Premenopausal

This article is about the midlife life stage in women. For so-called male menopause, see Andropause. For the effects from stopping estrogen therapy, see Estrogen therapy.

Menopause
Classification and external resources
ICD-10 9 DiseasesDB MedlinePlus eMedicine article/264088

Menopause refers to the time of cessation of a woman's reproductive ability.

Menopause literally means the "end of monthly cycles" (the end of monthly periods or menstruation), from the Greek word pausis (cessation) and the root men- (month). Menopause is an event that typically occurs in women in midlife, during their late 40s or early 50s, and it signals the end of the fertile phase of a woman's life.[1] In addition to being defined by the state of the uterus and the absence of menstrual flow, menopause can also be described as the permanent cessation of the primary functions of the ovaries:[2] the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining, and the subsequent shedding of the uterine lining (a.k.a. the menses or the period).

This transition from a potentially reproductive to a non-reproductive state is the result of changes in female hormonal production by the ovaries. This transition is normally not sudden or abrupt, tends to occur over a period of years, and is a consequence of biological aging. For some women, the accompanying signs and effects that can occur during the menopause transition years can significantly disrupt their daily activities and sense of well-being.

The word "menopause" was coined specifically for human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruations. However, menopause also exists in some other animals, many of which do not have monthly menstruation;[3] in this case, the term means a natural end to fertility that occurs before the end of the natural lifespan.

Age

Normal range

In the Western world, the most typical age range for menopause (last period from natural causes) is between the ages of 40 and 61[4] and the average age for last period is 51 years.[5] The average age of natural menopause in Australia is 51.7 years,[6] although this varies considerably from one woman to another. In India and the Philippines, the median age of natural menopause is considerably earlier, at 44 years.[7]

Youngest

In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40, and this is known as premature ovarian failure (POF). Spontaneous premature ovarian failure affects 1% of women by age 40, and 0.1% of women by age 30. POF is not considered to be due to the normal effects of aging.

Oldest

Due to vagaries in records systems throughout the world, an oldest age for which menopause has occurred in a female of the human species is not exactly known. Reports of normal conception and child birth around the age of 70 exist, but are usually subject to controversy. Reports of normal conception beyond age 70 are almost nonexistent. [8]

Additional factors

Women who have undergone hysterectomy with ovary conservation go through menopause on average 3.7 years earlier than the expected age. Various contemporary studies have asserted links to lifestyle factors that may promote an earlier onset (usually 1 to 3 years) of menopause, such as type of diet, smoking cigarettes, and exposure to industrial chemicals. [9]

The process of normal menopause

General Description

The menopause transition, and postmenopause itself, is a natural life change, not a disease state or a disorder. The transition itself has a variable degree of effects. It can be a difficult time of life.[10]

Menopause is perhaps most easily understood as the opposite process to menarche, the start of the monthly periods. However, menopause in women cannot satisfactorily be defined simply as the permanent "stopping of the monthly periods", because in reality what is happening to the uterus is quite secondary to the process; it is what is happening to the ovaries that is the crucial factor.

As an illustration of the central role that the ovaries play, it is worth pointing out that when for medical reasons the uterus has to be surgically removed (hysterectomy) in a younger woman, her periods will of course cease permanently, and the woman will be incapable of pregnancy, but as long as at least one of her ovaries is still functioning, the woman will not have reached menopause. Even without the presence of the uterus, ovulation and the release of the sequence of reproductive hormones will continue to cycle on, until menopause is reached. In contrast to this, in circumstances where a woman's ovaries are removed (oophorectomy), even if the uterus were to be left intact, the woman will immediately be in "surgical menopause". Surgical menopause is a menopause which is induced both suddenly and totally, by removal of both ovaries prior to the age of natural menopause.

On average, assuming there has been no surgical intervention, the first evidence of the onset of the menopause transition time is slight variations in the length of the menstrual cycle. These variations become more pronounced over time, and eventually lead to cycles that can be considerably longer or considerably shorter than usual, flow that can be significantly lighter or heavier than usual, skipped ovulations, skipped periods, and spans of time of many months with no flow at all, after which menstruation may resume. The transition is considered to be over once a woman has experienced 12 months without any menstrual bleeding at all, even though perimenopause effects may extend well beyond this point in time. The term "perimenopause", which literally means "around the menopause", refers to the menopause transition years, a span of time both before and after the date of the final episode of flow.

Premenopause

Premenopause is the years leading up to the last period, when the levels of reproductive hormones are already becoming lower and more erratic, and the effects of hormone withdrawal may be present.[11]

Perimenopause aka the menopause transition

Perimenopause is the menopause transition years. According to the North American Menopause Society, this transition can last for four to eight years.[12] The Centre for Menstrual Cycle and Ovulation Research describes it as a six to ten year phase ending 12 months after the last menstrual period.[13]

During perimenopause, estrogen levels average about 20-30% higher than during premenopause, often with wide fluctuations in levels.[13] These fluctuations cause many of the physical changes during perimenopause as well as menopause.[14] Some of these changes are hot flashes, night sweats, difficulty sleeping, vaginal dryness or atrophy, incontinence, osteoporosis, and heart disease.[13] During this period, fertility diminishes, but is not considered to reach zero until the official date of menopause. The official date is determined retroactively, once 12 months have passed after the last appearance of menstrual blood.

