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Has the age at which menopause occurs changed throughout history?

Has the age at which menopause occurs changed throughout history?



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I was reading recently that the age of menarche has decreased in the last 150 years, and was wondering if the age of menopause in humans has also changed recently?

Would there be selective pressure for it to increase currently, given that the average age of women having their first child is increasing in the West anyway?


Quick answer: Yes, but not in the last 150 years.

There seems to be no clear link between age at menarche and age at menopause (taken from [1]):

While earlier studies were able to establish an association between early age of menarche and later menopause (Frisch 1978; 1987), more modern studies have not been able to confirm this effect (Whelan et al., 1990; van Noord et al., 1997).

Aristotle's assessment was similar to those of Hippocrates and also Roman authors, so it seems that 2000 years ago most women entered the menopause in their early 40s. Mediaeval authors, however, gave the 50s as the age when menses ceased-much closer to the timing for twentieth century women.

Jean Ginsburg in [2] states (emphasis mine):

In the past 100 years data from schoolchildren have shown a steady fall in the age at menarche in industrialised communities. Has there been a corresponding change in the age at the menopause? Unfortunately, reported surveys of the menopause have suffered from methodological defects. [… ]

Nevertheless, those studies least subject to bias show a striking agreement that the median age at the menopause is currently around 50 in Western industrialised societies. In Britain it is 50.78, in the United States 49.8 and in white South Africans 48.7 with little apparent change over the past century. In non-European women, however, the menopause seems to occur earlier-in South Africa and the United States black women have an earlier menopause than white women.

So, while early menarche is, apparently, irrelevant, age of onset of menopause has increased since antiquity but has remained relatively stable since the middle ages. Therefore, there have been no significant changes in the age of onset of menopause in the time frame you defined (150 years).

Finally, Bengtsson et al [3] state that:

Our study has, thus, not supported the view that the menopausal age is rapidly changing.

  1. C. Keck, Predictive Factors to Determine Age of Onset of Menopause, PAMJ , 3, 2005

  2. Ginsberg J. What determines the age at the menopause? BMJ. 1991 Jun 1;302:1288-9.

  3. Calle Bengtsson, Olof Lindquist, Lasse Redvall, Is the menopausal age rapidly changing?, Maturitas, 1(3), February 1979, Pages 159-164


[Determinants of the age at natural menopause]

The age at natural menopause (ANM) varies due to environmental and genetic factors. Smoking accelerates ANM by about 1.5-2 years. Other factors which accelerate ANM are: nulliparity, short-length menstrual cycles and unilateral oophorectomy. In contrast, factors such as irregular menstrual cycles, height socioeconomic status, parity and giving birth before the age 25 all delay ANM. Nutritional factors also affect ANM. For example, vegetarian diet accelerates ANM by about 2 years a high intake of fat, cholesterol, coffee also accelerate menopause, while moderate alcohol consumption delays it. However, the influence of dietary factors has not been adequately documented due to a relatively small number of studies. Moreover, genetic factors seem to influence ANM: for example, early menopausal age of the mother correlates with early menopausal age of her daughter. Factors such as the age at menarche, spontaneous abortions, passive smoking, weight and height, breast feeding, using of oral contraceptives, employment and depression, have all been suggested to influence menopausal age, but their impact needs to be established. Therefore, there is a need for longterm, follow-up studies which would allow to evaluate the impact of life style factors, including dietary factors on ANM. The knowledge of factors influencing ANM is crucial for medical practice, public health and reproductive biology. Menopause is the period during which serious health problems such as cardiovascular diseases and osteoporosis occur with increasing frequency. Knowing the factors which determine menopausal age may lead to lifestyle changes (such as not smoking), which would result in delaying menopause, and therefore prolonging natural estrogen protection.


A Natural History of Menopause

Menopause is defined as an ending, a lack: you can't know you're in it till it's over. That's the dance, said a doctor I asked. To medicine, it's the one-year anniversary of a woman's last period. Just that day, that 24-hour spot of time.

To most women, the word carries much more weight. Hot flashes. Mood swings. A feeling of falling apart. Aches in the teeth, the joints, the eyes. Osteoporosis. The end of fertility—and of desire, too? The transformation from "babe" into "crone." The door to old age.

I fear beginning to look like my mother, with a very large stomach, said a woman in one survey. Others noted:

Wrinkling, pot-belly, old-looking skin.

It's a negative image of a body "drying up."

Weight gain is a constant struggle.

"Notable was the absence of any sense of achievement, or gained status, associated with becoming menopausal," noted the researchers who conducted the survey. "Rather, the anticipated benefits had more to do with the termination of currently annoying or troubling conditions."

Recently an anthropologist did find a biological reason for "the change": as a way to secure the health of the youngsters in a family while their mother is nursing a newborn. Post-menopausal females are prodigious food-gatherers, she found, and keep their grandchildren well fed. The news was uplifting: menopause may be a good thing for the species. But the anthropologist's work carried a downside as well. She named her idea "The Grandmother Hypothesis." (At menopause, I wonder, will I become white haired and apple-cheeked? Will I learn patience and pie-baking?)

Doctors talk about the perimenopause, those years (and we're talking five, more or less) of fluctuating fertility, when a woman's once punctual periods start wandering over the days and weeks. When it comes, the blood may gush—a sign frighteningly like that of some cancers. Just the irregularity of it all takes some getting used to. Especially when no one can tell you why.

"Why do women continue to feel they don't know anything about menopause when there are so many books on the bookshelves now?," asked Phyllis Mansfield, who had conducted the survey cited above. "Because every woman's menopause is unique," she answered herself, "and no study has validated that uniqueness."

Mathematics, oddly, may give women that validation: mathematics and almost a quarter of a million urine samples. These are the telling points of a $2 million study, funded by the National Institutes of Health last July, joining Mansfield and anthropologists Jim Wood, Darryl Holman, and Kathleen O'Connor at Penn State, with demographer Maxine Weinstein at Georgetown University and nurse-physiologist Ann Voda of The Tremin Trust at the University of Utah.

Mansfield is a psychologist, a health educator, and a scholar of women's studies. She has a reassuring manner and a soothing voice, yet she's effusive and energetic when talking about what drives her for an activist she's unusually optimistic. She offered me chocolate when I came to her office: someone baked brownies for a birthday treat. When she spoke of her new project she sat very still. "All my research is done with the aim of giving women the information that will empower them. I want to help women. I want to help women manage a very scary transition—and it's scary because they don't know what to expect."

"It's a hot topic," said anthropologist Jim Wood of the menopause. "Because of the aging of the Baby Boom and also the development of new interventions for infertility that aren't just "treatments.' It's now possible for a woman to become pregnant after menopause, with donor eggs, a simulated hormonal milieu. There's no overwhelming technical reason why she shouldn't be able to do this." Wood has the kind of enthusiasm that is barely contained in his frame. His gestures are large, his vocabulary lively. He does professorial stuff: writes flow charts on the blackboard, knits his fingers behind his head, yet he can discuss without blushing such things as breastfeeding and menstrual blood. His research landed him in New Guinea, just out of graduate school, collecting urine and trying to unravel, by reading hormonal signs, why women are sometimes fertile, sometimes not, why their cycles suddenly end. "To discover the dearth of information on these questions was absolutely mindboggling," he exclaimed.

Darryl Holman was one of Wood's graduate students and is now a postdoctoral fellow in the lab. He rivals Wood's enthusiasm (and though a younger man, beats him hands down on length of beard), but his is a more gentle, inquiring manner. He's quick to blame his own bad assumptions for the trick his data from Bangladesh played on him. With a team of Bangladeshi field workers, he collected 20,000 urine samples one year. He was assessing rates of fetal loss—how often women became pregnant but lost the fetus before they knew it—and menopause factored into his tests. "If I'd only known," he mused. "If I'd not read the literature, I would have done a better study." He laughed and explained: "I went to Bangladesh believing women over 43 had a good chance of being post-menopausal. There'd been a study in the early "80s in this same area, and it found the mean age at menopause was 43.6. That's on the low end, but it's consistent with studies of menopause in developing countries," the theory being that menopause has something to do with poor nutrition or stress. "So I only collected women up to age 48," Holman said. "By chance I got a few older than that because the field worker messed up." A statistical analysis including these strays showed the mean age at menopause to be between 49 and 51. "My conclusion now is that this belief that menopause occurs earlier in developing countries is not true. It's hooey. I went back and reviewed the literature very carefully, and in all the studies that showed a really early age at menopause, the statistical analyses were flawed."

Statistical analyses are Holman's cup of tea. He talked of being "the statistical interpreter" of the menopause group, of being interested in "building etiologic models, mechanistic models, of how we think the biology is working," of being "quite proud of the follicular depletion model" that he and Wood have developed to explain menopause. "But I want to apply it as well," he added. "We're trying to understand what menopause is."

"There's another reason why women want to do this, to be a part of this study," said Kathleen O'Connor. O'Connor, also a postdoc, actually runs the lab. She's the one who has to go down to Walmart to collect the 200 clipboards, 200 Tupperware freezer containers, and 1200 styrofoam boxes. She's the one who'll be in charge of packing and sending the stuff out to the women volunteers and organizing hormonal assays on the quarter of a million urine samples they return. She's assayed her own urine as well. "It's fun experimenting on yourself," she kidded. There's a quickness, a cut-to-the-chase efficiency about O'Connor that's lacking in the other three Penn Staters on the team. She sorted through a stack of files looking for something, grabbed a napkin when she couldn't come up with a blank scrap to draw a diagram on. She showed me the chart: two hormones fluctuating like out-of-sync waves across a span of 30 days. "It's so cool to see that," she said, "when you get a profile of your hormones across your cycle, it's so cool. You learn what your body is doing. It's a reward in itself."

"I'm taking urine samples myself, too," noted Mansfield. "Kathy and I can sit around and say, You know what it's like when you can't open the freezer box because your hands are too stiff first thing in the morning?" She smiled. "It's very important to know what you're asking other people to do."

The "other people," in this case, are a group of 150 to 200 35- to 55-year-old women selected from the Tremin Trust Menstruation and Reproductive History Program. Beginning in 1934, when Alan Treloar of the University of Minnesota enrolled the 2350 women of cohort 1, and continuing with the 1600 women of cohort 2, who were recruited in the 1960s and "70s, the Tremin Trust women have kept menstrual calendars, recording the beginning and ending dates of each of their periods on a standardized card and, on its reverse, any "unusual events" that might have affected their cycles, such as pregnancies, births, abortions, surgeries, illnesses, use of medication, or lapses in their record-keeping. A year-end health report recorded their living arrangements and household composition, education, medical and smoking histories, exercise routines, and sources of stress or support. "Since 1967," Wood and his colleagues wrote in their grant proposal, "analyses drawing upon the Tremin Trust database have made significant contributions to our understanding of the human menstrual cycle. . . . Most of what we know about age patterns of menstruation, including during the menopausal transition, is based upon the Tremin Trust sample."

Mansfield met Ann Voda, current director of the Tremin Trust, at a conference the year after the Trust moved to the University of Utah in 1984. Both were asking questions about the menstrual cycle: "Not medicalizing," Mansfield said, "but asking different questions, saying, What do women experience? We were not making assumptions that menstrual events were signs of illness. They may be different from what women experience at other times, but not illness."

In 1990, the two started a study using a subset of the Tremin Trust women, those aged 35 to 55 who were still menstruating. They focused on heavy bleeding. "We asked the women to report not just when their periods started and stopped, but we devised a scale to measure how much bleeding was occuring. Women do notice if their period is longer or shorter, but what they most notice is this heavy bleeding." The women's yearly health report was expanded to include questions about changes in their bodies, their cycles, moods, sexual response, hot flashes, and other conditions related to menopause. "We asked them how they negotiated decision-making with their physicians on hormone treatments, and where they got their information on menopause." Voda and Mansfield also asked, Why do you stay in this project? "Mostly to help other women, the subjects said. They felt they had been so much better informed by being in the project," Mansfield noted. Some had listed Edith Bunker of TV's "All in the Family" as one of their chief sources of information before joining the study. I can't talk to my physician about this, one said. Another: Two doctors told me when I asked about when to expect menopause, "Ask your mother.' Thanks anyway. A third: My mother told me nothing about the menstrual cycle or menopause. It was hush-hush.

Independently of Mansfield, Wood and Maxine Weinstein had contacted Voda about using the Tremin Trust to look at the hormonal profile over menopause. It was Voda who linked Wood and Mansfield, both at Penn State. "It was natural for us to put together a grant proposal," said Mansfield. But it took several rewrites before a federal agency agreed to fund it. ("Our fear was that the government would take so long that the women would be past menopause," Mansfield said. "This was going to be the last try, they're getting old.") Funding came through in July "97, and Mansfield admitted that the protocol was improved by the review process. "We did a quick pilot study," she explained, "with women in this area collecting their urine in a device Darryl devised. We were able to show the government that we did have a method women would easily comply with."

It's not a method easy on the lab. "We're getting daily samples from a large number of women over a long range of time," said O'Connor, "it's unprecedented. It'll open a window into the biology." It'll be a lot of work. Each woman will get a 15-pound "urine collection kit" each year: 185 "urine collection devices" (one a day for six months, then she can take a six-month break), a plastic freezer storage case, sheets of labels, sealing tape, seven 8-ounce refrigerant gel packs (one extra for travel), six postpaid polyfoam mailing boxes, and an instruction sheet on a clipboard. The easy-to-use urine collection device, which Holman hopes to patent, obviates the need for the subject to process urine in any way, e.g. to pour it from one container to another, according to the grant proposal. Each morning, the woman collects her own urine, seals the vial, attaches that day's sample identification number to the vial, and then places it into the plastic container provided for storing the specimens in her freezer. On the label she does "a little bit of record-keeping," noting if she's menstruating, taking birth control pills, eating large amounts of soy protein ("Some studies find an effect on the hormones we're looking at," said O'Connor. "It's controversial."), any medicines she might be using.

"Altogether," said O'Connor, "it should take her three to five minutes, max."

At the end of each month, she'll ship her 30-odd vials toUniversity Park via overnight express.

