Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: 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). Menopause typically (but not always) occurs in women in midlife, during their late 40s or early 50s, and signals the end of the fertile phase of a woman’s life.
The transition from reproductive to non-reproductive is the result of a major reduction in female hormonal production by the ovaries. This transition is normally slow, tends to occur over a period of years, and is a natural consequence of aging. However, for some women, the accompanying signs and effects that can occur during the menopause transition years can significantly disrupt their daily activities and their sense of well-being. In addition, women who have some sort of functional disorder affecting the reproductive system (i.e. 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 and create more significant health problems, both physical and emotional, for the affected woman.
The word “menopause” literally means the “end of monthly cycles” from the Greek word pausis (cessation) and the root men- (month), because the word “menopause” was created to describe this change in human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruation or menses. However, menopause also exists in some other animals, many of which do not have monthly menstruation, in this case, the term is synonymous with “end of fertility”.
The date of menopause in human females is formally medically defined as the time of the last menstrual period (or menstrual flow of any amount, however small), in those women who have not had a hysterectomy. Women who have their uterus removed but retain their ovaries do not immediately go into menopause, even though their periods cease. Adult women who have their ovaries removed however, go immediately into surgical menopause, no matter how young they are.
Menopause is an unavoidable change that every woman will experience, assuming she reaches middle age and beyond. It is helpful if women are able to learn what to expect and what options are available to assist the transition, if that becomes necessary. Menopause has a wide starting range, but can usually be expected in the age range of 42–58. An early menopause can be related to cigarette smoking, higher body mass index, racial and ethnic factors, illnesses, chemotherapy, radiation and the surgical removal of the uterus and/or both ovaries.
Menopause can be officially declared (in an adult woman who is not pregnant, is not lactating, and who has an intact uterus) when there has been amenorrhea (absence of any menstruation) for one complete year. However, there are many signs and effects that lead up to this point, many of which may extend well beyond it too. These include: irregular menses, vasomotor instability (hot flashes and night sweats), atrophy of genitourinary tissue, increased stress, breast tenderness, vaginal dryness, forgetfulness, mood changes, and in certain cases osteoporosis and/or heart disease. These effects are related to the hormonal changes a woman’s body is going through, and they affect each woman to a different extent. The only sign or effect that all women universally have in common is that by the end of the menopause transition every woman will have a complete cessation of menses.
In the Western world, the most typical age range for menopause (last period from natural causes) is between the ages of 40 and 61, and the average age for last period is 51 years. The average age of natural menopause (in Australia) is 51.7 years, although this varies considerably from one individual to another. In some countries however, such as India and the Philippines, the median age of natural menopause is considerably earlier, at 44 years.
On average, women who smoke cigarettes experience menopause significantly earlier than non-smokers. Women who have undergone hysterectomy with ovary conservation go through menopause on average three to seven years earlier than the expected age.
In rare cases, a woman’s ovaries stop working at a very early age, ranging anywhere from the age of puberty to age forty, and this is known as premature ovarian failure (POF). Spontaneous premature ovarian failure affects one percent of women by age forty, and 0.1% of women by age thirty. POF is not considered to be due to the normal effects of aging. Some 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.
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. Rates of premature menopause have been found to be significantly higher in fraternal and identical twins; approximately five percent of twins reach menopause before the age of forty. The reasons for this are not completely understood. Transplants of ovarian tissue between identical twins have been successful in restoring fertility.
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 for some women, less so for others.
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.
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.
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. 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.
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. 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. Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production. However, women who have had their ovaries surgically removed, who have had their ovaries damaged by chemotherapy or radiotherapy, or who have ovarian gonadotropin suppression, do have loss of ovarian androgen production as a result.
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). 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.
Clinically speaking, menopause is tied to a specific date. Assuming the woman still has a uterus, menopause is defined as the day after her 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 a 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 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.
Regarding the presence or absence of the definite article “the”, some speakers use it (“the menopause”) and many don’t. The article-less usage seems to be much more common judging from PubMed search results.
Perimenopause is the term used to describe the menopause transition years. In women who have a uterus, perimenopause describes the years before and after the final period (although it is only possible to determine in retrospect which episode of flow was indeed the final period). As a medical convenience, perimenopause is technically defined as the time from which menses start to become irregular and FSH levels have increased, through until 12 months after the last menstrual bleed. However the hormonal changes are gradual, both in onset and in termination, therefore the various possible perimenopause effects often start before and continue after this neatly-defined time slot.