Signs and effects of the menopause transition can begin as early as age 35, although most women become aware of the transition in their mid to late 40s, often many years after the actual beginning of the perimenopausal window. The duration of perimenopause with noticeable bodily effects can be as brief as a few years, but it is not unusual for the duration to last ten or more years. The actual duration and severity of perimenopause effects for any individual woman currently cannot be predicted in advance. Even though the process, or the course, of perimenopause or menopause can be difficult to predict, the age of onset is somewhat predictable: women will often, but not always, start these transitions (perimenopause and menopause) about the same time as their mother.[15]

During the perimenopause years, many women undergo noticeable and clinically observable physical changes resulting from hormonal fluctuations. The best-known of these is the "hot flash" or "hot flush", a sudden temporary increase in body temperature. The "flash" sensation occurs as the body temperature soars upward, reaching a peak very rapidly. The "hot" sensation is not the initial temperature rise; rather, it is a reaction to the slowness of the body's return to a more normal temperature range.

Hot flashes can be so strong that they raise the body temperature by many degrees in a very short period of time; this extreme temperature differential can cause the sufferer to feel weak and break out in heavy sweating. Despite the discomfort to the woman, hot flashes are not considered harmful by physicians. In most cases, flashes can be treated to ease extreme discomfort, using prescription medications such as hormone replacement therapy (HRT) or SSRI medications, or by using over-the-counter plant estrogens and herbal remedies. Many women manage hot flashes by dressing in ways that dissipate heat quickly (natural fibers, loose clothing, easily removable layers of lightweight garments) as well as mechanical means which help the body to remove excess heat, such as fans, drinking ice water, and staying in cool rooms.

Other common effects encountered during the perimenopausal period include mood changes, insomnia, fatigue, and memory problems.

Menopause may, in some women, bring about a sense of loss related to the end of fertility. In addition this change often occurs at a time of life when other stressors may be present in the life of a woman:

  • Having to deal with caring for, and/or the death of, elderly parents
  • Empty-nest syndrome when children leave home
  • The birth of grandchildren, which places people of "middle age" into a new category of "older people" (especially in those cultures where being older is a state that is not venerated but looked down on)

Recent research shows that melatonin supplementation in perimenopausal women can produce a significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[16]

Menopause

Clinically speaking, menopause is defined as a specific date. Assuming the woman still has a uterus, menopause is defined as the day after the woman's final episode of menstrual flow finishes. This date is fixed retrospectively, once 12 months have gone by with no menstrual flow at all. At this point a woman is considered to be one year into postmenopause, is considered to be infertile, and no longer needs to take into consideration the possibility of pregnancy.

In common parlance, however, the word "menopause" usually refers not to just one day, but to the whole of the menopause transition years. This span of time is also commonly called the change of life, the change, or the climacteric and more recently is known as "perimenopause", (literally meaning "around menopause").

The word menopause is also often used in popular parlance to mean all the years of postmenopause.

Postmenopause

The term postmenopause is applied to women who have not experienced a menstrual bleed for a minimum of 12 months, assuming that they do still have a uterus, and are not pregnant or lactating.[11] In women without a uterus, menopause or postmenopause is identified by a very high FSH level. Thus postmenopause is all of the time in a woman's life that take place after her last period, or more accurately, all of the time that follows the point when her ovaries become inactive.

A woman who still has her uterus (and who is neither pregnant nor lactating) can be declared to be in postmenopause once she has gone 12 full months with no flow at all, not even any spotting.[11] When she reaches that point, she is one year into postmenopause.

The reason for this delay in declaring a woman postmenopausal is because periods are usually extremely erratic at this time of life, and therefore a reasonably long stretch of time is necessary to be sure that the cycling has actually ceased completely.

At this point a woman is considered infertile, and no longer needs to consider the possibility of becoming pregnant. However the possibility of becoming pregnant has usually been very low (but not zero) for a number of years before this point is reached.

In women who have no uterus, and therefore have no periods, post-menopause can be determined by a blood test which can reveal the very high levels of Follicle Stimulating Hormone (FSH) that are typical of post-menopausal women.

A woman's reproductive hormone levels continue to drop and fluctuate for some time into post-menopause, so any hormone withdrawal symptoms that a woman may be experiencing do not necessarily stop right away, but may take quite some time, even several years, to disappear completely.

Any period-like flow that might occur during postmenopause, even just spotting, must be reported to a doctor. The cause may in fact be minor, but the possibility of endometrial cancer must be checked for and eliminated.

Biology of normal menopause

The hormonal context

The stages of the menopause transition have been classified according to a woman's reported bleeding pattern, supported by changes in the pituitary follicle-stimulating hormone (FSH) levels.[17]

In younger women, during a normal menstrual cycle the ovaries produce estradiol, testosterone and progesterone in a cyclical pattern under the control of FSH and luteinising hormone (LH) which are both produced by the pituitary gland. Blood estradiol levels remain relatively unchanged, or may increase approaching the menopause, but are usually well preserved until the late perimenopause. This is presumed to be in response to elevated FSH levels.[18] However, the menopause transition is characterized by marked, and often dramatic, variations in FSH and estradiol levels, and because of this, measurements of these hormones are not considered to be reliable guides to a woman's exact menopausal status.[19]

Menopause is based on the natural or surgical cessation of estradiol and progesterone production by the ovaries, which are a part of the body's endocrine system of hormone production, in this case the hormones which make reproduction possible and influence sexual behavior. After menopause, estrogen continues to be produced in other tissues, notably the ovaries, but also in bone, blood vessels and even in the brain.[20] However the dramatic fall in circulating estradiol levels at menopause impacts many tissues, from brain to skin.