"We'll probably need 12 freezers here in the lab," said O'Connor. "We're hoping to get 40,000 urine samples a year." From each daily sample O'Connor and her assistants will take a one-milliliter aliquot, freezing the rest of the 10-to-15 milliliter sample. The urine in each aliquot will be used in four hormone assays, testing for forms of estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). "Each of the assays," said O'Connor, "takes about a week to run. At 36 samples per plate, 30 plates at a time, we'll be doing about 1,000 samples a week. A robotic pipetter will do a lot of the work for us," she added. "That'll help prevent carpal tunnel syndrome from repeat pipetting. But it will still be an enormous amount of work. That's why other people haven't done this before."

Over the last year, processing Holman's 20,000 Bangladeshi urine samples, O'Connor has streamlined the assaying. "Every day of the week we take out the plates, line them up, and do something to them. It's like working in your kitchen. The samples have a wide range of colors. They're quite pretty. There is a distinctive odor—" She laughed. "I get a lot of comments from the genetics people down the hall, especially when we're boiling it. But it's better than working with blood or feces."

Mansfield, meanwhile, is in charge of keeping the samples coming in. "My job," she explained, "is to make calls to every woman on the project and find out how she's doing. To make sure she doesn't have questions, that her morale is good." Mansfield will also be the one integrating the women's label jottings and yearly surveys with the hormonal assays—"that is, placing what we're finding in the lab in the context of women's lives: the stressful events, new jobs, divorces, deaths what the women are taking, in terms of medical products or herbs and how they're feeling: What is going on when their LH and FSH are sky high?

"We've learned that all changes are alarming to women," Mansfield said, citing her earlier work with Voda. "A woman who has a 32-day cycle will become totally alarmed if she has a 35-day period, when for another woman that's totally normal. No one has documented what all the changes are over the menopause. Treloar did some of it, the man who started the Tremin Trust."

Nearly three million office visits are made by women between ages 25 and 54 each year for complaints related to menstrual disorders the annual visit rate for abnormal bleeding is 7.2 per 100 women, Mansfield and her colleagues note in their grant proposal. Changes in menstrual patterns have been linked to osteoporosis, cardiovascular risk, cancers of the breast and endometrium, thyroid and pituitary disorders, and other health problems. Yet no one knows the full range of "normal." Despite recent work on the biology of menopause, little is known at the population level about variation among women in the perimenopausal transition or how that variation relates to their earlier experiences.

"Here's the Reader's Digest Condensed Version," Wood began. He was giving me the lab's working model, their theory of what menopause is. When Holman had explained it to me, he used equations O'Connor scrapped the math and pulled out illustrations and graphs. Wood began with the basics.

"Up in your head you have the hypothalmus." He drew a box on the blackboard. "A little lower down in the head you have the pituitary gland. The hypothalmus releases gonadotropic releasing hormone, GnRH. That stimulates a couple of hormones known as FSH and LH, the gonadotropins, which in turn stimulate the ovary and are critical in maintaining regular cycles. These hormones select which follicle in the ovary is going to develop into an egg. What we think is happening with this selection process is that a lot of follicles begin developing, then randomly die by a process called atresia. Atresia is the default value. But the idea is that if a follicle has started to develop at such a time that it presents the right hormone receptor during a previous month's cycle, it will be selected—it will be rescued from atresia and go on to become an egg.

"The developing follicles in the ovary feed back to the pituitary gland by releasing steroids—estradiol, which is a form of estrogen, and progesterone are the most important." At the blackboard, Wood finished drawing boxes for the pituitary and ovary and linked them with a pattern of arrows. "Except for a brief period mid-cycle, these feedbacks are mostly negative, that is, they suppress the production of hormones. The exception is estradiol. Just before ovulation, it switches over in a way that's still mysterious to a positive feedback. But it's the negative feedback from the follicles at the beginning of the cycle that's critical for getting a normal cycle underway.

"We now know with fair confidence," Wood said, speaking for science in general, "that menopause is driven by this process of follicular depletion." Or, as O'Connor had put it, "Aging comes from the ovaries." It works like this: A girl is born with upwards of a million follicles in her ovaries. Like the cells in the brain and the eye, these follicles are never replaced when they die. Unlike brain cells, dying off is what follicles do naturally: by the time a girl reaches puberty and her hormones kick in, she will have lost all but some 100,000 of them. Every month after that, a dozen or more follicles will begin to grow, only one of which is usually selected to mature and be released at ovulation. By the time she is 45 (at least according to the handful of studies that have been done using autopsy cases or ovaries that had to be surgically removed), a woman's follicles will number only about a thousand. "What happens in menopause," said Wood, "is that once you've run out of follicles, all the hormonal feedback is removed. FSH and LH go up to very high levels and randomly fluctuate, which is what we believe is responsible for hot flashes.

"The big mysteries in this research have to do with the mechanisms of follicular depletion," Wood added. "But from the statistical information, it looks like a process that begins prenatally and randomly continues. There's a random exhaustion of follicles ending with menopause." That statistical pattern lends itself to "some fairly simple mathematical models," said Wood. (As Holman had noted. "It looks like an exponential process, like a radioactive half-life.") Wood continued, "As modelers, we thought, If the process is as straightforward as that, then we should be able to develop a mathematical model of follicular depletion that could tell us what the age distribution of menopause should look like, and it should tell us something about the variation in ages of when women reach menopause.

"So we developed a model. But as we started playing around with the model more, and the implications of the model, we thought, There really shouldn't be such a thing as menopause. It's an arbitrary definition: If you haven't experienced vaginal bleeding in 12 months, you're post-menopausal. But the model told us there should be a very long upper tail"—that is, that a graph of bleeding episodes over a woman's lifetime wouldn't show just monthly clusters of dots that suddenly stop the dots would instead at some point start spacing out and looking erratic, tailing off little by little until they eventually gave out.

"But then, we asked, Why do we see these long lags between bleeding at higher ages? It turns out that it has to do with interarrival times in superimposed pure-death processes."

Huh? Wood saw the blank look on my face and laughed, a great guffaw. "This loss of follicles can be modelled in a way that statistical modellers call a "pure-death process.' That's a subclass of what statisticians call "birth-death processes,' but here you have a stock of something and the only thing that can happen to them is that you can lose them.

"It's a very strange biological reality.

"What our model predicted was that at any age you had a possibility of having a period of time where there was no follicular development. In a young woman, that period of time might be milli-seconds long, but it's there. In an older woman, it can be very long indeed. Menopause, in a way, is just a very long phase before follicular development. Which means that a woman well past "menopause' could still get some vaginal bleeding. This is what our model predicts."

He smiled. "It's a lot nicer than thinking that something very wrong is going on if you get bleeding after menopause," he added.

Back to the science: "So then we got to wondering if these interarrival times left any hormonal signature? We searched the literature and we found it.

"We used to think that if you saw a combination of low steroids and high gonadotropins that it was the signature of menopause. But if our model was right, there should be a period in any woman's cycle when no steroids were released and we would see high gonadotropins. And we found a handful of cases. There was no explanation given. These were just weird times when the women were not producing steroids and their gonadotropins went real high. One endocrinologist went so far as to label this the "hypoestrogenic-hypergonadotrophic period.' He only saw it in one woman.

"At the same time, we were doing a pilot study for our NIH grant proposal. Kathy was collecting urine in women of a wide age range, and as data came in, hey presto! There was our own hypoestrogenic-hypergonadotrophic phase. It looked like what you'd expect during one of our interarrival times.

"Then we said—and this idea took a long time coming—we said, occasionally you'd expect to see one of these in a younger woman. We looked at our data on younger women and, by God, there it was. No steroids, and the gonadotropins would start to go up. They didn't get very far. As soon as you got hormonal evidence that another follicle was developing, the gonadotropins went right back down. When we looked at the full set of younger women, some showed no sign of this phase, some showed one day, some three or four days. But never very long phases.

"And we started to think the following brave thoughts. Let's call them hypotheses. We think these inactive phases will turn out to be a normal part of the perimenopausal transition. They will get longer—the age progression turned out to be quite regular. It makes sense to think of menopause as a very long inactive phase that could be followed by another round of follicular development if there are follicles left. And the fact that the inactive phase is getting longer, but that there's a lot of variability, explains why women's cycles are so different. It also explains a lot of what have been hitherto mysterious connections between hormone levels and menopause."

Just like women throughout the ages, I've long compared my cycles to the moon's. I wax and I wane. I come to a glowing fullness at ovulation, I get sharper and more prickly as I approach the dark respite and the cycle begins anew. The metaphor, woman as moon, doesn't bear up under too much analysis. Yet imagine this: If the moon were mortal, if she aged as I do, those dark nights that we call the new moon would increase. The month would linger. One night of darkness now, maybe two. Five nights when I'm 45. By the time I'm 55, years and years might go by without moonlight, and then, suddenly, a sliver of moon.

"We can predict, mathematically, how long it will take since the last cycle before an ovary begins putting out estradiol," Holman said, "and it depends on a woman's age. At 30 years of age, it's really short. At 45, it's really noticeable.

"We call this period the inactive phase of the cycle. We're proposing that there are three phases of the menstrual cycle, not two.

"The other two are the follicular phase and the luteal phase. During the follicular phase, the follicles are growing. The luteal phase is after ovulation, which means that the selected follicle has turned into a corpus luteum. That's when progesterone starts going up, to finish preparing the lining of the uterus for implantation." Sometimes in post-menopausal women, Holman noted, when their ovaries are removed for one reason or another, a corpus luteum is found inside. In other cases, a woman believed to be post-menopausal will get pregnant. A hysterectomy is often prescribed if a woman two or three years past menopause suddenly begins again to have vaginal bleeding, yet such a lag, in her case, could be normal: merely an extra-long phase before a last follicle develops.

To counteract some side effects of menopause, such as mood swings and hot flashes, as well as to protect against osteoporosis, physicians often suggest estrogen replacement therapy: According to the New York Times, Premarin, an estrogen replacement, is the most widely used prescription drug in the United States. "One of the things physicians typically do before a woman goes on estrogen replacement therapy," Holman explained, "is to take a blood test for hormones. If our model is right, a woman who has a single blood sample taken and looks menopausal may still have another bleeding episode. You need to know what part of her cycle the woman is in. It's not recognized that a woman can go six months in an inactive stage and yet suddenly have one of her follicles grow."

Plus, added O'Connor, "When is she going to go to the doctor? When she's unhappy. When she's in this inactive phase. Why does she feel lousy? Because her gonadotropins are high and her steroids are low. It's been a routine part of her cycle, but now it's become longer and more frequent because she's older. Those gonadotropin peaks used to be very narrow, only a day or less, before the steroids would also get high. Now it's a longer period of time."

"We're hopeful," said Wood, "that by gaining a clearer picture of the processes involved we can come up with much more reasonable guidelines for estrogen replacement therapy. For instance, how long might it be before a woman is likely to be making these hormones herself again? That's something we could predict."

Plus, added Mansfield, "There might be patterns in the way a woman's menstrual cycle changes during menopause. That's not interesting in itself, but what if we could predict patterns? For instance, what if every woman who had one child had a certain pattern, and it differed from that of a woman who had no children? Wouldn't that help women to know?"

"There might be other things that affect the rate of follicular depletion," said Holman. "We haven't identified specific ones, because the data are still being entered, but besides pregnancies, these might be the age at menarche, the use of birth control, the length of the cycle, even things like smoking. There's an epidemiological finding that women who smoke have earlier menopause. That might be purely a coincidence, nobody knows the mechanism, but smoking might kill follicles or it might affect a woman endocrinologically somehow. Right now there's not a lot of evidence that anything affects follicular depletion very much, but this study will let us look for factors that might somehow affect the underlying rate."

Said Wood, "Adding this inactive phase to our model of follicular depletion is really a powerful concept in understanding the aging of the reproductive system. It's an elegant way to explain some phenomena that haven't been tied together before. And it can make some pretty strong predictions. It can give a woman a better understanding of her own pattern, and some idea of what she is going to go through as she ages, based on her previous reproductive history. And it can tell us something about hormone patterns and the underlying biology of what is normal."

A compelling reason for studying changes in the pattern of menstrual bleeding during the perimenopause is related to the frequency of hysterectomies in the U.S., Wood and his colleagues write. Hysterectomy, still the most common surgical procedure performed on women, is often precipitated by self-diagnosed changes in bleeding pattern or menstrual disorders.

Knowledge of what sort of menstrual changes to expect is therefore essential to women's well-being.

"At what point do we say a bleeding pattern or a hormonal pattern is 'abnormal'?" Wood asked. "My own thought is that we've been too quick to label it that."

James W. Wood, Ph.D., is professor of anthropology in the College of the Liberal Arts, 517 Carpenter Bldg., University Park, PA 16802 814-865-1936 [email protected] Phyllis Kernoff Mansfield, Ph.D., is professor of women's studies and health education in the College of the Liberal Arts, 14 Sparks Bldg. 863-0356 [email protected] Darryl Holman, Ph.D., is a postdoctoral fellow in the Population Research Institute, Intercollege Research Programs, 714 Oswald Bldg. 863-1823 [email protected] Kathleen O'Connor, Ph.D., is also a postdoctoral fellow in the Population Research Institute, 510 Carpenter Bldg. 863-7740 [email protected] Their current research is funded by the National Institutes of Health.

Helen Redman's illustrations for this article appear on her Web site, "Birthing the Crone: Menopause and Aging Through the Artist's Eyes." The site combines powerful images and text to explore menopause and the physical, mental, emotional, and spiritual changes women experience as they age. She encourages women "to learn how to remain healthy and vital and to appreciate their bodies as they transform into the crone,' the pinnacle of femail life experience and wiseon," Redman says.


Difference between Menopause and Post Menopause?

Definition

Menopause is the stage of a woman’s life when menstruation comes to an end. Postmenopause is the stage that occurs after menopause has ended.

The age at which menopause usually begins is between 45 and 50 years old. The age at which postmenopause begins is on average 55 years but it depends when menopause ends.

