Reproductive Aging PDF

C H A P T E R 7 Reproductive Aging INTRODUCTION lifetime, and therefore their reproductive life span is not...

C H A P T E R 7 Reproductive Aging INTRODUCTION lifetime, and therefore their reproductive life span is not limited by availability of oocytes. Although other mam- The reproductive capacity of a woman varies greatly mals have a limited oocyte supply at birth, they typically over her lifetime, peaking in her twenties, then dimin- remain fertile throughout their adult lives, although ishing over several years, and finally coming to an end at sometimes at a gradually diminishing rate. Thus, most menopause. Over a million US women enter menopause other animals continue to reproduce as long as they each year. Because the average life span of humans has live. Only human females (and perhaps females of a few increased, especially in the past one hundred years, other large mammalian species) live a significant portion more women will live a larger proportion of their lives of their lives post-reproductively. Not only do women post-reproductively. Male fertility often continues differ in this way from other animals, their reproductive through adult life, although it also diminishes with age. aging contrasts with that of human males. There is some This chapter examines the aging of the reproductive sys- overall decline in reproductive function in certain older tem, comparing the two sexes in this regard. We discuss men (see discussion later), but men have been known to the patterns and consequences of endocrine changes at father children well into their nineties! menopause and during reproductive aging in men, and look at the pros and cons of therapeutically replacing diminishing reproductive hormones in older adults. TIMING OF MENOPAUSE Menopause is the permanent end of menstrual cycling MENOPAUSE associated with the loss of ovarian follicular activity. A woman is diagnosed in retrospect as having entered Most women who survive to the age of 50 can expect menopause after she has not had a menstrual cycle for a to live 20, 30, or even 40 more years in reasonably good full year. In the United States, the average age of the last health. A typical 50-year-old woman’s heart vigorously menstrual period is 51, with a normal range of 45–55. continues to pump blood, other internal organs such as The factors influencing the age at which a woman enters her kidneys and liver are properly functioning, and her menopause, when her ovaries are depleted of follicles, brain is active. In contrast, her ovaries undergo a dra- are mostly unknown. Possibly different women’s ova- matic decline, resulting in their complete loss of func- ries contain a variable number of oocytes at birth, or the tion. Her follicles deteriorate and her egg supply is lost, rate of follicular atresia differs among women. We know rendering her infertile. Levels of ovarian hormones that women who smoke cigarettes enter menopause one drop, affecting steroid-responsive tissues, especially the to two years earlier than nonsmokers. Some studies sug- uterus, vagina, and breast tissue. Loss of ovarian ste- gest that the number of ovulatory cycles experienced by roids causes menstrual cycles to cease. Thus, a woman’s a woman over her reproductive lifetime influences the reproductive system ages prematurely in comparison to timing of menopause. Women with a greater number the rest of her body. This period of reproductive decline of total ovulations may enter menopause earlier. For is called menopause. example, nulliparous women and those with few chil- Menopause is an unusual feature of human life his- dren tend to have earlier menopause than women who tory; it is not typical of other animals. Ectothermic verte- have had several full-term pregnancies. Some evidence brate females (fishes, amphibians, and reptiles) generally suggests that use of oral contraceptives (which inhibit have the ability to form new oocytes throughout their ovulation) tends to delay menopause. Thus, there seems Human Reproductive Biology, Fourth Edition. 119 Copyright © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/B978-0-12-382184-3.00007-6 120 7. REPRODUCTIVE AGING to be an effect of the number of lifetime ovulations on or indirectly by changes in circulating hormones, espe- the timing of menopause. Does each woman have a cially the drop in circulating estrogen. The symptoms limited number of ovulations after which her ovaries may end within a year or they may last for several years. are exhausted? If so, one would predict that girls who The most common symptom of menopause, experienced entered menarche early would also experience a rela- by over 75% of menopausal women in the United States, tively early menopause, but studies have not supported is the occurrence of hot flashes (or hot flushes). These are this hypothesis. Age at menopause is unrelated to birth sudden, intense feelings of heat experienced in the chest weight, but having a low relative adult weight or being and face, sometimes spreading over the body. They may on a weight-reduction diet may be associated with ear- be accompanied by profuse sweating. Hot flashes may lier menopause. occur at any time of the day or night, as often as every 10 min or less frequently, and they may last for 30 s to several minutes. For most women, hot flash symptoms PERIMENOPAUSE last for more than a year, and many postmenopausal women continue to suffer hot flashes for five years or Although the average age of menopause for ­American more. Some women experience hot flashes as only a women is 51, a woman can begin to experience pre- minor nuisance; for other women, they cause major dis- menopausal symptoms in her forties (average age, 47.5) turbances in sleep patterns and interfere with normal or even late thirties. The first indication of perimeno- daily activities. pause is a change in menstrual cycles. Menstruation Other physical symptoms of menopause include may occur more often or less frequently than before, slight shrinking of the external genitalia, breasts, and the menstrual flow may be heavier or lighter, and some uterus. The vagina can decrease in size, and its internal periods may be missed. Other symptoms can include lining becomes thinner and drier. For some women, loss hot flashes, sleep irregularities, mood changes, and of vaginal lubrication can lead to pain during sexual vaginal dryness. This stage preceding true menopause intercourse. An increased pH of vaginal fluids can make is called perimenopause and lasts an average of four the vagina more prone to infection (vaginitis; see Chapter years. Women who are smokers tend to have an ear- 17). Lower urinary tract disorders such as urinary tract lier and shorter perimenopause. Although a woman’s infections and incontinence are common. Other physical periods can be irregular during perimenopause, and changes, such as abdominal weight gain, deepening of there may be shorter cycles, she is usually still ovulat- the voice, and the appearance of hair on the chin and ing and should use contraceptives to avoid pregnancy upper lip, may occur during and after menopause. during this time. In fact, women using the combination The phrase female climacteric is used to refer to all of birth control pill (Chapter 13) likely will not experience the changes (psychological and emotional as well as hor- as many perimenopausal symptoms. Women who are monal and physical) of menopause. Menopause can be seeking to become pregnant will be less likely to achieve a period of psychological adjustment for some women. a successful pregnancy as perimenopause advances. Behavioral symptoms that can occur include irritability, insomnia, and fatigue. Whether these symptoms are a direct result of hormonal changes is not clear. Many of PREMATURE MENOPAUSE the psychological responses to menopause may result from physiological changes during this time. Hot flashes About one in 100 women enters menopause unusu- that can waken a woman repeatedly during the night ally early, before age 40. This condition, called premature may be a major cause of insomnia, fatigue, and mood ovarian failure, most often has a genetic cause. Premature swings. The psychological effects of a woman’s loss of menopause can also be caused by surgical removal of