During perimenopause, the ovarian production of the estrogens and progesterone becomes more irregular, often with wide and unpredictable fluctuations in levels. 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 thirtyfive, although most women become aware of the transition in their mid to late forties, 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 during the process, the course of an individual woman’s perimenopause can be difficult if not impossible to predict.
During the perimenopause years, many women undergo noticeable and clinically observable physical changes resulting from hormonal fluctuations. The most well-known of these is the “hot flash” or “hot flush”, a sudden temporary increase in body temperature. The “flash” sensation in a “hot flash” occurs as the body temperature soars upward, reaching a peak very rapidly. The “hot” sensation in a “hot flash” is not the initial temperature rise; instead, it is a reaction to the slowness of the body’s return to a more normal temperature range.
In some cases hot flashes can be so strong that they raise the body temperature multiple 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, as well as by using over-the-counter plant estrogens and herbal remedies. Many women choose not to treat hot flashes through pharmacology, and instead rely on dressing in ways to dissipate heat quickly (natural fibers, loose clothing, easily removable layers of lightweight garments) as well as mechanical means to aid the body in removing 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 are present in the life of a woman:
Having to deal with caring for and/or the death of elderly parents
The so-called “empty-nest syndrome” when children leave home
The birth of grandchildren, which places people of “middle age” into a new category of “older people”
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.
Premenopause is a word used to describe 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.
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. 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. 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 factor in 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.
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. Some of the 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. 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 is the Greene Climateric Scale questionnaire.
Hot flashes or hot flushes, including night sweats and, in a few people, cold flashes
Possible but contentious increased risk of atherosclerosis.
Urogenital atrophy, also known as vaginal atrophy
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.
Increased susceptibility to inflammation and infection, for example vaginal candidiasis, and urinary tract infections
Joint pain, Muscle pain
Osteopenia and the risk of osteoporosis gradually developing over time
Skin, soft tissue
breast tenderness +/- swelling
Decreased elasticity of the skin
Formication (itching, tingling, burning, pins and needles, or sensation of ants crawling on or under the skin)
Skin thinning and becoming drier
Depression and/or anxiety
Memory loss, and problems with concentration
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.
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. 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.
Evolutionary theories of menopause
In contrast to males, females invest more in their gametes, making them a highly valuable resource. Selection should therefore in theory favor a quantity of ova that would be sufficient for the female lifespan. Over-investment is resourcefully wasteful and under-investment leads to reduced fitness. Human females, however, spend over one third of their lifespan in a post-reproductive phase. Possible evolutionary explanations for survival beyond reproductive maturation range from the non-adaptive to the adaptive.
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 and the available data does not support this.
A recent increase in female longevity due to improvements in the standard of living and social care has also been suggested. It is difficult for selection; however, to favor aid from offspring to parents and grandparents Irrespective of living standards, adaptive responses are limited by physiological mechanisms. In other words, senescence is programmed and regulated by specific genes.
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.
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. Therefore, 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. 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). Differing assistance strategies for maternal and paternal grandmothers have also been demonstrated. Maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates.
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. 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). It also fails to explain the detrimental effects of losing ovarian follicular activity, such as osteoporosis, osteoarthritis, Alzheimer’s disease and coronary artery disease.
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
In the context of menopause Hormone replacement therapy or HRT, known in Britain as Hormone Therapy or HT, refers to 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. 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. Adverse effects of HRT appear to vary according to formulation and dose.
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.
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 might.
Until recently the most widely used estrogen preparation worldwide in postmenopausal women was an oral conjugated equine estrogen. Other oral estrogen preparations include synthetically derived piperazine estrone sulphate, estriol, micronized 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, estriol in pessary or cream form, dienoestrol and conjugated estrogens in the form of creams. Oral micronized estradiol and other oral estrogen preparations may result in up to 10 fold higher levels of circulating estrone sulphate than transdermally administered estradiol at comparable or even higher doses. This is of concern in that estrogen sensitive tissues such as breast and endometrium have high capacity to metabolize estrone sulphate through to estradiol. Orally administered estrogen therapy also increases sex hormone binding globulin (SHBG) largely than none 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 minimize 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 in order to protect against the development of endometrial hyperplasia and endometrial carcinoma.
Oral administration of progesterone is convenient, however the oral micronized form is rapidly metabolized and inactivated in the liver, and therefore high doses must be administered to achieve adequate circulating blood levels. Synthetic progestin’s 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. Synthetic progestins may cause irritability and mood changes in some women.