Hormones

Estrogen, progesterone and FSH levels diminish and fluctuate in menopause. The same hormones are at very low but stable levels in post menopause.

Antral follicle count

The antral follicle count in menopause is low while it is very low in post menopause.

Uterus

The uterus starts to shrink during menopause. The uterus is very small by the time post menopause takes place.

Symptoms

The symptoms of menopause include vaginal dryness, hot flushes, night sweats, difficulty sleeping, and irritability. The symptoms of post menopause include increased vaginal atrophy and possibly a decrease in the hot flushes and night sweats.

Duration

Menopause can last from 7 to 10 years. Post menopause remains for the remainder of a woman’s life.

Osteoporosis

There is a slightly increased risk of developing osteoporosis during menopause. There is a greatly increased risk of developing osteoporosis during post menopause.

Treatment

Treatment of menopause most often takes the form of prescription hormone replacement pills. Treatment of post menopause sometimes includes hormone replacement pills as well as the addition of medications such as Fosamax to prevent and treat osteoporosis.


Contents

During early menopause transition, the menstrual cycles remain regular but the interval between cycles begins to lengthen. Hormone levels begin to fluctuate. Ovulation may not occur with each cycle. [16]

The term menopause refers to a point in time that follows one year after the last menstruation. [16] During the menopausal transition and after menopause, women can experience a wide range of symptoms.

Vagina and uterus Edit

During the transition to menopause, menstrual patterns can show shorter cycling (by 2–7 days) [16] longer cycles remain possible. [16] There may be irregular bleeding (lighter, heavier, spotting). [16] Dysfunctional uterine bleeding is often experienced by women approaching menopause due to the hormonal changes that accompany the menopause transition. Spotting or bleeding may simply be related to vaginal atrophy, a benign sore (polyp or lesion), or may be a functional endometrial response. The European Menopause and Andropause Society has released guidelines for assessment of the endometrium, which is usually the main source of spotting or bleeding. [17]

In post-menopausal women, however, any genital bleeding is an alarming symptom that requires an appropriate study to rule out the possibility of malignant diseases.

Symptoms that may appear during menopause and continue through postmenopause include:

    [16][16] – thinning of the membranes of the vulva, the vagina, the cervix, and the outer urinary tract, along with considerable shrinking and loss in elasticity of all of the outer and inner genital areas.

Other physical Edit

Mood and memory effects Edit

Psychological symptoms include anxiety, poor memory, inability to concentrate, depressive mood, irritability, mood swings, and less interest in sexual activity. [16] [23]

Menopause-related cognitive impairment can be confused with the mild cognitive impairment that precedes dementia. [24] Tentative evidence has found that forgetfulness affects about half of menopausal women [25] and is probably caused by the effects of declining estrogen levels on the brain, [25] or perhaps by reduced blood flow to the brain during hot flashes. [26]

Long-term effects Edit

  • A possible but contentious increased risk of atherosclerosis. [27] The risk of acute myocardial infarction and other cardiovascular diseases rises sharply after menopause, but the risk can be reduced by managing risk factors, such as tobacco smoking, hypertension, increased blood lipids and body weight. [28][29]
  • Increased risk of osteopenia, osteoporosis, [30] and accelerated lung function decline. [31][32]

Women who experience menopause before 45 years of age have an increased risk of heart disease, [33] death, [34] and impaired lung function. [31]

Menopause can be induced or occur naturally. Induced menopause occurs as a result of medical treatment such as chemotherapy, radiotherapy, oophorectomy, or complications of tubal ligation, hysterectomy, unilateral or bilateral salpingo-oophorectomy or leuprorelin usage. [35]

Age Edit

Menopause typically occurs between 49 and 52 years of age. [2] Half of women have their last period between the ages of 47 and 55, while 80% have their last period between 44 and 58. [36] The average age of the last period in the United States is 51 years, in the United Kingdom is 52 years, in Ireland is 50 years and in Australia is 51 years. In India and the Philippines, the median age of natural menopause is considerably earlier, at 44 years. [37] The menopausal transition or perimenopause leading up to menopause usually lasts 7 years (sometimes as long as 14 years). [1] [11]

In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40. This is known as premature ovarian failure and affects 1 to 2% of women by age 40. [38]

Undiagnosed and untreated coeliac disease is a risk factor for early menopause. Coeliac disease can present with several non-gastrointestinal symptoms, in the absence of gastrointestinal symptoms, and most cases escape timely recognition and go undiagnosed, leading to a risk of long-term complications. A strict gluten-free diet reduces the risk. Women with early diagnosis and treatment of coeliac disease present a normal duration of fertile life span. [39] [40]

Women who have undergone hysterectomy with ovary conservation go through menopause on average 3.7 years earlier than the expected age. Other factors that can promote an earlier onset of menopause (usually 1 to 3 years early) are smoking cigarettes or being extremely thin. [41]

Premature ovarian failure Edit

Premature ovarian failure (POF) is when the ovaries stop functioning before the age of 40 years. [42] [43] It is diagnosed or confirmed by high blood levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) on at least three occasions at least four weeks apart. [44]

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. [43] However, in about 50–80% of spontaneous cases of premature ovarian failure, the cause is unknown, i.e., it is generally idiopathic. [42] [44]

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

An early menopause can be related to cigarette smoking, higher body mass index, racial and ethnic factors, illnesses, and the surgical removal of the ovaries, with or without the removal of the uterus. [45]

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.

Surgical menopause Edit

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). [46] Cessation of menses as a result of removal of the ovaries is called "surgical menopause". Surgical treatments, such as the removal of ovaries, might cause periods to stop altogether. [33] The sudden and complete drop in hormone levels usually produces extreme withdrawal symptoms such as hot flashes, etc. The symptoms of early menopause may be more severe. [33]

Removal of the uterus without removal of the ovaries does not directly cause menopause, although pelvic surgery of this type can often precipitate a somewhat earlier menopause, perhaps because of a compromised blood supply to the ovaries. [ citation needed ] . The time between surgery and possible early menopause is due to the fact that ovaries are still producing hormones. [33]

The menopausal transition, and postmenopause itself, is a natural change, not usually a disease state or a disorder. The main cause of this transition is the natural depletion and aging of the finite amount of oocytes (ovarian reserve). This process is sometimes accelerated by other conditions and is known to occur earlier after a wide range of gynecologic procedures such as hysterectomy (with and without ovariectomy), endometrial ablation and uterine artery embolisation. The depletion of the ovarian reserve causes an increase in circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels because there are fewer oocytes and follicles responding to these hormones and producing estrogen.

The transition has a variable degree of effects. [47]

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. [48]

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 luteinizing hormone (LH), which are both produced by the pituitary gland. During perimenopause (approaching menopause), estradiol levels and patterns of production remain relatively unchanged or may increase compared to young women, but the cycles become frequently shorter or irregular. [49] The often observed increase in estrogen is presumed to be in response to elevated FSH levels that, in turn, is hypothesized to be caused by decreased feedback by inhibin. [50] Similarly, decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause. [51] [52]

The menopausal transition is characterized by marked, and often dramatic, variations in FSH and estradiol levels. Because of this, measurements of these hormones are not considered to be reliable guides to a woman's exact menopausal status. [50]

Menopause occurs because of the sharp decrease of estradiol and progesterone production by the ovaries. After menopause, estrogen continues to be produced mostly by aromatase in fat tissues and is produced in small amounts in many other tissues such as ovaries, bone, blood vessels, and the brain where it acts locally. [53] The substantial 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. [54] Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production. [55]

Hot flashes and other vasomotor symptoms accompany the menopausal transition. While many sources continue to claim that hot flashes during the menopausal transition are caused by low estrogen levels, this assertion was shown incorrect in 1935, and, in most cases, hot flashes are observed despite elevated estrogen levels. The exact cause of these symptoms is not yet understood, possible factors considered are higher and erratic variation of estradiol level during the cycle, elevated FSH levels which may indicate hypothalamic dysregulation perhaps caused by missing feedback by inhibin. It has been also observed that the vasomotor symptoms differ during early perimenopause and late menopausal transition and it is possible that they are caused by a different mechanism. [49]

Long-term effects of menopause may include osteoporosis, vaginal atrophy as well as changed metabolic profile resulting in cardiac risks.

Ovarian aging Edit

Decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause. Hastened ovarian aging has been observed after endometrial ablation. While it is difficult to prove that these surgeries are causative, it has been hypothesized that the endometrium may be producing endocrine factors contributing to the endocrine feedback and regulation of the ovarian stimulation. Elimination of these factors contributes to faster depletion of the ovarian reserve. Reduced blood supply to the ovaries that may occur as a consequence of hysterectomy and uterine artery embolisation has been hypothesized to contribute to this effect. [51] [52]

Impaired DNA repair mechanisms may contribute to earlier depletion of the ovarian reserve during aging. [56] As women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that ordinarily accurately repairs DNA double-strand breaks. This repair system is called "homologous recombinational repair", and it is especially effective during meiosis. Meiosis is the general process by which germ cells are formed in all sexual eukaryotes it appears to be an adaptation for efficiently removing damages in germ line DNA. [57] [ citation needed ] (See Meiosis.)

Human primary oocytes are present at an intermediate stage of meiosis, termed prophase I (see Oogenesis). Expression of four key DNA repair genes that are necessary for homologous recombinational repair during meiosis (BRCA1, MRE11, Rad51, and ATM) decline with age in oocytes. [56] This age-related decline in ability to repair DNA double-strand damages can account for the accumulation of these damages, that then likely contributes to the depletion of the ovarian reserve.

Ways of assessing the impact on women of some of these menopause effects, include the Greene climacteric scale questionnaire, [58] the Cervantes scale [59] and the Menopause rating scale. [20]

Premenopause Edit

Premenopause is a term used to mean the years leading up to the last period, when the levels of reproductive hormones are becoming more variable and lower, and the effects of hormone withdrawal are present. [46] Premenopause starts some time before the monthly cycles become noticeably irregular in timing. [60]

Perimenopause Edit

The term "perimenopause", which literally means "around the menopause", refers to the menopause transition years before the date of the final episode of flow. [1] [11] [61] [62] According to the North American Menopause Society, this transition can last for four to eight years. [63] The Centre for Menstrual Cycle and Ovulation Research describes it as a six- to ten-year phase ending 12 months after the last menstrual period. [64]

During perimenopause, estrogen levels average about 20–30% higher than during premenopause, often with wide fluctuations. [64] These fluctuations cause many of the physical changes during perimenopause as well as menopause, especially during the last 1–2 years of perimenopause (before menopause). [61] [65] Some of these changes are hot flashes, night sweats, difficulty sleeping, mood swings, vaginal dryness or atrophy, incontinence, osteoporosis, and heart disease. [64] 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.

The menopause transition typically begins between 40 and 50 years of age (average 47.5). [66] [67] The duration of perimenopause may be for up to eight years. [67] Women will often, but not always, start these transitions (perimenopause and menopause) about the same time as their mother did. [68]

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

  • Caring for, and/or the death of, elderly parents when children leave home
  • The birth of grandchildren, which places people of "middle age" into a new category of "older people" (especially in cultures where being older is a state that is looked down on)

Some research appears to show that melatonin supplementation in perimenopausal women can improve thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing depression associated with menopause. [69]

Postmenopause Edit

The term "postmenopausal" describes women who have not experienced any menstrual flow for a minimum of 12 months, assuming that they have a uterus and are not pregnant or lactating. [46] In women without a uterus, menopause or postmenopause can be identified by a blood test showing a very high FSH level. Thus postmenopause is the time in a woman's life that takes place after her last period or, more accurately, after the point when her ovaries become inactive.

The reason for this delay in declaring postmenopause is because periods are usually erratic at this time of life. Therefore, a reasonably long stretch of time is necessary to be sure that the cycling has ceased. At this point a woman is considered infertile however, the possibility of becoming pregnant has usually been very low (but not quite zero) for a number of years before this point is reached.

A woman's reproductive hormone levels continue to drop and fluctuate for some time into post-menopause, so hormone withdrawal effects such as hot flashes may take several years to disappear.

A period-like flow during postmenopause, even spotting, may be a sign of endometrial cancer.