the fertility, which may represent an important aspect of her ovaries, the chemotherapy and radiation used to treat feminine identity, can affect her emotional state nega- cancers, or by autoimmune disorders in which the body tively at this time. One positive note for most women is destroys its own tissues. A woman who experiences pre- the end of the monthly menstrual flow and, for some, the mature ovarian failure will have the same menopausal PMS associated with menstrual cycling (see Chapter 3). symptoms as those who enter menopause at a later time. A study of 2500 women reported that 70% had positive or at least neutral feelings about end of their periods. It must be emphasized that menopause is a normal phase SYMPTOMS OF MENOPAUSE of the human life cycle, and most women adjust to this change in a healthy and comfortable way. Later in this Before and after reaching menopause, at least 85% of chapter we learn that older men can also experience a women have symptoms, the occurrence and intensity of more gradual decline in sex hormones, with associated which vary among individuals. These are caused directly symptoms (andropause). II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Endocrine Changes during Menopause 121 ENDOCRINE CHANGES DURING the follicular phase and speeding up cycles. The cycle MENOPAUSE length, however, can be quite variable, with some cycles longer and others shorter than normal. During perimenopause, one of the first changes in a During perimenopause a woman has an increasing woman’s endocrine status is a decline in the release of number of cycles that are anovulatory. In fact, female small glycoprotein hormones from her ovaries ­(Figure fertility declines beginning around age 27 and continues 7.1). The ovaries stop producing a glycoprotein called to decline through perimenopause (Figure 7.2). During anti-müllerian hormone (AMH). In Chapter 5 we this period of decreased fertility, it is common to have learned that this hormone is released by Sertoli cells missed periods. After a woman’s cycles have ended and in the developing testis and causes degeneration of she is in true menopause, the ovaries cease to respond the ­müllerian ducts in males. Although AMH does not to FSH and LH. Most of a woman’s stock of ovarian fol- appear to be present in the ovary during sex differen- licles is gone by this stage; only a few hundred remain at tiation, starting around the time of birth it is produced menopause. The depletion of ovarian follicles results in a and secreted by granulosa cells of primary, secondary, decrease in the production of estradiol to very low levels and early tertiary follicles. Because it is produced by (Figure 7.1). Because estradiol levels are so low, there is growing, but not primordial follicles, AMH reflects little if any negative feedback on gonadotropin secretion. the entrance of resting follicles into the pool available Thus, in the absence of estrogen feedback, levels of FSH for selection and ovulation each cycle. This hormone continue to rise. Secretion of LH also rises during meno- continues to be produced throughout a woman’s repro- pause (Figure 7.1). In fact, the pituitary gland secretes ductive life but begins to decline several years before 10 times as much FSH and four times as much LH as menopause, and by menopause it is not detectable in in younger women. When these gonadotropins are the blood. extracted from the urine of postmenopausal women, the In the years leading up to menopause, the ovaries extract is called human menopausal gonadotropin. GnRH also gradually stop producing inhibins. Inhibin-B is levels in the hypothalamus are low, and some studies a glycoprotein that selectively suppresses the release have demonstrated a decrease in GnRH pulse frequency. of FSH from the anterior pituitary. When the pituitary Androgen levels fall gradually as women age, but this is released from this inhibition, the secretion of FSH decrease is thought to be unrelated to menopause. How- rises. Higher levels of FSH can be detected in the blood ever, the adrenal glands and ovaries of postmenopausal of women in their forties who are still menstruating women continue to secrete androgens. Sex hormone regularly and showing no overt signs of menopause ­ binding globulin levels decrease, causing free androgen (Figure 7.1). A woman usually continues to menstruate levels to rise. These hormones, in the absence of estro- during perimenopause, although her cycles may become gens, cause some menopausal symptoms such as voice irregular. This may be because the higher levels of FSH deepening, enlargement of the clitoris, and appearance increase the rate of follicular maturation, thus shortening of facial hair. FSH Circulating hormone levels LH Inhibin-B Estrone E2 AMH –8 –6 –4 –2 0 2 4 6 8 Number of years around menopause FIGURE 7.1 Circulating levels of FSH, LH, estradiol (E2), estrone, AMH, and inhibin-B in women before, during, and after menopause. The y axis is unitless. Note that declines in AMH and inhibin-B precede the reduction in estradiol levels. The increase in circulating gonadotropins, especially FSH, seen during perimenopause remains elevated for years after menopause. II. SEXUAL DIFFERENTIATION AND DEVELOPMENT 122 7. REPRODUCTIVE AGING Because of the dramatic drop in estrogen secretion follicles below some critical number decreases fertility, during menopause, an average woman in the United and the drop in estrogen levels resulting from follicle States spends about one-third of her life with very low depletion changes the endocrine feedback on the hypo- levels of estrogens, which influence over 300 bodily thalamus and pituitary. Recently, scientists have also functions! The major circulating estrogen in postmeno- addressed the possible neural control of menopause, pausal women is estrone (Figure 7.1). Androstenedione, suggesting that age-related changes in the central ner- produced by the adrenal glands, is aromatized to estrone vous system may secondarily affect the hypothalamus, predominantly in adipose (fat) tissue. Obese women pituitary, and ovaries. therefore have higher levels of estrone compared to lean women. Hot flashes occur when estradiol levels are lowered DECLINE IN FERTILITY relatively slowly, such as in women in normal meno- pause, or abruptly, such as in premenopausal women Many women can observe changes in the length or after surgical removal of the ovaries or those given anti- regularity of their menstrual cycles during perimeno- estrogen treatment for cancer. Even men can experience pause. In addition, most women experience hot flashes hot flashes when their testosterone levels drop sud- and other perimenopausal symptoms as their reproduc- denly after surgical or chemical treatment for testicular tive life nears its end. Certainly they are aware of the ter- or prostate cancer. Treatment with estrogens reliably mination of their cycles at menopause, though this event relieves hot flashes in women. However, low estrogen is only observed in retrospect. However, the decline in levels alone cannot explain hot flashes as estrogen levels fertility during the years prior to menopause is mostly do not d ­ iffer between symptomatic and asymptomatic a silent phenomenon. How does reproductive poten- women. Hot flashes occur when a woman’s sympathetic tial change during a woman’s reproductive lifetime? nervous system is activated, causing dilation ­(widening) That is, given a sexually active woman between puberty of blood vessels in the skin, which results in warm blood and menopause, how do her chances of becoming preg- being carried to these regions. Sympathetic activation nant change as she ages? This question is surprisingly also causes sweating, as well as an increase in heart rate difficult to answer. One could simply look at the num- ­during the flashes. It had long been thought that hot ber of births at each maternal age in a population. But flashes were triggered by a brief, abrupt dysregulation with the widespread use of contraception, women can of the thermoregulatory system. Normally, body tem- suppress reproduction, which masks the true natural perature is maintained within a comfortable temperature fertility rate. Furthermore, the frequency of coitus may range known as the thermoneutral zone. If