After menopause a womans body no longer produces estrogen

Indian J Psychiatry. 2015 Jul; 57(Suppl 2): S222–S232.

Abstract

Menopause is one of the most significant events in a woman's life and brings in a number of physiological changes that affect the life of a woman permanently. There have been a lot of speculations about the symptoms that appear before, during and after the onset of menopause. These symptoms constitute the postmenopausal syndrome; they are impairing to a great extent to the woman and management of these symptoms has become an important field of research lately. This chapter attempts to understand these symptoms, the underlying pathophysiology and the management options available.

Keywords: Hot flushes, menopausal depression, postmenopausal syndrome

INTRODUCTION

Menopause is the permanent cessation of menstruation resulting in the loss of ovarian follicle development.[1,2] The age at menopause appears to be genetically determined and is unaffected by race, socioeconomic status, age at menarche, or number of prior ovulations. Factors that are toxic to the ovary often result in an earlier age of menopause; for example, women who smoke experience an earlier menopause,[3] etc. Women who have had surgery on their ovaries, or have had a hysterectomy, despite retention of their ovaries, may also experience early menopause.[4]

Premature ovarian failure is defined as menopause before the age of 40 years. It may be idiopathic or associated with toxic exposure, chromosomal abnormality, or autoimmune disorder.

Although menopause is associated with changes in the hypothalamic and pituitary hormones that regulate the menstrual cycle, menopause is not a central event, but rather a primary ovarian failure. At the level of the ovary, there is a depletion of ovarian follicles. The ovary, therefore, is no longer able to respond to the pituitary hormones, that is, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and ovarian estrogen and progesterone production cease. Androgen production from the ovary continues beyond the menopausal transition because of sparing of the stromal compartment. Menopausal women continue to have low levels of circulating estrogens, principally from peripheral aromatization of ovarian and adrenal androgens. Adipose tissue is a major site of aromatization, so obesity affects many of the sequelae of menopause. The ovarian-hypothalamic-pituitary axis remains intact during the menopausal transition; thus, FSH levels rise in response to ovarian failure and the absence of negative feedback from the ovary. Atresia of the follicular apparatus, in particular the granulosa cells, results in reduced production of estrogen and inhibin, resulting in reduced inhibin levels and elevated FSH levels, a cardinal sign of menopause.

Menopausal transition, or ‘perimenopause’, is a defined period of time beginning with the onset of irregular menstrual cycles until the last menstrual period, and is marked by fluctuations in reproductive hormones.[5] This period is characterized by menstrual irregularities; prolonged and heavy menstruation intermixed with episodes of amenorrhea, decreased fertility, vasomotor symptoms; and insomnia. Some of these symptoms may emerge 4 years before menses ceases.[6] During the menopausal transition, estrogen levels decline and levels of FSH and LH increase. The menopausal transition is characterized by variable cycle lengths and missed menses, whereas the postmenopausal period is marked by amenorrhea. The menopausal transition begins with variability in menstrual cycle length accompanied by rising FSH levels and ends with the final menstrual period.

Menopause is defined retrospectively as the time of the final menstrual period, followed by 12 months of amenorrhea. Post-menopause describes the period following the final menses.[7]

The ovary is a women's only source of oocytes, her primary source of estrogen and progesterone, and a major source of androgens. Menopause results in infertility secondary to oocyte depletion. Ovarian cessation of progesterone production appears to have no clinical consequences except for the increased risk of endometrial proliferation, hyperplasia, and cancer associated with continued endogenous estrogen production or administration of unopposed estrogen therapy in menopausal women.

The major consequences of menopause are related primarily to estrogen deficiency. It is very difficult to distinguish the consequences of estrogen deficiency from those of aging, as aging and menopause are inextricably linked.

Principal health concerns of menopausal women include vasomotor symptoms, urogenital atrophy, osteoporosis, cardiovascular disease, cancer, psychiatric symptoms, cognitive decline, and sexual problems. However, it has been difficult to distinguish between symptoms that result from loss of ovarian function and those from the aging process or from the socio-environmental stresses of midlife years. Many symptoms are found related to postmenopausal syndrome: Hot flushes, irritability, mood swings, insomnia, dry vagina, difficulty concentrating, mental confusion, stress incontinence, urge incontinence, osteoporotic symptoms, depression, headache, vasomotor symptoms, insomnia etc. They have been discussed below.

VASOMOTOR SYMPTOMS

Vasomotor symptoms affect up to 75% of peri-menopausal women. Symptoms last for 1–2 years after menopause in most women, but may continue for up to 10 years or longer in others. Hot flushes are the primary reason women seek care at menopause. Hot flushes not only disturb women at work and interrupt daily activities, but also disrupt sleep.[8] Many women report difficulty concentrating and emotional lability during the menopausal transition. Treatment of vasomotor symptoms should improve these cognitive and mood symptoms if they are secondary to sleep disruption and resulting daytime fatigue. The incidence of thyroid disease increases as women age; therefore, thyroid function tests should be performed if vasomotor symptoms are atypical or resistant to therapy.

The physiological mechanisms underlying hot flushes are incompletely understood. A central event, probably initiated in the hypothalamus, drives an increased core body temperature, metabolic rate, and skin temperature; this reaction results in peripheral vasodilation and sweating in some women. The central event may be triggered by noradrenergic, serotoninergic, or dopaminergic activation. Although an LH surge often occurs at the time of a hot flush, it is not causative because vasomotor symptoms also occur in women who have had their pituitary glands removed. Exactly what role estrogen plays in modulating these events is unknown. Vasomotor symptoms are a consequence of estrogen withdrawal, not simply estrogen deficiency.

Treatment

Systemic estrogen therapy is the most effective treatment available for vasomotor symptoms and the associated sleep disturbance. Healthy women in the perimenopausal transition who are experiencing bothersome hot flushes but still menstruating may benefit from oral contraceptives. Very-low-dose estrogen therapy also effectively treats hot flushes for many women. Low-dose oral esterified and conjugated estrogens (0.3 mg daily)[9,10] or transdermal estradiol (0.025 mg weekly)[11] often is effective and is associated with minimal side effects and endometrial stimulation. Progestin therapy must be given concurrently if a woman has not had a hysterectomy, although, with low-dose estrogen therapy, intermittent progestin treatment may be an option.

When estrogen is contraindicated, other options are available. Progestin therapy alone is an option for some women. Medroxyprogesterone acetate (MPA) (20 mg/day) and megestrol acetate (20 mg 2 times daily) effectively treat vasomotor symptoms.[12] Several drugs that alter central neurotransmitter pathways also are effective. Agents that decrease central noradrenergic tone, such as clonidine, relieve hot flushes.[13] Clonidine has been shown to significantly reduce vasomotor symptoms in randomized, placebo-controlled trials.[14] It may be used orally (0.1–0.2 mg/day) or as a weekly transdermal patch (0.1 mg/day). Potential side effects include orthostatic hypotension and drowsiness.

