onset premature ovarian failure)
• adrenals/thyroid function
• adrenals: dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone
• thyroid: thyroid-stimulating hormone, antithyroid antibodies
• autoimmune tests

Consequences and their management

Treat the underlying disease, such as an autoimmune disorder. Consequences:

• short-term: vasomotor symptoms, vaginal dryness, stress incontinence, psychological effects
• long-term: infertility, osteoporosis, cardiovascular effects

Managing infertility

• Pregnancy is possible with follicular forms of ovarian failure and resistant ovary.
• Low-dose hormone replacement therapy may stimulate the development of ovarian FSH receptors.
• Other options are in vitro fertilisation using donor eggs or adoption.
• Psychological support is very important.

Further reading

Van Kastern Y.M., Schoemaker J. Premature ovarian failure: a systemic review of therapeutic interventions to restore ovarian function and achieve pregnancy. Human Reproduction Update. 1999;5:483-492.

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