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.
Drug company marketing efforts (at least in the USA) 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 progesterone acetate (Premarin plus Provera, known as Prempro)), had an increased risk of breast cancer and heart disease.
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. 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 post menopause. In order 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 a increased incidence of breast cancer, heart attacks and strokes, lead to a sharp decline in HRT prescription throughout the world, which was followed by a decrease in breast cancer incidence.
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. Large and successively larger drops in new breast cancer diagnoses followed this sharp drop in usage 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 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.
Selective Estrogen Receptor Modulators
SERMs are a category of drugs, either synthetically produced or derived from a botanical source (Phytoserms), which act selectively as agonists on the body. The most commonly prescribed SERMs are raloxifene and tamoxifen. Raloxifene exhibits estrogen agonist activity on bone and lipids, and antagonist activity on breast and the endometrium. 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. While most SERMs are known to increase hot flushes, Femarelle (DT56a) decreases them. In addition to the relieving effects on menopausal symptoms, Femarelle also increases bone mass density (BMD), making it protective against osteoporotic fractures. 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 and uterus 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) .
Antidepressants such as paroxetine (Paxil), Fluoxetine hydrochloride (Prozac), and Venlafaxine hydrochloride (Effexor) have been used with some success in the treatment of hot flashes, improving sleep, mood, and quality of life. 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. 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 deregulation of serotonin pathways in the brain and to respond quickly and powerfully to SSRIs and Cannabinoids.
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.
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 from hot flashes.
It is important to examine the claim that herbal remedies help relieve menopausal symptoms. 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 co activators and co repressors 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.
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. 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 been described as having SERM qualities, 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.”
In the area of complementary and alternative therapies, acupuncture and acupressure treatments are promising. Numerous studies indicate positive effects, especially on hot flashes but also others showing no positive effects of acupuncture regarding menopause.
There are regular claims that soy isoflavones are beneficial concerning menopause. However, one study indicated that soy isoflavones did not improve or appreciably affect cognitive functioning in postmenopausal women.
Other remedies that work in some studies, but in other studies appear to be no better than a placebo, include red clover isoflavone extracts and black cohosh. Black cohosh (Cimicifuga racemosa, also known as Actaea racemosa) is a North American native plant. 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. Black cohosh has been associated with reports of acute liver toxicity and a concern has been raised regarding the stimulation of pre-existing breast cancer based on an animal study.
More promising data from an emerging treatment comprised of a multibotanical compound MF-101 (trade name Menerba).
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 US, it may often be the case that she has received no information from her physician, from her older female family members, or from her social group. In the US, there appears to be a lingering taboo that 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.
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, in order 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 layers when a hot flash strikes, 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.
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 to women that have suffered both bone loss and fractures.
Society and culture
The cultural context within which a woman lives can have a significant impact on the way she experiences the menopausal transition. 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. 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.
Ethnicity and geographical location also play a role in the experience of menopause. U.S. 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. 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 Asian women have an understanding of menopause that focuses on a sense of liberation, and celebrates the freedom from the risk of pregnancy. Diverging from these conclusions however, one study appeared to show that many U.S. women “experience this time as one of liberation and self-actualization.”
Generally speaking, women raised in the Western world 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 USA, the social and psychological ramifications of the menopause transition are frequently ignored or underestimated.
In other animals
Menopause in the animal kingdom appears perhaps to be somewhat 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, including rhesus monkeys, and chimpanzees. Menopause also has been reported in elephants, short-finned pilot whales and other cetaceans, as well as in a variety of other vertebrate species including the guppy, the platyfish, the budgerigar, the laboratory rat and mouse, and the opossum, as well as some whales. 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.
Cannabinoids and Menopausal syndrome
The cannabinoids in the marijuana plant help alleviate symptoms in menopausal syndrome.
Cannabinoids: A method of inhibiting vasomotor symptoms and attending psychological disturbances surrounding post-menopausal syndrome.
Cannabinoids provide benefits (eliminating symptoms) for menopausal syndrome. Merits of cannabinoids for post menopausal syndrome include: safe delivery system, potency, strength, shelf-life, dosing and toxicity. Cannabinoids provide an excellent way to manage menopause symptoms. Little or no side effects. Edibles, extract, suppository (vaginal or anal), tincture (under the tongue), oil, hash, butter, vaporizer, spray.
