**Menopause in Nonhuman Primates: A Comparative Study with Humans**

María de Jesús Rovirosa-Hernández, Marisela Hernández González, Miguel Ángel Guevara-Pérez, Francisco García-Orduña, Abril de los Ángeles Aguilar-Tirado, Abraham Puga-Olguín and Brisa Patricia Vásquez-Domínguez

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69657

### **Abstract**

Although menopause is a phenomenon predominantly studied in humans or laboratory animals, this chapter discussed the case of nonhuman primates (NHPs), not only with the objective of employing them as study models but also to better understand phylogenetic divergence among species. Those taxonomic differences are reflected in reproductive processes that may be similar to those of human beings, with the presence of a defined cycle or periods of estrus, but perhaps at different ages as well, where menopause plays a crucial role. First, it is important to delimit the concept of menopause by considering its anatomical, physiological, and biochemical parameters, including the cessation of menstrual bleeding or perineal swelling—when present—or follicular depletion and hormonal changes. Thus, the aim of this chapter is to discuss some of the similarities between NHPs and human females, during the menopause period. Studying these phenomena should help us achieve a better understanding of the social, physiological, and environmental factors without adopting any particular cultural view of menopause.

**Keywords:** nonhuman primate, ovarian cycle, reproductive cessation, new world monkeys, old world monkeys

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Menopause is a process of the reproductive aging [1] manifested in the depletion of ovarian follicles, the reduction of ovarian hormones to castration levels, and the increase in the concentration of serum gonadotropins [2]. In human beings, this process occurs in midlife, heralded by the gradual disappearance of menstrual cycles accompanied by the end of reproductive capacity, which correlates with functional and structural changes in the hypothalamic-pituitary-ovarian axis [3].

This process is not exclusive to humans, for it also occurs in all iteroparous organisms that exhibit declining fertility as a function of general senescence [4]. However, in contrast to human beings, nonhuman primates (NHPs) and even longer lived species like tortoises, elephants, and whales retain their capacity to reproduce until relatively advanced age [5]. Studies in NHPs, such as monkeys and apes, both in the wild and in conditions of captivity, have reported menopause as a physiological phenomena [6–8], but they clearly show that the reproductive changes observed in NHPs differ from those of human menopause, at least from a perspective of comparative life history [6]. This is because most of the oldest individuals in all wild species studied showed no signs of ovarian failure, while studies of captive primate species have observed that 67% of old females continued reproducing throughout their lives [7].

It has been suggested that the differences between the human fertility pattern and those of other NHPs are evident in the maximum age of reproduction and mean life expectancy at maturity of both. This refers to the fact that human beings have an early fertility peak that begins to decrease when they are in their mid-1920s, followed by a general decline and then a steep drop that normally begins around age 35; being this age the specific moment fertility functions of NHPs as macaques remain relatively constant over a long period, terminating abruptly only a few years before age death [9].

NHPs are used in medical and scientific research due to their similarities in physiology, neuroanatomy, reproduction, development, cognition, and social complexity to humans, which reflect their close phylogenetic relationship between NHPs and human beings. Primates are divided phylogenetically into strepsirrhines (galagos, lorises, and Malagasy lemurs) and haplorhines (tarsiers and anthropoids). There are three major branches of extant anthropoids or higher primates: the Platyrrhini or New World monkeys (South and Central America) and two groups of Catarrhini (the Cercopithecoids or Old World monkeys (Africa, Europe, and Asia) and Hominoids (Apes and human beings)) (**Figure 1**) [10].

The aim of the present chapter is to discuss and analyze some similarities between female NHPs and human females during natural or surgically induced menopause, since expanding our knowledge of this phenomenon in mammals with such a close phylogenetic relationship so to human beings should lead to a more comprehensive understanding of this biological process.

Menopause in Nonhuman Primates: A Comparative Study with Humans http://dx.doi.org/10.5772/intechopen.69657 27

**1. Introduction**

26 A Multidisciplinary Look at Menopause

lamic-pituitary-ovarian axis [3].

throughout their lives [7].

process.

abruptly only a few years before age death [9].

Asia) and Hominoids (Apes and human beings)) (**Figure 1**) [10].

