Menopause and its Management

Menopause is a retrospective diagnosis of the time when menstruation permanently ceases. It can only be defined with certainty after twelve months' spontaneous amenorrhoea. The climacteric is the period of change leading up to menopause. At a hormonal level - as ovarian follicular activity begins to fail, oestrogen and progesterone levels fall and the reduced negative feedback to the pituitary causes a rise in luteinising hormone (LH) and follicle stimulating hormone (FSH). Oestrogen reduction eventually results in menstrual cycle disruption and other menopausal symptoms.

Premature menopause (occurring before the age of 40) can occur in primary ovarian failure, surgically-induced menopause (hysterectomy with or without bilateral oophorectomy), radiation-induced menopause and chemotherapy-induced menopause.

• Early menopause is known as the menopausal transition stage or perimenopause, and usually begins when women are in their mid to late 40s. The final menstrual period (FMP) usually occurs between the ages of 40 and 58. Average age of menopause in the UK is 51.
• Population studies identify smoking and low socio-economic factors as being associated with premature menopause. Other factors that can affect the age at which women have their final period include age at menarche, parity, previous oral contraceptive history, BMI, ethnicity, family history, and a history of breast surgery.²
• A recent meta-analysis suggests that in an average woman, vasomotor symptoms increase from 2 years prior to the FMP, peak at 1 year following it and return to normal after 8 years. However, there is considerable variation between individual women.³
• Most women do not seek medical advice for menopausal symptoms. Variations in consultation patterns for menopause depend on many factors, including cultural and educational differences as well as psychosocial difficulties.

Epidemiological studies have identified only vasomotor dysfunction and vaginal dryness as being consistent with the menopausal phase. Other common symptoms, such as mood changes, sleep disturbances, urinary incontinence, cognitive changes, somatic complaints, sexual dysfunction and reduced quality of life, may be secondary to other causes.¹

Menstrual irregularity

• The majority of women notice irregularities to the menstrual cycle, which may last up to four years.
• The cycle may lengthen to many months or shorten to 2-3 weeks.
• A slight increase in the amount of menstrual blood loss is common.
• For some women, 3 consecutive months of amenorrhoea, or mean cycle lengths longer than 42 days, are predictors of impending menopause.¹
• Approximately 10% of women have an abrupt cessation of periods.⁴

Hot flushes and sweats

• These are hallmark symptoms. Hot flushes commonly affect the face, head, neck and chest, and last for a few minutes.
• Research into the cause of hot flushes has been hampered by the inability to make objective assessments, but is currently looking at genetic differences in the production of endogenous oestrogen and its handling at cellular level.

Sleep disturbance

• This is a common subjective symptom reported by women but not confirmed by polysomnography.⁵
• Symptoms may be affected by psychosocial factors, and may contribute to depression, irritability and poor concentration.

Urinary and vaginal symptoms

• These may include dyspareunia, vaginal discomfort and dryness, recurrent lower urinary tract infection and urinary incontinence.
• Vaginal discomfort is clearly linked to low oestrogen levels, but the association with urinary incontinence is less evidence-based. Further research is required to assess the effectiveness of hormone replacement in such cases.⁶

Mood changes

• These may include anxiety, nervousness, irritability, memory loss, depression and difficulty concentrating.⁴
• One study suggested a tendency to develop psychological symptoms may be linked to factors such as level of education, high BMI and low physical activity.⁷

Loss of libido

• This can be caused by a number of hormonal factors, and oestrogen, progesterone and testosterone have all been implicated.
• Vaginal dryness, performance of an ageing partner, loss of self-image and other psychosocial factors also play a part.

Other changes

These may include brittle nails, thinning of the skin, hair loss and generalised aches and pains. These are thought to be due to falling oestrogen levels.^4,8

The diagnosis will usually be obvious from the clinical picture but may be difficult in younger women in the early stages of the menopause.
Other causes of secondary amenorrhoea, such as pregnancy and hypogonadotrophic hypogonadism, may need to be considered.

Investigations are of limited value.