core tempera- change throughout a woman’s life, and this affects preg- ture rises above the thermoneutral zone, sweating results nancy rate. Other determinants of reproductive capacity to cool the body down, and if it drops below the ther- encompass physiological, behavioral, and sociological moneutral zone, shivering raises the core temperature. factors including the proportion of ovulatory cycles, Recent research has shown that women who experience length of cycles, rate of fetal loss, the length of time that a hot flashes have such a narrowed thermoneutral zone woman nurses her child, and male factors. The best infor- that even a small rise in temperature results in sweating. mation about female reproductive capacity comes from Women with a wider thermoneutral zone don’t tend to studies of married or cohabiting women in “natural fer- have hot flashes. Much of the basic physiology of this tility” populations using no contraception (Figure 7.2). very common menopausal symptom is still unknown. Data from these studies show that peak female fertil- We have described many changes in a woman’s ity occurs in the early to mid-twenties and begins to body that occur during menopause, but what aspect of decline by age 30. At 33, a woman’s fecundity (chance reproductive aging actually causes menopause? A post- of becoming pregnant) per cycle is only 75% of that in menopausal woman’s reproductive tract and external her 20s. By age 35, her ability to become pregnant has genitalia remain functional. She can continue to engage declined to less than 50% of her peak fertility years. in normal sexual activity. Using a younger woman’s egg, A 40-year-old woman, despite being 10 years away from her uterus retains the ability to sustain a full-term preg- menopause, has only a 30% chance of pregnancy com- nancy at least until her late sixties! But her ovaries age pared to in her twenties. After age 30, the rate of miscar- more rapidly than other reproductive organs. Both the riage also increases, and thus the chance of delivering quantity and quality of oocytes decline as a woman ages. a healthy baby is further reduced. Historical data from Continuing a steep reduction in the number of ovarian populations using no contraceptives show that women follicles through infancy and childhood, follicles are had their last child at an average age of 41; i.e. this is the steadily lost by atresia throughout a woman’s reproduc- average age of the loss of fertility. tive years (Figure 7.3). A reduction in number of oocytes During a woman’s reproductive years, both the quan- drives menopause. Clearly, the depletion of ovarian tity and quality of her oocytes decline. By the age of 15, II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Determining Female Reproductive Age 123 100 100 90 Probability of conception (%) Percentage of follicles remaining 80 80 70 60 60 40 50 40 20 30 20 0 15 20 25 30 35 40 45 50 10 Age (years) 0 FIGURE 7.2 Change in probability that conception will occur with- 15 20 25 30 35 40 45 50 55 in one menstrual cycle in women aged 15–50. Data are from natural Age (years) fertility populations, using no artificial contraceptive practices. Prob- ability of pregnancy depends on many factors including biological fer- FIGURE 7.3 Percentage of follicles remaining between ages 15–55. One hundred percent is set as the number of follicles at age 15, near the tility as well as frequency of intercourse. One hundred percent is the beginning of the female reproductive years. However, a 15-year-old conception rate of women age 22. female has already lost about half of the follicles she was born with. she has already lost half of the follicles she was born with. becoming stepmothers or adoptive mothers. However, Before the age of 25, her oocyte pool is again reduced by an understanding of the timing of the decline in female half (Figure 7.3). On average, by age 35 about 16,000 fol- fertility, and in particular a test that would inform indi- licles remain, and this is further reduced to a few hun- vidual women of their current fertility status, will help dred by menopause. Some studies show an accelerated women and their partners plan childbearing. decline starting at age 38. But this ongoing depletion of follicles does not tell the whole story. In addition to hav- ing fewer eggs ovulating, the quality of a woman’s eggs DETERMINING FEMALE REPRODUCTIVE declines. The follicles undergo a process of aging and AGE deterioration. This includes the introduction of genetic mutations in the oocyte nuclear DNA and cytoplasmic Because a woman’s fertility changes throughout her changes such as loss of mitochondria and mutations of lifetime, it is helpful for women to have information mitochondrial DNA. Aging of supporting cells in the fol- about their reproductive status to make informed choices licle wall may also occur. By age 40, half of a woman’s regarding the timing of pregnancy and/or contracep- eggs are chromosomally abnormal, and two years later tive use. To help provide this information to individual that figure rises to 90%. Figure 7.4 shows the dramatic women, researchers have developed a staging method increase in the number of trisomic embryos with increas- similar to the method used to determine the stages of ing maternal age. Thus, even if a woman in her thirties or puberty (Chapter 6). Two factors are taken into account forties is able to conceive, the risk of miscarriage increas- when determining “reproductive age.” One is the length ingly rises (see Box 7.1). Thus, if a woman is to become a and regularity of menstrual cycles. The second is the mother, she is most likely to first give birth in her twen- measurement of circulating levels of FSH. These stages ties. However, women today live longer and enjoy bet- are shown in Table 7.1. Note that there is no age range ter health than in previous generations. Many women for a given reproductive stage. This is because there is now delay childbearing because of their careers, educa- a great deal of individual variation in the age at which tion, and desire to pursue their interests before starting women enter reproductive stages and also in the length a family. Increasingly, women are becoming ready for of each stage. For example, if a woman in the late repro- childbearing at an older age, only to find that they are ductive stage decides to have a baby, it is not possible to in perimenopause and that their fertility is decreasing predict whether she will take five months or five years rapidly. Thus, the timing of fertility decline is becom- to become pregnant. Furthermore, women who have ing a greater constraint on women’s ability to plan their conditions that may alter their endocrine state (e.g. those families. In the United States, nearly one in five women who are extremely thin or obese, extremely athletic, have between the ages of 40 and 44 has not borne a child, and irregular cycles, have endometriosis or uterine fibroids, the rate of childlessness has doubled in the past 20 years. are heavy smokers, or who have had a hysterectomy) Of course, not all of these childless women desire to may be difficult to stage. Nevertheless, an awareness of have a family, and others achieve their family goals by the natural progression of the female reproductive stages II. SEXUAL DIFFERENTIATION AND DEVELOPMENT 124 7. REPRODUCTIVE AGING 35 and 10 mm in diameter can be visualized by transvaginal ultrasound, and this is usually done early in the follicular stage. However, like other tests of ovarian reserve, it does not provide information about oocyte quality. Inhibin-B is a hormone produced by granulosa and 30 theca cells of developing small antral follicles early in the follicular phase. It selectively inhibits the production and/or release of FSH from the pituitary gland. In the premenopausal ovary, inhibin-B levels are reduced as the 25 number of antral follicles declines, and inhibin-B is very low or undetectable about four years before the final men- strual period (Figure 7.1). Thus, a lowering of circulating inhibin-B is a marker of ovarian aging. Because levels of 20 this hormone fluctuate during the female cycle, it should be measured during the follicular phase of the cycle. Trisomies (%) As inhibin levels decline, the lifting of this feedback