Menopause is a process of the reproductive aging [1] manifested in the depletion of ovarian follicles, the reduction of ovarian hormones to castration levels, and the increase in the concentration of serum gonadotropins [2]. In human beings, this process occurs in midlife, heralded by the gradual disappearance of menstrual cycles accompanied by the end of reproductive capacity, which correlates with functional and structural changes in the hypotha-

This process is not exclusive to humans, for it also occurs in all iteroparous organisms that exhibit declining fertility as a function of general senescence [4]. However, in contrast to human beings, nonhuman primates (NHPs) and even longer lived species like tortoises, elephants, and whales retain their capacity to reproduce until relatively advanced age [5]. Studies in NHPs, such as monkeys and apes, both in the wild and in conditions of captivity, have reported menopause as a physiological phenomena [6–8], but they clearly show that the reproductive changes observed in NHPs differ from those of human menopause, at least from a perspective of comparative life history [6]. This is because most of the oldest individuals in all wild species studied showed no signs of ovarian failure, while studies of captive primate species have observed that 67% of old females continued reproducing

It has been suggested that the differences between the human fertility pattern and those of other NHPs are evident in the maximum age of reproduction and mean life expectancy at maturity of both. This refers to the fact that human beings have an early fertility peak that begins to decrease when they are in their mid-1920s, followed by a general decline and then a steep drop that normally begins around age 35; being this age the specific moment fertility functions of NHPs as macaques remain relatively constant over a long period, terminating

NHPs are used in medical and scientific research due to their similarities in physiology, neuroanatomy, reproduction, development, cognition, and social complexity to humans, which reflect their close phylogenetic relationship between NHPs and human beings. Primates are divided phylogenetically into strepsirrhines (galagos, lorises, and Malagasy lemurs) and haplorhines (tarsiers and anthropoids). There are three major branches of extant anthropoids or higher primates: the Platyrrhini or New World monkeys (South and Central America) and two groups of Catarrhini (the Cercopithecoids or Old World monkeys (Africa, Europe, and

The aim of the present chapter is to discuss and analyze some similarities between female NHPs and human females during natural or surgically induced menopause, since expanding our knowledge of this phenomenon in mammals with such a close phylogenetic relationship so to human beings should lead to a more comprehensive understanding of this biological

**Figure 1.** Taxonomic classification of extant primates with branch lengths in millions of years. Representative genus is shown in brackets (modified from Ref. [10]).

### **2. Reproductive cycles in nonhuman primate females and their relation with cycles in human beings**

For many mammals, estrus is not only confined to a brief portion of the reproductive cycle that is characterized by an increase in attractivity and in the proceptive and receptive behaviors of females but is also strictly seasonal. In NHPs the reproductive cycles occur for only a few weeks of the year, as occurs among Madagascar prosimians, such as the sifakas. In some New World primates, such as squirrel monkeys, sexual cycles occur only during 3 months of the year [11], but many catarrhine primates do not follow this strict pattern circumscribed by the estrous period [12]. The literature mentioned that apes, human beings, and many monkeys have reproductive cycles that differ in two ways: first, the cycles include menstruation, a cyclical sloughing of the uterine lining. Second, there is greater flexibility in the time of proceptive and receptive behaviors with a longer duration of estrus [13]. Apes and Old World monkeys, meanwhile, exhibit menstrual cycles that range from 25 to 35 days similar to those human females. Also in NHPs, mating activity is not restricted to the periovulatory period as occurs in other mammals since female receptivity is not under strict control of ovarian hormones, but is more closely related to the social context, also as in human beings [14]. Finally, circulating steroid hormones reflect the process of ovulation and ovarian cycling [15].

### **2.1. Ovarian cycle in nonhuman primates**

Ovarian cycles in primates begin with a follicular phase during which the follicle matures, follicular secretion of estrogen increases, and the circulating concentration of progesterone (P4 ) decreases [16]. In most primates, only one follicle ovulates in each cycle. It emerges during the mid-follicular phase and inhibits maturation of other follicles by secreting large amounts of estrogen that, in turn, reduce concentrations of the follicle-stimulating hormone (FSH) below the threshold level required for maturation of early antral follicle [17]. Second, ovulation occurs immediately after the follicular phase, and this maintains high circulating concentrations of estrogens from the mature follicle while exerting positive feedback on the hypothalamus and pituitary that triggers secretion of the gonadotropin-releasing hormone (GnRH), as well as FSH and luteinizing hormone (LH). The increased LH reaches the ovaries where it causes the follicle to rupture [18]. Third, during the luteal phase, the concentration of P4 rises, but that of estrogens declines. Fertilization can take place during the early luteal phase of the cycle only during the first 24 h after ovulation. This is because the oocyte has a short life span. If the ovum is fertilized, then the corpus luteum does not degrade and continues to secrete P4 until the placenta develops [19].