• FSH levels
  • These vary markedly during the perimenopause and single measures are unreliable. FSH levels may be helpful in confirming the menopause in later stages.
  • Women with suspected premature menopause (symptoms under the age of 40) or following a hysterectomy with ovarian conservation, should have serial FSH levels taken because of the implications of premature ovarian failure.
  • Levels should be tested when the woman is not taking oestrogen-based contraception or hormone replacement therapy (HRT).
  • FSH levels of greater than 30 IU/L are generally considered to be in the postmenopausal range, and should be repeated in 4-8 weeks to confirm this.
  • Levels above 12 IU/L are considered to be raised in women still having menstrual bleeds.⁴
• LH, estradiol and progesterone levels
  These are generally unhelpful in clinical practice.
• Thyroid function tests
  Thyroid-stimulating hormone (TSH) and free thyroxine (T4) are sometimes used to differentiate thyroid disease symptoms from menopausal symptoms, and may be particularly helpful if there is inadequate response to HRT.

The relationship between the menopause and the development of associated conditions is sometimes difficult to differentiate from age-related morbidity, but is best demonstrated in cases of premature primary and secondary ovarian failure.

• Cardiovascular disease - including coronary artery disease, stroke and peripheral vascular disease, is thought to be related to vascular endothelial dysfunction related to oestrogen deficiency.⁹
• Osteoporosis - the link of osteoporosis with oestrogen deficiency is well documented. The risk of developing post-menopausal osteoporosis is thought to be genetically driven, which may explain the variable response to HRT in some women.
• Urogenital atrophy - as outlined above. Symptoms of urogenital atrophy may appear for the first time more than 10 years after the last period.⁴
• Redistribution of body fat - body fat tends to be redistributed around the abdomen with age. This is recognised as being an independent risk factor for cardiovascular disease and diabetes.
• Alzheimer's disease - is two to three times more common in women than men, suggesting a hormonal association, but this is currently under review.¹⁰ There is no good evidence currently that HRT (oestrogen alone or oestrogen and progestogens) prevents cognitive decline in older postmenopausal women when given over the short- or longer-term.¹¹

Options include conservative management (viewing menopause as a normal period of physiological adaptation) to hormone replacement (seeing menopause as analogous to any other hormone deficiency state) or looking for alternative, and sometimes less evidence-based, therapies for tackling troublesome symptoms.

Reassurance, education and lifestyle adjustment

• This may be sufficient for women experiencing mild, short-term symptoms.
• The available literature suggests that vasomotor symptoms (i.e. hot flushes) are associated with smoking and greater body weight.¹² Alcohol may also play a part.¹³
• Physical activity appears to be beneficial,¹ especially in obesity prevention, but its impact on vasomotor symptoms cannot be assessed due to a lack of trials. HRT is undoubtedly more effective.¹⁴

Hormone replacement therapy

See separate article Combined Hormone Contraception and HRT (Risks vs Benefits).
See also separate articles Hormone Replacement Therapy, HRT Initial Consultation, and HRT Follow-up Assessments.

The current evidence base supports the use of the following:

• Oestrogens plus progestogens (for women with an intact uterus).
  Despite the barrage of adverse publicity, HRT is undoubtedly an effective treatment for vasomotor symptoms associated with menopause. It is also thought to be effective in improving urogenital symptoms, sleep disturbance and quality of life. There is less evidence to support their use in the relief of depressive or other psychological symptoms.¹⁵

  The advice from the MHRA is that HRT should only be used for the short-term relief of menopausal symptoms but no single recommendation for optimum duration of treatment or safe upper-age limit for use of HRT is given. For all women, the lowest effective dose should be used for the shortest possible time, with annual review and assessment of any change in the balance of risks and benefits.16

  Increasingly there is interest in the use of lower dose therapies (so-called 'micro-dose oestrogen therapy') which appear effective in reducing hot flushes.¹⁷
  HRT is not currently indicated for long-term use to prevent other diseases. Although HRT is effective in preventing osteoporosis, its beneficial effect swiftly diminishes after stopping treatment.
• Oestrogens alone.
  There is a similar wide evidence base to support the use of unopposed oestrogens for the relief of vasomotor symptoms, urogenital symptoms and for improved quality of life in post-hysterectomised women. Evidence for their use in the relief of psychological symptoms is more equivocal.
  Topical oestrogens are widely used (including in women with an intact uterus) to treat urogenital atrophy.¹⁸
• Tibolone.
  This is a selective oestrogen receptor modulator (SERM) which has oestrogenic, progestogenic and androgenic properties. It improves sexual function¹⁹ and vasomotor symptoms²⁰ but increases the risk of stroke in older women²¹ and, in general, the risks associated with its use outweigh the benefits in the over 60s.²² It also appears to increase the risk of breast cancer recurrence in those with a history of breast cancer.²³
• Progestogens.
  These are not widely used alone, but have been found useful for the treatment of hot flushes.²⁴ Randomised trials do not, however, support their use for the relief of psychological or urogenital symptoms.¹
• Testosterone.
  Testosterone plus HRT appears to improve libido and sexual function compared to HRT alone²⁵ but safety remains to be proven.