Recommendation: Indica x Sativa hybrid (whole plant extract).
1. a b Walker ML and Herndon JG (2008). “Menopause in nonhuman primates?”. Biology of Reproduction 79 (3): 398–406.doi:10.1095/biolreprod.108.068536. PMC 2553520. PMID 18495681.
2. Bucher, et al. 1930
3. Bucher, et al. 1930
4. Bucher, et al., 1931
5. Minkin, et al. (1997), What Every Woman Needs to Know about Menopause, Yale University Press, ISBN 0300072619
6. Kato I, Toniolo P, Akhmedkhanov A, Koenig KL, Shore R, Zeleniuch-Jacquotte A (1998). “Prospective study of factors influencing the onset of natural menopause”. J Clin Epidemiol 51 (12): 1271–1276. doi:10.1016/S0895-4356(98)00119-X. PMID 10086819.
7. Do KA, Treloar SA, Pandeya N et al. (1998). “Predictive factors of age at menopause in a large Australian twin study”. Hum Biol 70 (6): 1073–91.PMID 9825597.
8. Ringa, V. .(2000). Menopause and treatments. Quality of life research 9(6): 695-707.
9. Kaufman DL, Slone D, Rosenberg L, Miettinen OS, Shapiro S. Cigarette smoking and age of natural menopause. American Journal of Public Health 70 (4): 420-422.
10. a b Kalantaridou SN, Davis SR, Nelson LM.Endocrinol Metab Clin North Am. 1998 Dec;27(4):989-1006.
11. Soules MR, Sherman S, Parrott E et al. (2001). “Executive summary: Stages of Reproductive Aging Workshop (STRAW)”. Climacteric 4 (4): 267–72.PMID 11770182.
12. Burger HG (1994). “Diagnostic role of follicle stimulating hormone (FSH) measurements during menopausal transition- an analysis of FSH, oestradiol and inhibin”. European Journal of Endocrinology 130 (1): 38–42. doi:10.1530/eje.0.1300038. PMID 8124478.
13. Burger HG (1994). “Diagnostic role of follicle stimulating hormone (FSH) measurments during menopausal transition- an analysis of FSH, oestraiol and inhibim”. European Journal of Endocrinology 130 (1): 38–42. doi:10.1530/eje.0.1300038. PMID 8124478.
14. Simpson ER, Davis SR (2001). “Minireview: aromatase and the regulation of estrogen biosynthesis some new perspectives”. Endocrinology 142(11): 4589–94. doi:10.1210/en.142.11.4589. PMID 11606422.
15. Davison SL, Bell R, Donath S, Montalto JG, Davis SR (2005). “Androgen levels in adult females: changes with age, menopause, and oophorectomy”. J Clin Endocrinol Metab 90 (7): 3847–53. doi:10.1210/jc.2005-0212. PMID 15827095.
16. Bellipanni G, DI Marzo F, Blasi F, et al. Effects of melatonin in perimenopausal and menopausal women: our personal experience. 2005. Ann N Y Acad Sci 1057:393-402. DOI: 10.1196/annals.1356.030 PMID 16399909
17. a b Twiss JJ, Wegner J, Hunter M, Kelsay M, Rathe-Hart M, Salado W (2007). “Perimenopausal symptoms, quality of life, and health behaviors in users and nonusers of hormone therapy”. J Am Acad Nurse Pract 19 (11): 602–13. doi:10.1111/j.1745-7599.2007.00260.x. PMID 17970860.
18. Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology: With Student Consult Online Access. Philadelphia: Saunders. pp. 344. ISBN 1-4160-2973-7. 8th edition.
19. a b Freeman EW, Sammel MD, Lin H, et al. (2007). “Symptoms associated with menopausal transition and reproductive hormones in midlife women”. Obstetrics and gynecology 110 (2 Pt 1): 230–40. doi:10.1097/01.AOG.0000270153.59102.40. PMID 17666595.
20. Pien GW, Sammel MD, Freeman EW, Lin H, DeBlasis TL (July 2008). “Predictors of sleep quality in women in the menopausal transition”. Sleep 31(7): 991–9. PMC 2491505. PMID 18652094.
21. Peter Kenemans, MD, PhD. Menopause, Perimenopause & Postmenopause: Definitions, Terms & Concepts
22. Richard Dawkins (1976), The selfish gene Oxford University Press, Oxford
23. Gaulin S.J.C. (1980). “Sexual Dimorphism in the Human Post-reproductive Life-span: Possible Causes”. Journal of Human Evolution 9 (3): 227–232. doi:10.1016/0047-2484(80)90024-X.