restraint allows FSH levels to rise during female repro- ductive aging (Figure 7.1). Elevated FSH usually occurs 15 in women starting at age 35–40, when the oocyte pool has shrunk to about 10% of that present at puberty. A rise in FSH is therefore a marker of ovarian aging. Anti-müllerian hormone (AMH) is a small glycopro- 10 tein that is released by Sertoli cells in the developing testis and causes degeneration of the müllerian ducts in males (see Chapter 5) Although this hormone probably plays no role in the ovary during sex differentiation, starting around the time of birth AMH is produced and secreted 5 by granulosa cells of primary, secondary, and early ter- tiary follicles. Its role may be to limit initial recruitment of primordial follicles into the growing follicular pool, and to limit the response of small growing follicles to FSH. 0 Blood levels of AMH are a good indication of the number 15 20 25 30 35 40 42 of healthy early tertiary follicles. Because the number of Age (years) early antral (tertiary) follicles is related to the number of FIGURE 7.4 Genetic analysis of clinically recognized pregnancies primordial follicles, the level of AMH also indicates the shows a dramatic increase in trisomies after a maternal age of 35. Tri- size of the ovarian reserve. Circulating AMH levels begin somy 16 is the most common trisomy; it results in miscarriage, usually to decrease after the peak fertility years, and are very low within the first trimester. This contributes to the decrease in fertility of women in their later reproductive years. The slightly higher incidence or undetectable by five years prior to the last menstrual of trisomies in women under the age of 17 may reflect non-disjunction period (Figure 7.1). This reduction in AMH can be seen in meiosis during the earliest cycles after puberty. before changes in other age-related markers such as FSH and inhibin-B. Because AMH does not fluctuate during may help women move more comfortably through their the menstrual cycle, it can be tested at any stage of the reproductive life span and beyond. cycle. For these reasons, a decline in AMH is considered Other methods to help women determine their fertility the most promising marker of the loss of fertility. status focus on assessing the number of primordial folli- It should be noted that many of the studies of markers cles in the ovary, called the ovarian reserve. For a woman of ovarian reserve have focused on the markers’ ability in her peak reproductive years, at the beginning of each to predict an ovarian response to gonadotropin stimu- monthly cycle several antral follicles are present in each lation for assisted fertility treatments (see Chapter 15). ovary; these follicles are selectable for further growth More information is needed about the changes in these and maturation. As the ovary ages, fewer early antral markers in women of normal fertility. oocytes are present in each cycle. Because the antral fol- Is it possible to push the frontiers of female fertility licle count mirrors the size of the ovarian reserve, it is a into a woman’s forties, fifties, and beyond? In 1994, a reasonably good indicator of potential fertility. Thus, one 63-year-old Italian woman gave birth to a baby using way to assess fertility is to count the number of antral fol- an egg donated by a younger woman (see Chapter 15). licles available during a cycle. Antral follicles between 2 Since then, many other women even older have used II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Determining Female Reproductive Age 125 BOX 7.1 EGG AGING In women, the chances of infertility increase with age. ognized pregnancy, and aneuploidy explains about 60% of For example, infertility rates in American women are 4.1% at these. The number of preembryos that have chromosomal ages 20 to 24, 5.5% at ages 25 to 29, 9.4% at ages 30 to 34, and abnormalities and fail to implant is high (by one estimate, 19.7% at ages 35 to 39. An individual woman’s fertility de- about 31% of all conceptions). For a woman in her 20s pends on her age and also how close in years she is to meno- with a clinically recognized pregnancy, the rate of trisomy pause. Up to age 40, the main cause of infertility in women is only about 2–3%. But this increases to about 35% for is not the failure to ovulate or the inability of the uterus to a woman in her 40s. Many of these pregnancies end in implant an egg, but instead the increasing loss of preembryos ­spontaneous abortion, and surviving children born with or early implanted embryos. Only after age 40 does female trisomies face developmental disabilities. infertility increase rapidly due to a failing of ovarian function There is, however, another theory to explain the ­increase and of the ability to conceive. Thus, the decline in ovulated in aneuploid births in older women. This theory says that egg quality precedes the decline in ovulated egg quantity. the higher incidence of late miscarriages and birth defects Remember from Chapter 5 that each ovary has about in older women is due to a decrease in the efficiency of the 500,000 oocytes in follicles at birth and that these primary mechanism that causes spontaneous abortion of abnormal oocytes are arrested in prophase of the first meiotic divi- embryos. This theory assumes that a mother has a screen- sion for up to 50 years unless they die by atresia or are ing system, probably of uterine origin, that regulates off- ovulated. As a result, most of the oocytes in the ovary age spring quality, and that this system falters with age. This for many years or even decades, and apparently this aging relaxed screening of abnormal embryos then causes the can cause problems in the selected few that finally reiniti- observed increase in defective embryos in miscarriages ate meiosis and ovulate. and the increase in genetically abnormal fetuses carried Problems in meiosis can produce embryos that have too to term in older mothers. The evolutionary explanation many sets of chromosomes, having cells that are 3N or even for this relaxation could be that, since an older woman is 4N instead of 2N. This is called polyploidy, and all of these nearing menopause, it benefits her to relax the screen and polyploid embryos are lost through spontaneous abortion. to allow more successful implantation, taking the “good“ A more common chromosomal error is aneuploidy, in which embryos with the “bad”, since this is her final chance to both members of a homologous pair of chromosomes end pass on her genes. This theory is in contrast to the first up in one cell during meiosis (resulting in embryonic theory because it predicts that older and younger women ­trisomy), with the other cell of the abnormal division hav- ovulate the same percentage of embryos with chromosom- ing no chromosomes of that pair (resulting in monosomy). al abnormalities. Perhaps the homologous sets of chromosomes are unable What about the sperm of older men? Aneuploidy dur- to separate as well during meiosis in older oocytes, thus ing meiosis and other genetic abnormalities do occur in leading to aneuploidy. Although most trisomic embryos the testes, with increased frequency in older men. It is are aborted spontaneously, trisomies of chromosomes 13, ­likely that a great majority of these abnormal sperm do not 18, and 21 are often born, but with severe developmental fertilize an egg. Some do, however, as evidenced by the and mental disorders. Trisomies of sex chromosomes (XXY, increase in miscarriages associated with fertilization by XYY, XXX) are discussed in Chapter 5. Monosomic new- sperm from older men. Male fertility decreases with age. borns with Turner’s syndrome (XO) develop mental and At age 24, the probability of a man producing a pregnancy developmental abnormalities (Chapter 5). within a year of frequent, unprotected coitus is about 92%. Because the incidence of chromosomal abnormalities From then on, this probability decreases about 3% for in newborns increases with the mother’s age, one theory ­every subsequent year, regardless of the age of the woman. has been that there are more oocytes ovulated with chro- Chance of conceiving a child with Down syndrome or with mosomal abnormalities in older women, which lowers any aneuploidy at different maternal ages female fertility. Central to this hypothesis is that certain preembryos are rejected by the uterus before or during Maternal age (years) Down syndrome Any implantation through some as yet unknown mechanism. 