Selective serotonin reuptake inhibitors (SSRIs) also are effective in relieving hot flushes. In a double-blind, randomized, placebo-controlled trial of paroxetine controlled release (12.5 and 25 mg/day), menopausal women with hot flushes experienced a significant reduction in both the frequency and severity of episodes.[15] Hot flush composite scores decreased by 62% in the paroxetine group versus 38% in the placebo group. The actual hot flush frequency decreased by 3.3 hot flushes per day with paroxetine versus 1.8 on placebo. The improvement in vasomotor symptoms was independent of any significant change in mood or anxiety symptoms. Both doses were effective, but the lower dose was better tolerated. The most common side effects were headache, nausea, and insomnia. A modest improvement in symptoms also occurred in a randomized, double-blind, placebo-controlled, crossover trial of fluoxetine (20 mg/day).[16] Not all studies showed an improvement in vasomotor symptoms with SSRIs. In a 9-month, double-blind, parallel-group trial, there was no significant improvement in hot flushes with either fluoxetine or citalopram (10–30 mg/day) compared with placebo.[17]

Modulation of other central neurotransmitters with different antidepressants also may be effective, but have greater potential for adverse effects. Venlafaxine (75 mg/day), significantly reduced hot flushes in a controlled trial.[18] Hot flush scores decreased 61% in the venlafaxine group compared with 27% in the placebo group. The active treatment group experienced significantly more side effects, including dry mouth, nausea, and anorexia.

Although often recommended, Vitamin E (800 IU/day) only minimally reduced hot flushes in a placebo-controlled, randomized, crossover trial.[19]

Overweight women and those who smoke have more severe vasomotor symptoms than women of normal weight and nonsmokers. These findings provide additional reasons to encourage women to lose weight and stop smoking.[20,21]

UROGENITAL ATROPHY

Urogenital atrophy results in vaginal dryness and pruritus, dyspareunia, dysuria, and urinary urgency. These common problems in menopausal women respond well to therapy.

Systemic estrogen therapy is effective for the relief of vaginal dryness, dyspareunia, and urinary symptoms. Another option is a topical application. Because systemic absorption is low, endometrial stimulation is minimal. Low-doses of estrogen cream (0.5 g) are effective when used only 1–3 times weekly.[22] An estradiol vaginal tablet (25 μg) inserted twice weekly, which may be less messy and easier to use than estrogen cream.

Women using vaginal estrogen therapy should be asked to report any vaginal bleeding, and this bleeding should be evaluated thoroughly. Typically, systemic progestin therapy is not prescribed to women using low-dose vaginal estrogen.

Lubricants are a non-hormonal alternative for reducing discomfort with intercourse in the presence of urogenital atrophy.

Vaginal estrogen therapy appears to reduce urinary symptoms, such as frequency and urgency and has been shown to reduce the likelihood of recurrent urinary tract infections in postmenopausal women.[23] The effect of estrogen therapy on urinary incontinence is unclear. Whereas the results of some studies suggest improvement in incontinence with estrogen therapy, others show a worsening of symptoms.[24]

OSTEOPOROSIS

Musculoskeletal symptoms characterized by backache, fractures on minimal trauma, decreased height, and mobility are common due to osteoporosis. It is important to review a woman's risk factors for osteoporosis when making treatment decisions and to consider bone mineral density screening for high-risk women. Non-modifiable risk factors include age, Asian or Caucasian race, family history, small body frame, history of a prior fracture, early menopause, and prior oophorectomy. Modifiable risk factors include decreased intake of calcium and Vitamin D, smoking, and a sedentary lifestyle. Medical conditions associated with an increased risk of osteoporosis include anovulation during the reproductive years (e.g., secondary to excess exercise or an eating disorder), hyperthyroidism, hyperparathyroidism, chronic renal disease, and diseases requiring systemic corticosteroid use.

Counseling women to alter modifiable risk factors are important for both the prevention and treatment of osteoporosis. Many women have diets deficient in calcium and Vitamin D and will benefit from dietary changes and supplementation. Women should receive 1000–1500 mg of calcium and 400–800 IU of Vitamin D daily. This may be achieved through diet or vitamin and mineral supplementation. Reduction in the risk of osteoporosis is another of the many health benefits of smoking cessation and regular exercise. Treatment is indicated for all women with osteoporosis as well as for those with osteopenia and additional risk factors. Drug therapies for the prevention and treatment of osteoporosis are principally anti-resorptive drugs that reduce bone loss and anabolic agents that stimulate new bone formation.

Hormone therapy (HT) is effective in preventing and treating osteoporosis. In observational studies, estrogen therapy had been shown to reduce osteoporosis-related fractures by approximately 50% when started soon after menopause and continued long term. It also significantly decreases fracture rates in women with established disease.[25] The Women's Health Initiative (WHI) randomized controlled trial confirmed a significant (34%) reduction in hip fractures in healthy women receiving HT (conjugated equine estrogen 0.625 mg with MPA 5 mg) after a mean follow-up of 5 years.[26] Recent studies demonstrate that even very-low-dose estrogen therapy (estradiol 0.25 mg/day; conjugated equine estrogen 0.3 mg/day with MPA 1.5 mg/day; transdermal estradiol 0.025 mg/day), combined with calcium and Vitamin D, produce significant increases in bone mineral density compared with placebo.[27,28,29]

Bisphosphonates, including alendronate (35–70 mg weekly), risedronate (35 mg weekly), and ibandronate (150 mg monthly) specifically inhibit bone resorption and are very effective for both osteoporosis prevention and treatment.[30,31]

Selective estrogen receptor modulators (SERMs) are compounds that act as both estrogen agonists and antagonists, depending on the tissue. Raloxifene (60 mg) is a SERM that has been approved for both the prevention and treatment of osteoporosis.[32] Calcitonin nasal spray (200 IU) is another approved treatment for established osteoporosis.