In contrast to the sudden fall in estradiol during menopause, the levels of total and free testosterone, as well as dehydroepiandrosterone sulfate (DHEAS) and androstenedione appear to decline more or less steadily with age. An effect of natural menopause on circulating androgen levels has not been observed.[21] Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production. [22]

Indications and signs

During the menopause transition years, as the body responds to the rapidly fluctuating and dropping levels of natural hormones, a number of effects may appear. Not every woman experiences bothersome levels of these effects; the range of effects and the degree to which they appear is very variable from person to person.

Effects that are due to low estrogen levels (for example vaginal atrophy and skin drying) will continue after the menopause transition years are over; however, many effects that are caused by the extreme fluctuations in hormone levels (for example hot flashes and mood changes) usually disappear or improve significantly once the perimenopause transition is completely over. All the various possible perimenopause effects are caused by an overall drop, as well as dramatic but erratic fluctuations, in the absolute levels and relative levels of estrogens and progesterone. Effects such as formication (crawling, itching, or tingling skin sensations), may be associated directly with hormone withdrawal.

Both users and non-users of hormone replacement therapy identify lack of energy as the most frequent and distressing effect.[23] Other effects can include vasomotor symptoms such as hot flashes and palpitations, psychological effects such as depression, anxiety, irritability, mood swings, memory problems, and lack of concentration, and atrophic effects such as vaginal dryness and urgency of urination.

The average woman also has increasingly erratic menstrual periods, due to skipped ovulations. Typically, the timing of the flow becomes unpredictable. In addition the duration of the flow may be considerably shorter or longer than normal, and the flow itself may be significantly heavier or lighter than was previously the case, including sometimes long episodes of spotting. Early in the process it is not uncommon to have some 2-week cycles. Further into the process it is common to skip periods for months at a time, and these skipped periods may be followed by a heavier period. The number of skipped periods in a row often increases as the time of last period approaches. At the point when a woman of menopausal age has had no periods or spotting for 12 months, she is considered to be one year into post-menopause.

One way of assessing the impact on women of some of these menopause effects are the Greene Climacteric Scale questionnaire,[24] the Cervantes Scale[25] and the Menopause Rating Scale[26]

Urogenital atrophy, also known as vaginal atrophy

Main article: Atrophic vaginitis
  • Thinning of the membranes of the vulva, the vagina, the cervix, and also the outer urinary tract, along with considerable shrinking and loss in elasticity of all of the outer and inner genital areas.
  • Itching
  • Dryness
  • Young women who are approaching menopause may experience dysfunctional bleeding due to the hormonal changes that accompany the menopausal transition. Genital bleeding is an alarming symptom for postmenopausal women that requires an appropriate study to discard malignant diseases. Spotting or bleeding may be related to a benign sore (polyp or lesion) or functional endometrial response. The European Menopause and Andropause Society has released Guidelines for assessment of the endometrium which is main origin of the spotting or bleeding.[28]
Skeletal
Skin, soft tissue
  • Breast atrophy
  • Breast tenderness ± swelling
  • Decreased elasticity of the skin
  • Formication (itching, tingling, burning, pins, and needles, or sensation of ants crawling)
  • Skin thinning and becoming drier
Psychological
Sexual

Cohort studies have reached mixed conclusions about medical conditions associated with the menopause. For example, a 2007 study found that menopause was associated with hot flashes; joint pain and muscle pain; and depressed mood.[36] In the same study, it appeared that menopause was not associated with poor sleep, decreased libido, and vaginal dryness.[36] However, in contrast to this, a 2008 study did find an association with poor sleep quality.[37]


Cause

The causes of menopause can be considered from complementary proximate (mechanistic) perspectives (how it happens) or from ultimate (adaptive evolutionary) perspectives (why it happens). The latter group are hypotheses only.

Proximate perspective

Natural or physiological menopause occurs as a part of a woman's normal aging process. It is the result of the eventual depletion of almost all of the oocytes and ovarian follicles in the ovaries.[38] This causes an increase in circulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels because there are a decreased number of oocytes and follicles responding to these hormones and producing estrogen. This decrease in the production of estrogen leads to the perimenopausal symptoms of hot flashes, insomnia and mood changes. Long term effects may include osteoporosis and vaginal atrophy.

Depletion of the ovarian reserve

Titus et al. proposed an explanation for the depletion of the ovarian reserve during aging.[39] They found that as women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that ordinarily accurately repairs DNA double-strand breaks. This repair system is called “homologous recombinational repair”, and it is especially effective during meiosis. Meiosis is the general process by which germ cells are formed in all sexual eukaryotes, and it appears to be an adaptation for efficiently removing damages in germ line DNA.[40] (See Meiosis.)

Human primary oocytes are present at an intermediate stage of meiosis, termed prophase I (see Oogenesis). Titus et al. further demonstrated that expression of four key DNA repair genes that are necessary for homologous recombinational repair during meiosis (BRCA1, MRE11, Rad51, and ATM) decline with age in oocytes.[39] This age-related decline in ability to repair DNA double-strand damages can account for the accumulation of these damages, that then likely contributes to the depletion of the ovarian reserve.

Evolutionary rationale for menopause

The evolution of menopause in human females is not completely understood. Various theories have been developed that try to explain benefits to the species arising from nature cutting off the reproductive capability of large numbers of females. Human females typically spend over one third of their lifespan in a post-reproductive phase. Explanations for limited reproductive time can be categorized as adaptive and non-adaptive.