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

Hormone replacement therapy Edit

In the context of the menopause, hormone replacement therapy (HRT) is the use of estrogen in women without a uterus and estrogen plus progestin in women who have an intact uterus. [70]

HRT may be reasonable for the treatment of menopausal symptoms, such as hot flashes. [71] It is the most effective treatment option, especially when delivered as a skin patch. [72] [73] Its use, however, appears to increase the risk of strokes and blood clots. [74] When used for menopausal symptoms some recommend it be used for the shortest time possible and at the lowest dose possible. [74] Evidence to support long-term use, however, is poor. [72]

It also appears effective for preventing bone loss and osteoporotic fracture, [75] but it is generally recommended only for women at significant risk for whom other therapies are unsuitable. [76]

HRT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer. [76] There is some concern that this treatment increases the risk of breast cancer. [77]

Adding testosterone to hormone therapy has a positive effect on sexual function in postmenopausal women, although it may be accompanied by hair growth, acne and a reduction in high-density lipoprotein (HDL) cholesterol. [78] These side effects diverge depending on the doses and methods of using testosterone. [78]

Selective estrogen receptor modulators Edit

SERMs are a category of drugs, either synthetically produced or derived from a botanical source, that act selectively as agonists or antagonists on the estrogen receptors throughout the body. The most commonly prescribed SERMs are raloxifene and tamoxifen. Raloxifene exhibits oestrogen agonist activity on bone and lipids, and antagonist activity on breast and the endometrium. [79] 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. [80]

Other medications Edit

Some of the SSRIs and SNRIs appear to provide some relief from vasomotor symptoms. [6] Low dose paroxetine is the only non-hormonal medication that was FDA-approved to treat moderate-to-severe vasomotor symptoms associated with menopause as of 2016. [81] [82] They may, however, be associated with appetite and sleeping problems, constipation and nausea. [6] [83]

Gabapentin or clonidine may help but do not work as well as hormone therapy. [6] Gabapentin can decrease the amount of hot flashes. Side effects associated with its use include drowsiness and headaches. Clonidine is used to improve vasomotor symptoms and may be associated with constipation, dizziness, nausea and sleeping problems. [6] [83]

Therapy Edit

One review found mindfulness and cognitive behavioural therapy decreases the amount women are affected by hot flushes. [84] Another review found not enough evidence to make a conclusion. [85] A 2018 study found that 85% of study participants reported reduced hot flashes and night sweats when using a climate control system in their beds. [86]

Exercise Edit

Exercise has been thought to reduce postmenopausal symptoms through the increase of endorphin levels, which decrease as estrogen production decreases. [87] Additionally, high BMI is a risk factor for vasomotor symptoms in particular. However, there is insufficient evidence to support the benefits of weight loss for symptom management. [88] There are mixed perspectives on the benefits of physical exercise. While one review found that there was a lack of quality evidence supporting a benefit of exercise, [87] another review recommended regular healthy exercise to reduce comorbidities, improve mood and anxiety symptoms, enhance cognition, and decrease the risk of fractures. [89] Yoga may help with postmenopausal symptoms similar to other exercise. [90] There is insufficient evidence to suggest that relaxation techniques reduce menopausal symptoms. [91]

Alternative medicine Edit

There is no evidence of consistent benefit of alternative therapies for menopausal symptoms despite their popularity. [92]

The effect of soy isoflavones on menopausal symptoms is promising for reduction of hot flashes and vaginal dryness. [15] [93] Evidence does not support a benefit from phytoestrogens such as coumestrol, [94] femarelle, [95] or the non-phytoestrogen black cohosh. [15] [96] As of 2011 there is no support for herbal or dietary supplements in the prevention or treatment of the mental changes that occur around menopause. [97]

Hypnosis may reduce the severity of hot flashes. In addition, relaxation training with at-home relaxation audiotapes such as deep breathing, paced respiration, and guided imagery may have positive effects on relaxing muscles and reducing stress. [98]

There is no evidence to support the efficacy of acupuncture as a management for menopausal symptoms. [99] [92] A 2016 Cochrane review found not enough evidence to show a difference between Chinese herbal medicine and placebo for the vasomotor symptoms. [100]

Other efforts Edit

  • 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 complain that their genitalia are uncomfortably dry all the time, and they may do better with moisturizers. Those who need only lubricants do well using them only during intercourse.
  • Low-dose prescription vaginal estrogen products such as estrogen creams are generally a safe way to use estrogen topically, to help vaginal thinning and dryness problems (see vaginal atrophy) while only minimally increasing the levels of estrogen in the bloodstream.
  • In terms of managing hot flashes, lifestyle measures such as drinking cold liquids, staying in cool rooms, using fans, removing excess clothing, and avoiding hot flash triggers such as hot drinks, spicy foods, etc., may partially supplement (or even obviate) the use of medications for some women.
  • Individual counseling or support groups can sometimes be helpful to handle sad, depressed, anxious or confused feelings women may be having as they pass through what can be for some a very challenging transition time. can be minimized by smoking cessation, adequate vitamin D intake and regular weight-bearing exercise. The bisphosphonate drug alendronate may decrease the risk of a fracture, in women that have both bone loss and a previous fracture and less so for those with just osteoporosis. [101]
  • A surgical procedure where a part of one of the ovaries is removed earlier in life and frozen and then over time thawed and returned to the body has been tried. While at least 11 women have undergone the procedure and paid over £6,000, there is no evidence it is safe or effective. [102]

The cultural context within which a woman lives can have a significant impact on the way she experiences the menopausal transition. Menopause has been described as a subjective experience, with social and cultural factors playing a prominent role in the way menopause is experienced and perceived.

The word menopause was invented by French doctors at the beginning of the nineteenth century. Some of them noted that peasant women had no complaints about the end of menses, while urban middle-class women had many troubling symptoms. Doctors at this time considered the symptoms to be the result of urban lifestyles of sedentary behaviour, alcohol consumption, too much time indoors, and over-eating, with a lack of fresh fruit and vegetables. [103] 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. [104] The paradigm within which a woman considers menopause 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. [105]

Ethnicity and geography play roles in the experience of menopause. American women of different ethnicities report significantly different types of menopausal effects. One major study found Caucasian women most likely to report what are sometimes described as psychosomatic symptoms, while African-American women were more likely to report vasomotor symptoms. [106]

It seems that Japanese women experience menopause effects, or konenki, in a different way from American women. [107] Japanese women report lower rates of hot flashes and night sweats this can be attributed to a variety of factors, both biological and social. Historically, konenki was associated with wealthy middle-class housewives in Japan, i.e., it was a "luxury disease" that women from traditional, inter-generational rural households did not report. Menopause in Japan was viewed as a symptom of the inevitable process of aging, rather than a "revolutionary transition", or a "deficiency disease" in need of management. [107]

In Japanese culture, reporting of vasomotor symptoms has been on the increase, with research conducted by Melissa Melby in 2005 finding that of 140 Japanese participants, hot flashes were prevalent in 22.1%. [108] This was almost double that of 20 years prior. [109] Whilst the exact cause for this is unknown, possible contributing factors include significant dietary changes, increased medicalisation of middle-aged women and increased media attention on the subject. [109] However, reporting of vasomotor symptoms is still significantly lower than North America. [110]

Additionally, while most women in the United States apparently have a negative view of menopause as a time of deterioration or decline, some studies seem to indicate that women from some Asian cultures have an understanding of menopause that focuses on a sense of liberation and celebrates the freedom from the risk of pregnancy. [111] Diverging from these conclusions, one study appeared to show that many American women "experience this time as one of liberation and self-actualization". [112]

Etymology Edit

Menopause literally means the "end of monthly cycles" (the end of monthly periods or menstruation), from the Greek word pausis ("pause") and mēn ("month"). This is a medical calque the Greek word for menses is actually different. In Ancient Greek, the menses were described in the plural, ta emmēnia, ("the monthlies"), and its modern descendant has been clipped to ta emmēna. The Modern Greek medical term is emmenopausis in Katharevousa or emmenopausi in Demotic Greek.

The word "menopause" was coined specifically for human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruations. However, menopause exists in some other animals, many of which do not have monthly menstruation [113] in this case, the term means a natural end to fertility that occurs before the end of the natural lifespan.

Few animals have a menopause: humans are joined by just four other species in which females live substantially longer than their ability to reproduce. The others are all cetaceans: beluga whales, narwhals, killer whales and short-finned pilot whales. [114] Various theories have been suggested that attempt to suggest evolutionary benefits to the human species stemming from the cessation of women's reproductive capability before the end of their natural lifespan. Explanations can be categorized as adaptive and non-adaptive:

Non-adaptive hypotheses Edit

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, [115] and the available data do not support this. [116]

A recent increase in female longevity due to improvements in the standard of living and social care has also been suggested. [117] It is difficult for selection, however, to favor aid to offspring from parents and grandparents. [118] Irrespective of living standards, adaptive responses are limited by physiological mechanisms. In other words, senescence is programmed and regulated by specific genes. [119]

Early human selection shadow Edit

While it is fairly common for extant hunter-gatherers to live past age 50 provided that they survive childhood, fossil evidence shows that mortality in adults has decreased over the last 30,000 to 50,000 years and that it was extremely unusual for early Homo sapiens to live to age 50. This discovery has led some biologists to argue that there was no selection for or against menopause at the time at which the ancestor of all modern humans lived in Africa, suggesting that menopause is instead a random evolutionary effect of a selection shadow regarding aging in early Homo sapiens. It is also argued that since the population fraction of post-menopausal women in early Homo sapiens was so low, menopause had no evolutionary effect on mate selection or social behaviors related to mate selection. [120] [121]

Adaptive hypotheses Edit

"Survival of the fittest" hypothesis Edit

This hypothesis suggests that younger mothers and offspring under their care will fare better in a difficult and predatory environment because a younger mother will be stronger and more agile in providing protection and sustenance for herself and a nursing baby. The various biological factors associated with menopause had the effect of male members of the species investing their effort with the most viable of potential female mates. [122] [ page needed ] One problem with this hypothesis is that we would expect to see menopause exhibited in the animal kingdom, [113] and another problem is that in the case of extended child development, even a female who was relatively young, still agile, and attractive when producing a child would lose future support from her male partner due to him seeking out fertile mates when she reaches menopause while the child is still not independent. That would be counterproductive to the supposed adaptation of getting male support as a fertile female and ruin survival for children produced over much of the female's fertile and agile life, unless children were raised in ways that did not rely on support from a male partner which would eliminate that type of resource diverting selection anyway. [123] [124]

Young female preference hypothesis Edit

The young female preference hypothesis proposes that changes in male preferences for younger mates allowed late-age acting fertility mutations to accumulate in females without any evolutionary penalty, giving rise to menopause. A computer model was constructed to test this hypothesis, and showed that it was feasible. [125] However, in order for deleterious mutations that affect fertility past roughly age fifty to accumulate, human maximum lifespan had to first be extended to about its present value. As of 2016 it was unclear if there has been sufficient time since that happened for such an evolutionary process to occur. [126]

Male-biased philopatry hypothesis Edit

The male-biased philopatry theory proposes that male-biased philopatry in social species leads to increased relatedness to the group in relation to female age, making inclusive fitness benefits older females receive from helping the group greater than what they would receive from continued reproduction, which eventually led to the evolution of menopause. [127] In a pattern of male-biased dispersal and local mating, the relatedness of the individuals in the group decreases with female age, leading to a decrease in kin selection with female age. [127] This occurs because a female will stay with her father in her natal group throughout life, initially being closely related to the males and females. Females are born and stay in the group, so relatedness to the females stays about the same. However, throughout time, the older male relatives will die and any sons she gives birth to will disperse, so that local relatedness to males, and therefore the whole group, declines. The situation is reversed in species where males are philopatric and either females disperse, or mating is non-local. [127] Under these conditions, a female's reproductive life begins away from her father and paternal relatives because she was either born into a new group from non-local mating or because she dispersed. In the case of female-biased dispersal, the female is initially equally unrelated with every individual in the group, and with non-local mating, the female is closely related to the females of the group, but not the males since her paternal relatives are in another group. As she gives birth, her sons will stay with her, increasing her relatedness to males in the group over time and thus her relatedness with the overall group. The common feature that connects these two otherwise different behaviors is male-biased philopatry, which leads to an increase in kin selection with female age.

While not conclusive, evidence does exist to support the idea that female-biased dispersal existed in pre-modern humans. The closest living relatives to humans, chimpanzees, bonobos, and both mountain gorillas and western lowland gorillas, are female-biased dispersers. [128] Analysis of sex specific genetic material, the non-recombining portions of the Y chromosome and mitochondrial DNA, show evidence of a prevalence of female-biased dispersal as well however, these results could also be affected by the effective breeding numbers of males and females in local populations. [129] Evidence of female-biased dispersion in hunter-gatherers is not definitive, with some studies supporting the idea, [128] and others suggesting there is no strong bias towards either sex. [130] In killer whales, both sexes mate non-locally with members of a different pod but return to the pod after copulation. [131] Demographic data shows that a female's mean relatedness to the group does increase over time due to increasing relatedness to males. [132] While less well-studied, there is evidence that short-finned pilot whales, another menopausal species, also display this behavior. [133] However, mating behavior that increases local relatedness with female age is prevalent in non-menopausal species, [128] making it unlikely that it is the only factor that determines if menopause will evolve in a species.

Mother hypothesis Edit

The mother hypothesis suggests that menopause was selected for 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. [134]

Grandmother hypothesis Edit

The grandmother hypothesis suggests that menopause was selected for humans because it promotes the survival of grandchildren. According to this hypothesis, post-reproductive women feed and care for children, adult nursing daughters, and grandchildren whose mothers have weaned them. Human babies require large and steady supplies of glucose to feed the growing brain. In infants in the first year of life, the brain consumes 60% of all calories, so both babies and their mothers require a dependable food supply. Some evidence suggests that hunters contribute less than half the total food budget of most hunter-gatherer societies, and often much less than half, so that foraging grandmothers can contribute substantially to the survival of grandchildren at times when mothers and fathers are unable to gather enough food for all of their children. In general, selection operates most powerfully during times of famine or other privation. So although grandmothers might not be necessary during good times, many grandchildren cannot survive without them during times of famine.

Post-reproductive female killer whales tend to lead their pods, especially during years of food scarcity. [135] Furthermore, the increased mortality risk of a killer whale individual due to losing a grandmother is stronger in years food scarcity [136]

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. [137] 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). [138] Differing assistance strategies for maternal and paternal grandmothers have also been demonstrated. Maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates. [139]

Some believe a problem concerning the grandmother hypothesis is that it requires a history of female philopatry, while in the present day the majority of hunter-gatherer societies are patrilocal. [140] However, there is disagreement split along ideological lines about whether patrilineality would have existed before modern times. [141] Some believe 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). [142] Notably, the survival time past menopause is roughly the same as the maturation time for a human child. That a mother's presence could aid in the survival of a developing child, while an unidentified father's absence might not have affected survival, could explain the paternal fertility near the end of the father's lifespan. [143] A man with no certainty of which children are his may merely attempt to father additional children, with support of existing children present but small. Note the existence of partible paternity supporting this. [144] Some argue that the mother and grandmother hypotheses fail to explain the detrimental effects of losing ovarian follicular activity, such as osteoporosis, osteoarthritis, Alzheimer's disease and coronary artery disease. [145]

The theories discussed above assume that evolution directly selected for menopause. Another theory states that menopause is the byproduct of the evolutionary selection for follicular atresia, a factor that causes menopause. Menopause results from having too few ovarian follicles to produce enough estrogen to maintain the ovarian-pituitary-hypothalamic loop, which results in the cessation of menses and the beginning of menopause. Human females are born with approximately a million oocytes, and approximately 400 oocytes are lost to ovulation throughout life. [146] [147]

Reproductive conflict hypothesis Edit

In social vertebrates, the sharing of resources among the group places limits on how many offspring can be produced and supported by members of the group. This creates a situation in which each female must compete with others of the group to ensure they are the one that reproduces. [148] The reproductive conflict hypothesis proposes that this female reproductive conflict favors the cessation of female reproductive potential in older age to avoid reproductive conflict, increasing the older female's fitness through inclusive benefits. Female-biased dispersal or non-local mating leads to an increase in relatedness to the social group with female age. [127] In the human case of female-biased dispersal, when a young female enters a new group, she is not related to any individual and she reproduces to produce an offspring with a relatedness of 0.5. An older female could also choose to reproduce, producing an offspring with a relatedness of 0.5, or she could refrain from reproducing and allow another pair to reproduce. Because her relatedness to males in the group is high, there is a fair probability that the offspring will be her grandchild with a relatedness of 0.25. The younger female experiences no cost to her inclusive fitness from using the resources necessary to successfully rear offspring since she is not related to members of the group, but there is a cost for the older female. As a result, the younger female has the advantage in reproductive competition. Although a female killer whale born into a social group is related to some members of the group, the whale case of non-local mating leads to similar outcomes because the younger female relatedness to the group as a whole is less than the relatedness of the older female. This behavior makes more likely the cessation of reproduction late in life to avoid reproductive conflict with younger females.