DEPRESSION

Although most women transition to menopause without experiencing psychiatric problems, an estimated 20% have depression at some point during menopause.[33]

Studies of mood during menopause have generally revealed an increased risk of depression during perimenopause with a decrease in risk during postmenopausal years. The Penn Ovarian Aging Study, a cohort study, showed depressive symptoms increased during the menopausal transition, and decreased after menopause. The strongest predictor of depressed mood was a prior history of depression, along with fluctuations in reproductive hormone levels associated with depressed mood.[34]

In a cross-sectional population survey from the Netherlands, 2103 women were asked to rate their symptoms of depression before menopause and 3.5 years later, during the menopausal transition. The women experienced most symptoms of depression during the menopausal transition. In the United States, a study of a community sample of women undergoing natural menopause also demonstrated an increase in depressive symptoms during perimenopause.[35]

Investigators from the Harvard Study of Moods and Cycles recruited premenopausal women aged 36–44 years with no history of major depression and followed up these women for 9 years to detect new onsets of major depression. Women who entered peri-menopause were twice as likely as women who had not yet made the menopausal transition to have clinically significant depressive symptoms.[36]

Pathophysiology

Depression during perimenopause is likely due to fluctuating and declining estrogen levels in part. Steroid hormones, such as estrogen, act in the central nervous system (CNS) by means of various mechanisms. For instance, they stimulate the synthesis of neurotransmitters, the expression of receptors, and influence membrane permeability.[37]

Estrogen increases the effects of serotonin and norepinephrine, which are thought to be the neurotransmitters most related to the physiologic cause of depression. Among other mechanisms, estrogen decreases monoamine oxidase (MAO) activity in the CNS, hindering the breakdown of serotonin and norepinephrine.[2] In addition, estrogen increases serotonin synthesis, upregulates 5-hydroxytryptamine (5-HT1) receptors, and downregulates 5-HT2 receptors. Estrogen also increases norepinephrine activity in the brain, perhaps by decreasing reuptake and degradation due to inhibition of the enzymes MAO and catechol-O-methyltransferase.[38]

Although the precise mechanisms are yet unknown, regulation of serotonin and norepinephrine may change as estrogen levels fluctuate and thus contribute to depression. Because estrogen facilitates the actions of serotonin and norepinephrine, a decline in estrogen concentrations may, in turn, decrease levels of these hormones.[2,37,38] Changes in estrogen levels, perhaps due to mechanisms involving these neurotransmitters, may be related to depressive symptoms in the menopausal transition of some women.

Hormonal changes

Depression seems to be significantly linked to times of hormonal change in women. Several observations and study data support this theory. For example, the disparity between rates of depression in women and men begins at puberty. Furthermore, hormonal changes are thought to be major contributors to premenstrual dysphoric disorder, as well as mood changes experienced in the postpartum period and at the menopausal transition.[39,40] Furthermore, estrogen affects both serotonin and norepinephrine, the 2 neurotransmitters thought to be most directly associated with depression.

Of note, absolute levels of gonadal hormones are not correlated with depression. Estrogen and progesterone levels do not distinguish a woman with depression from one without depression. When hormone concentrations were measured in peri-menopausal or postmenopausal women with depression, no abnormal levels were found.[41] Rather, a certain subset of women seem to be predisposed to have mood disturbances triggered by hormonal fluctuations. This subset includes women with a history of mood disorders or of premenstrual and postpartum mood-related symptoms. The risk of depression appears to be higher during perimenopause, when hormone levels are changing, than during postmenopause, when estrogen and progesterone levels are low but stable.[34,37,42]

Life stressors

Societal roles and expectations may contribute to the heightened rate of depression in women. Women with particular types of stressors seem to be at increased risk for perimenopausal depression. Such stressors include the following:[33,40]

• Lack of social support

• Unemployment

• Surgical menopause

• Poor overall health status.

The dysphoric mood during the early perimenopausal transition is most common in women with relatively low educational status. Therefore, low levels of education may be a marker for other stressors, such as ongoing low socioeconomic status.[43]

An Australian study of women transitioning to menopause revealed more depression in women with the following states:[44]

• Negative mood before menopause

• Negative attitude toward menopause and aging

• Smoking

• Little or no exercise

• No partner

• Poor self-perceived health

• Negative feelings toward partner

• A number of perceived problems

• Interpersonal stress.

Other stressors that tend to correspond with perimenopause and that are postulated to relate to depression include the following:

• Onset of illness in self or others

• Care of aging parents

• Changes in employment.

Psychological or social conditions

Numerous psychological and social theories have been proffered to explain why women may become depressed during perimenopause. Some of these are related to the following factors:

• Change in the childbearing role

• Loss of fertility, which may be associated with a loss of an essential meaning of life

• Empty nest syndrome

• The societal value of youth (in societies where age is valued, women tend to report having fewer symptoms at the menopause transition).

Pre-existing tendency to develop depression

A personal or family history of major depression, postpartum depression, or premenstrual dysphoric disorder seem to be a major risk factor for depression in the perimenopausal period.[33] However, the perimenopausal depressive syndrome is a risk even in women without a history of depression.

Treatment

For major depression, standard antidepressants are first-line treatments. SSRIs are the antidepressants most commonly used in the treatment of perimenopausal depression.[45] SSRIs are thought to be generally safe and effective. The onset of action is 4–6 weeks. They do pose a risk of serotonin syndrome, as well as several common adverse effects such as gastrointestinal effects (nausea, diarrhea, and anorexia), excessive sweating, decreased libido and/or anorgasmia, headache, jitteriness, dizziness, sedation or activation, insomnia, and akathisia.

Although results from studies of hormone treatments for depression have been inconsistent, such treatments have been helpful for managing depressive symptoms in peri-menopause, but not in the postmenopausal period.[6,46] For mild depression, hormone replacement therapy (HRT) alone may be appropriate. Estrogen (0.45–0.625 mg conjugated estrogen QD, 1.5–5 mg medroxyprogesterone QD) may be used when traditional antidepressants fail, when patients refuse psychotropic medications, or when patients experience other clinically significant vasomotor symptoms.[46,47] Data from several studies suggested that estrogen replacement therapy had antidepressant effects or that it enhanced the effects of antidepressant treatment in perimenopausal women.[47,48,49,50,51,52] Other studies did not show that estrogen adds to the effects of SSRIs.[51,53] Debate exists regarding whether the antidepressant effect of estrogen is attributable to the effect of estrogen on vasomotor symptoms. Some studies reveal an antidepressant benefit of estrogen only in women with vasomotor symptoms. Results of other studies suggest an independent antidepressant effect.[54,55] The effects of estrogen treatment have been studied in perimenopausal women without depression to see if it has a positive effect on mood or quality of life. Results from small studies have suggested a small positive impact on mood.[56,57] However, most data suggest that, among healthy women without depression, estrogen has no favorable effect on quality of life or mood.[54,58,59]

Negative anticipation of menopause seems to be associated with elevated rates of depression and physical symptoms of menopause. Educational groups that help women learn what to expect during menopause decrease anxiety, depression, and irritability, both immediately after the group therapy and 1-year later.[60]

COGNITIVE FUNCTIONS

Memory problems are common complaints in perimenopausal and recent postmenopausal women. The increased frequency of cognitive complaints in menopausal women suggests that memory problems in this population are related to the menopause transition rather than to the aging process.[61,62] Clinical trials describing the enhancement of cognition with HRT support the etiologic role of estrogen in cognitive difficulties expressed by perimenopausal and recent postmenopausal women.[63,64,65,66] Specific cognitive domains (e.g., attention, verbal memory, and learning capacity) that may be influenced by the menopause transition have not been well characterized. The apparent relationship between the menopause transition and cognitive difficulties in some women suggests that such cognitive disturbance may be related to the hormonal changes of the menopause.[67] Cognitive difficulties may be a consequence of sleep disruption secondary to nocturnal hot flushes or a result of the effects of the changing hormonal milieu in brain regions that influence cognition.