Alternative treatments

See separate article HRT - Alternatives.

1. Nelson H; Menopause. Lancet. 2008 Mar 1;371(9614):760-70. Review
2. Hefler LA, Grimm C, Bentz EK et al; A model for predicting age at menopause in white women
3. Politi MC, Schleinitz MD, Col NF; Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. J Gen Intern Med. 2008 Sep;23(9):1507-13. Epub 2008 Jun 3. [abstract]
4. Menopause, Clinical Knowledge Summaries (January 2008)
5. Young T, Rabago D, Zgierska A, et al; Objective and subjective sleep quality in premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep. 2003 Sep;26(6):667-72. [abstract]
6. Van Voorhis BJ; Genitourinary symptoms in the menopausal transition. Am J Med. 2005 Dec 19;118(12 Suppl 2):47-53. [abstract]
7. Di Donato P, Giulini NA, Bacchi Modena A, et al; Factors associated with climacteric symptoms in women around menopause attending menopause clinics in Italy. Maturitas. 2005 Nov-Dec;52(3-4):181-9. [abstract]
8. Hall G, Phillips TJ; Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin. J Am Acad Dermatol. 2005 Oct;53(4):555-68; quiz 569-72. [abstract]
9. Kalantaridou SN, Naka KK, Bechlioulis A, et al; Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement. Trends Endocrinol Metab. 2006 Apr;17(3):101-9. Epub 2006 Mar 3. [abstract]
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11. Lethaby A, Hogervorst E, Richards M, et al; Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003122. [abstract]
12. Daley A, Macarthur C, Stokes-Lampard H, et al; Exercise participation, body mass index, and health-related quality of life in women of menopausal age. Br J Gen Pract. 2007 Feb;57(535):130-5. [abstract]
13. Sievert LL, Obermeyer CM, Price K; Determinants of hot flashes and night sweats. Ann Hum Biol. 2006 Jan-Feb;33(1):4-16. [abstract]
14. Daley A, MacArthur C, Mutrie N, et al; Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD006108. [abstract]
15. Hays J, Ockene JK, Brunner RL, et al; Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003 May 8;348(19):1839-54. Epub 2003 Mar 17. [abstract]
16. Hormone-replacement therapy: safety update - UK Public Assessment Report; MHRA July 2007.
17. Andrews J; Both low-dose and micro-dose 17beta-oestradiol reduced hot flushes. Evid Based Med. 2008 Apr;13(2):43.
18. Pitkin J, Rees M; Urogenital atrophy. Menopause Int. 2008 Sep;14(3):136-7. [abstract]
19. Nathorst-Boos J, Hammar M; Effect on sexual life--a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas. 1997 Jan;26(1):15-20. [abstract]
20. Al-Azzawi F, Wahab M, Habiba M, et al; Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol. 1999 Feb;93(2):258-64. [abstract]
21. Cummings SR, Ettinger B, Delmas PD, et al; The effects of tibolone in older postmenopausal women. N Engl J Med. 2008 Aug 14;359(7):697-708. [abstract]
22. CSM Drug Safety Update Vol 1, Issue 2, Sept 2007
23. Kenemans P, Bundred NJ, Foidart JM, et al; Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol. 2009 Feb;10(2):135-46. Epub 2009 Jan 23. [abstract]
24. Loprinzi CL, Michalak JC, Quella SK, et al; Megestrol acetate for the prevention of hot flashes. N Engl J Med. 1994 Aug 11;331(6):347-52. [abstract]
25. Davis SR, Moreau M, Kroll R, et al; Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008 Nov 6;359(19):2005-17. [abstract]

• Hormone-replacement therapy: safety update - UK Public Assessment Report; MHRA July 2007.
• Utian WH, Archer DF, Bachmann GA, et al; Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause. 2008 Jul-Aug;15(4 Pt 1):584-602. [abstract]
• The British Menopause Society; for healthcare professionals