15–24 1/1300 1/500 Even if these abnormal embryos implant and a pregnancy 25–29 1/1100 1/385 is established, many miscarry early in the first trimester. 35 1/350 1/178 Most estimates suggest that chromosomal abnormalities 40 1/100 1/63 account for about one-half of early miscarriages after a rec- 45 1/25 1/18 II. SEXUAL DIFFERENTIATION AND DEVELOPMENT 126 7. REPRODUCTIVE AGING TABLE 7.1 Stages of a Woman’s Reproductive Life at a greater rate, and a condition called osteoporosis can 0. Prereproductive develop. In this condition, the bones become weak and prone to fracture, and a woman may lose height because 1. Early reproductive her vertebrae compress. Menstrual cycles are variable to regular, FSH levels are normal In the United States, about one in four women over age 50 develops osteoporosis or osteopenia (low bone 2. Peak reproductive density that increases risk for osteoporosis). This means Menstrual cycles are regular; FSH levels are normal that today about 25 million American women have this 3. Late reproductive condition. Osteoporosis results in about 1.3 million bone fractures, leading to 30,000 deaths each year. Black and Menstrual cycles are regular; FSH levels are elevated Hispanic women tend to suffer less from osteoporosis. 4. Early menopausal transition The primary cause of osteoporosis is a lowering of estro-  Length of cycles varies by seven days or more; FSH levels are gen levels in a woman’s blood. This can occur after natu- elevated ral menopause, after “induced” menopause (i.e. surgical 5. Late menopausal transition removal of the ovaries for some other reason), or dur- ing amenorrhea. Factors that increase the risk of osteo- Two or more cycles missed; FSH levels are elevated porosis include low physical activity or chronic intense 6. Early postmenopause exercise, low calcium intake, smoking, the use of alcohol  Lasts for four years after menopause begins; FSH levels are or caffeine, a fair complexion, being thin, never having elevated been pregnant, early menopause (natural or induced), and a family history of osteoporosis. Obese women 7. Late postmenopause tend to have fewer problems with osteoporosis, perhaps Lasts until death; FSH levels remain elevated because they have higher estrogen production from fat cells. Older women are at increased risk for a variety of this method to become pregnant. In the future, it may be other diseases, which may be caused by hormonal possible for women to prolong their own fertility after changes at menopause or may simply be associated natural menopause. Some studies suggest that, contrary with the aging process. For example, women seldom to long-standing views, female mammals may retain have cardiovascular disease before menopause, but the ovarian stem cells well into adulthood. If this holds true risk increases greatly in postmenopausal women (pos- for humans, it may be possible to develop therapies that sibly related to postmenopausal abdominal fat deposi- prolong fertility through the proliferation and mainte- tion), making heart disease the leading cause of death in nance of these stem cells. This approach may also lessen US women. The incidence of cancer, including cancers or delay menopausal symptoms. of the reproductive organs, increases after menopause. Some have questioned whether an older woman has Another group of diseases found predominantly in a “right” to raise a child. Others feel that this is an out- postmenopausal women are various types of demen- dated argument. Indeed, many grandparents are now tia, including Alzheimer’s. Because of the association raising their grandchildren successfully. It has been between the natural loss of hormones at menopause and shown that women in their fifties, after undergoing IVF the onset of these diseases, it was hoped that replacing treatment with donor eggs (see Chapter 15), are able to some of a woman’s lost hormones artificially would pre- carry a pregnancy as successfully as younger women. vent the diseases. Indeed, early studies, many of which Older parents tend to have the financial and emotional were observational, demonstrated a widespread benefit stability necessary for child rearing, and women (and of hormone replacement. However, as we shall see, the men) who have the advantage of good health care and earlier promise of hormones as a “fountain of youth” has living conditions can now expect to have more years of been sobered by the results of more recent studies. excellent health than past generations. However, as sci- ence and medicine stretch the boundaries of menopause, these ethical and practical arguments will continue. TREATMENTS FOR MENOPAUSAL SYMPTOMS: BENEFITS AND RISKS OSTEOPOROSIS AND OTHER Some women have mild menopausal symptoms and POSTMENOPAUSAL DISORDERS may not seek medical treatment. Those women who have moderate to severe symptoms before, during, or During menopause and the postmenopausal state, after menopause may decide to take hormone replacement calcium and phosphorus are lost from women’s bones therapy (HRT) to alleviate the symptoms. An estrogen II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Treatments for Menopausal Symptoms: Benefits and Risks 127 or a combination of estrogen plus progestin is taken to Taking HRT appears to increase the risk of devel- “replace” the hormones released previously by the ova- oping breast cancer, elevating the risk about 2.3% for ries. Estrogens are commonly delivered by pill form or every year of use. A study of 122,000 American nurses through a skin patch. The estrogen may be synthesized indicated that those aged 55 to 59 who were taking ERT from a plant source or obtained from the urine of preg- for at least five years had a 54% increased risk of breast nant horses. The latter, such as Premarin (a mixture of six cancer, and ERT at age 60–64 years increased the risk to estrogens derived from pregnant mare’s urine) is admin- 71%. In this study, there was no ERT effect on breast can- istered most commonly as a pill. Women who are still cer if used for less than five years. Other studies have cycling often take an estrogen pill daily, adding proges- concluded that the risk of breast cancer from combined tin for 12–14 days a month, followed by progestin with- estrogen plus progestin use is greater than that from the drawal to allow menstruation to occur. A daily estrogen use of estrogen only. The good news is that five years plus progestin pill is given most commonly to women after having stopped HRT treatment, a woman’s risk of who have stopped cycling. ­Estrogen-containing vaginal breast cancer is no greater than that of a woman who creams are also used to decrease vaginal dryness and never used HRT. lessen painful coitus. A strong correlation exists between ERT and inci- Hormone replacement therapy is very effective in dence of endometrial cancer. Estrogen alone for at alleviating the hot flashes, night sweats, and sleep dis- least one year increases risk of this cancer 6–14 times, turbances of menopause. These symptoms are the main depending on estrogen dose and duration of treat- reason for prescribing HRT. In addition, the hormone(s) ment. It is not clear if this increased risk goes away relieves urogenital discomfort (vaginal dryness and pain after ERT is discontinued. Unlike for breast cancer, and frequent urination). Early HRT, especially if taken however, adding a progestin to the estrogen decreases starting in the first three years after menopause, reduces the estrogenic effect on endometrial cancer signifi- the spine and hip fractures due to osteoporosis. How- cantly. Therefore, it is recommended that women who ever, one must continue to take estrogen for the benefits have their uterus (i.e. those who have not had a hys- to persist; the bones begin to lose density when HRT is terectomy) should use the combined HRT instead of discontinued. Other nonhormonal treatments for osteo- estrogen alone (ERT). porosis are available. Combined estrogen plus proges- One study of 240,000 American women showed that tin (but not estrogen alone) appears to reduce the risk of ERT given for