Non-adaptive hypotheses

The high cost of female investment in offspring may lead to physiological deteriorations that amplify susceptibility to becoming infertile. This hypothesis suggests the reproductive lifespan in humans has been optimized, but it has proven more difficult in females and thus their reproductive span is shorter. If this hypothesis were true however, age at menopause should be negatively correlated with reproductive effort[41] and the available data does not support this.[42]

A recent increase in female longevity due to improvements in the standard of living and social care has also been suggested.[43] It is difficult for selection, however, to favour aid to offspring from parents and grandparents[44] Irrespective of living standards, adaptive responses are limited by physiological mechanisms. In other words senescence is programmed and regulated by specific genes.[45]

Adaptive hypotheses

The Survival of the Fittest hypothesis

This hypothesis suggests that younger mothers and offspring under their care will fair better in a difficult and predatory environment because a younger mother will be stronger and more agile in providing protection and sustenance for herself and a nursing baby. The various biological factors associated with menopause had the effect of male members of the species investing their effort with the most viable of potential female mates. [46] One problem with this hypothesis is that we would expect to see menopause exhibited more often throughout the animal kingdom. [47]

The mother hypothesis

The mother hypothesis suggests that menopause was selected for in humans because of the extended development period of human offspring and high costs of reproduction so that mothers gain an advantage in reproductive fitness by redirecting their effort from new offspring with a low survival chance to existing children with a higher survival chance.[48]

The grandmother hypothesis

The Grandmother hypothesis suggests that menopause was selected for in humans because it promotes the survival of grandchildren. According to this hypothesis, post reproductive women feed and care for children, adult nursing daughters, and grandchildren whose mothers have weaned them. Human babies require large and steady supplies of glucose to feed the growing brain. In infants in the first year of life, the brain consumes 60% of all calories, so both babies and their mothers require a dependable food supply. Some evidence suggests that hunters contribute less than half the total food budget of most hunter-gatherer societies, and often much less than half, so that foraging grandmothers can contribute substantially to the survival of grandchildren at times when mothers and fathers are unable to gather enough food for all of their children. In general, selection operates most powerfully during times of famine or other privation. So although grandmothers might not be necessary during good times, many grandchildren cannot survive without them during times of famine. Arguably, however, there is no firm consensus on the supposed evolutionary advantages (or simply neutrality) of menopause to the survival of the species in the evolutionary past.

Indeed, analysis of historical data found that the length of a female's post-reproductive lifespan was reflected in the reproductive success of her offspring and the survival of her grandchildren.[49] Interestingly, another study found comparative effects but only in the maternal grandmother – paternal grandmothers had a detrimental effect on infant mortality (probably due to paternity uncertainty).[50] Differing assistance strategies for maternal and paternal grandmothers have also been demonstrated. Maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates.[51]

A problem concerning the grandmother hypothesis is that it requires a history of female philopatry and yet present day evidence shows that the majority of hunter-gatherer societies are patriarchal.[52] In addition, all variations on the mother, or grandmother effect fail to explain longevity with continued spermatogenesis in males (oldest verified paternity is 94 years, 35 years beyond the oldest documented birth attributed to females).[53] It also fails to explain the detrimental effects of losing ovarian follicular activity, such as osteoporosis, osteoarthritis, Alzheimer's disease and coronary artery disease.[54]

Management

Perimenopause is a natural stage of life. It is not a disease or a disorder, and therefore it does not automatically require any kind of medical treatment at all. However, in those cases where the physical, mental, and emotional effects of perimenopause are strong enough that they significantly disrupt the everyday life of the woman experiencing them, palliative medical therapy may sometimes be appropriate.

Hormone replacement therapy

See also Hormone replacement therapy (menopause)

In the context of the menopause hormone replacement therapy or HRT (known in the UK as hormone therapy or HT) is the use of estrogen plus progestin for a woman who has an intact uterus, or estrogen alone for a woman who has had a hysterectomy.[55] Traditionally such therapy was provided as tablets but now is available in a range of formulations including skin patches, gels, skin sprays, subcutaneous implants and so forth. A popular alternative to conventional HRT is a synthetic hormone (derived from the Mexican yam) called tibolone. Of the non hormonal therapies for hot flushes, some of the SSRIs appear to provide some pharmaceutical relief.[56] Adverse effects of HRT appear to vary according to formulation and dose. See the section below on "Adverse effects of conjugated equine estrogens".

In addition to relief from hot flashes, hormone therapy can alleviate vaginal dryness, improve sleep quality and joint pain. It is also extremely effective for preventing bone loss and osteoporotic fracture.[57]

A woman and her doctor should carefully review her situation, her complaints and her relative risk before determining whether the benefits of HT/HRT or other therapies outweigh the risks. Until more becomes understood about the possible risks, women who elect to use hormone replacement therapy are generally well advised to take the lowest effective dose of hormones for the shortest period possible, and to question their doctors as to whether certain forms might pose fewer dangers of clots or cancer than others.

Until recently the most widely used estrogen preparation worldwide in postmenopausal women was oral conjugated equine estrogens. Other oral oestrogen preparations include synthetically derived piperazine estrone sulphate, estriol, micronised estradiol, and estradiol valerate. Estradiol may also be used transdermally as a patch or gel, as a slow release percutaneous implant, and more recently as a metered dose skin spray. Intravaginal estrogens include topical estradiol in the form of a ring or pessary, estriol in pessary or cream form, dienoestrol and conjugated oestrogens in the form of creams. Oral micronised estradiol and other oral estrogen preparations may result in up to tenfold higher levels of circulating estrone sulphate than transdermally administered estradiol at comparable or even higher doses.[58] This is of concern in that estrogen sensitive tissues such as breast and endometrium have high capacity to metabolise estrone sulphate through to estradiol. Orally administered estrogen therapy also increases sex hormone binding globulin (SHBG) to a greater extent than non orally administered estrogens. SHBG binds estrogen and testosterone in the blood and this may result in a clinically significant reduction in the bioavailability of these hormones. Thus it would seem that the prescription of oral estrogen therapy should be at the lowest available dose to minimise effects on circulating estrone sulphate and SHBG.