Women are at greater risk for developing Alzheimer's disease than men. Several small trials and observational studies have suggested that HT use may decrease the risk of Alzheimer disease.[67] A randomized, controlled study in women with mild to moderate Alzheimer disease, however, showed that 1-year of estrogen treatment neither slowed disease progression nor improved cognition.[68] The effect of HT on cognitive function in women without dementia was studied in the WHI Memory Study (WHIMS), a randomized, double-blind, placebo-controlled trial of women aged 65 years or older enrolled in the WHI trial. In contrast to the findings of observational studies, women randomized to HT in WHIMS experienced a significant twofold increased risk of dementia, most commonly Alzheimer disease.[69] In addition, HT use was associated with an adverse effect on cognition. Compared with placebo-treated women, women in the HT group scored significantly lower on the Modified Mini-Mental State Examination.[70] Given the increased incidence of stroke identified in HT users in the WHI trial, it is possible that small, undetected cerebrovascular events were more likely to occur in the HT group, increasing the risk of dementia.

SEXUAL DYSFUNCTION

Many women experience sexual dysfunction during menopause, although the exact incidence and etiology are unknown. Sexual dysfunction may involve decreased interest or desire to initiate activity, as well as decreased arousal or ability to achieve an orgasm during sexual relations. The etiology of sexual dysfunction often is multifactorial, including psychological problems such as depression or anxiety disorders, conflict within the relationship, issues relating to prior physical or sexual abuse, medication use, or physical problems that make sexual activity uncomfortable, such as endometriosis or atrophic vaginitis.

Female sexual dysfunction after menopause is a complex problem with many etiologies. Careful evaluation of physiological, psychological, lifestyle, and relationship variables is required to optimize therapy. Treatment of anxiety and depression, adjustment of antidepressant medication, and relationship counseling may improve sexual function. Specific exercises and activities, often performed under the guidance of a sex therapist, help many women and couples with sexual dysfunction. Specific treatment of genitourinary atrophy with systemic or local vaginal estrogen therapy or vaginal lubricants effectively reduces dyspareunia and may improve sexual arousal and response. Sildenafil citrate was ineffective in a large randomized, double-blind, placebo-controlled study of women with sexual dysfunction.[71]

Androgen therapy may have a role in the treatment of sexual dysfunction in menopausal women who have low androgen levels and no other identifiable cause for their sexual problem.[72]

In a double-blind, crossover study of surgically menopausal women, the administration of supraphysiologic doses of intramuscular testosterone resulted in significantly higher scores of sexual desire, fantasy, and arousal than did treatment with estradiol alone or placebo.[73] In a double-blind, randomized study of the effects on libido of oral methyltestosterone (1.25 mg/day) combined with esterified estrogens (0.625 mg/day), women randomized to treatment with the estrogen-androgen combination reported significantly improved sexual interest and desire compared with women treated with estrogen alone.[74] In randomized, double-blind, placebo-controlled studies of estrogen-treated women without ovaries who had sexual dysfunction, physiologic testosterone therapy administered by a transdermal patch resulted in significant increases in sexual activity and pleasure.[75,76]

Potential risks of androgen therapy include hirsutism, acne, irreversible deepening of the voice, and adverse changes in liver function and lipid levels. As most androgens are aromatized to estrogens, androgen therapy may pose the same risks as estrogen therapy.

PROBLEMS WITH SLEEP

Insomnia occurs in 40–50% of women during the menopausal transition, and problems with sleep may or may not be connected to mood disorders.[77] Women with insomnia are more likely than others to report problems such as anxiety, stress, tension, and depressive symptoms.

Sleep disturbances during menopause have been associated with estrogen deficiency, as exogenous estrogen has been shown to improve both subjective and objective sleep, attributed to a decrease in hot flushes. A recent study proposed elevated LH levels during late menopause produce poor sleep quality through a thermoregulatory mechanism, resulting in high core body temperatures.[78] Whether the sleep problems are associated with age-related changes in sleep architecture, hormonal status or other symptoms of menopause (e.g., vasomotor symptoms) is unclear.

Rates of a sleep apnea increase with age, rising from 6.5% in women aged 30–39 years to 16% in women aged 50–60 years. The pathophysiology is not known, but theories include a relationship to postmenopausal weight gain or to decreased progesterone levels because progesterone stimulates respiration.[79,80] In addition to undergoing changes in estrogen and progesterone levels, postmenopausal women experience a decline in melatonin and growth hormone levels, both of which have effects on sleep.[81]

Estrogen may be helpful in relieving vasomotor symptoms that disrupt sleep, or that may have a direct effect on sleep itself.[80] In a study of postmenopausal women with hot flushes, night sweats, insomnia, anxiety, and/or mood swings, low-dose estrogen and low-dose micronized progesterone improved sleep to a greater extent than could be explained by a reduction in vasomotor symptoms.[56]

COURSE OF SOME IMPORTANT PSYCHIATRIC DISORDERS DURING MENOPAUSE

Schizophrenia

In most cases, schizophrenia first manifests in young adulthood, with the rate of new cases declining in both male and female individuals after early adulthood. A second peak in the incidence of schizophrenia is noted among women aged 45–50 years; this second peak is not observed in men.[82]

Some researchers have observed a worsening of the course of schizophrenia in women during the menopausal transition. These observations may suggest that estrogen plays a modulatory role in the pathophysiology of schizophrenia.[46]

Bipolar disorder

Exacerbation of mood symptoms during menopause has been noted in women with the pre-existing bipolar disorder. Research has suggested that women with bipolar disorder have higher rates of depressive episodes during the menopausal transition. The frequency of depressive episodes in this population appears to be higher than during premenopausal years.[83] Earlier studies suggested an increase in rapid cycling during the menopausal transition; however, this finding has not been reproduced.[84]

Panic disorder

Panic disorder is common during perimenopause. New-onset panic disorder may occur during menopause, or pre-existing panic disorder may worsen. Panic disorder may be most common in women with many physical symptoms of menopause.[85]

In a cross-sectional survey of 3369 postmenopausal women aged 50–79 years, panic attacks were most prevalent among women in the menopausal transition. Panic attacks were associated with negative life events, functional impairment, and medical comorbidity.[86]

Obsessive-compulsive disorder

New-onset obsessive-compulsive disorder (OCD), a relapse of OCD, or a change in OCD symptoms may occur during menopause. Fluctuations in OCD have been correlated with the menstrual cycle and with pregnancy, suggesting that hormone levels may contribute to the disorder.[87]

STATUS OF HORMONE REPLACEMENT THERAPY

Assessment of the risks versus the benefits of HRT has become a challenging task for the physicians. Controversial issues have surrounded the status of HRT for postmenopausal women lately. Several randomized controlled trials present contradicting evidence and have raised questions about the short-term risks of long-term benefits of HRT. Evidence from clinical trials like the WHI and The Heart and Estrogen/Progestin Replacement Study (HERS) trial does not support HRT use for prevention of cardiovascular disease. The association of HRT with cancer, stroke, cognition, cardiovascular disease, venous thromboembolism, osteoporosis, gallbladder disease is under scrutiny. The latest controversial results of randomized controlled trials in recent years have posed newer challenges for the physicians in prescribing HRT for postmenopausal women.