24. Holmberg, I. (1970), “Fecundity, Fertility and Family Planning”. Demography Institute University of Gothenburg Reports. 10: 1-109
25. Washburn, S.L. (1981). “Longevity in Primates”. In: Aging: Biology and Behavior by McGaugh, J.L. and S. B. Kiesler, S.B. (eds). Pp.11-29. Academic Press.
26. Hawkes K (2004). “Human longevity: The grandmother effect”. Nature 428 (6979): 128–129. doi:10.1038/428128a. PMID 15014476.
27. Ricklefs R.E., Wikelski M. (2002). “The Physiology/Life-history Nexus”. Trends in Ecology & Evolution 17 (10): 462–468. doi:10.1016/S0169-5347(02)02578-8.
28. Peccei, J. S. (2001) “Menopause: Adaptation or Epiphenomenon?” Evolutionary Anthropology, 10(2): 43-57, doi:http://dx.doi.org/10.1002/evan.1013
29. Lahdenperä M., Lummaa V., Helle S., Tremblay M., Russell A. F. (2004). “Fitness benefits of prolonged post-reproductive lifespan in women”.Nature 428 (6979): 178–181. doi:10.1038/nature02367. PMID 15014499.
30. Voland, E. and Beise, J. (2002). “Opposite Effects of Maternal and Paternal Grandmothers on Infant Survival in Historical Krummörn”. MPIDR WP 2001-026.
31. Mace, R and Sear, R. (2004). Are Humans Communal Breeders? In: Voland, E., Chasiotis, A. and Schiefenhoevel, W. (eds). Grandmotherhood – the Evolutionary Siginificance of the Second Half of Female Life. Rutgers University Press.
32. Peccei J. S. (2001). “A critique of the grandmother hypotheses: Old and new”. American Journal of Human Biology 13 (4): 434–452.doi:10.1002/ajhb.1076. PMID 11400215.
33. 10. Finch, C.E. 1990. Longevity senescence and the genome. University of Chicago Press. London.
34. Massart F. Reginster, Brandi M.L. (2001). “Genetics of Menopause-Associatred Diseases”. Maturitas 40 (2): 103–116. doi:10.1016/S0378-5122(01)00283-3. PMID 11716989.
35. The Woman’s Health Program Monash University, Oestrogen and Progestin as hormone therapy;http://womenshealth.med.monash.edu.au/documents/oestrogen-progestin-hormone-therapy.pdf.
36. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB (2005). “Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial”. Obstet Gynecol 105 (1): 161–6. doi:10.1097/01.AOG.0000147840.06947.46. PMID 15625158.
37. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society.Menopause. 2010 Mar;17(2):242-55
38. Slater C, Hodis H, Mack W, Shoupe D, Paulson R, Stanczyk F (2001). “Markedly elevated levels of estrone sulfate after long term oral, but not transdermal, administration of estradiol in postmenopausal women”. Menopause 8 (3): 200–3. doi:10.1097/00042192-200105000-00009.PMID 11355042.
39. Arafat E.S., Hargrove J.T., Maxson W.S. ET AL (1988). “Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites”. Am J Obstet Gynecol 159 (5): 1203–1209. PMID 3189454.
40. Davis SR, Dinatale I, Rivera-Woll L, Davison SR. Postmenopausal hormone therapy: from monkey glands to transdermal patches. J Endocrinol. 2005 May;185(2):207-22
41. Writing Group for Women’s Health initiative I. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002(288):321-33
42. Anderson GL, Limacher M, Assaf AR et al. (2004). “Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial”. JAMA 291 (14): 1701–12. doi:10.1001/jama.291.14.1701. PMID 15082697.
43. Menon U, Burnell M, Sharma A, et al. (2007). “Decline in use of hormone therapy among postmenopausal women in the United Kingdom”.Menopause 14 (3 Pt 1): 462–7. doi:10.1097/01.gme.0000243569.70946.9d. PMID 17237735.
44. Du Y, Dören M, Melchert HU, Scheidt-Nave C, Knopf H (2007). “Differences in menopausal hormone therapy use among women in Germany between 1998 and 2003”. BMC Womens Health 7: 19. doi:10.1186/1472-6874-7-19. PMC 2233614. PMID 17945013.