In those women who have no uterus (usually due to a previous hysterectomy), estrogen alone is a suitable hormone therapy and is in fact preferable to continuing to use progesterone when its function as a moderating influence on growth of the endometrium (uterine lining) is no longer required. Women who still have a uterus need to take progesterone in addition to estrogen to protect against the development of endometrial hyperplasia and endometrial carcinoma.

Oral administration of progesterone is convenient, however the oral micronised form is rapidly metabolized and inactivated in the liver, therefore high doses must be administered to achieve adequate circulating blood levels. Synthetic progestins have been developed and are prescribed to overcome this problem. Synthetic progestins are more resistant to liver metabolism, therefore lower doses can be used to achieve the desired endometrial effect. It is not uncommon for women to experience side effects with progesterone or progestin therapy. Progesterone may cause sedation so is best taken at bedtime.[59] Synthetic progestins may cause irritability and mood changes in some women.[60]

Conjugated equine estrogens

Conjugated equine estrogens contain estrogen molecules conjugated to hydrophilic side groups (e.g. sulfate) and are produced from the urine of pregnant Equidae (horses) mares. Premarin is the prime example of this, either alone or in Prempro, where it is combined with a synthetic progestin, medroxyprogesterone acetate.

Women had been advised for many years by numerous doctors and drug company marketing efforts (at least in the United States) that hormone therapy with conjugated equine estrogens after menopause might reduce their risk of heart disease and prevent various aspects of aging. However, a large, randomized, controlled trial (the Women's Health Initiative) found that women undergoing HT or HRT with conjugated equine estrogens (Premarin), in combination with a synthetic progestin (medroxy pogesterone acetate (Premarin plus Provera, known as Prempro)), had an increased risk of breast cancer and heart disease.[61] An increase in breast cancer risk was not seen in the Women's Health Initiative study of conjugate estrogen alone (Premarin) versus placebo, however this study was stopped prematurely as an increased risk of stroke was observed in women treated with Premarin.[62] Although this increase in risk was small overall, it passed the thresholds that had been established by the researchers in advance as sufficient to ethically require stopping the study.

When these results were first reported in 2002, the popular media sensationalized the story and exaggerated the risk, while the manufacturer continued to attempt to minimize the degree of risk. However most news stories failed to mention that the average age of the women in WHI was 62 years old, significantly older than the time when most women start HRT, and in fact many years into postmenopause. To enroll in the study, patients had to be asymptomatic of hot flashes, so they would not know whether they received the placebo. For these reasons, WHI was not representative of generally accepted clinical practice.

The 2002 and 2003 announcements of the Women's Health Initiative of the American National Institute of Health and The Million Women Study of the UK Cancer Research and National Health Service collaboration respectively, that HRT treatment coincides with an increased incidence of breast cancer, heart attacks and strokes, lead to a sharp decline in HRT prescription throughout the world,[63][64][65] which was followed by a decrease in breast cancer incidence.[66][67]

On hearing the news about the WHI study, many women discontinued equine estrogens altogether, with or without their doctor's knowledge. The number of prescriptions written for Premarin and PremPro in the United States dropped within a year almost to half of their previous level. This sharp drop in usage was followed by large and successively larger drops in new breast cancer diagnoses, at six months, one year, and 18 months after the drop in Premarin and Prempro prescriptions, for a cumulative 15% drop by the end of 2003. However, the apparent meaning of this correlation is called into question by the fact that prescriptions of Prempro and Premarin fell dramatically in Canada as well, but no similarly dramatic drop in Canada's breast cancer rates was observed during the same time period. Studies designed to track the further progression of this trend after 2003 are under way, as well as studies designed to quantify how much of the drop was related to the reduced use of HT/HRT.[62]

The WHI study results have created a new scenario for postmenopausal women.[68]

Researchers at the University of North Carolina at Chapel Hill are currently undergoing a study to determine if estrogen replacement therapy can improve cardiovascular health and prevent depression in perimenopausal women between the ages of 45 and 55.[69] David Rubinow, UNC's chair of Psychiatry, and one of two principal investigators on the NIH-funded five-year study, notes there is a very important difference between the UNC study and the WHI estrogen study. Rubinow states that "the Women's Health Initiative study led to the mistaken belief that estrogen replacement therapy is bad for all women. And as a result, it has served to deprive some women of a treatment that might greatly and favorably impact their lives. Much of the negative impact of estrogen that they found was related to the fact that most of the women in the Women's Health Initiative study were far past the menopause and up to 79 years old". Rubinow continues by explaining that "there are now a large number of studies that demonstrate what has been called the timing hypothesis. That is, giving estrogen within a year or two of menopause has beneficial effects, but giving estrogen in women more than five years beyond the menopause can actually be harmful. When the women who were close to menopause were looked at separately, the adverse effects on the heart were not seen and in fact some suggestion of beneficial effects was seen. Perimenopausal women in the Women's Health Initiative who received estrogen had significantly lower coronary artery calcification compared to the women who didn't take estrogen". As Rubinow states, "given the mortality and morbidity associated with depression and heart disease, and the tremendous increase in risk of these disorders during the perimenopause, it is critical that we identify those women who will be helped by estradiol".[70]

Selective estrogen receptor modulators

SERMs are a category of drugs, either synthetically produced or derived from a botanical source (phytoserms), that act selectively as agonists or antagonists on the estrogen receptors throughout the body. The most commonly prescribed SERMs are raloxifene and tamoxifen. Raloxifene exhibits oestrogen agonist activity on bone and lipids, and antagonist activity on breast and the endometrium.[71] Tamoxifen is in widespread use for treatment of hormone sensitive breast cancer. Raloxifene prevents vertebral fractures in postmenopausal, osteoporotic women and reduces the risk of invasive breast cancer.[72] While most SERMs are known to increase hot flushes, Femarelle (DT56a) decreases them.[73][74] In addition to the relieving effects on menopausal symptoms, Femarelle also increases bone mass density (BMD), making it protective against osteoporotic fractures.[75] These effects are achieved by an agonistic interaction with estrogen receptors in the brain and bone. On the other hand, an antagonist interaction with estrogen receptors in the breast[76] and uterus,[77][78] has no effect on these tissues.

