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Menopause And Its Management 

Menopause And Its Management

 

 
 
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Published:  September 03, 2010
 
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Slide 1: Menopause and its Management The menopause may be defined as the time when menstruation permanently ceases. It can only be defined with certainty after twelve months' of spontaneous amenorrhoea. 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, surgical -induced menopause (hysterectomy with or without bilateral oophorectomy), radiation-induced menopause and chemotherapy-induced menopause. Studies measuring the menopausal symptoms have led to attempts to classify substages of the menopause and seven such stages have been identified. To date, these classifications have been of more theoretical than practical benefit and currently it is sufficient to consider three main categories of patient - premenopausal, menopausal and post-menopausal. Epidemiology1 Early menopause is known as the menopausal transition stage and usually begins when women are in their mid to late 40s. The final menstrual period usually occurs between the ages of 40 and 58. Population studies identify smoking and low socioeconomic factors2 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, parity, and a history of breast surgery.3 Large surveys done in different countries indicate a global variation and can range from 47-52. Presentation Many women do not seek medical advice for menopausal symptoms. Studies of those that do suggest that such women are characterised by greater psychiatric morbidity, a lower level of diffused social support, social dissatisfaction and a greater frequency of severe life events. There are also considerable ethnic differences in presenting symptoms.4 One large American study found that nervousness, memory loss, vaginal dryness, loss of sexual interest and night sweats were more prevalent in white women, whilst painful sex and hot flushes were more prevalent in African American women.5 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 symptoms or causes.1
Slide 2: • • • • • • • 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.6 Hot flushes and sweats (including night 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 ability to make objective assessments,7 but is currently centred on the genetic factors8 controlling the production of endogenous oestrogen and its handling at cellular level.9 Sleep disturbance - is a common subjective symptom reported by women but not confirmed by polysomnography.10 Symptoms may be affected by psychosocial factors, and may contribute to depression, irritability and poor concentration.11 Urinary and vaginal symptoms - 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.12 Mood changes - may include anxiety, nervousness, irritability, memory loss, depression, and difficulty concentrating.6 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.13 Loss of libido - this can be caused by a number of hormonal factors, and oestrogen, progesterone and testosterone have all been implicated.14 Vaginal dryness, performance of an ageing partner, loss of self-image and other psychosocial factors also play a part.15 Other changes - this 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.6,16,17 Differential diagnosis The diagnosis will usually be obvious from the clinical picture but may be difficult in younger women in the early stages of the menopause (also known as the perimenopause). Other causes of secondary amenorrhoea such as pregnancy, and hypogonadotrophic hypogonadism18 may need to be considered. Investigations Investigations are of limited value. • Follicle-stimulating hormone (FSH) levels - these vary markedly during the perimenopause, but may he helpful in confirming the menopause in later stages. However, in women with suspected premature menopause (symptoms under the age of 40) or those who have had a hysterectomy with