Controversial issues have surrounded the area of HRT for postmenopausal women in the past years. Many recent evidence-based studies have highlighted that HRT use led to a decreased risk of atherosclerosis, osteoporosis fractures, along with no significantly increased risk of breast cancer.[88] In a study, low risks of colon cancer and Alzheimer's disease with HRT use were reported.[89] Another analysis in 1994 revealed benefits exceeding the risks with estrogen replacement therapy.[90] Improved longevity and decreased morbidity in 99% of US postmenopausal women morbidity were proposed by another decision analysis.[91] The benefit in symptoms of menopause, improvement in quality of life, protection from cardiovascular disease and osteoporosis were some of the proposed benefits of HRT. However, in the past several years, evidence-based medicine has brought forward the results of several randomized double-blind placebo-controlled trials, especially the results of WHI study,[26] which have radically affected routine prescribing of HRT in clinics. The randomized controlled trials present contradicting evidence and has raised questions about the short-term risks of long-term benefits of HRT.

Some of the risks are mentioned below: An increase in the risk of venous thromboembolism was reported in both WHI and HERS, with the highest risk in the 1st year of use. Contradictory results have been reported in various studies for effects of HRT on the incidence of stoke. WHI study exhibited an increased risk whereas some other studies reported a protective effect. Estrogen is implicated in tumorogenesis in experimental animals.[92] A meta-analysis of available data has shown an increased risk of breast carcinoma. The Collaborative Group on Hormonal Factors in Breast Cancer showed no significant increase in breast cancer risk in 52,000 women using HRT for <5 years, however, in women in estrogen replacement therapy, for >5 years, an increased risk was shown.[93] Combined estrogen-progestin use has been associated with rather increased risk of breast cancer than estrogen used alone in various trials.[94] Higher dosage and prolonged unopposed estrogen use have been associated with endometrial hyperplasia increasing the risk of endometrial cancer.[95] There have been inconsistent results with HRT use in relation to ovarian and colorectal cancer. A direct carcinogenic action of HRT on ovarian cells to induce proliferation of ovarian cells has been confirmed. Amongst evidence-based studies, HERS study had shown no decrease in colorectal cancer risk in women which was contradicted by the results of WHI suggesting a decrease risk of colorectal cancer by estrogen. The Nurses’ Health Study reported a positive association of HRT and cholecystitis in short-term users of HRT.

REVIEW OF INDIAN LITERATURE ON POSTMENOPAUSAL SYNDROME

The average age of menopause in India is 47.5 years, with an average life expectancy of 71 years. Therefore, Indian women are likely to spend almost 23.5 years in menopause (Indian Menopause Society, 2007).

About 35–40% women between 40 and 65 years have been diagnosed to suffer from osteopenia and 8–30% suffer from osteoporosis. All women over 65 years have been found to suffer from osteopenia or osteoporosis (Indian Menopause Society, 2007).

A study[96] found that Indian women are now attaining menopause as early as at the age of 30. It also puts them at a higher risk of being affected with osteoporosis, heart diseases, diabetes, hypertension, and breast cancer, says the study conducted by Bangalore's Institute for Social and Economic Change. The study said that women living in rural areas are more prone to “premature menopause.” Natural menopause occurs between the ages of 45 and 55 years with a mean age of incidence around 51 years worldwide. The data for the study, which was based on the National Family Health Survey of 1998–1999, collected information from a sample of more than 90,000 married women aged between 15 and 49 and covering 99% of India's population living in 26 states. The report, which was presented in Parliament, has said that in India 3.1% of the women are already in menopause by the age of 30–34, and the incidence rises to 8% for the age bracket of 35–39 with menopause setting in quite rapidly after the age of forty. The study said that there are a higher number of illiterate women who are in premature menopause as against those who are educated.

There is a wide variation in the frequency with which women from different ethnic groups and different socioeconomic and educational backgrounds report the occurrence of symptoms associated with menopause.[97] Socioeconomic status is an important determinant of health and nutritional status, as well as morbidity and mortality. The variables that affect the socioeconomic status are different in the urban and rural population. Musculoskeletal symptoms characterized by backache, fractures on minimal trauma, decreased height, and mobility are common due to osteoporosis. The most common symptoms observed in a study[98] were musculoskeletal symptoms, which were seen in 98 (48%) subjects, followed by vasomotor symptoms, which were seen in 84 (42%) patients. Genitourinary symptoms like incontinence, frequency, urgency, difficulty in voiding etc., were seen in 52 patients, and psychological symptoms were seen in 45 patients. The study showed that perimenopausal women showed greater symptoms when compared to menopausal women. Another study[99] also showed that menopausal symptoms peak at the perimenopausal period, followed by a decline in symptoms during the postmenopausal period. In contrast to the Srilankan study,[100] an Indian study showed that vasomotor symptoms were more prevalent in the perimenopausal group, while musculoskeletal symptoms were common in the postmenopausal age group. One study[101] showed that women of low socioeconomic status had a greater prevalence of biological and psychological symptoms. Another study[102] demonstrated that women of the lower socioeconomic group have more severe menopausal symptoms and poorer subjective adaptation to daily life than women of the higher socioeconomic class. This is in contrast to the Indian study, which showed a greater prevalence of musculoskeletal and psychological symptoms in the middle socioeconomic group, while vasomotor symptoms were found to be more prevalent in the lower socioeconomic group. The difference found in the study could be due to sociocultural factors that are known to modify the experience of menopause and midlife.

A study[103] observed low to moderate level of anxiety, depression, social dysfunction and somatic symptoms as well as psycho-social stress in middle-aged women working as school teacher. It was noted that level of these factors was comparatively higher in postmenopause group than during menopause group. However, as far as these psychological factors are concerned this study could not find statistically significant difference between the groups. According to the authors, one of the reasons of low and similar scoring between the groups may be due to the fact that these women were not psychological cases. In a study[104] on 32 postmenopausal and 32 premenopausal patients aged between 40 and 55 years to investigate the anxiety and depression in postmenopausal women, the beck depression scale showed highly significant difference whereas, State-Trait Anxiety Inventory I and II showed no statistically significant difference and, therefore, concluded that depression rate is significantly higher in menopausal women. This study concluded that changes occurring in women during 40–60 years of age require proper attention. Working women preferably may require more care due to dual role responsibility. It may become slightly difficult to manage all activities with the same efficiency as before. That may cause feeling of guilt, irritation, stress etc., in these working women. Physical relaxation, emotional support, and essential care are needed for healthy living. Certain modifications in life-style and some programmed interventions can provide the enhancement of positive, healthy habits, reduce stress and can add quality to their life.