Research using both human and killer whale demographic data has been published that supports the role of reproductive conflict in the evolution of menopause. Analysis of demographic data from pre-industrial Finnish populations found significant reductions in offspring survivorship when mothers-in-laws and daughters-in-laws had overlapping births, [149] supporting the idea that avoiding reproductive conflict is beneficial to offspring survivorship. Humans, more so than other primates, rely on food sharing for survival, [150] so the large survivorship reduction values could be caused by a straining of community resources. Avoiding such straining is a possible explanation for why the reproductive overlap seen in humans is much lower than other primates. [151] Food sharing is also prevalent among another menopausal species, killer whales. [152] Reproductive conflict has also been observed in killer whales, with increased calf mortality seen when reproductive overlap between a younger and older generational female occurred. [132]

Other animal Edit

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

Menopause has been observed in several species of nonhuman primates, [113] including rhesus monkeys [153] and chimpanzees. [154] Some research suggests that wild chimpanzees do not experience menopause, as their fertility declines are associated with declines in overall health. [155] Menopause also has been reported in a variety of other vertebrate species including elephants, [156] short-finned pilot whales, [157] killer whales, [158] narwhals, [159] beluga whales, [159] the guppy, [160] the platyfish, [ citation needed ] the budgerigar, [ citation needed ] the laboratory rat and mouse, [ citation needed ] and the opossum. [ citation needed ] However, with the exception of the short-finned pilot whale, killer whale, narwhals, and beluga whales, [159] such examples tend to be from captive individuals, and thus they are not necessarily representative of what happens in natural populations in the wild.

Dogs do not experience menopause the canine estrus cycle simply becomes irregular and infrequent. Although older female dogs are not considered good candidates for breeding, offspring have been produced by older animals. [161] Similar observations have been made in cats. [162]


THE CORE 4 SYMPTOMS: VASOMOTOR, VAGINAL, INSOMNIA, AND MOOD

Epidemiology

Population-based, epidemiologic studies of menopausal women have recently been conducted and are yielding reliable and consistent information about the incidence, prevalence, and severity of several menopausal symptoms. However, the field is relatively new, and it is likely that there are subsets of women who are more or less vulnerable to particular symptoms or sets of symptoms. In 2005, a state-of-the-science conference on menopausal symptoms was convened, with a worldwide panel of expert evaluators who were tasked with determining which among the large set of midlife symptoms are most likely to be due to menopause. Symptoms were evaluated for their proximity to menopause, apart from the aging process, and the likelihood that estrogen is effective in relieving symptoms. 2 Based on this evidence review, 3 symptoms emerged as having good evidence for linkage to menopause: vasomotor symptoms, vaginal dryness/dyspareunia, and difficulty sleeping/insomnia. After this conference and based on 3 seminal studies, 3,5,6 adverse mood/depression was added to the list. Adequate longitudinal studies on cognitive function during the menopause were not yet available but have also become subsequently widely reported. 2,3,5,7,8

It is clear that there are many other symptoms that are reported by menopausal women. These include joint and muscle aches, changes in body contour, and increased skin wrinkling. 1 Several studies have examined the associations between these symptoms and menopause. Given the methods of ascertainment, the subjective nature of the complaints, the likelihood that there is publication bias (wherein positive studies demonstrating linkage to menopause are more likely to be published than negative studies), and their variation over time, it has been difficult to establish a true relationship between these symptoms and menopause. Other symptoms, such as urinary incontinence (UI) and sexual function, have mixed data for efficacy of estrogen treatment and linkage to menopause, apart from the aging process. For these reasons, this article addresses the core 4 symptoms and includes cognitive issues because they are of great importance and concern to aging women.

Vasomotor symptoms

Vasomotor symptoms afflict most women during the menopausal transition, although their severity, frequency, and duration vary widely between women. Hot flashes are reported by up to 85% of menopausal women. 7 Hot flashes are present in as many as 55% of women even before the onset of the menstrual irregularity that defines entry into the menopausal transition 9 and their incidence and severity increases as women traverse the menopause, peaking in the late transition and tapering off within the next several years. 10� The average duration of hot flashes is about 5.2 years, based on an analysis of the Melbourne Women’s Health Project, a longitudinal study that included 438 women. 11 However, symptoms of lesser intensity may be present for a longer period. Approximately 25% of women continue to have hot flashes up to 5 or more years after menopause. A meta-analysis of 35,445 women taken from 10 different studies confirmed a 4-year duration of hot flashes, with the most bothersome symptoms beginning about 1 year before the final menstrual period and declining thereafter. 10

The exact cause of the hot flash has not been elucidated. The most accessible theory purports that there is a resetting and narrowing of the thermoregulatory system in association with fluctuations in or loss of estrogen production. In the past, hot flashes were thought to be related solely to a withdrawal of estrogen however, there is no acute change in serum estradiol during a hot flash. Others have related hot flashes to variability in both estradiol and follicle-stimulating hormone (FSH) levels. 6 It is thought that decreased estrogen levels may reduce serotonin levels and thus upregulate the 5-hydroxytryptamine (serotonin) (5-HT2A) receptor in the hypothalamus. As such, additional serotonin is then released, which can cause activation of the 5-HT2A receptor itself. This activation changes the set point temperature and results in hot flashes. 13 Regardless of the exact cause of the hot flash, both hormone therapy and nonhormonal regimens can help to relieve vasomotor symptoms ( Table 1 ).

Table 1

Hormonal and nonhormonal formulations for the treatment of hot flashes

Trade NameEstrogenProgestinFDA
Approved
Dose
Hormonal Therapies
PremarinCEEYes0.3𠄱.25 mg po daily
CenestinSynthetic CEYes0.3𠄱.25 mg po daily
MenestEsterified estrogenYes0.3𠄱.25 mg po daily
Estrace17β-estradiolYes1𠄲 mg po daily
EstinylEthinyl estradiolYes0.02𠄰.05 mg po 1𠄳
  times daily
Evamist17β-estradiolYes1𠄳 sprays daily
Alora, Climara,
 ਎sclim, Menostar,
  Vivelle, Vivelle-
 ਍ot, Estraderm
17β-estradiolYes1 patch weekly to
  twice weekly
EstroGel17β-estradiolYes1.25 g daily
  transdermal
  gel (equivalent to
 ਀.75 mg
 ਎stradiol)
Estrasorb17β-estradiolYes2 foil pouches daily
  of
  transdermal
  topical
 ਎mulsion
ActivellaEstradiol 1 mgNETA 0.5 mgYes1 tablet po daily
FemhrtEthinyl estradiol
 ਅ µg
NETA 1 mgYes1 tab po daily
Ortho-Prefest17β-estradiol 1 mgNorgestimate
 ਀.09 mg
YesFirst 3 tablets
 ਌ontain
 ਎strogen, next 3
 ਌ontain both
  hormones
 ਊlternate pills
 ਎very 3 d
PremphaseCEE 0.625 mgMPA 5 mgYesFirst 14 tablets
 ਌ontain
 ਎strogen only and
  remaining 14
  tablets
 ਌ontain both
  hormones.
1 tab po daily
PremproCEE 0.625 mgMPA 2.5 or
 ਅ mg
Yes1 tab po daily
CombiPatch17β-estradiolNETAYes1 patch transdermal
  twice weekly
Climara Pro17β-estradiolLNGYes1 patch weekly
Estrace17β-estradiol
  vaginal cream
Yes2𠄴 g daily for 1 wk,
  then 1 g 3 times
  weekly
FemringEstradiol vaginal
  ring
Yes1 ring inserted
  vaginally
 ਎very 3 mo
DuaveeCEE 0.45 mg/
 ꂺzedoxifine
 ꀠ mg
Yes1 tablet daily
Nonhormonal Therapies
BrisdelleParoxetine a 7.5 mgYes7.5 mg daily
EffexorVenlafaxine
 ꀶ.5� mg
No37.5� mg daily
PristiqDesvenlafaxineNo50� mg daily
LexaproEscitalopramNo10� mg daily
CelexaCitalopramNo10 mg daily
ProzacFluoxetine a No10� mg daily
ZoloftSertralineNo50� mg daily
NeurontinGabapentinNo300� mg up to
  tid
LyricaPregabalinNo50� mg tid

Abbreviations: CE, conjugated estrogen CEE, conjugated equine estrogen LNG, levonorgestrel MPA, medroxyprogesterone acetate NETA, norethindrone acetate.

Vulvovaginal atrophy

Urogenital tissues are exquisitely sensitive to estrogen, and the fluctuations in estrogen that occur during the menopausal transition, followed by sustained low levels after menopause, can render these tissues fragile and cause distressing symptoms. Multiple population- and community-based studies confirm that about 27% to 60% of women report moderate to severe symptoms of vaginal dryness or dyspareunia in association with menopause. 14,15 In addition to vaginal atrophy, narrowing and shortening of the vagina and uterine prolapse can also occur, leading to high rates of dyspareunia. Furthermore, the urinary tract contains estrogen receptors in the urethra and bladder, and as the loss of estrogen becomes evident, patients may experience UI. Unlike vasomotor symptoms, vulvovaginal atrophy does not improve over time without treatment.

Menopausal hormone therapy (MHT) is an effective treatment of vaginal atrophy and dryness. For this purpose, systemic or vaginal estrogen can be used, although locally applied estrogen is recommended and can be administered in very low doses ( Table 2 ). These low doses are believed to be safe for the uterus, even without concomitant use of a progestin. Data are currently insufficient to define the minimum effective dose, but vaginal rings, creams, and tablets have all been tested and demonstrated to reduce vaginal symptoms. 16

Table 2

Treatments for vulvovaginal atrophy

Trade NameHormoneFDA
Approved
Dose
Premarin vaginal 0.625 gmConjugated equine
 ਎strogens
Yes0.5𠄲 gm qd × 2𠄳 wk, off
 ਁ wk, repeat prn a
Estrace vaginal 0.01%
 ਌ream
EstradiolYes1 gm biweekly to triweekly
Estring 2 mgEstradiolYesOne ring every 3 mo
OsphenaOspemifeneYes60 mg po qd

Although MHT is effective in reversing changes associated with vaginal atrophy, 17,18 it is not beneficial for UI. The Women’s Health Initiative Hormone Trial found that women who received MHT and who were continent at baseline had an increase in the incidence of all types of UI at 1 year. The risk was highest for women in the conjugated equine estrogens (CEE)-alone arm. Among women experiencing UI at baseline, the frequency of symptoms worsened in both arms, and these women reported that UI limited their daily activities. This evidence clearly shows that the use of MHT increases the risk of UI among continent women and worsened the characteristics of UI among symptomatic women after 1 year of use. 19

Women who have urogenital atrophy symptom require long-term treatments. Over-the-counter lubricants and moisturizers may have some effectiveness for milder symptoms however, for those with severe symptoms, hormonal treatment is the mainstay. Vaginal estrogen can be given locally in very small doses (see Table 2 ). Until recently, there were no alternatives available. However, the FDA approved ospemifene, a systemically administered selective estrogen receptor modulator, for vulvovaginal atrophy in 2013. Dehydroepiandrosterone vaginal preparations are also being tested for effectiveness in treating menopausal urogenital atrophy. 20 These 2 compounds may be particularly helpful for women who have estrogen-sensitive cancers, such as breast cancer, in whom exogenous estrogen use is contraindicated. It is too early to evaluate the comparative effectiveness of these treatments.

Sleep disturbances and insomnia

Sleep quality generally deteriorates with aging, and menopause seems to add an additional, acute layer of complexity to this gradual process. Women report more trouble sleeping as they enter into the menopausal transition, and sleep has been shown to be worse around the time of menses, both by self-report as well as by actigraphy. 21,22 Actigraphy studies indicate that as much as 25 minutes of sleep per night can be lost when a woman is premenstrual in her late reproductive years. 21

Women report sleep difficulties approximately twice as much as do men. 23 Further compromise in sleep quality is associated with the hormonal changes associated with the menopausal transition and with aging, apart from hormones. Over time, reports of sleep difficulties increase in women such that by the postmenopause more than 50% of women report sleep disturbance. 2 Women seem to experience more detrimental effects on sleep in association with aging, when compared with men. 24

Hormonal changes alone are not likely to provide the complete explanation for the relationship between sleep difficulty and menopause. Consistent with this concept is the fact that hormones are not always successful in treating sleep problems in midlife and beyond. 25 Chronic poor sleep hygiene habits and mood disorders contribute further to sleep problems.

The nature of the sleep disturbance can help guide the clinician to appropriate treatment. Women who report nighttime awakening in association with night sweats are candidates for hormone therapy. However, the clinical history is not often so simple. Women with mood disorders, particularly anxiety and depression, may experience difficulty falling asleep and/or early awakening. Women aged 40 years and older also frequently report difficulty staying asleep. Lower socio-economic status (SES), white race, and low marital happiness are social factors that have all been associated with worse sleep. 26 Disorders such as sleep apnea and restless leg syndrome need to be considered. The clinical consequences of a poor night’s sleep include daytime fatigue and sleepiness, which can be subjectively measured and form the basis for a referral for a sleep study. Table 3 displays a clinically useful scale that can help the clinician estimate the daytime impact of the sleep complaint.