at least six years increases the risk of fatal colorectal cancer. It is not known whether the protective ovarian cancer by 40%, and this risk increased to 70% benefits of HRT on this type of cancer continue after a if ERT continued for 11 years. This was confirmed by woman stops taking the hormones. another study that found a 60% greater risk of devel- Earlier studies had indicated that estrogen lowered oping ovarian cancer in women taking estrogen-only the incidence and mortality rate of cardiovascular dis- HRT for 10 years or more. The effect of combined ease in postmenopausal women. Based on this informa- estrogen plus progestogen HRT on ovarian cancer is tion, many women used HRT to protect against heart inconclusive. attacks and stroke, as well as osteoporosis, even if their Finally, ERT and combined HRT increase the risk menopausal symptoms were not distressing. However, of gallbladder disease, and ERT appears to cause the in 2002, a large federally funded study examining the growth of benign uterine fibroids. health effects of HRT on 16,000 postmenopausal women In summary, HRT has benefits for some women but was halted abruptly when it was found that women tak- can have dangerous side effects in others (Table 7.2). ing estrogen and progestin were actually at higher risk Certainly, a woman’s individual and family history of of heart disease, strokes, and blood clots. Combined hor- cancer of the reproductive tract should be considered monal treatment increased the risk of heart disease by before she chooses HRT. One must also consider relative 29% and the risk of stroke by 41%. Thus, HRT should not risks. HRT raises the risk of heart disease, which kills be used to protect against cardiovascular disease. After 250,000 American women each year, and also increases the results of this study were made public, many women the risk of breast cancer, which kills 46,000 women each discontinued their use of HRT. year. Thus, women who are at high risk for heart dis- Earlier studies also reported that HRT increased short- ease or who have a family history of breast cancer are term memory and the ability to learn new tasks and usually discouraged from using HRT. However, estro- decreased the risk of developing Alzheimer’s disease by gen maintains bone density, protecting against osteopo- 40%. However, a large controlled study of nearly 3000 rosis and the resulting hip and spinal fractures that can women found that estrogen replacement therapy (ERT) in be debilitating for older women and kill 30,000 women postmenopausal women who have had a hysterectomy per year. Some women may choose to take HRT for one not only failed to prevent memory loss, but actually or more years to alleviate menopausal symptoms and increased the risk of dementia. then discontinue its use because of associated health II. SEXUAL DIFFERENTIATION AND DEVELOPMENT 128 7. REPRODUCTIVE AGING TABLE 7.2 Possible Benefits and Risks of Estrogen Replacement contains a precursor of estrogens (see Chapter 2) Therapy for Menopause that has been proposed as an antiaging substance. Benefits Risks In summary, the Food and Drug Administration now recommends that women with moderate to severe Relieves hot flashes, night sweats, Increased risk of endometrial menopausal symptoms use HRT at the lowest effective insomnia cancer (unless a progestin is used with estrogen) dose and for the shortest possible time. Results from the Women’s Health Initiative dispelled the notion that HRT Relieves vaginal and skin dryness, Increased risk of breast cancer should be used broadly as an antiaging drug. HRT may genital shrinking be prescribed for women at high risk of osteoporosis, but Reduced osteoporosis (especially if Increased risk of heart disease hormone therapy should not be used to prevent heart a progestin is also used) disease or dementia. Reduced risk of colorectal cancer Increased risk of gallbladder disease Increased risk of fatal ovarian ANDROPAUSE cancer Increased risk of benign uterine Testicular Function in Old Age fibroids Some older men undergo a phenomenon that is similar to menopause in women; it is commonly called risks. Those entering menopause prematurely can andropause. In women, menopause usually occurs over probably safely take HRT for longer. Whether to add a period of a few months or years, but andropause typi- a progestin to the ERT is also a choice. Both estrogens cally occurs over decades, usually between the ages of and progestins cause mitosis of mammary gland cells. 48 and 70. It may begin in a man’s forties or later. One In contrast, estrogens increase, but progestins decrease, sign of andropause is that erections may take longer to mitosis of endometrial cells. Because increased mitosis achieve, and it may require more active stimulation of raises the chance of genetic error and cancer, progestins foreplay to enable a couple to have sexual intercourse support the increased risk of breast cancer after ERT (see Chapter 8). Male libido may also decrease, and but reduce the risk of endometrial cancer after ERT. men may experience fatigue, depression, and cognitive Progestins may even enhance the beneficial effects of decline. These and other symptoms are at least partly a ERT in relation to osteoporosis. However, the addition result of a decline in testosterone levels in some older of progestin increases the incidence of premenstrual men. Male sexual characteristics also may change: the syndrome, menstrual cramps, and unpredictable men- voice may rise in pitch, facial hair growth may decrease, strual bleeding. Most women today take a progestin as and the scrotum and penis may shrink. Sex accessory part of their HRT. Some recommend “natural” proges- structures, such as the seminal vesicles and other glands, terone derived from a progesterone building block in may become reduced in size. There is also a decline in plants such as the wild yam. muscle mass and strength, and osteoporosis can begin. Often women choose other remedies besides ERT for Men over 70 who are sexually active have higher blood menopausal symptoms. Factors that reduce the risk of testosterone levels than those abstaining from sex, but it osteoporosis include weight-bearing exercise as well as is not clear if the high levels in these men increased their prescription drugs that inhibit bone breakdown, such as sexual motivation or if their sexual activity increased calcitonin, etidronate sodium, and alendronate. Calcium their testosterone levels. supplements appear to help, especially later on in post- The term andropause has been criticized because menopausal years and when accompanied by weight- androgen production does not cease and normally bearing exercise. The National Institutes of Health declines very slowly. Some have suggested that the con- recommend 1000–1500 mg per day of calcium for post- stellation of symptoms resulting from lower androgen menopausal women and 1000 mg per day for women aged levels in older men be renamed ADAM (androgen defi- 25 to 50. These calcium requirements can be obtained by ciency in the aging male). However, age-related changes diet (about 400 mg per day, excluding dairy products) or in males also include reductions in other hormones such calcium supplements, but a caution is that greater than as DHEA, growth hormone, insulin-like growth factor-I, 2000 mg per day can cause kidney damage. Potassium and melatonin. bicarbonate taken orally has been shown to decrease The reduction in sex hormones in men is gradual. It bone loss. Natural foods also contain hormones that may is estimated that male testosterone levels typically drop slightly alleviate menopausal symptoms. Many of these 0.8% per year after age 40. However, this relatively small contain small amounts of phytoestrogens (Chapter 2); decrease may underestimate the physiological effects examples include soy products. Wild yam root also of testosterone reduction during aging. Because levels II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Summary 129 of steroid-binding proteins in the blood of older men potential risks are well understood. One of the concerns increase by 1.6% per year, bioavailable testosterone drops to be addressed is the possibility that ART could increase by 2% per year. One study found that 30% of men aged the risk