There is more promising data from an emerging SERM treatment based on a multibotanical compound MF-101 (trade name Menerba) can be located here.

DHEA

In postmenopausal women, within a randomized placebo-controlled trial, no statistically significant effect of DHEA supplementation on muscle strength during a 12 week combined endurance and weight training program.[79][80]

Antidepressants

Antidepressants such as paroxetine (Paxil), Fluoxetine hydrochloride (Prozac), and Venlafaxine hydrochloride (Effexor) have been used with some success in the treatment of hot flashes. Paroxetine and venlafaxine may cause nausea and insomnia. In addition, venlafaxine may cause dry mouth, constipation, and decreased appetite whereas paroxetine may cause headaches. There is a theoretical reason why SSRI antidepressants might help with memory problems: they increase circulating levels of the neurotransmitter serotonin in the brain and restore hippocampal function.[81] Fluoxetine hydrochloride (Sarafem) is also prescribed for premenstrual dysphoric disorder (PMDD), a mood disorder often exacerbated during perimenopause. PMDD has been found by PET scans to be associated with dysregulation of serotonin pathways in the brain[82] and to respond quickly and powerfully to SSRIs.

Gabapentin

Gabapentin (sometimes called by its brand name, Neurontin) and other GABA analogs are anti-seizure medications. Several GABA analogs are prescribed off-label for a variety of other conditions (such as pregabalin being used to treat the symptoms of fibromyalgia under the brand name Lyrica); gabapentin itself has been shown to be as effective as estrogen at reducing hot flashes.[83]

Blood pressure medicines

Blood pressure medicines including clonidine (Catapres) are about as effective as antidepressants for hot flashes, but do not have the other mind and mood benefits of antidepressants. However they may merit special consideration by women suffering both from high blood pressure and hot flashes.[84]

Alternative medicine

Some botanical sources, referred to as phytoestrogens, do not simply mimic the effects of human steroidal estrogen but exhibit both similar and divergent actions. The ultimate actions of these compounds in specific cells is determined by many factors including the relative levels of the estrogen receptors ER alpha and beta and the diverse mix of coactivators and corepressors present in any given cell type. Thus they have been described to act somewhat like selective estrogen receptor modulators (SERMs). Effects vary according to the phytoestrogen studied, cell line, tissue, species, and response being evaluated.[85]

Systematic reviews of intervention studies question the validity of the proposed benefits of phytoestrogen supplementation, with little data in postmenopausal women to support a role for phytoestrogens as an alternative for conventional HT.[86] Femarelle is a mixture of DT56a soy derivative and ground flaxseed at a ratio of 3:1, for oral administration. Each capsule contains 344 mg soy and 108 mg flaxseed—altogether 430 mg powder. It is being promoted for the treatment of menopause and prevention of bone loss and has also been described as having SERM qualities,[87] thereby reducing the safety risks involved in estrogenic-like treatments. In 2008 the European Food Safety Authority concluded that "a cause and effect relationship has not been established between the consumption of Femarelle and increased BMD, increased bone formation, or decreased risk of osteoporosis or other bone disorders in post-menopausal women.".[88]

In the area of complementary and alternative therapies, acupuncture and acupressure treatments are promising. Numerous studies indicate positive effects, especially on hot flashes[89][90] [91] but also others[92] showing no positive effects of acupuncture regarding menopause.

There are regular claims that soy isoflavones are beneficial concerning some symptoms of menopause. Isoflavones are naturally occurring compounds, and daidzein and genistein are the main isoflavones found in soy.[93] After consuming soy containing daidzein some, but not all, humans produce S-equol (7-hydroxy-3-(49-hydroxyphenyl)-chroman),[94] which may have some health benefits, particularly the reduction of some menopausal symptoms.

The ability to transform daidzein into S-equol is based on the presence of certain intestinal bacteria. In fact, several studies indicate that only 25 to 30 percent of the adult population of Western countries produces S-equol after eating soy foods containing isoflavones,[95][96][97][98] significantly lower than the reported 50 to 60 percent frequency of equol-producers in adults from Japan, Korea, or China.[99][100][101][102] S-equol is not of plant origin. Kenneth Setchell, Ph.D., et al., proposed in 2002 that S-equol had potential for disease prevention and treatment. The scientists stated "There is good rationale for expecting greater efficacy in equol-producers because equol binds with greater affinity to estrogen receptor than daidzein."[103]

Recent human clinical studies showed that S-equol provided as a standardized soygerm-based dietary supplement helped reduce menopausal symptoms, bone loss and crow's feet skin wrinkles in menopausal women. Studies of Japanese postmenopausal women documented that those who can produce S-equol after soy consumption had milder menopause symptoms than those who were equol nonproducers.[104][105] Key basic animal and human studies, in both women in Japan and the United States, have documented the efficacy and safety of the soygerm-based supplement containing S-equol to modify menopause symptoms, particularly the reduction of the severity and frequency of hot flashes and neck and shoulder stiffness.[106][107][108][109]

However, one study[110] indicated that soy isoflavones did not improve or appreciably affect cognitive functioning in postmenopausal women.