Table 3

The Epworth sleepiness scale

SituationChance of Dozing
Sitting and reading
Watching television
Sitting inactive in a public place (eg, a theater or meeting)
As a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking to someone
Sitting quietly after a lunch without alcohol
In a car, while stopped for a few minutes in traffic

Responses are recorded on a 4-point scale of 0 to 3 (0, no 1, light 2, moderate 3, high chance of dozing). A total score of greater than 9 merits further evaluation.

Adapted from Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 199114:541 with permission.

Polysomnography has become a clinically useful tool for assessing sleep complaints. 26 When polysomnography is not available, clinicians can use sleep questionnaires to ascertain the principal issues surrounding the sleep complaint. Using polysomnography, investigators in the Study of Women’s Health Across the Nation (SWAN) study observed 20% of women with clinically significant apnea/hypopnea and 8% with periodic leg movements. 26

Treatment of sleep complaints depends on the clinical findings. For insomnia, the reader is referred to the practical clinical review by Buysse. 27 Sleep apnea is often treated with continuous positive airway pressure devices. Restless leg syndrome can be treated with dopamine agonists, gabapentin, and opioids. 28 Hormone therapy can be considered for women with difficulty maintaining sleep because of vasomotor symptoms but seems to be effective mostly in postmenopausal women with surgically induced menopause.

Adverse mood

One-fifth of the US population will have an episode of depression in their lifetime, and women are twice as likely to be affected. 29 Although depression is more likely to occur in young adults, with peak onset in the fourth decade of life, there is evidence that the perimenopause represents another period of vulnerability for women. Several large prospective cohort studies have shown an increased risk of depressed mood during the menopause transition and an approximately 3-fold risk for the development of a major depressive episode during perimenopause compared with premenopause. 3,5,30,31 Although a previous episode of depression has been shown to confer an increased risk, women with no previous episode of depression are still 2 to 4 times more likely to experience a depressive episode during the menopause transition compared with the premenopause. Anxiety symptoms have been found to precede depression in some instances, and anxiety may also be viewed as increasing a woman’s vulnerability to a midlife depressive episode. 32

Other independent risk factors for the development of depressed mood during the menopause transition include poor sleep, stressful or negative life events, lack of employment, higher body mass index, smoking, younger age, and race (African Americans twice as likely to have depressive symptoms). In addition, there is evidence that hormonal changes occurring during menopause play a role, as evidenced by increased risk for depression in association with variability in estradiol levels, increasing FSH levels, surgical menopause, the presence of hot flashes, and a history of premenstrual syndrome. Contrary to prior belief, hot flashes are not necessary to the development of depression. Some have proposed the cascade theory, in which hot flashes lead to sleep disturbance and then to daytime fatigue, poor quality of life, and then depressive symptoms. Research instead shows that depressive symptoms more often precede hot flashes when they co-occur. 33

There may also be significant environmental stressors present at the time that a woman reaches menopause. During midlife, a woman may be faced with changes in her marriage and family structure, with children no longer living in the home. She may experience changes in her career path, possibly returning to work or retiring. She may be taking on new responsibilities as a caregiver to her parents or in-laws, a well-known risk factor for depression. Although these factors do not likely cause depression on their own, they can certainly contribute and should be considered, particularly if supportive resources may be of help (Box 1).

Box 1

Science revisited

Estrogen affects the mood-regulating pathways of the brain: Depression is thought, albeit in part, to be caused by dysregulation of the monoaminergic pathways in the central nervous system, and changing estrogen levels can lead to alterations of these serotonergic and noradrenergic systems. In animal models, estrogen administration can induce changes in serotonin neurotransmission in the amygdala, hippocampus, and hypothalamus, brain regions that are involved in affect regulation. In humans, studies of menopausal women undergoing estrogen treatment showed changes in mood as well as serotonin transmission relative to hormonal status. 34

As the menopause transition involves significant instability in estrogen levels, with intense irregular fluctuations, many researchers have focused on understanding the association between estrogen level and mood changes. As stated above, in longitudinal prospective studies, women who developed depression were more likely to have increased variability in estrogen levels, particularly in the early to midperimenopause. 30 The absolute level of estrogen is not associated with risk, however. Some studies have used gonadotropin-releasing hormone (GnRH) agonists in order to induce menopausal changes in premenopausal women, so that measurement of hormones, evaluation for mood symptoms, and response to add-back hormone therapy can be more easily determined. 35 In a group of healthy premenstrual women, without a psychiatric history, administration of a GnRH agonist did not uniformly precipitate depressive symptoms. In another related study involving withdrawal of estradiol treatment in women with and without a history of perimenopausal depression, those with history of this type of depression were more likely to experience depressive symptoms as a result of withdrawal of estradiol therapy (Box 2).

Box 2

Evidence at a glance

Timing is everything: A 4-year cohort study by Freeman and colleagues, 30 involving a balanced randomly identified sample of African American and white women aged 35 to 47 years showed an increased risk for depressive symptoms in early menopause (with variable cycle length more than 7 days) compared with late menopause (at least 2 skipped cycles and 㹠 days of amenorrhea) and no elevated risk in the postmenopause. Other researches have suggested that the late menopause transition represents a time of increased risk for depression 5,30,31 overall, perimenopause seems to pose more risk than premenopause or postmenopause.

A major depressive episode is defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) (1994) as 5 or more of the following symptoms, present most of the day nearly every day for a minimum of 2 consecutive weeks. At least 1 symptom is either depressed mood or loss of interest or pleasure.

The DSM-IV criteria for depressive disorders, as for other mental disorders, require that the depressive episode cause significant distress or dysfunction. A depressive episode can be classified as mild, moderate, or severe, with or without psychotic symptoms. Psychotic symptoms can include hallucinations (usually auditory perceptual disturbances) and delusions (false beliefs). A depressive disorder may be recurrent if a patient has had an episode in the past. A person whose depressive symptoms do not meet criteria for a major depressive episode may be classified as having minor depression or/and adjustment disorder with depressed mood if a significant recent stressor is present. Chronic symptoms of depression not meeting criteria for a major depressive episode may represent a dysthymic disorder.

A depressive episode can also occur in the setting of bipolar disorder, a mood disorder that also involves at least 1 previous manic episode. Before treatment of depression, a bipolar-type disorder should be ruled out because of different effective treatment regimens. As anxiety disorders are very common in women with depression, assessment for panic symptoms, generalized worry, as well as obsessive thoughts and compulsive behaviors should be included. In addition, evaluation for substance abuse and dependence, which can significantly affect mood, should be included. Medical workup for illnesses that can present with depressive symptoms, such as hypothyroidism and anemia, is also appropriate.

A complete interview for depressive symptoms in every perimenopausal patient is not necessary or time efficient. Screening tools can be used to determine who will need further evaluation. Referral of patients to a mental health specialist depends on the primary care provider’s level of expertise in assessment and treatment of depression, the availability of mental health resources, and patient/family preference. Even if a provider initiates treatment, there may be reason for referral at a later point ( Table 4 ).

Table 4

DSM-IV criteria for major depressive disorder and reasons for further psychiatric evaluation

Major DepressionIndications for Further Psychiatric Evaluation
At least one of these must be present:Evidence of suicidal ideation, inability to care
 ਏor self or dependent others, or
 ਊggressivity/homicidal ideation
 ꃞpressed mood
  Loss of interest or pleasure in most or all
   ꂬtivities
Four or more of the following must be
  present:
Failure to respond to or is intolerant of initial
  treatment trial
  Insomnia or hypersomniaPatient or clinician interested in modalities
  requiring specialty expertise
  (psychotherapy or electroconvulsive
  therapy, transcranial magnetic
  stimulation)
 ਌hange in appetite or weight
  Psychomotor retardation or agitation
  Low energy
  Poor concentration
  Thoughts of worthlessness or guiltPsychotic symptoms present
  Recurrent thoughts about death or suicideHistory of bipolar disorder or psychotic
 ਍isorder
Significant psychiatric comorbidity (anxiety
 ਍isorders, substance use, cognitive
 ਍isorder)
Unclear diagnosis of depression

First-line treatment of a major depressive episode may involve psychotherapy, antidepressants, or a combination thereof. Treatment is often tailored to patient preference and severity of depression. Certainly, a more severe episode would require combined psychotherapy and pharmacotherapy. A mild to moderate episode may respond to either psychotherapy or an antidepressant alone, and if a patient is interested in a trial of medication, it may benefit significantly if this is started soon after the diagnosis is made. Primary care practitioners frequently make the initial diagnosis of depression and are in a position to begin this treatment in a timely manner when possible.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line medications used in the treatment of depression. These SSRIs include fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), sertraline (Zoloft), and paroxetine (Paxil). Each of these medications is equally likely to be effective and share similar side effect profiles. Patients often describe gastrointestinal upset, jitteriness, or headache, but these symptoms usually abate in the first few weeks of therapy. Once initiated, it may take 6 to 8 weeks for a patient to respond however, often, patients notice a difference within the first month of treatment. Dosage can be titrated to achieve improved effectiveness, with increases approximately every month as tolerated. Of particular concern in this population is the risk for sexual side effects (decreased libido and difficulty with arousal and achieving orgasm). As depression can also affect a woman’s sexual function, however, the risks of discontinuation of medication may outweigh the burden of these side effects. A switch to a different SSRI or another antidepressant class or the addition of bupropion (Wellbutrin), which acts on the dopaminergic system, may be helpful. As stated previously, estrogen can be helpful in treating perimenopausal depression and changes in sexual function as well. Conversely, several different SSRI antidepressants have been shown to be effective in treating perimenopausal vasomotor symptoms (Box 3). 38

Box 3

Evidence at a glance

SSRIs are the first choice: In a treatment study by Soares and colleagues, 36 the SSRI escitalopram proved superior to a combination of estrogen and progesterone in treating depression as well as other menopausal symptoms. Almost 75% of women on escitalopram achieved remission of depression compared with 25% of those on hormone replacement therapy. In this study, however, subjects’ depressive symptoms did not necessarily begin during the menopause transition. Other treatment studies showing benefit of estrogen in treating depressive symptoms have focused solely on women with depression beginning during menopause. 37

Serotonin and norepinephrine reuptake inhibitors, such as venlafaxine (Effexor) or duloxetine (Cymbalta) can be particularly helpful in patients with comorbid anxiety. Bupropion can be helpful when patients have low energy, but it can exacerbate anxiety and insomnia. Psychostimulants such as modafinil (Provigil) or methylphenidate (Ritalin) can sometimes be useful in these cases but have less evidence for efficacy. Tricyclic antidepressants and monoamine oxidase inhibitors are useful in treatment-resistant depression but often have more significant side effects, particularly in older patients. Electroconvulsive therapy is often very well tolerated, safe, and effective in these older patients who fail to respond to or do not tolerate medications. There is also growing evidence for the utility of transcranial magnetic stimulation in this group (Box 4).

Box 4

Tips and tricks

Watch out for drug-drug interactions: In older women, with multiple medical comorbidities, citalopram or escitalopram are often preferred because they have fewer interactions with the metabolism of other medications.

Start low and go slow: Older women may be more prone to side effects of antidepressants however, doses of antidepressants in the higher range may be necessary to achieve remission, particularly when comorbid anxiety is also present. So continue to adjust the dose as necessary while monitoring the patient every few weeks.

Several forms of psychotherapy may be beneficial for patients with depression, including cognitive behavioral therapy, interpersonal therapy, and psychodynamic psychotherapy. A range of providers with psychotherapy training are available (social workers, psychologists, nurse practitioners, psychiatrists), but resources may be limited because of the patient’s insurance, location, and financial situation.

In double-blind placebo-controlled trials, perimenopausal women receiving short-term 17β-estradiol transdermally had remission rates as high as 80%. 37,39 In other randomized controlled trials, when estrogen was given to postmenopausal women with depression, there were no significant improvements in symptoms 40 or the treatment was not superior to an SSRI agent. 36 So it seems that the low estrogen levels involved in the menopause transition is an important factor in the development of depression in some women but does fully explain the increased risk for depression in this population. Moreover, these data indicate a window of opportunity for estradiol’s antidepressant effects, with women with perimenopausal but not postmenopausal depression responding to estrogen therapy (Box 5).

Box 5

Caution!

Use hormone replacement therapy with care: Estrogen can be helpful in treating depression in some perimenopausal women. Although estrogen is often recommended to treat hot flashes, women with depression with comorbid vasomotor symptoms are not more likely to respond to estrogen therapy. 37 Estrogen should be avoided in treating depressive symptoms in postmenopausal women, however, with lack of evidence for efficacy and increased risk of adverse events and side effects.

Menopause and cognition

Many women complain of changes in their cognitive function during the menopause transition, with the majority reporting worsening of memory. Verbal memory (word list learning and recall), which women generally excel at when compared with men, is often the type of complaint noted. Women may notice difficulty remembering names and other verbally told information. In addition, they may report other cognitive challenges, with more trouble organizing and planning or possibly with concentration. In one study of 205 menopausal women, 72% reported some subjective memory impairment. 41 Symptoms were more likely to be associated with perceived stress or depressive symptoms than perimenopausal stage, but overall, cognitive symptoms were more prevalent early in the menopause transition. Aside from being bothersome, these symptoms raise women’s concerns regarding their risk for dementia however, it remains unclear whether these symptoms correspond to an increased risk for more serious chronic issues.

The first cross-sectional study to measure cognitive change in association with menopause showed that women in early menopause, late menopause, and postmenopause did not vary in memory performance according to stage and did not have abnormalities in memory testing. 42 Overall, women who had initiated any form of hormone replacement therapy before their last period performed better on memory testing than those who started it after menopause. Longitudinal study of menopausal status and measured cognitive performance 8 showed no impairments in overall cognitive function, but women entering menopause failed to improve as much on repeated tests compared with premenopausal women (they would be expected to improve over time with practice on the same test) (Box 6).

