Menopause

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Introduction

The menopause affects womens normal quality of life and is marked by the ending of menstruation. This fact has been proved and highlighted by researchers from time to time. In the UK and other developed countries enormous decline in maternal mortality, leads to increasing proportions of women are surviving up to the menopause age and years of active life beyond it. The average life expectancy for women in developed countries is around 75 years (Khaw, 1992). According to Rees et al number of older people will rise because increase in life expectancy and decline in fertility rate (Rees et al, 2009). Majority of women in advanced societies experience menopause and can expect to live approximately 30 years beyond this event (McKinlay et al, 2008).

This means most of women will face changes during menopausal age which includes vasomotor symptoms, sexual dysfunction, psychological symptoms and the long term effects of menopause on bone. Osteoporosis increases the risk of fracture and loss of mobility which leads to dependence of others. Consultations for the menopause are increasing with the increase population and there high life expectancy. Health care professionals associated with women's health, will be dealing with this ever increasing problem more frequently.

This literature review will help trainee gynaecologist, general practitioners and consultants to improve their understanding of menopause symptoms and there relative management

Aim and Objective

This review article is aimed to refresh and improve knowledge of trainee gynaecologists, general practitioners and consultants dealing with menopausal women. An attempt is made to simplify the basic concepts in menopause based on critical analysis of best available evidence.

Method

The completed review article was sent to five gynaecologists who have interested in menopause for peer review and feedback. These included specialist registrars, consultants, and general practitioners. The feedback questionnaires include questions about content, relevance to targeted audience and usefulness in practice. The quality scale with five point response options from '1 for poor' through to '5 for excellent' was used. The free text questions about areas for improvement and dissemination of this article were also included. The feedback forms were collected and analysed anonymously. In the reflexion section, ideas and suggestions from peer review forms the core discussion.

Literature review

What is Menopause?

The menopause is defined as the cessation of the menstrual cycle and is caused by ovarian failure. The term is derived from the Greek meno, meaning month, and pause, meaning an ending. (Rees et al 2009). The perimenopause includes the period beginning with the first features of approaching menopause and ends 1 year after the last menstrual period. Menopausal transition is period of time of the perimenopause that ends with the final menstrual period (Burger et al, 2002).

What happens (biology of menopause)?

The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers (Burger et al, 2002). The total numbers of oocyte are maximum at intrauterine life. The total number of germ cells appears to rise steadily, around 600,000 at 2 months which reaching a peak of 6,800,000 at 5 month. By the time of birth, the number of oocyte will decline. In newborn infants around 100,000 oocytes remains and at the age of 7 years only 300,000 oocytes survives (Baker, 1963). The number of follicles decreases with increased age, change occurs when number of follicle falls to the critical figure of 25,000 at age 37.5 years. The number of follicle reduced to around 1000 at 51 years and it was adopted as the menopausal threshold because it corresponds to the median age of menopause in the general population (Faddy et al, 1992).

In one study it was demonstrated that number of follicle was 10-fold higher in normal menstruating women than that in perimenopausal women. Follicles were virtually absent in the postmenopausal ovaries (Richardson et al, 1987). Menopause is triggered by the number of ovarian follicles falling below a threshold number and is irreversible because oogonial stem cells disappear after birth (Faddy et al, 1992).

When it happens?

In one study it is demonstrated that the average age at natural menopause was 51.4 years. If the menopause occurs in a woman who is less than 45 years of age, it is known as premature menopause (have to find out). Smoking, lower educational attainment and nonemployment were related to earlier age at natural menopause and prior use of oral contraceptives and parity were associated with later age at menopause (Gold, et al, 2001). What are the common symptoms of menopause?

In menopause, there is reduction in production of oestrogen and increase in level of gonadotropin. Follicular stimulating hormone gets increase in circulation and decrease in level of oestradiol and inhibin B (Burger et al, 2002). Thus during the climacteric decline in the level of oestrogen, can cause a number of symptoms. The major menopausal symptoms are hot flushes, night sweats and urogenital symptoms, including vaginal dryness, loss of lubrication with sexual intercourse, and urinary frequency (Farrell 2003). Some symptoms are discussed in detail below;

Vasomotor symptoms

Hot flushes and night sweats are the primary and most common symptoms of menopause. Hot flushes have great variability in their frequency and severity in women; they may persist for several months or last for 10 years (Utian, WH, 2005). Hot flushes are episodes of inappropriate heat loss mediated by cutaneous vasodilatation over the upper trunk (Rees et al, 2009). Vasomotor symptoms are highly prevalent in most societies. The prevalence of these symptoms varies widely and may be influenced by a range of factors, including climate, diet, lifestyle, women's roles, and attitudes regarding the end of reproductive life and aging. Patterns in hot flush prevalence were apparent for menopausal stages and, to a lesser degree, for regional variation (Freeman et al, 2007).