45. Watson J, Wise L, Green J (September 2007). “Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005”. Eur. J. Clin. Pharmacol. 63 (9): 843–9. doi:10.1007/s00228-007-0320-6. PMID 17598097.
46. Clarke CA, Glaser SL, Uratsu CS, Selby JV, Kushi LH, Herrinton LJ (November 2006). “Recent declines in hormone therapy utilization and breast cancer incidence: clinical and population-based evidence”. J. Clin. Oncol. 24 (33): e49–50. doi:10.1200/JCO.2006.08.6504. PMID 17114650.
47. Ravdin PM, Cronin KA, Howlader N, et al. (April 2007). “The decrease in breast-cancer incidence in 2003 in the United States”. N. Engl. J. Med. 356(16): 1670–4. doi:10.1056/NEJMsr070105. PMID 17442911.
48. Glass AG, Lacey JV, Carreon JD, Hoover RN (August 2007). “Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status”. J. Natl. Cancer Inst. 99 (15): 1152–61. doi:10.1093/jnci/djm059.PMID 17652280.
49. Davis SR, Dinatale I, Rivera-Woll L, Davison SR (2005). “Postmenopausal hormone therapy: from monkey glands to transdermal patches”.JEndocrinol 185 (2): 207–22. doi:10.1677/joe.1.05847. PMID 15845914.
50. Bevers TB. The STAR Trial: Evidence for Raloxifene as a Breast Cancer Risk Reduction Agent for Postmenopausal Women. J Natl Compr Canc Netw 2007;5(8):817-22.
51. Yoles I, Yogev Y, Frenkel Y, Hirsch M, Nahum R, Kaplan B (2004). “menopausal symptoms”. Clin Exp Obstet Gynecol 31 (2): 123–6.PMID 15266766.
52. Somjen D, Katzburg S, Knoll E, et al. (May 2007). “DT56a (Femarelle): a natural selective estrogen receptor modulator (SERM)”. J. Steroid Biochem. Mol. Biol. 104 (3–5): 252–8. doi:10.1016/j.jsbmb.2007.03.004. PMID 17428655.
53. Yoles I, Yogev Y, Frenkel Y, Nahum R, Hirsch M, Kaplan B (2003). “Tofupill/Femarelle (DT56a): a new phyto-selective estrogen receptor modulator-like substance for the treatment of postmenopausal bone loss”. Menopause 10 (6): 522–5. doi:10.1097/01.GME.0000064864.58809.77.PMID 14627860.
54. Yoles I, Lilling G (January 2007). “Pharmacological doses of the natural phyto-SERM DT56a (Femarelle) have no effect on MCF-7 human breast cancer cell-line”. Eur. J. Obstet. Gynecol. Reprod. Biol. 130 (1): 140–1. doi:10.1016/j.ejogrb.2006.02.010. PMID 16580119.
55. Somjen D, Yoles I (July 2003). “DT56a (Tofupill/Femarelle) selectively stimulates creatine kinase specific activity in skeletal tissues of rats but not in the uterus”. J. Steroid Biochem. Mol. Biol. 86 (1): 93–8. doi:10.1016/S0960-0760(03)00252-8. PMID 12943748.
56. Oropeza MV, Orozco S, Ponce H, Campos MG (2005). “Tofupill lacks peripheral estrogen-like actions in the rat reproductive tract”. Reprod. Toxicol.20 (2): 261–6. doi:10.1016/j.reprotox.2005.02.007. PMID 15878261.
57. *Rosack, Jim. “Antidepressants May Prevent Hippocampus From Shrinking”, Psychiatric News, Volume 38 Number 17 Page 24, September 5, 2003.
58. Jovanovic H, Cerin A, Karlsson P, Lundberg J, Halldin C, Nordström AL.A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria.Psychiatry Res. 2006 Dec 1;148(2-3):185-93
60. “Herbal medicines for menopausal symptoms”. Drug Ther Bull 47 (1): 2–6. January 2009. doi:10.1136/dtb.2008.12.0031. PMID 19129428.
61. Murkies, A., Wilcox, G Davis SR Phytoestrogens: A Clinical Review J.Clin.Endocrinol Metab 1998; 83: 297-303|pmid=9467531
62. Lethaby A, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007(4):CD001395.
63. Somjen D, Katzburg S, Knoll E, et al. (May 2007). “DT56a (Femarelle): a natural selective estrogen receptor modulator (SERM)”. J. Steroid Biochem. Mol. Vol. 104 (3–5): 252–258. doi:10.1016/j.jsbmb.2007.03.004. PMID 17428655.