Box 6

Evidence at a glance

Again, timing may be key: The SWAN study 8 was a 4-year, multisite longitudinal study of cognitive function in women aged 42 to 52 years. Results showed that verbal memory and processing speed were improved with repeated testing in premenopausal, early perimenopausal, and postmenopausal women, but not in late perimenopausal women. Hormone use before the final menses was associated with better processing speed and verbal memory in all groups compared with current hormone use in postmenopause.

An important question is whether women who have cognitive difficulties during the menopause transition are at greater risk for cognitive impairment later in life. Patients and their clinicians can be reassured, however, that for most women cognitive function is not likely to worsen in the postmenopause in any pattern other than that expected with normal aging. Although it is not likely that cognitive function returns to a woman’s premenopausal baseline in postmenopause, she may adapt to and compensate for the symptoms with time.

A gradual decline in some cognitive functions is expected to occur with normal aging, beginning in midlife, around the age of 50 years. Decreases in processing speed are often present, and sometimes mild changes in memory for newly learned information and executive function can also occur. However, some types of cognitive changes, collectively called mild cognitive impairment (MCI), are thought to be a manifestation of very early dementia. MCI and dementia are highly unlikely in people younger than 50 years, but risk increases significantly with age, with greater than 10% of the population older than 65 years at risk for developing dementia. (Those diagnosed with MCI have an increased risk of conversion to dementia like that in Alzheimer disease [AD], with approximately 10% developing dementia each year). 43 AD is by far the most common type of dementia, but other types of dementia can occur with varying presentations, including vascular dementia, Lewy body dementia, and frontotemporal dementia. AD often presents with impaired memory first, but other types of dementia can present with impaired language, behavioral changes, or motor abnormalities (Box 7).

Box 7

Tips and tricks

Some cognitive changes are normal in aging

More difficulty recalling newly learned lists, names, and other verbal information

Decreased ability to perform newly learned complex tasks

Some changes may be warning signs

Loss of vocabulary or language skills

Impaired reading comprehension

Loss of older memories/fund of knowledge

Inability to perform independent activities of daily living (shopping, handling finances, using transportation, using telephone, housekeeping, food preparation)

In some individuals with MCI, dementia may never develop and cognition can even improve over time. Depression can also be present with MCI, and it can be difficult to discern whether the depression is causing the memory impairment, if a common pathologic process is causing depression and cognitive MCI, or if MCI puts one at risk of developing depression. Depression can also be an early manifestation of cognitive decline. In the unlikely situation that MCI presents in an individual younger than 50 years, it rarely represents a predementia syndrome, and search for another, possibly more treatable cause is important.

Dementia is more common in women than in men, even after controlling for the effects of the female population’s greater longevity. For this reason, many have focused on the role that estrogen plays in the risk for developing dementia. Estrogen interacts with both the cholinergic and serotonergic systems that are the main brain systems involved in normal cognitive functioning. In animal models, estrogen has positive effects on the cholinergic system, interacting with trophic factors for neuronal development and plasticity, with associated improved cognitive functioning. 44 Furthermore, studies have shown that estradiol can improve cognitive deficits produced by anticholinergic agents in normal postmenopausal women (Box 8). 45

Box 8

Science revisited

Serotonin plays a role here too: There is ample evidence from animal studies showing that changes in serotonergic transmission can have effects on memory tasks. Administration of estradiol in ovariectomized rodents also does result in changes in serotonin levels and metabolism. 34 In humans, memory has repeatedly been shown to be impaired by tryptophan (TRP) depletion, a manipulation that results in rapid reduction of brain TRP and serotonin levels, and there is now some evidence that estrogen therapy may protect menopausal subjects from these effects. 34

Evidence supports a significant role for estrogen in cognitive functioning. In premenopausal women, higher achievements in verbal memory performance occurred during phases of the menstrual cycle associated with high estrogen levels, 46 and hormone users in the SWAN sample had better cognitive performance in the perimenopause (although the same was not true for postmenopausal hormone use 8 ). There was also early evidence in observational studies for a decreased risk of AD in women on hormone replacement therapy. 47 The relationship between estrogen and cognitive function has proved to be complicated, however, with varying effects with different formulations/combinations and when initiated during menopause, before the age of 65 years in postmenopause, and after the age of 65 years in the postmenopause. In several studies, estrogen alone in younger postmenopausal women showed some benefit to verbal memory but had neutral effects on older postmenopausal women. 48 CEE plus medroxyprogesterone acetate resulted in a negative change in the memory of younger and older postmenopausal women. Other formulations may be beneficial, with one study showing promise for the combination of estradiol valerate and dinogest in younger postmenopausal women 49 and another demonstrating a positive effect with cyclic oral estradiol and norethindrome in older postmenopausal women (Box 9).

Box 9

Evidence at a glance

Is there a critical window? The Women’s Health Initiative Memory Study 51 demonstrated that MHT would not protect women from dementia as once thought and even showed an increased risk when used in older postmenopausal women. This study was limited to women between the ages of 65 and 79 years, however, and there is further evidence that hormone replacement therapy initiated earlier in the postmenopausal period may not present the same risk. More research is needed to determine whether a critical window exists when estrogen or combined MHT might protect cognitive function.

Women experiencing a surgical menopause after hysterectomy and bilateral oophorectomy have also been a focus of study, because cognitive complaints are common in this subgroup and hormonal changes are certainly more abrupt and clearly defined. There is evidence that these women do develop impairments in verbal memory that can be prevented by administration of estrogen therapy. 46,50

When a perimenopausal or postmenopausal woman presents with cognitive complaints, the practitioner is most often able to reassure the patient that these complaints are common and not necessarily progressive and may even improve over time. As in those with depressive symptoms, patients with cognitive impairment often present to primary care providers first and the gynecologist is in the position to evaluate for more serious issues and to provide education regarding prevention of chronic conditions such as dementia.

In 2001, the American Academy of Neurology (AAN) published practice guidelines for the early detection of memory problems (Petersen and colleagues, 2001). The AAN workgroup of specialists identified the criteria for an MCI diagnosis ( Table 5 ). Patients with MCI do not meet criteria for dementia (see Table 5 ), which involves impaired daily functioning.

Table 5

Differentiation of MCI and dementia

MCIDementia (DSM-IV Criteria)
Memory complaint, preferably confirmed by
 ਊn informant
Impairment in handling complex tasks
Objective memory impairment on standard
  neuropsychological batteries assessing
  memory (for age and education)
Impairment in reasoning ability
Normal general thinking and reasoning skillsImpaired spatial ability and orientation
Ability to perform normal daily activitiesImpaired language
The cognitive symptoms must significantly
  interfere with the individual’s work
  performance, usual social activities, or
  relationships with other people
This must represent a significant decline from
 ਊ previous level of functioning

The evaluation for MCI and dementia includes a thorough history provided by the patient and preferably a partner or family members in close contact with the patient. Medical history and review of systems aid in determining if any other medical illnesses could be contributing (particularly infectious illnesses or disorders of the cardiovascular, neurologic, or endocrine systems). A medication history is also particularly important because often analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics can affect cognition. Family history to elicit information regarding family member with dementia possibly early onset before the age of 60 years and other neurologic disorders is also important. Physical examination, including a basic neurologic examination and some cognitive assessment should also be completed.

The cognitive test most often used as a screen for cognitive impairment is the mini mental state exam (MMSE), 52 which takes approximately 7 minutes to complete. MMSE tests a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis (Box 10).

Box 10

MMSE Sample Items

“Listen carefully. I am going to say three words. You say them back after I stop.

APPLE (pause), PENNY (pause), TABLE (pause). Now repeat those words back to me.” [Repeat up to 5 times, but score only the first trial.]

“What is this?” [Point to a pencil or pen.]

“Please read this and do what it says.” [Show examinee the words on the stimulus form.]

Reproduced by special permission of the Publisher, Psychological Assessment Resources, Inc., 16204 North Florida Avenue, Lutz, Florida 33549, from the Mini Mental State Examination, by Marshal Folstein and Susan Folstein, Copyright 1975, 1998, 2001 by Mini Mental LLC, Inc. Published 2001 by Psychological Assessment Resources, Inc. Further reproduction is prohibited without permission of PAR, Inc. The MMSE can be purchased from PAR, Inc. by calling (813) 968�.

MMSE scores may be influenced by age and education, as well as language, motor, and visual impairments. Other cognitive tests are available for use in the office, such as the Montreal cognitive assessment test. 53 When a diagnosis of MCI is possible, however, a referral for more complete neuropsychological testing may be best. Initial laboratory work should include assessing thyrotropin and vitamin B12 levels to rule out potentially reversible causes of cognitive impairment (hypothyroidism and vitamin B12 deficiency). Brain imaging (computed tomography or preferably MRI) should be completed if MCI or dementia diagnosis is determined.

Once a diagnosis of MCI or dementia is made, these patients should often be referred to a neurologist or geriatric psychiatrist for further evaluation and/or treatment. Studies can be done to more clearly determine the risk for developing dementia in those with MCI (such as APOE allele, lumbar puncture with cerebrospinal fluid studies, functional imaging studies, and neuropsychological testing) and to clarify the type of dementia.

Medications are not clearly helpful in addressing these cognitive issues. Acetylcholinesterase inhibitors have been to shown to provide benefit for patients with early dementia but have not been shown to decrease the rate of progression to dementia in patients with MCI. As noted before, estrogen may be useful in some women, but its use is not recommended for this purpose. Antidepressant medications may result in improved cognition if comorbid depression is also present. Atomoxetine, the selective norepinephrine reuptake inhibitor often used to treat adult attention deficit disorder, has recently been shown to provide significant subjective improvement in memory and attention in perimenopausal and postmenopausal women presenting with midlife-onset subjective cognitive difficulties. 54 Similarly, stimulant medication may have a role in the treatment of subjective cognitive impairment, particularly for women with comorbid fatigue or impaired concentration, who are not showing evidence of objective impairment (Box 11).

Box 11

Caution!

Hormone replacement therapy for memory? A trial of estrogen therapy or combined estrogen/progesterone may prove beneficial for some types of cognitive complaints in some perimenopausal or early postmenopausal women. However, estrogen therapy has not been shown to be useful in treatment and prevention of cognitive decline in older postmenopausal women (㹥 years old). Monitor patients on HRT often and be sure to thoroughly explain known risks and benefits to your patient.

There is some evidence that modifying lifestyle factors can decrease the risk for dementia and even cognitive decline associated with normal aging. Patients should be encouraged to exercise regularly to eat a nutritious diet, with adequate fruits, vegetables, and fish to engage in regular social activities and to participate in cognitive exercise (reading, crossword puzzles, etc.) Patients should also be encouraged to maintain good cardiovascular health, with treatment of hyperlipidemia, hypertension, and diabetes mellitus.


The Most Common Hormonal Changes During Menopause

“Periods may be shorter or longer and bleeding may be heavier or lighter. Essentially, your body will feel like it is on a hormonal roller coaster ride.”

The most common hormonal changes that occur are an overall decrease in the amount of estrogen and progesterone. Although women have low levels compared to men, testosterone levels may also decrease. Changes in levels of estrogen and progesterone affect breast tissue, the vagina, the lining of the uterus, and bone density. Changes in levels of testosterone can decrease sex drive.

Although there is an overall decrease in estrogen and progesterone, at times, levels may also increase creating fluctuations that lead to irregularities in the menstrual cycle. You may skip periods for one month or several months. Periods may be shorter or longer and bleeding may be heavier or lighter. Essentially, your body will feel like it is on a hormonal roller coaster ride.


Breast Cancer and Menopause

Estrogen therapy is known to benefit postmenopausal women in a multitude of ways, mostly through the relief of vasomotor symptoms associated with postmenopause. Estrogen is also beneficial for the prevention and treatment of osteoporosis.

Much controversy exists about the use of estrogen and breast cancer. Some studies show an increased risk of breast cancer with postmenopausal estrogen use others show a decrease. A possible link to cancer is also suggested by the finding that breast cancer risk is increased in women with an earlier age at menarche and a later age at menopause. However, a reduction in risk is observed with early age at pregnancy and the interruption of menstrual hormonal changes. The role of estrogen in the development of breast cancer continues to be studied.

In the Women’s Health Initiative (WHI), the incidence of breast cancer increased in the estrogen-plus-progestin versus placebo arm of the study (38 vs 30 per 10,000 person years) however, the incidence of breast cancer decreased in the estrogen-only versus placebo arm of the study (26 vs 33 per 10,000 person years). [39, 40]

Additional follow-up in patients from the WHI suggested similar results: Breast cancer incidence and mortality were increased in the estrogen-plus-progestin group as compared with the placebo group. [58] The role of combined estrogen-plus-progesterone therapy (associated with most of the breast cancer risk) continues to be puzzling in the development of breast cancer.

Data suggest a slightly increased relative risk with estrogen use, approximately 1.1-1.3, [59, 60] but not all of the evidence supports this finding. [61] The risk appears to be related to duration of use, with longer-term users being more affected. [62]

Data suggest that the addition of sequential progestin to the regime increases the RR of subsequently developing breast cancer beyond the risk associated with estrogen alone, though some believe that continuous combined hormone therapy using much smaller doses of progestin may attenuate this risk. [63] Most earlier studies evaluating breast cancer risk and estrogen therapy were conducted at a time when the progestin in hormone therapy was administered on a cyclical basis.

Notably, women with a history of using hormone therapy have more localized tumors, as well as better survival rates. That is, women receiving hormone therapy who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis, [60] including smaller tumor size, negative lymph node involvement, and better-differentiated tumor histology. [64, 65, 66, 67, 68, 69, 70, 71, 72]

Breast cancer survivors (BCSs) may suffer genitourinary syndrome of menopause (GSM) (vaginal and urinary symptoms related to menopause) after receiving aromatase inhibitor therapy for hormone-dependent tumors. [73] BCS are typically not candidates for conventional menopause therapies (eg, systemic hormonal therapy, vaginal estrogens at standard doses) and nonhormonal vaginal moisturizers/lubricants have limited use over the long term, newer management options have become available including the use of androgens, low-dose/ultra low-dose estrogens, or selective estrogen receptor modulators, vaginal laser therapy, and psychosocial interventions. [73]

A beneficial effect on breast cancer mortality has been documented in postmenopausal women who have received hormone therapy as compared with controls who have no prior history of hormone therapy use. [59] Study findings do not agree on whether the benefit is due to earlier detection or to effects of the therapy itself on breast tissue.

