Menopause is the permanent cessation of menstruation which occurs a considerable length of time before the end of the lifespan.
The word was first applied to humans, and because of this it literally means the cessation of monthly cycles or menstrual cycles, from the Greek roots meno (month) and pausis (a halt). However, the word is not only applied to humans, and menopause is the permanent stopping of female reproductive cycles of various lengths and kinds; menopause is indeed present in a number of mammal species other than humans.
In adult human females who still have a uterus, and who are not pregnant or lactating, postmenopause is identified by a permanent (at least one year's) absence of monthly periods or menstruation. In women without a uterus, menopause or postmenopause is identified by a very high FSH level.
In human females, menopause usually happens more or less in midlife, signaling the end of the fertile phase of a woman's life. 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.
For medical reasons, the uterus must sometimes be surgically removed (hysterectomy) in a younger woman; her periods will cease permanently, and the woman will technically be infertile, but as long as at least one of her ovaries is still functioning, the woman will not have reached menopause, because even without the uterus, ovulation and the release of the sequence of reproductive hormones will continue to cycle on until menopause is reached. But 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".
Thus menopause is based on the shutting down (or surgical removal) of 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. The process of the ovaries shutting down is a phenomenon which involves the entire cascade of a woman's reproductive functioning, from brain to skin, and this major physiological event usually has some effect on almost every aspect of a woman's body and life.
The menopause transition, and post-menopause itself, is a natural life change, not a disease state or a disorder. The transition itself can be challenging for a number of women, but for others it is not difficult.
Menopause starts as the functioning of the ovaries begin to change. The ripening and release of the ovum (which, during the reproductive years leads to ovulation and then menstruation if pregnancy does not occur), becomes unpredictable. Ovulations start to be skipped, and the menstrual cycle starts to become less reliable in timing. As these changes become more pronounced, periods start to be skipped, and other perimenopausal symptoms may appear.
After a number of years of erratic functioning, the ovaries almost completely stop producing progesterone and two out of the three estrogen hormones: estradiol and estriol. Estrone is one estrogen which is still produced in reasonable amounts in post-menopausal women. Testosterone levels decrease; however, a decrease in testosterone levels begins gradually in young adulthood. Testosterone levels are thought not to drop significantly during the menopause transition because the stroma of the postmenopausal ovary and the adrenal gland still continue to secrete small amounts of testosterone, even during post-menopause.
Menopause is the end of the reproductive years rather than the beginning, and thus it is the opposite of menarche, nonetheless it can usefully be compared with that event: the menopause transition years are in many ways similar to puberty in reverse, and the psychological and social challenges of menopause are also somewhat similar to those encountered during adolescence.
The typical age range for the occurrence of menopause is between the age of 45 and 55[1]. The average age of menopause varies according to geographic location. In the Western world, the average age of menopause is 51 years[2]. In some developing countries, such as India and the Philippines, the median age of natural menopause is 44 years[3]. Last period ever occurring between the ages of 55 to 60 is known as a "late menopause". "Early menopause" is defined as having one's final period between the age of 45 to 50.
Rarely, the ovaries stop working at a very early age, anywhere from the age of puberty to age 20, and this is known as premature ovarian failure (POF), also commonly referred to as "premature menopause". 1% of women experience POF, and it is not considered to be due to the normal effects of aging. Some known causes of premature menopause include autoimmune disorders, thyroid disease, diabetes mellitus, chemotherapy, eating disorders, and radiotherapy. However, in the majority of spontaneous cases of premature menopause, the cause is unknown.
Premature menopause is diagnosed or confirmed by measuring the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH); the levels of these hormones will be abnormally high if menopause has occurred. 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.
On average, women who smoke cigarettes experience menopause significantly earlier than non-smokers.[4]
Menopause in the animal kingdom appears perhaps to be somewhat uncommon, although the incidence in different species has by no means been thoroughly researched. However, it is already quite apparent that humans are not the only species that experience it. Menopause has been observed in rhesus monkeys[5], some cetaceans[6], as well as in a variety of other species of vertebrates including the guppy[7], the platyfish, the budgerigar, the laboratory rat and mouse, the opossum, and all manner of primates.
The Grandmother hypothesis suggests that menopause evolved 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 the 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.
The shutting down of the female reproductive system in midlife ushers in the third part of a woman's life, also known as the "third age". Many women in Western culture live long enough that half of their adult life is spent in post-menopause. The menopause transition is a major life change, similar to menarche in the magnitude of its social and psychological significance.
In the ancient past, menarche and menopause were considered to mark the transitions from "maiden" to "matron", and from "matron" to "crone", (in other words, from little girl to reproductive woman and then to older woman.) Although the significance of the changes that surround menarche is still fairly well recognized, in countries such as the USA, the social and psychological ramifications of the menopause transition are frequently ignored or underestimated.
Clinically speaking, menopause is a date. For those women who still have a uterus, menopause is defined as the day after a woman's final period 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 everyday parlance however, the word "menopause" is usually not used to refer to one day, but to the whole of the menopause transition years. This span of time is also referred to as 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.