A study[105] which analyzed a sample consisting of menopausal, premenopausal and postmenopausal women in the age range of 35–50 years using a two-stage screening procedure for identifying and screening psychiatric morbidity General Health Questionnaire and Standard Psychiatric Interview, found highest psychiatric co-morbidity in the menopausal group, in terms of age maximum number of cases with psychiatric co-morbidity were from 41 to 45 years. Menopausal women suffered more symptoms of menopause as well as psychiatric symptoms as compared to premenopausal women. Both set of symptoms was found to be less in the postmenopause group also. The most common reported symptoms in the group were depression, depressive thoughts, anxiety, and excessive concern about bodily functions. Supporting the findings of the earlier study[106] the predominant symptom in menopausal women was depression.

Another study,[107] including a sample of 30 married women in the age range of 39–52 years from middle socioeconomic group noted, mean age of menopause was 44.59 years and women reported problems like backache, uneasiness, fatigue, increased headache, hot flushes and sleep disturbances during the menopausal period. This study was on the perception of women towards physiological problems faced at menopause. It was revealed from this study that women who were undergoing menopause were suffering from more difficulties during the perimenopausal phase than the menopausal phase, this in turn can affect the mental health of women and thus may increase psychosocial problems in their life. In this study, 89% of women complained of hot flushes as short waves of hot sensations sweeping all over the body. It was also found that women complained more of backache, loss of sight, pain in joints and fatigue during the menopausal phase than the perimenopausal phase. The women in the perimenopausal phase perceived more physiological difficulties (irregular periods with the heavy menstrual flow) as compared to the menopausal women.

GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS

It has been difficult to distinguish between symptoms that result from loss of ovarian function and those from the aging process or from the socio-environmental stresses of midlife years. Symptoms which result from loss of ovarian function should resolve by hormone replacement, but it has not been found so. Further research is required in this direction.

Symptoms have variable onset in relation to menopause. Some women experience symptoms earlier during perimenopause while some experience them at a later time. When should treatment start is also (prophylaxis or management) an issue for debate.

As recent data from the WHI establish the risks of long-term HRT use, concern about using HRT, even as a short-term intervention, has increased substantially. Although HRT remains the first-line treatment for hot flushes, the WHI findings have drawn attention to nonhormonal treatments of hot flushes and other menopausal symptoms. Growing evidence to support the efficacy of serotonergic antidepressants and other psychoactive medications in the treatment for hot flushes suggests that nonhormonal interventions will prove important alternatives to HRT. As further evidence of the benefits of psychoactive medications for menopausal symptoms is established, the choice between using hormonal and nonhormonal therapies for the management of menopausal symptoms will continue to evolve.

Footnotes

Source of Support: Nil

Conflict of Interest: None declared

REFERENCES

1. Sherwin B. Menopause: Myths and realities. Psychological aspects of women's health care. In: Stotland NL, Stewart DE, editors. The Interface Between Psychiatry and Obstetrics and Gynecology. Arlington: American Psychiatric Publishing; 2001. pp. 241–59. [Google Scholar]

2. Spinelli MG. Depression and hormone therapy. Clin Obstet Gynecol. 2004;47:428–36. [PubMed] [Google Scholar]

3. Adena MA, Gallagher HG. Cigarette smoking and the age at menopause. Ann Hum Biol. 1982;9:121–30. [PubMed] [Google Scholar]

4. Siddle N, Sarrel P, Whitehead M. The effect of hysterectomy on the age at ovarian failure: Identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril. 1987;47:94–100. [PubMed] [Google Scholar]

5. Soares CN, Taylor V. Effects and management of the menopausal transition in women with depression and bipolar disorder. J Clin Psychiatry. 2007;68(Suppl 9):16–21. [PubMed] [Google Scholar]

6. Baram D. Physiology and symptoms of menopause. In: Steward DE, Robinson GE, editors. A Clinician's Guide to Menopause. Health Press International: Washington DC; 1997. pp. 9–28. [Google Scholar]

7. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW) Fertil Steril. 2001;76:874–8. [PubMed] [Google Scholar]

8. Schiff I, Regestein Q, Tulchinsky D, Ryan KJ. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA. 1979;242:2405–4. [PubMed] [Google Scholar]

9. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75:1065–79. [PubMed] [Google Scholar]

10. Genant HK, Lucas J, Weiss S, Akin M, Emkey R, McNaney-Flint H, et al. Low-dose esterified estrogen therapy: Effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med. 1997;157:2609–15. [PubMed] [Google Scholar]

11. Weiss SR, Ellman H, Dolker M. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol. 1999;94:330–6. [PubMed] [Google Scholar]

12. Schiff I, Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA. 1980;244:1443–5. [PubMed] [Google Scholar]

13. Freedman RR, Woodward S, Sabharwal SC. Alpha 2-adrenergic mechanism in menopausal hot flushes. Obstet Gynecol. 1990;76:573–8. [PubMed] [Google Scholar]

14. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol. 1987;156:561–5. [PubMed] [Google Scholar]

15. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA. 2003;289:2827–34. [PubMed] [Google Scholar]

16. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002;20:1578–83. [PubMed] [Google Scholar]

17. Suvanto-Luukkonen E, Koivunen R, Sundström H, Bloigu R, Karjalainen E, Häivä-Mällinen L, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause. 2005;12:18–26. [PubMed] [Google Scholar]

18. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet. 2000;356:2059–63. [PubMed] [Google Scholar]

19. Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol. 1998;16:495–500. [PubMed] [Google Scholar]

20. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000;152:463–73. [PubMed] [Google Scholar]

21. Whiteman MK, Staropoli CA, Langenberg PW, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003;101:264–72. [PubMed] [Google Scholar]

22. Handa VL, Bachus KE, Johnston WW, Robboy SJ, Hammond CB. Vaginal administration of low-dose conjugated estrogens: Systemic absorption and effects on the endometrium. Obstet Gynecol. 1994;84:215–8. [PubMed] [Google Scholar]

23. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180:1072–9. [PubMed] [Google Scholar]

24. Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T, et al. Postmenopausal hormones and incontinence: The Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol. 2001;97:116–20. [PubMed] [Google Scholar]