Some of these processes are similar to the ovarian cycles in the human beings [20]; however, studies have found that in all primate species studied, follicular development, ovulation, and corpus luteum formation occur spontaneously and independent of mating-induced stimuli [21]. Also, NHPs have been shown to have extended ovarian cycles, especially prolonged luteal phases, compared to those of other mammals [22]. Also, the duration of the follicular and luteal phases differs among NHPs. Cycle lengths vary among different primate groups: in prosimians, from 30 to 50 day; in New World monkeys, from 16 to 30 days; in Old World monkeys, from 24 to 35 days; in lesser apes, from 20 to 30 days; and in great apes—including humans—from 25 to 50 days [14, 15, 21, 23]. In contrast, squirrel monkeys have a mean cycle length of just 7–12 days, with a follicular phase of about 5 days [24].

Menstruation appears to be absent in all prosimians and possibly in tarsiers, presumably associated with the noninvasive form of placentation characteristic of these primates [21]. However, menstruation does occur in most Old World monkeys and apes, as well as in several New World monkeys [25], and prosimians may be considered to have an estrous cycle, because they exhibit distinct cyclical changes in relation to sexual receptivity, with a peak during the periovulatory period. Finally, many New World monkeys do not exhibit either menstruation or strict estrous cyclicity [20].

### **2.2. Ovarian cycle in humans**

In human beings menstrual bleeding is the visible sign of cyclicity; it has a length of 3–6 days and occurs at the end of the luteal phase and the beginning of the follicular. While fertile phase has a length of 5 days and is associated with the end of follicular phase and an increase of estradiol (E2 ) before ovulation, during this period conception can occur. Recent studies have found that human females possess dual sexuality, which consists of a fertile phase where they are more sexually attractive to men and a phase extended (non-fertile), which presents a motivation or interest in sex with the aim of obtaining some benefits, without conception occurring [26].

### **2.3. Reproductive aging**

)

rises, but that of estrogens

until the placenta develops [19].

monkeys, meanwhile, exhibit menstrual cycles that range from 25 to 35 days similar to those human females. Also in NHPs, mating activity is not restricted to the periovulatory period as occurs in other mammals since female receptivity is not under strict control of ovarian hormones, but is more closely related to the social context, also as in human beings [14]. Finally,

Ovarian cycles in primates begin with a follicular phase during which the follicle matures, follicular secretion of estrogen increases, and the circulating concentration of progesterone (P4

decreases [16]. In most primates, only one follicle ovulates in each cycle. It emerges during the mid-follicular phase and inhibits maturation of other follicles by secreting large amounts of estrogen that, in turn, reduce concentrations of the follicle-stimulating hormone (FSH) below the threshold level required for maturation of early antral follicle [17]. Second, ovulation occurs immediately after the follicular phase, and this maintains high circulating concentrations of estrogens from the mature follicle while exerting positive feedback on the hypothalamus and pituitary that triggers secretion of the gonadotropin-releasing hormone (GnRH), as well as FSH and luteinizing hormone (LH). The increased LH reaches the ovaries where it causes the follicle

declines. Fertilization can take place during the early luteal phase of the cycle only during the first 24 h after ovulation. This is because the oocyte has a short life span. If the ovum is fertilized, then

Some of these processes are similar to the ovarian cycles in the human beings [20]; however, studies have found that in all primate species studied, follicular development, ovulation, and corpus luteum formation occur spontaneously and independent of mating-induced stimuli [21]. Also, NHPs have been shown to have extended ovarian cycles, especially prolonged luteal phases, compared to those of other mammals [22]. Also, the duration of the follicular and luteal phases differs among NHPs. Cycle lengths vary among different primate groups: in prosimians, from 30 to 50 day; in New World monkeys, from 16 to 30 days; in Old World monkeys, from 24 to 35 days; in lesser apes, from 20 to 30 days; and in great apes—including humans—from 25 to 50 days [14, 15, 21, 23]. In contrast, squirrel monkeys have a mean cycle