In biomedicine, perimenopause is the term describing the menopause transition years. In women who have a uterus, perimenopause describes the years both before and after the final period (although it is only possible to determine in retrospect which episode of flow was indeed the final period). During perimenopause, the production of most of the reproductive hormones, including the estrogens, progesterone and testosterone, diminish and become 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 is determined retroactively 12 months after the last menstrual cycle. Signs and effects of the menopause transition can begin as early as age 35, although most women who become aware of the transition do so about 10 years later, often in their mid to late 40s. The duration of perimenopause with noticeable bodily effects can be a few years, ten years or even longer. The actual duration and severity of perimenopause in any individual woman cannot be predicted in advance or during the process.
In the perimenopause years, many women undergo significant bodily changes resulting from hormonal fluctuation. Most women will gain weight, especially in the lower abdomen, buttocks, and thighs, a bodily adaptation in humans over time to both retain what little estrogen is left in the body longer (estrogens are fat-soluable) and to protect the long bones with padding as estrogen levels decrease and the risk of osteoporosis increases. The most well-known symptom of menopause, though, is the "hot flash", a sudden increase in body temperature caused by declining estrogen levels; the "flash" sensation in a "hot flash" occurs as the body temperature peaks and begins a rapid return to normal. Hot flashes can become so strong that they can raise the body temperature multiple degrees in a very short period of time and 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 and can be treated to ease discomfort in a variety of ways, such as hormone replacement therapy, SSRI medications, and plant-based estrogens. Other common symptoms encountered during the perimenopausal period include mood changes, insomnia, fatigue, and memory problems. Some of these complaints may not be related to the actual hormonal fluctuations involved in menopause, but not enough research has been done to determine why women in menopause suffer from so many of these non-hormonally triggered problems. Even women who are free of any troublesome physical effects of perimenopause may nonetheless find themselves suffering from psychological issues related to societal perceptions of aging; these issues also lend themselves to medical treatment to lessen their overall impact on a woman's life.
One piece of recent research shows that melatonin supplementation in perimenopausal women can produce a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[8]
Perimenopause is a relatively new term. The use of it was criticized by some cultural commentators , because they feel that it extends the negative connotations of menopause over many more years of a woman's life.
Premenopause is a word used to describe the years leading up to the last period ever, when the levels of reproductive hormones are already becoming lower and more erratic, and the effects of hormone withdrawal may be present.
Postmenopause is all of the time in a woman's life that take place after her last period ever, or more accurately, all of the time that follows the point when her ovaries become inactive.
A woman who still has her uterus 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.
The causes of menopause can be considered from complementary proximate (mechanistic) and ultimate (adaptive evolutionary) perspectives.
A natural or physiological menopause is that which occurs as a part of a woman's normal aging process. It is the result of the eventual atresia of almost all oocytes in the ovaries. This causes an increase in circulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels as there are a decreased number of oocytes 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, as well as post-menopausal osteoporosis and vaginal atrophy.
However, menopause can be surgically induced by bilateral salpingo-oophorectomy (removal of both ovaries and both fallopian tubes), which is often, but not always, done in conjunction with hysterectomy. Cessation of menses as a result of removal of the ovaries is called "surgical menopause". The sudden and complete drop in reproductive hormone levels usually produces extreme hormone-withdrawal symptoms such as hot flashes, etc.
As mentioned above, removal of the uterus, hysterectomy, does not itself cause menopause, although pelvic surgery can often precipitate a somewhat earlier menopause, perhaps because of a compromised blood supply to the ovaries. Removing the ovaries however, causes an immediate and powerful "surgical menopause", even if the uterus is left intact.
Cigarette smoking has been found to decrease the age at menopause by as much as one year, and women who have undergone hysterectomy with ovary conservation go through menopause 3.7 years earlier than average. However, premature menopause (before the age of 40) is generally idiopathic.
(An ultimate perspective on menopause is above in the "Menopause in human evolution" section.)
As the body responds to the rapidly changing levels of natural hormones, a number of effects can appear.
It is however worth pointing out, that not every woman experiences bothersome levels of these effects, and even in those women who do experience strong effects, the range of effects and the degree to which they appear is very variable from person to person.
Those effects that are due to low estrogen levels (for example vaginal atrophy and skin drying) remain present even after the menopause transition years are over, however, many of the 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 time has been completed.
Both users and non-users of hormone replacement therapy identify lack of energy as the most frequent and distressing effect.[9] 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. As mentioned above, when a woman of menopausal age has not had a period or any spotting for 12 months, at that point she is considered to be one year into post-menopause. However, a period after 6 months of no flow at all is sometimes considered worthy of investigation by a doctor.
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, may be associated directly with hormone withdrawal.
Vascular instability
Urogenital atrophy, also known as vaginal atrophy, (main article: Atrophic vaginitis)
Skeletal
Skin, soft tissue
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.[11] In the same study, it appeared that menopause was not associated with poor sleep, decreased libido, and vaginal dryness.[11] However, a 2008 study found an association with poor sleep quality.[12]
Many women arrive at their menopause 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, or from her older female family members, or from her social group. In the US, 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.[9]
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. However, in cases where the physical, mental, and emotional effects of perimenopause are severe, and disrupt the everyday life of the woman experiencing them, palliative medical therapy may sometimes be appropriate and helpful.