Other remedies which work in some studies, but in other studies appear to be no better than a placebo,include red clover isoflavone extracts and black cohosh (Cimicifuga racemosa, also known as Actaea racemosa), a plant native to North America.[111][112] It has common usage internationally for the treatment of hot flushes and sweats experienced by postmenopausal women. However, study results do not support a benefit of black cohosh for the treatment of menopausal symptoms.[112] Black cohosh has been associated with reports of acute liver toxicity[113] and a concern has been raised regarding the stimulation of pre-existing breast cancer based on an animal study.[114] One study found that when compared to a placebo, black cohosh and red clover did not reduce the number of vasomotor symptoms, although safety monitoring indicated that chemically and biologically standardized extracts of black cohosh and red clover were safe during daily administration for 12 months.[115] Another study reported that black cohosh used in isolation, or as part of a multibotanical regimen, had little potential to relieve vasomotor symptoms.[116]

There is promising data from an emerging treatment comprising a multibotanical compound MF-101 (trade name Menerba).


Education

Many women arrive at their menopause transition years without knowing anything about what they might expect, or when or how the process might happen, and how long it might take. Very often a woman has not been informed in any way about this stage of life; at least in the United States, it may often be the case that she has received no information from her physician, or from her older female family members, or from her social group. In the United States there appears to be a lingering taboo which hangs over this subject. As a result, a woman who happens to undergo a strong perimenopause with a large number of different effects, may become confused and anxious, fearing that something abnormal is happening to her. There is a strong need for more information and more education on this subject.[23]

Other therapies

  • Lack of lubrication is a common problem during and after perimenopause. Vaginal moisturizers can help women with overall dryness, and lubricants can help with lubrication difficulties that may be present during intercourse. It is worth pointing out that moisturizers and lubricants are different products for different issues: some women feel unpleasantly dry all of the time apart from during sex, and they may do better with moisturizers all of the time. Those who need only lubricants are fine just using the lubrication products during intercourse.
  • Low-dose prescription vaginal estrogen products such as estrogen creams are generally a safe way to use estrogen topically, to help vaginal thinning and dryness problems (see vaginal atrophy) while only minimally increasing the levels of estrogen in the bloodstream.
  • In terms of managing hot flashes, lifestyle measures such as drinking cold liquids, staying in cool rooms, using fans, removing excess clothing, and avoiding hot flash triggers such as hot drinks, spicy foods, etc., may partially supplement (or even obviate) the use of medications for some women.
  • Individual counseling or support groups can sometimes be helpful to handle sad, depressed, anxious or confused feelings women may be having as they pass through what can be for some a very challenging transition time.
  • Osteoporosis can be minimized by smoking cessation, adequate vitamin D intake and regular weight-bearing exercise. The bisphosphate drug alendronate can help prevent loss of bone mass, reducing the risk of fractures, according to a Cochrane review of studies. This applies both to women that have suffered bone loss but have not yet suffered fractures, and women that have suffered both bone loss and fractures.[117]

Abnormalities, dysfunction, and surgery

POF (premature ovarian failure)

premature ovarian failure (POF) is diagnosed or confirmed by high blood levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) on at least 3 occasions at least 4 weeks apart.[120]

Known causes of premature ovarian failure include autoimmune disorders, thyroid disease, diabetes mellitus, chemotherapy, being a carrier of the fragile X syndrome gene, and radiotherapy. However, in the majority of spontaneous cases of premature ovarian failure, the cause is unknown, i.e. it is generally idiopathic.[120]

Women who have some sort of functional disorder affecting the reproductive system (e.g., endometriosis, polycystic ovary syndrome, cancer of the reproductive organs) can go into menopause at a younger age than the normal timeframe. The functional disorders often significantly speed up the menopausal process.

An early menopause can be related to cigarette smoking, higher body mass index, racial and ethnic factors, illnesses,and the surgical removal of the ovaries, with or without the removal of the uterus.[121]

Rates of premature menopause have been found to be significantly higher in fraternal and identical twins; approximately 5% of twins reach menopause before the age of 40. The reasons for this are not completely understood. Transplants of ovarian tissue between identical twins have been successful in restoring fertility.


Various

Menopause can be surgically induced by bilateral oophorectomy (removal of ovaries), which is often, but not always, done in conjunction with removal of the Fallopian tubes (salpingo-oophorectomy) and uterus (hysterectomy)..[11] Cessation of menses as a result of removal of the ovaries is called "surgical menopause". The sudden and complete drop in hormone levels usually produces extreme withdrawal symptoms such as hot flashes, etc. Removal of the uterus without removal of the ovaries, a hysterectomy, does not cause menopause, although pelvic surgery can often precipitate a somewhat earlier menopause, perhaps because of a compromised blood supply to the ovaries.