The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for estrogen therapy or hormone therapy on an individual basis, with the overall balance of risks and benefits taken into account. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly. At present, the main indication for hormone therapy and estrogen therapy remains the relief of vasomotor symptoms.


Has the age at which menopause occurs changed throughout history? - Biology

Geneva Foundation for Medical Education and Research

D. de Ziegler
Department of Obstetrics and Gynecology, Nyon Hospital
Department of Obstetrics and Gynecology, Geneva University Hospital

Menopause has received various definitions. Most commonly, menopause is said to exist after amenorrhea has been established for = 6 months as a result of ovarian failure. Today however, we believe that the best definition of menopause refers to physiological mechanisms rather than remaining arbitrarily anchored in scholastic definitions. With this in mind, menopause should be seen as the ultimate phase of an aging process of the ovary that unravels for several years (6-8) and ultimately results in amenorrhea.

Based on cross sectional studies, the median age at menopause has been estimated between 50 and 52. This has remained remarkably constant throughout history (first reference about age at menopause given by the Greeks) with very little/no differences among races, irrespective of the variety of social status or dietary habits. Interestingly, the secular trend towards earlier puberty observed in Europe and Northern America in the 50's and 60's has not been followed by changes in menopausal age. Similarly, the factors that affect ovarian function and limit the total number of ovulations do not affect the age of menopause. This is particularly the case of repeated pregnancies or prolonged use of the birth control pill.

Menopause is genetically determined probably through information coded on the X chromosome. There are families with higher incidence of premature menopause (< 40 years of age) but this also occurs sporadically. Exposure to toxic agents such as chemotherapy or environmental substances and notably tobacco advance the age of menopause.

Ovarian aging and menopause

Menopause or the cessation of ovarian function is the end stage of an aging process that starts some 6 to 8 years earlier. Originally, only the few months/years before menopause were recognized to be hormonally abnormal. During these months/years preceding menopause, abnormal, unscheduled and often heavy menses are common. Most often, these are the results of persistent and/or intermittent anovulation that leads to dysfunctional/breakthrough bleeding. These episodes have been recognized and linked to menopause for a long time. Collectively, they are known as perimenopausal disorders or symptoms. The common denomination of perimenopausal troubles is a loss of ovulatory function with a lack of cyclical production of progesterone before estrogen production stops. After some time (weeks/months) this results in unopposed proliferation of the endometrium and ultimately breakthrough bleeding. It may or may not be associated with endometrial hyperplasia which should always be ruled out, when confronted to perimenopausal bleeding disorders (endometrial aspiration). Collectively, these bleeding disorders reflect the tail end (last 1 to 2 years) of the whole aging process of the ovary. Most often but not always, perimenopause symptoms announce the imminence of menopause. The earlier years (4 to 6 before menopause) of the aging process of the ovary are clinically silent except for a sharp decline in fecundity. These early stages of ovarian aging whose only manifestations are infertility and some discrete hormonal changes (early follicular phase FSH) are often called "incipient" or "occult" ovarian failure.

Symptoms and consequences

The loss of the ovarian function and the resulting hypoestrogenaemia are the source of an array of symptoms experienced by women. These include the well-known hot flushes (HF) and sleep disorders. Women also often encounter psychological symptoms at/or just before the age of menopause that used to receive psychiatric interpretations but are now attributed to declining E2 levels. These include depressive feelings, psychological irritability and cognitive impairments (approximately 15 years later, on average).

Aside of easily recognizable symptoms, menopause is responsible for an increase in daily bone loss and overall risk of coronary heart disease (CHD). Ultimately, postmenopausal bone loss increases the risk of osteoporosis that becomes clinically evident. The increase in CHD seen after menopause leads to similar CHD incidences among men and women above 50. On the contrary, women appear to benefit from relative protection prior to that age. This observation has let to believe that ovarian hormones can prevent coronary heart disease.

Hot flushes

Hot flushes (or flashes) (HF) are the emblematic symptoms of menopause. They consist of episodic phenomenons characterized by a sudden onset of upper body vasodilation (flashes) associated with intense perspiration (flushes). The sudden episode is often preceded by short unpleasant psychological symptoms (such as feeling oppressed) that are often strong enough to awaken patients at night. HFs occur at variable frequency which can be up to one every 60 minutes at the maximum. Each episode lasts 2 to 3 minutes. They are timely related to (but not dependant upon) episodic LH elevations. They do not occur in circumstances where no GnRH is produced endogenously (e.g. Kalmann syndrome). Any phenomenon which occurs more often than once an hour or which last more than 10 minutes is likely not to be a true HF. Characteristically, individuals who have never been exposed to E2 such as untreated Turner syndromes for example never experience HF. Exposure to E2 followed by withdrawal from treatment however, results in HF in these patients.

HF are generated by episodic resetting of the hypothalamic center that controls basal body temperature (BBT), or thermostat. In castrated individuals (male or female), the thermostat looses some of its precision for controlling BBT.

This is reflected by a tendency for a slight but constant upward slide over time of the reference temperature setting. The thermostat therefore lets BBT progressively increase above its original reference value. Yet, at intermittent intervals the thermostat resets itself, readjusting the original setting for BBT. Intermittent resetting of the reference temperature results in abrupt deployment of physiological mechanisms aiming at rapidly dissipating excess heat. This triggers profuse perspiration and upper body vasodilatation. The phenomenon is abrupt in its onset and ends when the new temperature setting has been reached, usually after a few minutes. Rather than reflecting an isolated phenomenon, HF should be seen as a readily identifiable manifestation of E2 deprivation on brain function. Hence, improper functioning of the hypothalamic center that controls BBT should be linked to other neurological symptoms of E2 deprivation less easy clinically measurable.

Bone mass and osteoporosis

Throughout life, bone undergoes a constant remodeling process. Hence, at any given time in life, bone mass is the net result of bone formation and resorption. A variety of factors influence both bone formation and resorption. Adults in hypoestrogenic state display an increase in bone resorption resulting in increased urinary calcium excretion that hampers bone mass if it persits over time. The same is seen in castrated males. Recent data indicate that in females and males, bone resorption is controlled by E2 (in males, after local aromatization of T). The net rate of bone loss varies during the post-menopausal years. Rapid at first, bone loss becomes less important over time but the bone balance remains negative throughout post-menopausal years. Bone mass or mineral density can now be easily and precisely measured non evasively with a variety of densitometer systems. The precision of measurements allows to detect hormone related changes in bone mass occurring within 6 to 12 months. When enough bone has been lost so that the deficit becomes identifiable on simple X-rays, or spontaneous fractures occur, the condition known as osteoporosis is considered existent. By and large, in the absence of hormone replacement therapy (HRT), osteoporosis is feared starting approximately 15 years after menopause. A variety of factors can hasten or delay the appearance of osteoporosis. Genetic and racial factors will influence both total bone mass at the time of menopause and the rate of loss after menopause. At one end of the spectrum, women of Northern European descent (blond, blue eyes), show frailer bones than women of Southern Europe or of black origin. Within each race, individuals may have higher or lower post-menopausal loss rates. Finally, environmental factors and notably smoking are known to increase bone loss and osteoporosis risk. The feared consequences of osteoporosis are fractures including stress fractures of vertebrae resulting in disgracious and potentially painful deformations of the spine. Hip fracture is another dreadful consequence of menopause. Bone mass or minerolometry can be measured in women who hesitate about using HRT and in individuals whose risk is unexpectedly high in order to document that the HRT regimen selected suffices. Repeated measurements must be done at 12 or 24 months.

Coronary heart disease (CHD)

Before menopause, the incidence of CHD is notably lower in women when compared to men of the same age. After menopause however, the incidence of CHD increases in women and starts to parallel that of men. This observation has been the starting point of our current views on female hormones and CHD. Specifically, the lower incidence of CHD in women before menopause has been seen as reflecting a relative protective factor of ovarian hormones against CHD.

Because oral estrogens induce a favourable alteration of the lipid profile, the beneficial effect of ovarian hormones on the cardiovascular system has been originally attributed to E2. There are now numerous evidences that E2 also exerts beneficial effects directly on vessels. This includes NO mediated vasodilatation, decreased intra luminal proliferation of smooth muscle cells and favourable vasoreactive response to Ach (vasodilatation). The above not withstanding, there are now preliminary albeit, converging indications that progesterone, the second ovarian hormone, also exerts beneficial cardiovascular effects of its own.

Based on the observation of an increase in CHD after menopause, it has become crucial to determine the possibility of prolonging with HRT the relative protection endowed to women during their reproductive years.

Recent data (HERS study) indicate that synthetic progestins and medroxy progesterone acetate (MPA) notably, completely antagonize the beneficial effects of estrogens. Recent data indicated that natural progesterone on the contrary, does not negate the benefit of estrogen therapy and may even have a positive action of its own.

Premature menopause

Menopause can occur prematurely (< 40 years of age) either idiopathically or as a result of identifiable endogenous (autoimmune disease associated or not with other endocrine disorders) or exogenous causes (exposure to toxic substances such as chemotherapy). Premature ovarian failure (POF) differs from regular menopause by the age of its occurrence and its consequences on fecundity in women of reproductive age.

The diagnosis of POF is usually simple. The finding, low E2 and high FSH levels, should be confirmatory. Results however, must be repeated with > 2 measurements because of the important consequences linked to this diagnosis. Assessing the ovarian volume by ultrasounds helps to distinguish idiopathic cases (premature menopause) from rare occurrences of insensitive ovaries such as encountered in isolated or multiple autoimmune endocrine deficiencies. The latter cases are more prone to have, yet rarely and unpredictably, clinical recoveries of ovarian function. This also warrants attempts at inducing ovulations, a futile exercise in true premature menopause. On the contrary, POF with small (atrophic) ovaries is definitive.

The consequences of POF are more dreadful than regular menopause because in the end, the amount of bone lost depends directly from the number of year spent after menopause. Hence, in the absence of treatment, a person having reached menopause at 35 will suffer at 60 the same amount of bone loss as normally expected at the age of 75, i.e., 15 years after menopause. Early menopause is therefore a strong indication for HRT in order to avoid osteoporosis.

When menopause occurs during the normal reproductive years, women commonly query about the possibilities to restore their reproductive potential. Since the advent of IVF, it is now possible to allow POF women to become pregnant and give birth through oocyte donation. Here exogenous hormones are used to prime endometrial receptivity in the POF recipient. Oocytes are offered by a surrogate donor. Larger (physiologic) amounts of E2 are needed as compared to common HRT regimens. Moreover, natural progesterone should be used exclusively because of the possibility of terratogenicity linked to synthetic progestins.

Blood levels and ultrasounds

In real time medicine, hormone replacements are not very helpful when natural menopause occurs at the expected age (

50). In these cases, the symptomatology is most often amply confirmatory. Menopausal or premenopausal symptoms encountered in younger individuals warrant hormonal measurements and pelvic ultrasounds for definitive diagnosis. FSH and E2 levels reflect ovarian function. In perimenopause, important changes can accompany intermittent episodes of ovarian function and failure. Hence, results should be interpreted as solely providing a trend. Ultrasounds allow measurements of ovarian volume, a marker of ovarian ageing less likely to be affected by intermittent fluctuations.


Stages of Menopause

Menopause is the normal, natural transition in life that begins between the ages of 35-55. During this time, your ovaries get smaller and stop producing the hormones estrogen and progesterone that control the menstrual cycle, your eggs are depleted and fertility declines. Eventually, you are no longer able to become pregnant.

Perimenopause/Before

The 3-5 year period before menopause when your estrogen and hormone levels begin to drop is called perimenopause. You typically enter into perimenopause in your late 40's and could begin to experience irregular menstrual cycles and symptoms such as:

  • Hot flashes
  • Sleep disturbances-insomnia
  • Night sweats
  • Elevated heart rate
  • Mood changes—irritability, depression, anxiety
  • Vaginal dryness or discomfort during sexual intercourse
  • Urinary issues

There is still a chance that you could get pregnant during this time and if you want to avoid this, a form of birth control is recommended until one year after your last period. A form of progestin therapy may also be an option to control menstrual bleeding and address vasomotor symptoms. Lifestyle changes are often recommended to help relieve other unpleasant symptoms.

Early Menopause

Certain events other than natural aging can result in an earlier menopause:

  • Hysterectomy (uterus removed)—symptoms appear gradually
  • Oophorectomy (ovaries removed)—symptoms appear immediately
  • Premature Ovarian Failure (POF)—underactive or inactive ovaries due to genetics, surgery, or cancer treatments, such as radiation therapy or chemotherapy. POF can also be due to ovarian dysfunction or insufficient follicles, which mature into eggs.

Menopause/During

On average, most women are about 51 to 52 when they enter menopause. Technically, you are in menopause after you've missed your period for 12 straight months without experiencing other causes, such as illness, medication, pregnancy or breastfeeding. The transition from perimenopause through menopause to postmenopause can take 1-3 years. It's important to remember every woman is unique and will experience menopause differently. Some women experience few, if any symptoms, and for those who do, the symptoms can vary widely.

Postmenopause/After

Postmenopause starts after one year has passed since your last menstrual cycle. Other symptoms that might have started in perimenopause can continue through menopause and postmenopause. It's not unusual to experience:

  • Hot flashes
  • Night sweats
  • Elevated heart rate
  • Sleep disturbances-insomnia
  • Mood changes—irritability, depression, anxiety
  • Urinary issues
  • Vaginal dryness—which can lead to discomfort during sexual intercourse

Additionally, due to the decrease in estrogen, there's an increased risk of heart disease, osteopenia and osteoporosis.