of prostate cancer or exacerbate existing (possibly 60–70 and 70% of men aged 70–80 have low bioavail- undiagnosed) prostate cancer. able testosterone. A primary cause of lowered testoster- The trend toward delaying marriage and childbearing one appears to be a decrease in the ability of the testes means that men, like women, are increasingly seeking to to respond to pituitary gonadotropins. There is also a reproduce at a later age. Although men do not experi- reduction in the number of Leydig cells in the ­testes that ence an inevitable final end to reproductive functioning produce testosterone. Men who are chronically ill, obese, like women do, their fertility often declines gradually take prescription medications, or drink alcohol exces- after about age 40. Increased paternal age (above age 40) sively have lower average testosterone levels than found also increases the risk for miscarriage. In addition, older in healthy older men. In some older men, lower blood fathers have a higher risk of having children with neu- levels of testosterone cause a decrease in negative feed- rological disorders, especially autism spectrum disorder back of testosterone on LH secretion, resulting in higher and schizophrenia. This well-documented association LH levels. Reduced inhibin production by the Sertoli may be explained by an increase in the rate of small cells results in a rise in circulating FSH levels. Blood lev- mutations in the sperm of older men. A recent study of els of estrogens also rise in older men. The testes may be Icelandic families analyzed the number of small muta- less functional because their blood supply is, for some tions in the DNA of children with and without autism; unknown reason, reduced. The seminiferous tubules these new mutations were not inherited from either of show damage in some older men, and semen volume, as their parents. Children of older fathers tended to have well as sperm motility and percent normal morphology, more of these de novo mutations. It was estimated that, decrease with age. However, there is wide variation in on average, newborns have 60 spontaneous small muta- the fertility of individual males, and some men continue tions. Surprisingly, the number of mutations is strongly to be fertile into very old age. dependent on paternal age. At age 20, a father trans- Treatment of older men with an androgen (androgen mits about 25 mutations to his offspring; this increases replacement therapy; ART), along with short-term psycho- to 65 mutations when the father is 40. Thus, each addi- logical counseling, may reverse some of the symptoms tional year of paternal age loads on two new mutations. associated with the reduction in testosterone secretion. (In comparison, mothers transmit about 15 mutations Testosterone can be given as an injection, but the rapid regardless of their age. These small mutations con- increase in circulating levels of the hormone could have trast with the more major chromosomal errors such as adverse side effects. Thus, testosterone is usually given trisomies, which clearly increase with maternal age. as a skin patch or a topical gel. Another androgen, DHEA Although most small mutations are harmless, any del- (see Chapter 4), is also popular as a nonprescription eterious mutations would be especially likely to affect remedy for andropause. neurological functioning, as brain development extends Studies indicate that ART can protect against osteopo- over a long period of time and more genes are expressed rosis in older men. One study showed that testosterone in the brain than in any other organ. Of course, many increases bone density in the lower spine by about 10% older fathers have perfectly healthy children, but young and in the hip by at least 2%. As an additional protec- men who plan to delay fatherhood until their forties or tion against osteoporosis in men, the National Institutes fifties may want to store their sperm for later use! of Health recommends a calcium intake (through diet or calcium supplements) of 1000 mg daily for men aged 25–65 and 1000–1500 mg daily for men over 65, not to SUMMARY exceed 2000 mg/day. Weight-bearing exercise can assist these other therapies. Menopause occurs as menstrual cycles cease when a The use of ART in older men has been shown to increase woman reaches 45–55 years of age. At this time, ovar- muscle mass and decrease body fat. In younger men with ian function declines, resulting in a syndrome of physi- decreased testosterone due to testicular cancer or injury, cal changes. Menopause is preceded by perimenopause, ART can cause the secondary sex characteristics and sex a stage of gradual loss of ovarian function, which lasts accessory structures to return to their normal condition. In about four years. In addition to loss of fertility, symp- addition, sex drive and the ability to have an erection often toms of menopause include hot flashes, sleep distur- improve in these men. It is not yet clear, however, whether bances, weight gain, and loss of bone mineralization. ART can significantly improve energy, sex drive, ­sexual Other changes in female physiology during this time function, or depression in older men. More research is may be caused by menopause or by the aging process. needed to examine the effects of hormone replacement in Endocrine changes during menopause include an early older men; currently neither the potential benefits nor the drop in AMH and inhibin, followed by increases in FSH II. SEXUAL DIFFERENTIATION AND DEVELOPMENT 130 7. REPRODUCTIVE AGING BOX 7.2 T H E E V O L U T I O N O F M E N O PAU S E I N H U M A N S Human females are unique among mammals in that ­ owever, risking death during childbirth might jeop- H the ovaries stop functioning after about 50 years, at meno- ardize the well-being of her existing older children by pause, which is often followed by a long postreproductive abruptly ending her continuing care of them. The increas- life. Only a very few other mammals undergo menopause ing possibility of unsuccessful pregnancies or nursing (e.g. the short-finned pilot whale, the African elephant, and difficulties in older mothers would also drain important African chimpanzee). There are two general ideas about maternal resources. The trade-off may favor nurturing her the presence of menopause in humans: (1) it is a deleteri- existing children and foregoing additional pregnancies. ous effect of civilization or (2) it is an adaptive trait in our A third adaptive a­ dvantage of menopause is related to this species that evolved under the forces of natural selection. concept. The idea is that older females could contribute The idea that menopause is a deleterious condition is more of their genes to the population by investing their ­inspired by the fact that the risk of some life-threatening behavioral energy in kin, especially their grandchildren. disorders such as breast cancer, osteoporosis, and cardio- This would have been their “best” evolutionary choice at vascular disease increases markedly after menopause, an older age. This is called the grandmother hypothesis and when the ovaries stop producing estrogen. This theory is currently the most prevalent hypothesis about the evo- says that menopause is a condition of civilization result- lution of human menopause. Older women who help their ing from the increase in life expectancy, which in turn is children care for their own offspring would allow their caused by better sanitation, nutrition, and healthcare in the daughters (and perhaps daughters-in-law) to have more ­modern world. Implied is that our hunter-gatherer female children. This would increase a grandmother’s own evo- ancestors died on average much earlier than the 50 years lutionary success. Grandmothers even today often care for it would have taken for their ovaries to run out of follicles. their grandchildren and perform duties perhaps similar Studies of the bones of our hunter-gatherer ancestors have in general to our hunter-gatherer ancestors, e.g. gathering suggested that most did not live past their thirties, which food, patrolling against danger, assigning tasks, nurturing supports the aforementioned theory. However, older skel- (holding and rocking), assessing, coaching, caretaking, and etons do not preserve as well, and it is