Society and culture

The cultural context within which a woman lives can have a significant impact on the way she experiences the menopausal transition. Menopause has been described as a subjective experience, with social and cultural factors playing a prominent role in the way menopause is experienced and perceived. Research has shown Japanese women experience menopause, or konenki, as it is called in Japan, in vastly different ways then American women.[122] Japanese women report lower rates of common symptoms such as hot flashes and night sweats, which can be attributed to a variety of factors, both biological and social. Historically, konenki was associated with wealthy middle-class housewives in Japan, a “luxury disease” that women from traditional, inter-generational rural households had no time for. This perception constructs menopause as a symptom of the inevitable process of aging, rather than a “revolutionary transition”, or a “deficiency disease” in need of management.[122]

Within the United States, social location affects the way women perceive menopause and its related biological effects. Research indicates that whether a woman views menopause as a medical issue or an expected life change is correlated with her socio-economic status.[123] The paradigm within which a woman considers menopause also influences the way she views it: women who understand menopause as a medical condition rate it significantly more negatively than those who view it as a life transition or a symbol of aging.[124]

Ethnicity and geographical location also play a role in the experience of menopause. American women of different ethnicities report significantly different types of menopausal effects. One major study found Caucasian women most likely to report what are sometimes described as psychosomatic symptoms, while African-American women were more likely to report vasomotor symptoms.[125] Specifically in Japan, reporting on vasomotor symptoms has been on the increase, with research conducted by Melissa Melby in 2005 finding that of 140 Japanese participants, hot flashes were prevalent in 22.1%.[126] This was almost double that of 20 years prior.[127] Whilst the exact cause for this is unknown, possible contributing factors include significant dietary changes, increased medicalisation of middle aged women and increased media attention on the subject.[127] However, reporting of vasomotor symptoms is still significantly lower than North America.[128] Additionally, while most women in the United States have a negative view of menopause as a time of deterioration or decline, some studies seem to indicate that women from certain Asian cultures have an understanding of menopause that focuses on a sense of liberation, and celebrates the freedom from the risk of pregnancy.[129] Diverging from these conclusions however, one study appeared to show that many American women "experience this time as one of liberation and self-actualization".[130] Postmenopausal Indian women can enter Hindu temples and participate in rituals, marking it as a celebration for reaching an age of wisdom and experience.

Generally speaking, women raised in the Western world or developed countries in Asia live long enough so that a third of their life is spent in post-menopause. For some women, the menopausal transition represents a major life change, similar to menarche in the magnitude of its social and psychological significance. Although the significance of the changes that surround menarche is fairly well recognized, in countries such as the United States, the social and psychological ramifications of the menopause transition are frequently ignored or underestimated.

In other animals

Menopause in the animal kingdom appears to be uncommon, but the presence of this phenomenon in different species has not been thoroughly researched. Life histories show a varying degree of senescence; rapid senescing organisms (e.g., Pacific salmon and annual plants) do not have a post-reproductive life-stage. Gradual senescence is exhibited by all placental mammalian life histories.

Menopause has been observed in several species of nonhuman primates,[3] including rhesus monkeys,[131] and chimpanzees.[132] Menopause also has been reported in a variety of other vertebrate species including elephants,[133] short-finned pilot whales[134] and other cetaceans,[135] [136] the guppy,[137] the platyfish, the budgerigar, the laboratory rat and mouse, and the opossum. However, with the exception of the short-finned pilot whale, such examples tend to be from captive individuals, and thus they are not necessarily representative of what happens in natural populations in the wild.

Dogs do not experience menopause; the estrus cycle simply becomes irregular and infrequent, and though older individuals are not considered good candidates for breeding, offspring have been produced by older animals.[138] Similar observations have been made in cats.[139]

Glossary of Medical Terminology

There is some overlap in the meaning of the various terms used to refer to menopause and the menopause transition years. In addition, some of the terms are used differently in common parlance than they are by medical professionals.


  • Menopause: Is recognized after 12 months of amenorrhea (absence of menstruation). The ovaries reduce production of estrogen and progesterone severely. The terms menopause and postmenopause are often used interchangeable.
  • Perimenopause: transition from reproductive life to menopause. Characterized by irregularities in menstrual cycle. Average age is 45 to 47, but may occur as early as 35. Some hallmark symptoms of perimenopause: shortening of menstrual cycle, shorter or longer duration of bleeding, heavier bleeding, increased mood disturbances, sleeplessness, or hot flashes. Women have reported having up to 50 a day.
  • Natural Menopause: Spontaneously, without medical intervention. Occurs when not had a menstrual period for one year. Average age in Western world is 51, with the average range being between 45 to 55 years old. Two things that may influence the age of onset of natural menopause are smoking and genetics. Women who smoke may reach menopause two years earlier than nonsmoking counterparts. Also, daughters tend to experience menopause at nearly the same age as their mother.
  • Induced Menopause: When medical intervention results in the loss of ovarian function. This can occur as a result of when the ovaries are removed (with a hysterectomy), or due to chemotherapy, radiation, or medications that affect the hormones. During induced menopause, this abrupt stop of the menstruation often results in more profound vasomotor systems (hot flashes and night sweats). Also, these women are at a greater risk for cardiovascular disease and osteoporosis than women who experience menopause naturally.
  • Premature menopause: menopause before the age of 40. Often referred to as premature ovarian failure. Uncommon, less than 0.3% of women in United States of America.
  • POF: an abbreviation for "premature ovarian failure".

(Information above is cited from):[11]

  • Menarche: The time of a female's first menstruation. (menarche)


  • ovary: A gland in female invertebrates that produces eggs for reproduction.
  • oocyte: An immature egg cell produced in the ovary during gametogenesis.
  • hormone: A product of living cells that circulates in body fluids and produces a specific and often stimulatory affect on cells usually remote from its point of origin.
  • estrogen: Estrogens are steroid compounds important in female sexual development and reproduction.

See also

References

External links

  • European Menopause and Andropause Society
  • Menopause: MedlinePlus
  • Menopause and Menopause Treatments
  • Menopause.org, The Official Website of The North American Menopause Society
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