Slide 3: • • ovarian conservation, serial FSH levels should be taken because of the implications of premature ovarian failure. Levels should be tested when the woman is not taking oestrogen-based contraception or 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.6 Luteinising hormone (LH) , oestradiol and progesterone levels - are generally unhelpful in clinical practice, although LH levels are occasionally contributory in the perimenopause. 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 hormone replacement therapy (HRT). Associated diseases 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 - includes coronary artery disease, stroke and peripheral vascular disease, and is thought to be related to vascular endothelial dysfunction related to oestrogen deficiency. 19 Osteoporosis - the link with oestrogen deficiency is well documented.20 The risk of developing post-menopausal osteoporosis is thought to be genetically driven, which may explain the variable response to HRT in some women.21 Urogenital atrophy - as outlined above. Symptoms of urogenital atrophy may appear for the first time more than 10 years after the last period.6 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.22 Alzheimer's Disease - is two to three times commoner in women than men, suggesting a hormonal association, but this is currently under review.23 Management 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.24 Alcohol may also play a part.25 There is some evidence that fat restriction is beneficial.26 Physical activity appears to be beneficial,1 especially in obesity prevention.27 Alternative and complementary therapies1 Trials involving non-prescribed medications are difficult to interpret due to variabilities in formulation and doses. Soy isoflavine extracts may have some effect on reducing hot sweats, but there is no evidence to support the use of dietary soy.. Alternative therapies are not without adverse effects: black cohosh is thought to
Slide 4: reduce hot flushes by one flush per day but has been reported to be associated with liver damage. There is no evidence to support the use of aerobic exercise, reflexology or magnets. Trials using acupuncture for the treatment of hot flushes were equivocal. Non-hormonal therapies These have principally been tried for the management of hot flushes. A systematic review of SSRIs, clonidine and gabapentin suggests that there is evidence for efficacy, but most trials have methodological deficiencies, and adverse effects and cost may restrict use for many women. They may be indicated for highly symptomatic women where oestrogen is contraindicated.1,28 Clonidine is thought to reduce hot flushes by reducing peripheral vasoreactivity. 50% of trials showed a significant event and 50% did not. On balance the evidence suggests that clonidine reduces hot flushes by one flush per day. 1 HRT Benefits The advice issued by the Committee on Safety of Medicines (CSM) in 2002, which remains current, is that HRT should only be used for the short-term relief of menopausal symptoms29 (see Risks, below). The current evidence base supports the use of the following: • • • • Progestogens. These are not widely used alone, but have been found useful for the treatment of hot flushes.30 Randomised trials do not however support their use for the relief of psychological or urogenital symptoms.1 Oestrogens plus progestogens (for women with an intact uterus). A wide evidence base confirms their benefits in the relief of vasomotor symptoms,31 urogenital symptoms,32 sleep disturbance,33 and quality of life.34 There is less evidence to support their use in the relief of depressive or other psychological symptoms.33 Oestrogens alone (for post-hysterectomised women). There is a similar wide evidence base to support the use of unopposed oestrogens for the relief of vasomotor symptoms,35 urogenital symptoms,36 and quality of life.37 Evidence for their use in the relief of psychological symptoms is more equivocal.38 Tibolone - is a selective oestrogen receptor modulator (SERM) which has oestrogenic, progestogenic and androgenic properties. Randomised controlled trials suggest it may be a useful in improving sexual function39 and vasomotor symptoms.40 Risks The press release issued by the CSM in 200229 was based on data from several sources, including the Women's Health Initiative (WHI) study,41 the Women's Health Initiative Memory Study (WHIMS),42 and the UK Million Women Study.43,44 The consensus view arising from these studies was that HRT should no longer be used