Menstruation appears to be absent in all prosimians and possibly in tarsiers, presumably associated with the noninvasive form of placentation characteristic of these primates [21]. However, menstruation does occur in most Old World monkeys and apes, as well as in several New World monkeys [25], and prosimians may be considered to have an estrous cycle, because they exhibit distinct cyclical changes in relation to sexual receptivity, with a peak during the periovulatory period. Finally, many New World monkeys do not exhibit either

In human beings menstrual bleeding is the visible sign of cyclicity; it has a length of 3–6 days and occurs at the end of the luteal phase and the beginning of the follicular. While fertile phase

circulating steroid hormones reflect the process of ovulation and ovarian cycling [15].

to rupture [18]. Third, during the luteal phase, the concentration of P4

length of just 7–12 days, with a follicular phase of about 5 days [24].

menstruation or strict estrous cyclicity [20].

**2.2. Ovarian cycle in humans**

the corpus luteum does not degrade and continues to secrete P4

**2.1. Ovarian cycle in nonhuman primates**

28 A Multidisciplinary Look at Menopause

Female reproductive output differs markedly in relation to species and time. As females of many species age, a period of reproductive instability with perimenopausal-like hormonal changes has been observed. Like many other mammals, NHP females show fertility parameters that are related to age [7]. Anovulation, insufficient luteolysis, and impairment of gestation and lactation processes all become more common toward the end of reproductive life [27]. Female reproductive senescence differs among mammalian taxonomic groups. For example, in NHPs, the end of reproductive life is characterized by the loss of the follicular pool, whereas in rodents, variations are seen in the size of the follicular pool that remains at the end of reproductive life. In humans, experiencing follicular depletion early in the maximum life span is not usual; rather, it is the result of an extended period of altered hormonal environments. These alterations may be caused by reduced circulating estrogens, P4 , and inhibin, resulting in elevated gonadotropin concentrations (GTHs) for a time, followed by their decline [28]. Monkeys and apes also experience follicular depletion and associated hormonal alterations [8, 29], but the stage of life at which these occur is generally later than in humans. Some reports on lemurs and callitrichids indicate an age-related decline in reproduction in many species that is reflected in diminished reproductive success [30]. Older female sifakas (*Propithecus edwardsi*), a Madagascar lemur, show decreased rates of infant survival, and studies have affirmed that this effect can be attributed to the females' deteriorating dentition resulting in inability to support lactation [31]. This indicates that reduced fertility in old age does not, in and of itself, reflect impaired neuroendocrine or gonadal function [20].

Considering the taxonomic scale of primates, we can observe the variability in physiological characteristics, like it is reflected in aging process. As much NHPs get closer to human beings, more similarities are found, going through estrous cycles for strepsirrhines (galagos, lorises, and lemurs), to ovarian cycles, and hormonal profiles similar to human being females, in great apes (orangutans, gorillas, and chimpanzees), and Old World monkeys (macacos and baboons). Also in both cases, at the end of their reproductive life, different physiological and hormonal changes occur, which are associated with the loss of ovarian function that are characteristic of aging, where this gives us the opportunity to study in a comparative way different alterations that could be related to the absence of ovarian hormones.

### **3. Menopause in** *Homo sapiens* **females and nonhuman primates**

Menopause has been defined as a series of changes in the termination of reproductive viability, of which the discontinuation of menstruation is but one component. Menstrual bleeding is a marker of the ovarian and neuroendocrine phenomena of reproductive viability in humans [32], but not all NHPs exhibit this [24]. Consequently, menopause must encompass hormonal, physiological, and biochemical changes that play essential roles in the cessation of ovarian cyclicity, regardless of whether menstrual bleeding is present. However, Walker and Herndon [1] have defined menopause in NHPs as the permanent, non-pathological, age-associated cessation of ovulation, so to infer this event would require considering such biological parameters as menstrual bleeding, perineal swelling, follicular depletion, and hormonal changes.