Urogenital atrophy and urinary incontinence

Atrophic changes occur in the vulva, vagina, urethra and bladder subsequent to oestrogen deprivation (Iosif, 1992). This changes leads to reduced sexual activity. The oestrogen receptors decline in the vaginal mucosa after the menopause, Cavallini study shows ER as dominant oestrogen receptor in the human vagina and no substantial difference has been seen in its expression between pre-menopausal and post-menopausal groups. While a decline of the ERß mRNA level has been found in the post-menopausal women only. Thus, Oestrogen receptors never disappear completely and, in response to exogenous oestrogens, the number of receptors in the vagina can return to pre-menopausal levels (Cavallini et al, 2008). Thus, this activation of oestrogen receptors produces an increase in vaginal secretions and epithelial proliferation and vascularisation leading to glycogen deposition and a reduction in vaginal pH due to higher lactic acid production (Galhardo et al, 2006). Some symptoms of urogenital atrophy are listed in Table 1.

Psychological Symptom

Depressed mood, anxiety, irritability, mood swings are symptoms associated with menopause (Freeman et al, 2008). There is evidence of increased risk for developing depression. Depression during the perimenopause may have a substantial impact on personal, family and professional spheres of life (Cohen et al, 2005). Women are at a higher risk than men to develop depression. Menopausal transition is associated with higher risk for new onset and recurrent depression. Ovarian hormones modulate serotonin and noradrenaline neurotransmission, a process that may be associated with underlying pathophysiological processes involved in the emergence of depressive symptoms during periods of hormonal fluctuation in biologically predisposed subpopulations (Frey et al, 2008). In one study following psychological symptoms were included; (Greene, 2008). The psychological symptoms are listed in Table 2.

Osteoporosis

Osteoporosis is a disease characterized by low bone mass, micro architectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk (Consensus Development Conference, 1991). The classic osteoporotic fractures are hip, vertebral and wrist fractures. These osteoporotic fractures such as hip fractures have a very high morbidity and mortality. The lifetime risk of any osteoporotic fracture is very high and lies within the range of 40-50% in women and 13-22% for men. Fractures occurring at a site associated with low BMD and which increase in incidence after the age of 50 years (Johnell and Kanis, 2005).

Dementia and Cognitive function

According to one study evidence suggests that oestrogen failure associated with menopause and post menopause, which is related to cognitive and affective disorders and to increased risk of Alzheimer's disease (Solerte et al, 1999). A gradual decline in cognitive functions is part of the normal aging process. However, marked confusion, disorientation, memory loss and other changes may signal a developing dementia. A wide variety of disorders can cause dementia like Alzheimer disease, vascular dementia and dementia with Lewy bodies (Rees et al, 2009). Alzheimer disease is the most common type of dementia and is characterized by memory loss, confusion and cognitive deficits (). Oestrogen influences memory, cognition and attenuates the extent of cell death resulting from brain injuries (Wise et al, 2001). Several studies suggested that oestrogen is essential for optimal brain functions as oestrogen has been shown to increase cerebral blood flow, act as an anti-inflammatory agent, and enhance activity at neuronal synapses (Behl, 2002).

Which are the treatments for menopausal symptoms?

Onlyone in 10women seeks medical advice when they go through the menopause, and many do not need any treatment. However, if your menopausal symptoms are severe enough to interfere with your daily life, there are treatments that can help.

Treatment for vasomotor symptoms

Hormone replacement therapy is highly effective in alleviating hot flushes and night sweats. In one systematic review 21 studies, duration from 3 month to 3 years were included with 2511 participants. There was a significant reduction of intensity and frequency of hot flushes in the HRT group compared to placebo group was observed (Maclennan et al, 2001). Patches, gels and implants have been found to reduce hot flushes with the same degree of efficacy as oral therapy (Farrell 2003).

One randomised trial demonstrates that black cohosh used in isolation or in a multibotanical product helps in relief of vasomotor symptoms (Newton et al, 2006). In one double blind, randomised, parallel group, outpatient, multicenter study total 177 postmenopausal women were experiencing five or more hot flushes per day were randomized to receive either soy isoflavone extract or placebo. Decreases in the incidence and severity of hot flushes occurred as soon as 2 weeks in the soy group, whereas the placebo group experienced no relief for the first 4 weeks. Soy isoflavone extract has effective in reducing frequency and severity of flushes and provide an attractive addition to the choices available for relief of hot flushes. (Upmalis et al, 2000).

Treatment for Urogenital atrophy and urinary incontinence

Oestrogen therapy is first choice of treatment for urogenital atrophy (Palacios, 2009). A meta-analysis of studies of oestrogen therapy demonstrated that, oestrogen is efficacious in the treatment of urogenital atrophy. Low-dose vaginal oestradiol preparations are as effective as systemic oestrogen therapy in the treatment of urogenital atrophy in postmenopausal women (Cardozo et al, 1998). Oestrogen cream 1 or 2 times/week may prevent recurrence after symptoms are resolved (Laurie, 2001). In one review it was concluded, that oestrogen given systematically or locally in all dosage regimen is effective, but topical vaginal application alone is preferred if systematic treatment is not needed (Palacios, 2009). Cochrane systematic review also concluded that vaginal oestrogen reduces the number of urinary tract infections in postmenopausal women's, with recurrent urinary tract infection (Perrotta et al, 2008).