Slide 5: for the long-term prevention of menopause-associated diseases. However, the situation remains under review.The average age of women in the WHI study was 63.3 years,44 and the opinion of some authorities is that further research is required to clarify the relevance of the findings to all women.45 The current guidance is as follows: • • • • • • • Progestogens - randomised trials have not reported any risks although the Royal College of Obstetrics and Gynaecology advises that progestogens should be avoided in patients with progesterone-dependent tumours such as breast carcinomas.46 Oestrogens plus progestogens and oestrogen alone. The WHI study found an increase from 30 to 37 cases per 10,000 women in coronary heart disease. It also found that the incidence of stroke increased from 21 to 29 cases per 10,000 women, and that the incidence of breast cancer increased from 21 to 29 cases per 10,000 women.41 A recent study found that HRT use in postmenopausal women at high risk of breast cancer (those with a BRCA1 mutation) , HT was not associated with increased risk of breast cancer, and may even decrease the risk.47 This study requires further evaluation. The UK Million Women study confirmed the increased risk of endometrial cancer with unopposed oestrogen and that this was substantially reduced by the addition of a progestogen.44 There appears to be a small but increased risk of ovarian cancer in patients taking sequential HRT for more than ten years.48 Contrary to previous studies, the WHIM study found that cognitive function deteriorated rather than improved in women given combined HRT over the age of 65. The findings were similar for women on oestrogen-only therapy. 49 The CSM acknowledged in their advice that there was a reduction in colon cancer and hip fracture, that the absolute risks were small, that the overall rates of death and all cancers were not increased by combined HRT, and that the situation should be kept under constant review.29 They also confirmed that continuous combined HRT should only be indicated for non-hysterectomised women who were at least 12 months postmenopausal, and that peri-menopausal women should generally be treated with sequential or cyclical combined HRT. Only hysterectomised women should receive oestrogen-only HRT.41 Tibolone. The UK Million women study found a 1.5 increased risk of breast cancer, and a further study using a general practice data base found that the risk of developing endometrial cancer was double that of women using sequential combined HRT.50 The risk of thromboembolic events needs further evaluation. Document references 1. Nelson H; Menopause. Lancet. 2008 Mar 1;371(9614):760-70. Review 2. Ayatollahi SM, Ghaem H, Ayatollahi SA; Sociodemographic factors and age at natural menopause in Shiraz, Islamic Republic of Iran. East Mediterr Health J. 2005 Jan-Mar;11(1-2):146-54. [abstract] 3. Hefler LA, Grimm C, Bentz EK et al; A model for predicting age at menopause in white women
Slide 6: 4. Montero I, Ruiz I, Hernandez I; Social functioning as a significant factor in women's help-seeking behaviour during the climacteric period. Soc Psychiatry Psychiatr Epidemiol. 1993 Aug;28(4):178-83. [abstract] 5. Xu J, Bartoces M, Neale AV, et al; Natural history of menopause symptoms in primary care patients: a MetroNet study. J Am Board Fam Pract. 2005 SepOct;18(5):374-82. [abstract] 6. Menopause, Clinical Knowledge Summaries (January 2008) 7. Miller HG, Li RM; Measuring hot flashes: summary of a National Institutes of Health workshop. Mayo Clin Proc. 2004 Jun;79(6):777-81. [abstract] 8. Takeo C, Negishi E, Nakajima A, et al; Association of cytosine-adenine repeat polymorphism of the estrogen receptor-beta gene with menopausal symptoms. Gend Med. 2005 Jun;2(2):96-105. [abstract] 9. Malacara JM, Perez-Luque EL, Martinez-Garza S, et al; The relationship of estrogen receptor-alpha polymorphism with symptoms and other characteristics in post-menopausal women. Maturitas. 2004 Oct 15;49(2):1639. [abstract] 10. 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] 11. O'Connell E; Mood, energy, cognition, and physical complaints: a mind/body approach to symptom management during the climacteric. J Obstet Gynecol Neonatal Nurs. 2005 Mar-Apr;34(2):274-9. [abstract] 12. Van Voorhis BJ; Genitourinary symptoms in the menopausal transition. Am J Med. 2005 Dec 19;118(12 Suppl 2):47-53. [abstract] 13. 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] 14. Gregersen N, Hilmand CB, Jensen PT, et al; Sexual dysfunction in the menopause. Incidence, pharmacological treatment and side effects. Ugeskr Laeger. 2006 Feb 6;168(6):559-63. [abstract] 15. Pearce MJ, Hawton K; Psychological and sexual aspects of the menopause and HRT. Baillieres Clin Obstet Gynaecol. 1996 Sep;10(3):385-99. [abstract] 16. 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] 17. Chaopotong P, Titapant V, Boriboonhirunsarn D; Menopausal symptoms and knowledge towards daily life and hormone replacement therapy among menopausal women in Bangkok. J Med Assoc Thai. 2005 Dec;88(12):176874. [abstract] 18. Bielak K, Harris G; Amenorrhoea, eMedicine, May 2008. 19. 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] 20. Beck-Peccoz P, Persani L; Premature ovarian failure. Orphanet J Rare Dis. 2006 Apr 6;1(1):9. [abstract] 21. Kung AW, Lai BM, Ng MY, et al; T-1213C polymorphism of estrogen receptor beta is associated with low bone mineral density and osteoporotic fractures. Bone. 2006 Jun 12. [abstract]