There are several types of hormone therapies, with various possible side effects. Hormone replacement therapy or HRT, known in Britain as Hormone Therapy or HT, and the SSRIs appear to provide the most reliable pharmaceutical relief. However, adverse effects of one kind of HRT (equine estrogen combined with a synthetic progestin) are now well documented. See the section below on "Adverse effects of conjugated equine estrogens".
In addition to relief from hot flashes, hormone therapy remains an effective treatment for osteoporosis.
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.
In HT or HRT, one or more estrogens, usually in combination with progesterone, (and sometimes testosterone) are administered, not only to partially compensate for the body's loss of these hormones, but also in an attempt to keep the levels of these hormones in the body much more consistent than they are naturally in perimenopause.
In those women who have no uterus (usually due to a previous hysterectomy) estrogen alone is a suitable hormone therapy. Women who still have a uterus need to take progesterone in addition to estrogen, in order to ensure that the endometrium, the lining of the uterus, does not build up too much, which would be a risk for cancer of the endometrium.
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. However Premarin, and especially Prempro, are associated with serious health risks.[13]
In January 2003, the U.S. FDA required Wyeth to affix a "black box" warning to PremPro, stating:
"WARNING: Estrogens and progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations of estrogens and progestins were not studied in the WHI ..."
Women had been advised for many years by numerous doctors and 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), whether or not used in combination with a synthetic progestin (Premarin plus Provera, known as Prempro), had an increased risk of breast cancer, heart disease, stroke, and Alzheimer's disease. 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 doctors start patients on HRT, and in fact many years into postmenopause. 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 [14][15][16], which was followed by a decrease in breast cancer incidence [17][18][19].
On hearing the news about the WHI study, many women discontinued equine estrogens altogether, with or without their doctor's approval. 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.
The adverse biological effects of xenoestrogens and progestins revealed by studies of Premarin and PremPro do not necessarily generalize to supplementation with human forms of estrogen and progesterone. For example, a pilot study reported in JAMA by Smith, Heckbert, et al.[20] found clinical evidence that oral conjugated equine estrogens caused clotting, but the other estrogen compound tested in the same study, bioidentical esterified estrogens, did not. conjugated equine estrogens were found to be associated with increased venous thrombotic risk. In sharp contrast, the study found that users of esterified estrogen had no increase in venous thrombotic risk.
Due to the controversy about Premarin-based hormone therapy, a number of doctors are now moving patients who request hormone therapy to help them through perimenopause, to bioidentical hormone products.
Estrace is a form of the precursor to estrogen in the human body known as estradiol, which products have produced fewer side effects than conjugated equine estrogens[21]. Prometrium is a bioidentical progesterone which can be used in conjunction with Estrace.
However, all hormone replacement therapies probably do carry some health risks, including high blood pressure, blood clots, and increased risks of breast and uterine cancers. Women who have had a hysterectomy seem to tolerate estrogen-only therapy with fewer risks than apply to mixed-hormone therapy in women who still have a uterus.
The anti-seizure medication gabapentin (Neurontin) seems to be second only to HRT in relieving hot flashes.[22]
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. While most SERMs are known to increase hot flushes, Femarelle (DT56a) decreases them.[23][24] In addition to the relieving effects on menopausal symptoms, Femarelle also increases bone mass density (BMD),[25] 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[26] and uterus,[27][28] has no effect on these tissues.
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. 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. Prozac has been repackaged as Sarafem and is approved and prescribed for premenstrual dysphoric disorder (PMDD), a mood disorder often exacerbated during perimenopause and early menopause. PMDD has been found by PET scans to be accompanied by a sharp drop in serotonin in the brain, and to respond quickly and powerfully to SSRIs.
This is a seizure medication that has also been used off-label for a variety of other conditions. It appears to be as effective as estrogen at reducing hot flashes. [2]
About as effective as antidepressants for hot flashes, but without the other mind and mood benefits of antidepressants, are blood pressure medicines including clonidine (Catapres). These drugs may merit special consideration by women suffering both from high blood pressure and hot flashes.
Alternative dietary supplements for treatment of menopause symptoms afford anywhere from significant to moderate relief of these symptoms. Some botanical sources, referred to as phytoestrogens, are known to have an estrogenic effect on the body and therefore create a moderated estrogenic effect. Others, such as femarelle, were found to have Selective Estrogen Receptor Modulator (SERM) qualities [29], thereby reducing the safety risks involved in estrogenic-like treatments.
In the area of complementary and alternative therapies, acupuncture treatment is promising. There are some studies indicating positive effects, especially on hot flashes [30] [31] [32] but also others [33] showing no positive effects of acupuncture regarding menopause.
There are claims that soy isoflavones are beneficial concerning menopause. However, one study [34] indicated that soy isoflavones did not improve or appreciably affect cognitive functioning in postmenopausal women.
Other remedies which in some studies appear to work well, but in other studies appear to be no better than a placebo include red clover isoflavone extracts and black cohosh. Black cohosh can cause the stimulation of pre-existing breast cancer.
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