25. Cauley JA, Zmuda JM, Ensrud KE, Bauer DC, Ettinger B. Study of Osteoporotic Fractures Research Group. Timing of estrogen replacement therapy for optimal osteoporosis prevention. J Clin Endocrinol Metab. 2001;86:5700–5. [PubMed] [Google Scholar]

26. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, 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;288:321–33. [PubMed] [Google Scholar]

27. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: A randomized controlled trial. JAMA. 2003;290:1042–8. [PubMed] [Google Scholar]

28. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668–76. [PubMed] [Google Scholar]

29. Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, Yankov V, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: A randomized clinical trial. Obstet Gynecol. 2004;104:443–51. [PubMed] [Google Scholar]

30. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA. 1998;280:2077–82. [PubMed] [Google Scholar]

31. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344–52. [PubMed] [Google Scholar]

32. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637–45. [PubMed] [Google Scholar]

33. Soares CN. New York, Arlington, VA: American Psychiatric Publishing; 2004. Perimenopause-related Mood Disturbance: An Update on Risk Factors and Novel Treatment Strategies Available. In: Meeting Program and Abstracts. Psychopharmacology and Reproductive Transitions Symposium. American Psychiatric Association 157th Annual Meeting; May 1.6, 2004; pp. 51–61. [Google Scholar]

34. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61:62–70. [PubMed] [Google Scholar]

35. Maartens LW, Knottnerus JA, Pop VJ. Menopausal transition and increased depressive symptomatology: A community based prospective study. Maturitas. 2002;42:195–200. [PubMed] [Google Scholar]

36. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: The Harvard study of moods and cycles. Arch Gen Psychiatry. 2006;63:385–90. [PubMed] [Google Scholar]

37. Steiner M, Dunn E, Born L. Hormones and mood: From menarche to menopause and beyond. J Affect Disord. 2003;74:67–83. [PubMed] [Google Scholar]

38. Halbreich U. Role of estrogen in postmenopausal depression. Neurology. 1997;48:16–9. [PubMed] [Google Scholar]

39. Huttner RP, Shepherd JE. Gonadal steroids, selective serotonin reuptake inhibitors, and mood disorders in women. Med Clin North Am. 2003;87:1065–76. [PubMed] [Google Scholar]

40. Sloan DM, Kornstein SG. Gender differences in depression and response to antidepressant treatment. Psychiatr Clin North Am. 2003;26:581–94. [PubMed] [Google Scholar]

41. Charney DA, Stewart DE. Psychiatric aspects. In: Steward DE, Robinson GE, editors. A Clinician's Guide to Menopause. Health Press International: Washington DC; 1997. pp. 129–44. [Google Scholar]

42. Payne JL. The role of estrogen in mood disorders in women. Int Rev Psychiatry. 2003;15:280–90. [PubMed] [Google Scholar]

43. Bromberger JT, Assmann SF, Avis NE, Schocken M, Kravitz HM, Cordal A. Persistent mood symptoms in a multiethnic community cohort of pre- and perimenopausal women. Am J Epidemiol. 2003;158:347–56. [PubMed] [Google Scholar]

44. Dennerstein L, Lehert P, Burger H, Dudley E. Mood and the menopausal transition. J Nerv Ment Dis. 1999;187:685–91. [PubMed] [Google Scholar]

45. Rasgon NL, Dunkin J, Fairbanks L, Altshuler LL, Troung C, Elman S, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: A pilot study. J Psychiatr Res. 2007;41:338–43. [PubMed] [Google Scholar]

46. Genazzani AR, Gambacciani M, Simoncini T, Schneider HP. Hormone replacement therapy in climacteric and aging brain. International Menopause Society Expert Workshop, 15-18 March 2003, Pisa, Italy. Climacteric. 2003;6:188–203. [PubMed] [Google Scholar]

47. Klaiber EL, Broverman DM, Vogel W, Kobayashi Y. Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry. 1979;36:550–4. [PubMed] [Google Scholar]

48. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996;347:930–3. [PubMed] [Google Scholar]

49. Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH, et al. Estrogen replacement in perimenopause-related depression: A preliminary report. Am J Obstet Gynecol. 2000;183:414–20. [PubMed] [Google Scholar]

50. Schneider MA, Brotherton PL, Hailes J. The effect of exogenous oestrogens on depression in menopausal women. Med J Aust. 1977;2:162–3. [PubMed] [Google Scholar]

51. Schneider HP. Cross-national study of women's use of hormone replacement therapy (HRT) in Europe. Int J Fertil Womens Med. 1997;42(Suppl 2):365–75. [PubMed] [Google Scholar]

52. Zweifel JE, O’Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology. 1997;22:189–212. [PubMed] [Google Scholar]

53. Amsterdam J, Garcia-España F, Fawcett J, Quitkin F, Reimherr F, Rosenbaum J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55:11–7. [PubMed] [Google Scholar]

54. Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: Results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA. 2002;287:591–7. [PubMed] [Google Scholar]

55. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: A double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58:529–34. [PubMed] [Google Scholar]

56. Gambacciani M, Ciaponi M, Cappagli B, Monteleone P, Benussi C, Bevilacqua G, et al. Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women. Maturitas. 2005;50:91–7. [PubMed] [Google Scholar]

57. Schiff R, Bulpitt CJ, Wesnes KA, Rajkumar C. Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study. Psychoneuroendocrinology. 2005;30:309–15. [PubMed] [Google Scholar]

58. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003;348:1839–54. [PubMed] [Google Scholar]

59. Heinrich AB, Wolf OT. Investigating the effects of estradiol or estradiol/progesterone treatment on mood, depressive symptoms, menopausal symptoms and subjective sleep quality in older healthy hysterectomized women: A questionnaire study. Neuropsychobiology. 2005;52:17–23. [PubMed] [Google Scholar]

60. Robinson GE, Stirtzinger R. Psychoeducational programs and support groups at transition to menopause. In: Steward DE, Robinson GE, editors. A Clinician's Guide to Menopause. Washington, DC: Health Press International; 1997. pp. 165–80. [Google Scholar]

61. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351–8. [PubMed] [Google Scholar]

62. La Rue A. New York: Plenum Press; 1992. Aging and Neuropsychological Assessment. [Google Scholar]

63. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13:345–57. [PubMed] [Google Scholar]

64. Duka T, Tasker R, McGowan JF. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl) 2000;149:129–39. [PubMed] [Google Scholar]

65. Caldwell BM, Watson RI. An evaluation of psychologic effects of sex hormone administration in aged women. I. Results of therapy after six months. J Gerontol. 1952;7:228–44. [PubMed] [Google Scholar]

66. Hackman BW, Galbraith D. Replacement therapy and piperazine oestrone sulphate (’Harmogen’) and its effect on memory. Curr Med Res Opin. 1976;4:303–6. [PubMed] [Google Scholar]

67. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. JAMA. 1998;279:688–95. [PubMed] [Google Scholar]

68. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000;283:1007–15. [PubMed] [Google Scholar]

69. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA. 2003;289:2651–62. [PubMed] [Google Scholar]

70. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2959–68. [PubMed] [Google Scholar]

71. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med. 2002;11:367–77. [PubMed] [Google Scholar]

72. Bachmann G, Bancroft J, Braunstein G, Burger H, Davis S, Dennerstein L, et al. Female androgen insufficiency: The Princeton consensus statement on definition, classification, and assessment. Fertil Steril. 2002;77:660–5. [PubMed] [Google Scholar]

73. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: A double-blind, cross-over study. Psychoneuroendocrinology. 1985;10:325–35. [PubMed] [Google Scholar]

74. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril. 2003;79:1341–52. [PubMed] [Google Scholar]

75. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682–8. [PubMed] [Google Scholar]

76. Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, et al. Testosterone patch for low sexual desire in surgically menopausal women: A randomized trial. Obstet Gynecol. 2005;105:944–52. [PubMed] [Google Scholar]

77. Soares CN, Joffe H, Steiner M. Menopause and mood. Clin Obstet Gynecol. 2004;47:576–91. [PubMed] [Google Scholar]

78. Murphy PJ, Campbell SS. Sex hormones, sleep, and core body temperature in older postmenopausal women. Sleep. 2007;30:1788–94. [PMC free article] [PubMed] [Google Scholar]

79. Krystal AD. Depression and insomnia in women. Clin Cornerstone. 2004;6(Suppl 1B):S19–28. [PubMed] [Google Scholar]

80. Miller EH. Women and insomnia. Clin Cornerstone. 2004;6(Suppl 1B):S8–18. [PubMed] [Google Scholar]

81. Shin K, Shapiro C. Menopause, sex hormones, and sleep. Bipolar Disord. 2003;5:106–9. [PubMed] [Google Scholar]

82. Häfner H. Gender differences in schizophrenia. Psychoneuroendocrinology. 2003;28(Suppl 2):17–54. [PubMed] [Google Scholar]

83. Marsh WK, Templeton A, Ketter TA, Rasgon NL. Increased frequency of depressive episodes during the menopausal transition in women with bipolar disorder: Preliminary report. J Psychiatr Res. 2008;42:247–51. [PubMed] [Google Scholar]

84. Burt VK, Rasgon N. Special considerations in treating bipolar disorder in women. Bipolar Disord. 2004;6:2–13. [PubMed] [Google Scholar]

85. Claudia P, Andrea C, Chiara C, Stefano L, Giuseppe M, Vincenzo DL, et al. Panic disorder in menopause: A case control study. Maturitas. 2004;48:147–54. [PubMed] [Google Scholar]

86. Smoller JW, Pollack MH, Wassertheil-Smoller S, Barton B, Hendrix SL, Jackson RD, et al. Prevalence and correlates of panic attacks in postmenopausal women: Results from an ancillary study to the Women's Health Initiative. Arch Intern Med. 2003;163:2041–50. [PubMed] [Google Scholar]

87. Lochner C, Hemmings SM, Kinnear CJ, Moolman-Smook JC, Corfield VA, Knowles JA. Corrigendum to gender in obsessive-compulsive disorder: Clinical and genetic findings. Eur Neuropsychopharmacol. 2004;14:437–45. [PubMed] [Google Scholar]

88. Bluming AZ. Hormone replacement therapy: Benefits and risks for the general postmenopausal female population and for women with a history of previously treated breast cancer. Semin Oncol. 1993;20:662–74. [PubMed] [Google Scholar]

89. Burkman RT, Collins JA, Greene RA. Current perspectives on benefits and risks of hormone replacement therapy. Am J Obstet Gynecol. 2001;185:S13–23. [PubMed] [Google Scholar]

90. Gorsky RD, Koplan JP, Peterson HB, Thacker SB. Relative risks and benefits of long-term estrogen replacement therapy: A decision analysis. Obstet Gynecol. 1994;83:161–6. [PubMed] [Google Scholar]

91. Col NF, Eckman MH, Karas RH, Pauker SG, Goldberg RJ, Ross EM, et al. Patient-specific decisions about hormone replacement therapy in postmenopausal women. JAMA. 1997;277:1140–7. [PubMed] [Google Scholar]

92. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276–85. [PubMed] [Google Scholar]

93. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52, 705 women with breast cancer and 108, 411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:1047–59. [PubMed] [Google Scholar]

94. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328–32. [PubMed] [Google Scholar]

95. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstet Gynecol. 1995;85:304–13. [PubMed] [Google Scholar]

96. Syamala TS, Sivakami M. New Delhi: Benett Coleman and Co; 2007. India Women Reaching Menopause at 30: Study, in Times of India. [Google Scholar]

97. Brambilla DJ, McKinlay SM, Johannes CB. Defining the perimenopause for application in epidemiologic investigations. Am J Epidemiol. 1994;140:1091–5. [PubMed] [Google Scholar]

98. Chowta NK, Sebastian J, Chowta MN. Comparative study of menopausal symptoms in post menopausal and perimenopausal women. J Clin Diagn Res. 2008;2:959–62. [Google Scholar]

99. Taylor DL, Fonseka P. Symptom experience of Filipino American midlife women. Menopause. 1999;6:105–14. [PubMed] [Google Scholar]

100. Goonaratna C, Fonseka P, Wijeywardene K. Perimenopausal symptoms in Sri Lankan women. Ceylon Med J. 1999;44:63–9. [PubMed] [Google Scholar]

101. Lagos X, Navarro N, Illanes E, Bustos L. Prevalence of biological and psychological symptoms in perimenopausal women from different socioeconomic levels in the city of Temuco. Rev Med Chil. 1998;126:1189–94. [PubMed] [Google Scholar]

102. Schindler BA. The psychiatric disorders of midlife. Med Clin North Am. 1987;71:71–85. [PubMed] [Google Scholar]

103. Singh M, Singh G. A comparison of mental health status during menopause and post-menopause middle-aged working women. Internet J World Health Soc Politics. 2007;4:61–9. [Google Scholar]

104. Sagsöz N, Oguztürk O, Bayram M, Kamaci M. Anxiety and depression before and after the menopause. Arch Gynecol Obstet. 2001;264:199–202. [PubMed] [Google Scholar]

105. Prakash IJ, Murthy VN. Psychiatric morbidity and the menopause. Indian J Psychiatry. 1981;23:242–6. [PMC free article] [PubMed] [Google Scholar]

106. Indira SN, Murthy VN. Nature of psychiatric disturbances in menopausal women. Indian J Clin Psychol. 1980;7:7. [Google Scholar]

107. Nagar S, Dave P. Perception of women towards physiological problems faced at menopause. Anthropologist. 2005;7:173–5. [Google Scholar]

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