Slide 7: 22. Despres JP; Intra-abdominal obesity: an untreated risk factor for Type 2 diabetes and cardiovascular disease. J Endocrinol Invest. 2006;29(3 Suppl):77-82. [abstract] 23. Markou A, Duka T, Prelevic GM; Estrogens and brain function. Hormones (Athens). 2005 Jan-Mar;4(1):9-17. [abstract] 24. Greendale GA, Gold EB; Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side effects of hormone therapy? Am J Med. 2005 Dec 19;118(12 Suppl 2):148-54. [abstract] 25. Sievert LL, Obermeyer CM, Price K; Determinants of hot flashes and night sweats. Ann Hum Biol. 2006 Jan-Feb;33(1):4-16. [abstract] 26. Clapauch R, Athayde A, Meirelles RM, et al; Hormonal therapy of menopause: 2004 position of the Department of Female Endocrinology and Andrology of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2005 Jun;49(3):449-54. Epub 2006 Mar 16. [abstract] 27. Simkin-Silverman LR, Wing RR, Boraz MA, et al; Lifestyle intervention can prevent weight gain during menopause: results from a 5-year randomized clinical trial. Ann Behav Med. 2003 Dec;26(3):212-20. [abstract] 28. Nelson HD, Vesco KK, Haney E, et al; Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006 May 3;295(17):2057-71. [abstract] 29. MHRA; Risks and Benefits of HRT 2002. 30. 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] 31. Maclennan AH, Broadbent JL, Lester S, et al; Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002978. [abstract] 32. Hickey M, Davis SR, Sturdee DW; Treatment of menopausal symptoms: what shall we do now? Lancet. 2005 Jul 30-Aug 5;366(9483):409-21. [abstract] 33. 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] 34. Hilditch JR, Lewis J, Ross AH, et al; A comparison of the effects of oral conjugated equine estrogen and transdermal estradiol-17 beta combined with an oral progestin on quality of life in postmenopausal women. Maturitas. 1996 Jul;24(3):177-84. [abstract] 35. MacLennan A, Lester S, Moore V; Oral oestrogen replacement therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2001;(1):CD002978. [abstract] 36. Cardozo L, Lose G, McClish D, et al; A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (HUT) committee. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12(1):15-20. [abstract] 37. Wiklund I, Karlberg J, Mattsson LA; Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebocontrolled study. Am J Obstet Gynecol. 1993 Mar;168(3 Pt 1):824-30. [abstract] 38. Zweifel JE, O'Brien WH; A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology. 1997 Apr;22(3):189-212. [abstract]
Slide 8: 39. 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] 40. 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] 41. Rossouw JE, Anderson GL, Prentice RL, et al; Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. [abstract] 42. Espeland MA, Rapp SR, Shumaker SA, et al; Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68. [abstract] 43. Beral V; Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27. [abstract] 44. Beral V, Bull D, Reeves G; Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005 Apr 30-May 6;365(9470):1543-51. [abstract] 45. Bhavnani BR, Strickler RC; Menopausal hormone therapy. J Obstet Gynaecol Can. 2005 Feb;27(2):137-62. [abstract] 46. Alternatives to HRT for the management of symptoms of the menopause. Scientific Advisory Committe; Royal College of Obstetrics and Gynecology Scientific Advisory Committee Opinion 2006. 47. Eisen A, Lubinski J, Gronwald J, et al; Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers. J Natl Cancer Inst. 2008 Sep 23. [abstract] 48. Riman T, Dickman PW, Nilsson S, et al; Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst. 2002 Apr 3;94(7):497-504. [abstract] 49. Shumaker SA, Legault C, Kuller L, et al; Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. [abstract] 50. No authors listed; Tibolone: cancers of the breast and endometrium. Prescrire Int. 2006 Jun;15(83):107. [abstract] Internet and further reading • Hormone-replacement therapy: safety update - UK Public Assessment Report; MHRA July 2007. Acknowledgements EMIS is grateful to Dr Laurence Knott for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2008. DocID: 735 Document Version: 22 DocRef: bgp44 Last Updated: 30 Oct 2008 Review Date: 30 Oct 2010

   
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