64. Scientific Opinion of the Panel on Dietetic Products Nutrition and Allergies on a request from the Se- Cure Pharmaceuticals Ltd on Femarelle® and bone mineral density. The EFSA Journal (2008) 785, 1-10
65. Nir Y, Huang MI, Schnyer R, Chen B, Manber R (April 2007). “Acupuncture for postmenopausal hot flashes”. Maturitas 56 (4): 383–95.doi:10.1016/j.maturitas.2006.11.001. PMID 17182200.
66. Cohen SM, Rousseau ME, Carey BL (2003). “Can acupuncture ease the symptoms of menopause?”. Holistic Nursing Practice 17 (6): 295–9.PMID 14650571.
67. Zaborowska E, Brynhildsen J, Damberg S, et al. (February 2007). “Effects of acupuncture, applied relaxation, estrogens and placebo on hot flushes in postmenopausal women: an analysis of two prospective, parallel, randomized studies”. Climacteric 10 (1): 38–45.doi:10.1080/13697130601165059. PMID 17364603.
68. Vincent A, Barton DL, Mandrekar JN, et al. (2007). “Acupuncture for hot flashes: a randomized, sham-controlled clinical study”. Menopause 14 (1): 45–52. doi:10.1097/01.gme.0000227854.27603.7d. PMID 17019380.
69. Fournier LR, Ryan Borchers TA, Robison LM, et al. (2007). “The effects of soy milk and isoflavone supplements on cognitive performance in healthy, postmenopausal women”. J Nutr Health Aging. 11 (2): 155–164. PMID 17435957.
70. Krebs E, Ensrud K, Macdonald R, Wilt T. Phytoestrogens for treatment of menopausal symptoms; a systematic review Obstet Gynecol 2004; 104: 824–36.
71. a b Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med 2006;166(14):1453-65.
72. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust 2003;179:390-1.
73. Davis VL, Jayo MJ, Ho A, Kotlarczyk MP, Hardy ML, Foster WG, Hughes CL.Black cohosh increases metastatic mammary cancer in transgenic mice expressing c-erbB2.Cancer Res. 2008 Oct 15;68(20):8377-83
74. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001155. DOI: 10.1002/14651858.CD001155.pub2 http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD001155/frame.html
75. Winterich, J. (August, 2008). “Gender, medicine, and the menopausal body: How biology and culture influence women’s experiences with menopause”. Paper presented at the annual meeting of the American Sociological Association, New York. Retrieved November 11, 2008 fromAllacademic.com
76. Gannon L., Ekstrom B. (1993). “Attitudes toward menopause: The influence of sociocultural paradigms”. Psychology of Women Quarterly 17: 275–288.
77. Avis N., Stellato R. Crawford, Bromberger J., Gan P., Cain V., Kagawa-Singer M. (2001). “Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic group”. Social Science & Medicine 52 (3): 345–356. doi:10.1016/S0277-9536(00)00147-7.
78. Maoz B., Dowty N., Antonovsky A., Wisjenbeck H. (1970). “Female attitudes to menopause”. Social Psychiatry 5: 35–40. doi:10.1007/BF01539794.
79. Stotland N.L. (2002). “Menopause: Social expectations, women’s realities”. Archives of Women’s Mental Health 5: 5–8.doi:10.1007/s007370200016.
80. Walker ML (1995). “Menopause in female rhesus monkeys”. Am J Primatol 35: 59–71. doi:10.1002/ajp.1350350106.
81. Bowden, D.M. and Williams, D.D. (1985). Aging. Adv.Vet.Sci.Comp.Med. 28: 306-341
83. Marsh, H and Kasuya, T. (1986). Evidence for Reproductive Senescence in Female Cetaceans. Report of the International Whaling Commission. 8: 57-74.
84. McAuliffe K, Whitehead H (2005). “Eusociality, menopause and information in matrilineal whales”. Trends Ecol Evolution 20 (12): 650.doi:10.1016/j.tree.2005.09.003. PMID 16701451.
85. Reznick D, Bryant M, Holmes D (January 2006). “The evolution of senescence and post-reproductive lifespan in guppies (Poecilia reticulata)”.PLoS Biology 4 (1): e7. doi:10.1371/journal.pbio.0040007. PMC 1318473. PMID 16363919.