now believed from managing. Our ancestral grandmothers may have helped studies of present hunter-gatherers that a short average their children, and therefore their grandchildren, by par- life span does not mean that no postmenopausal women ticipating in foraging and hunting activities. In t­oday’s were present. In fact, in present-day hunter-gatherers the modern world, they can watch the grandchildren while life expectancy from birth averages in the thirties, but the their parents work. In this and other ways, g ­ randmothers average life span for women who have already reached can assist in passing on their genes to future generations, age 45 is 50–60. And this is an average, so there are many the measure of evolutionary success. women who live past their seventies. The lower average What about older men? As you know, the reproduc- life expectancy from birth is because many children die tive system of older men does not suddenly cease to func- before age 15 in present hunter-gatherer cultures, so there tion as it does in women. Instead, andropause in men probably were many women in our ancestors who were involves a slow, highly variable decline in sperm quality postmenopausal, and menopause is not simply an artifact and quantity as well as plasma testosterone levels. Nev- of prolonging life span in modern societies. ertheless, men of our hunter-gatherer ancestors probably Instead, menopause may have evolved as an adaptive lived as long as women, and there must have been an age trait in our species. What might be the adaptive a­ dvantage period when they could “help their genetic success” by of menopause? First, it limits the ovulation of o ­ ocytes assisting in the care of their grandchildren through some with chromosomal abnormalities, which increase with of the same activities as older women instead of going on age in humans. This argument is challenged by the fact relatively unsuccessful hunts. In fact, this is so in present- that most older mothers have genetically normal children day hunter-gatherer societies. Perhaps an additional im- despite the increased risk of chromosomal ­errors. Second, portant role of elders of both sexes was as a repository of menopause ensures that mothers are young enough to information critical to the survival of the group, such as withstand the stresses of pregnancy, birth, and child care. how to survive a sporadic climatic event that may occur One might a­ rgue that any chance to have additional off- only once a lifetime. So perhaps there should also be a spring would increase a woman’s evolutionary success. “grandfather hypothesis.” II. SEXUAL DIFFERENTIATION AND DEVELOPMENT  Summary 131 and LH and a steep decline in estrogen; the loss of estro- Hassoid, T., Hunt, P., 2009. Maternal age and chromosomally abnor- gen probably causes most of the menopausal symptoms. mal pregnancies: what we know and what we wish we knew. Curr. Opin. Pediatr. 21, 703–708. Estrogen replacement therapy relieves the symptoms of Hawkes, K., 2003. Grandmothers and the evolution of human longev- menopause but may increase the risk of breast, endome- ity. Am. J. Hum. Biol. 15, 380–400. trial, and ovarian cancer, as well as cardiovascular dis- Holman, D.J., Wood, J.W., 2001. Pregnancy loss and fecundability in ease. This treatment, however, lowers the risk of bone women. In: Ellison, P. (Ed.), Reproductive Ecology and Human fractures in postmenopausal women. Evolution, Aldine de Gruyter, New York. Hooper, L., et al., 2009. Effects of soy proteins and isoflavones on Women differ from most other vertebrates in that they ­circulating hormone concentrations in pre- and post-menopausal live for a significant portion of their lives postreproduc- women: a systematic review and meta-analysis. Hum. Reprod. tively. The evolution of menopause in humans may be ­Update 15, 423–440. related to the role of grandmothers in human societies Johnson, J., et al., 2004. Germline stem cell and follicular renewal in the (see Box 7.2). postnatal mammalian ovary. Nature 428, 145–150. Jordan, V.C., 1998. Designer estrogens. Sci. Am. 279 (4), 60–69. The testes of older men may decline in function, and Kong, A., et al., 2012. Rate of de novo mutations and the importance of the resultant hormonal changes can influence some men father’s age to disease risk. Nature 488, 471–475. physiologically and psychologically, a process called Lacey, J.V., et al., 2002. Menopausal hormone replacement therapy and andropause. Treatment with testosterone can reverse risk of ovarian cancer. J. Am. Med. Assoc. 288, 334–341. some of these symptoms, but more research must be Leidy, L.E., 1999. Menopause in evolutionary perspective. In: ­Trevathan, W.R. (Ed.), Evolutionary Medicine, Oxford Univ. Press, done to understand the potential benefits and risks of New York, pp. 407–428. ART. Older paternal age is associated with a higher rate Marlowe, F., 2000. The patriarch hypothesis: an alternative explanation of miscarriage and of some neurological disorders in the of menopause. Hum. Nat. 11, 27–42. offspring. Orwell, E.S., Klein, R.F., 1995. Osteoporosis in men. Endocr. Rev. 16, 87–116. Peccei, J.S., 2000. Genetic correlation between ages of menarche and menopause. Hum. Nat. 11, 43–63. Further Reading Perls, T.T., et al., 1997. Middle-aged mothers live longer. Nature 389, 133. Pietschmann, P., et al., 2009. Osteoporosis: an age-related and gender- Advanced Reading specific disease—a mini-review. Gerontology 55, 3–12. Blurton Jones, N.G., et al., 2002. Antiguity of postreproductive life: are Rashidi, A., Shanley, D., 2009. Evolution of the menopause: life histo- there modern impacts on hunter-gatherer postreproductive life ries and mechanisms. Menopause Int. 15, 26–30. spans? Am. J. Hum. Biol. 14, 184–205. Rossmanith, W.G., Ruebberdt, W., 2009. What causes hot flushes? The Broekmans, F.J., et al., 2009. Ovarian aging: mechanisms and clinical neuroendocrine origin of vasomotor symptoms in the menopause. consequences. Endocrine. Rev. 30, 465–493. Gynecol. Endocrinol. 25, 303–314. Bukovsky, A., et al., 2005. Oogenesis in adult mammals, including Rossouw, et al., 2002. Risks and benefits of estrogen plus progestin ­humans: a review. Endocrine 26, 301–316. in healthy postmenopausal women: principal results from the Burger, H., 2008. The menopausal transition—endocrinology. J. Sex. women’s health initiative randomized controlled trial. J. Am. Med. Med. 5, 2226–2273. ­Assoc. 288, 321–333. Butts, S.F., Seifer, D.B., 2009. Racial and ethnic differences in reproduc- Schmidt, P.J., Rubinow, D.R., 2009. Sex hormones and mood in the peri- tive potential across the life cycle. Fertil. Steril. 93, 681–690. menopause. Ann. N.Y. Acad. Sci. 1179, 70–85. Caspari, R., Lee, S., 2004. Older age becomes common late in evolution. Sievert, L.L., et al., 2001. Marital status and age at natural menopause: Proc. Natl. Acad. Sci. USA 101, 10895–10900. considering pheromonal influence. Am. J. Hum. Biol. 13, 479–485. Cohen, J., 2002. Sorting out chromosome errors. Science 296, 2164–2166. Sievert, L.L., 2001. Aging and reproductive senescence. In: Ellison, De la Rochebrochard, E., Thonneau, P., 2002. Paternal age and maternal P.T. (Ed.), Reproductive Ecology and Human Evolution, Aldine de age are risk factors for miscarriage: results of a multicentre Euro- ­Gruuyter, New York, pp. 267–292. pean study. Hum. Reprod. 17, 1649–1656. Simon, H.B., 1999. Longevity: the ultimate gender gap. Sci. Am. 10 (2), Enserink, M., 2002. The vanishing promises of hormone replacement. 106–112. Science 297, 325–326. Swerdloff, R.S., et al., 1992. Effect of androgens on the brain and other Forbes, L.S., 1997. The evolutionary biology of spontaneous abortion in organs during development and aging. Psychoneuroendocrinology humans. Trends Ecol. Evol. 12, 446–450. 17, 375–383. Genazzani, M.C., et al., 2009. Menopausal hot flashes: still an undis- Tenover, J.S., 2003. Declining testicular function in aging men. Int. J. covered territory. Menopause 16, 851–853. Impot. Res. (Suppl. 4), S3–S8. Hall, J.E., 2007. Neuroendocrine changes with reproductive aging in Travis, J., 2000. Boning up: turning on cells that build bone and turning women. Semin. Reprod. Med. 25, 344–351. off cells that destroy it. Sci. News 157, 41–43. II. SEXUAL DIFFERENTIATION AND DEVELOPMENT