Vaginal lubricants and moisturizers are also helpful; it provides longer relief by changing the fluid content of endometrium and lowering vaginal pH. Women with contraindications to ERT-HRT could use lubricants for intercourse-related dryness or moisturizers for more continuous relief (Laurie, 2001). Lubricants are temporary measures to relieve vaginal dryness during intercourse and moisturizers give longer symptomatic relief (Palacios, 2009). Agrimony, black cohosh, chaste tree, dong quai, witch hazel, and phytoestrogens are useful to reduce the vaginal dryness and dyspareunia but no evidence exists to support these specific claims (Laurie, 2001).

Treatment for psychological symptom

Transdermal oestradiol, serotonergic and noradrenergic antidepressants are efficacious in the treatment of depression in symptomatic midlife women (Frey et al, 2008). There is insufficient evidence that HT improves mood, depression and other mood symptoms (Farrell 2003). Socioculture and family factors are more important in the aetiology of mental illness in menopausal women; in such cases antidepressants are more effective than oestrogen therapy (Ballinger, 1990).

Treatment for osteoporosis

Oestrogen therapy is the drug of choice for preventing bone loss in menopausal women. Women's Health Initiative (WHI) study reported significant reduction in the risk of clinical fractures in a population-based sample of healthy postmenopausal women aged 50-79 years. In this large randomized controlled trial, 16 608 women were recruited to the oestrogen-plus-progestogen arm of the study. Treatment consisted, of one daily tablet containing conjugated equine estrogen (CEE), 0.625 mg, and medroxyprogesterone acetate (MPA), 2.5 mg. Trial were stopped with mean follow-up period of 5.2 year. In this study, a significant reduction was demonstrated in clinical vertebral and non-vertebral fractures, including hip fractures (WHI, 2002). Calcitonin also helps by decreasing further bone loss at vertebral and femoral sites. Orally administered bisphosphonates reduce bone loss and the incidence of vertebral deformity in patients with established postmenopausal osteoporosis. In menopausal women adequate calcium intake is necessary. A minimum intake of 800 mg of calcium daily is recommended for all adults. Fluoride, anabolic steroids and parathyroid hormone stimulate bone formation. Vitamin D deficiency increases the risk of hip fracture; hence vitamin D deficiency should be prevented and treated (Consensus Development Conference, 1991).

Treatment for Dementia and Cognitive function

One study demonstrates that oestrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older and did not prevent mild cognitive impairment in these women (Shumaker et al, 2003). There are no reliable data to show the benefit of oestrogen replacement therapy on dementia with respect to cognition, prevention or delay in development of Alzheimer dementia (Mulnard et al, 2000). Women are more likely to be dietary supplement and natural remedy, phytoestrogens; particularly isoflavones have protective effects in these conditions.

Hormone Replacement Therapy (HRT)

Hormone replacement therapy (HRT) is effective in treating several of the most common menopausal symptoms, including hot flushes and night sweats, vaginal symptoms and cystitis. The main indication for HRT use in postmenopausal women remains the relief of menopausal symptoms. Treatment for up to 5 years does not add significant life time risk but small increase in risk of breast cancer after long-term therapy (Skouby et al, 2005). Hormone replacement therapy consists of an oestrogen with progestogen. Oestrogen therapy on daily basis with a progestogen either cyclically or continuously are being used in non-hysterectomized women. After hysterectomy it is usual to prescribe oestrogen alone (Farrell, 2003).

Testosterone therapy is given to young women going through a premature menopause and to women who exhibit symptoms of testosterone deficiency (Farrell 2003). Tibolone is a steroid compound structurally related to 19-nortestosterone derivatives (such as norethisterone), which exhibits a concomitant weak estrogenic, progestational, and androgenic activity. Tibolone is described as a tissue-specific therapy because of its mechanisms of action, a classical receptor response, enzyme inhibition within the breast and uterus and specific local metabolism as in the uterus. It is metabolized to three metabolites, with the 3a- and 3ß- hydroxytibolone metabolites functioning only by binding to the oestrogen receptor and therefore having oestrogen-like actions, and the ?4 isomer having progesterone and androgen-like actions but no oestrogen action (Palacios, 2001).

The routes of administration of hormones (for HRT) that are available are oral, Transdermal, subcutaneous, vaginal, intramuscular, intrauterine, buccal and intranasal. There are also many different types of oestrogen, including oestradiol, oestrone, oestriol and conjugated equine oestrogen preparations, and progestogen such as micronized progesterone, dydrogestrone, norethisterone, medroxyprogesterone acetate, levonorgestrel and other newer progestins (Farrell 2003). The risk and benefits of HRTs are listed in Table 3.

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