Some species of NHPs seem to present processes that are quite similar to what human females experience during menopause, but differences also exist, such as the shorter postmenopausal life span and differences in the timing of hormonal changes during the menopausal transition [33]. It is important to consider the time of menopause relative to the average and maximum life span of individuals. For example, humans may be unique among primates in that they have a long post-reproductive survival potential [34]. In human females, the reproductive function does not begin with puberty nor does it end with menopause at a certain chronological age. Instead, both of these are dynamic periods for the reproductive axis, during which development or senescence occurs relatively rapidly. In fact, the reproductive axis ages to a nonfunctional state (menopause) much earlier than other organs, while the reproductive system reaches the point of failure at a relatively young average age of 51 + 8 years [35]; considering that the maximum span for humans is around 80 years, they spend nearly 35% of her life in a post-reproductive state and in very special cases to 60% (122 years). Also, there are significant differences between species of NHPs and humans in terms of life span. For example, the life span of animals after menopause is short compared to humans, as they usually die not long after menopause [1].

Human females are born with a finite number of oocytes; thus, reproductive aging entails the steady loss of these oocytes through atresia and ovulation, processes that do not necessarily occur at constant rates [36]. Peak fertility in humans occurs in the mid-20s, after which it declines steadily until a steep decrease begins after age 35 [37]. This decline in fertility occurs despite normal hormone secretion by the ovaries of "older" reproductive-age humans, which continues until 3–4 years prior to menopause [38].

In spite of the wide age range at which ovarian dysfunction and reproductive failure occur in these species, the sequence of terminal events is fairly predictable. At the beginning of the process, the menstrual cycle length is shortened due to early follicular development and ovulation [39], which reduces fertility (premenopause). This is followed by disruption of regular menstrual cyclicity (perimenopause) and, finally, complete ovarian failure (menopause). Studies have observed that perimenopause is an indication that the number of remaining ungrown ovarian follicles has dropped below a critical threshold [40]. The period of transition from the reproductive phase to the nonreproductive state is called climacteric. Finally, postmenopause is the period following climacteric and occurs when the hormonal instability that characterizes perimenopause is replaced by the relative stability of the post-reproductive life stage when the reproductive function has ceased [41].

Declining fertility with age is manifested more commonly in monkeys and apes, to the point that some females cease to reproduce altogether before they die. Some reports on Old World monkeys in the wild mention that old toque macaque (*Macaca sinica*) and gray-cheeked mangabey (*Lophocebus albigena*) females no longer breed, perhaps due to increasingly long birth intervals that terminate with death or the cessation of ovulation [42]. In contrast, NHP females living in captivity may show life cycles marked by irregular and lengthened menstrual cycles, reduced estrogen levels, very long birth spacing and, in a few cases—such as chimpanzees total cessation of ovulation [8, 43]. In captive rhesus monkeys (*Macaca mulatta*), menstruation ends at approximately 25 years of age [44], and their maximum life span is around 30 years [45]; thus, this species may have a maximum post-reproductive life span of approximately 20%, similar to what happens in chimpanzees (*Pan troglodytes*). There are also differences in life span among species of NHPs and humans. For example, the life span of other animals after menopause is short compared to humans, since they usually die after only a short time, while humans have an extended postmenopausal life expectancy [1].

humans [32], but not all NHPs exhibit this [24]. Consequently, menopause must encompass hormonal, physiological, and biochemical changes that play essential roles in the cessation of ovarian cyclicity, regardless of whether menstrual bleeding is present. However, Walker and Herndon [1] have defined menopause in NHPs as the permanent, non-pathological, age-associated cessation of ovulation, so to infer this event would require considering such biological parameters as menstrual bleeding, perineal swelling, follicular depletion, and

Some species of NHPs seem to present processes that are quite similar to what human females experience during menopause, but differences also exist, such as the shorter postmenopausal life span and differences in the timing of hormonal changes during the menopausal transition [33]. It is important to consider the time of menopause relative to the average and maximum life span of individuals. For example, humans may be unique among primates in that they have a long post-reproductive survival potential [34]. In human females, the reproductive function does not begin with puberty nor does it end with menopause at a certain chronological age. Instead, both of these are dynamic periods for the reproductive axis, during which development or senescence occurs relatively rapidly. In fact, the reproductive axis ages to a nonfunctional state (menopause) much earlier than other organs, while the reproductive system reaches the point of failure at a relatively young average age of 51 + 8 years [35]; considering that the maximum span for humans is around 80 years, they spend nearly 35% of her life in a post-reproductive state and in very special cases to 60% (122 years). Also, there are significant differences between species of NHPs and humans in terms of life span. For example, the life span of animals after menopause is short compared to humans, as they usu-

Human females are born with a finite number of oocytes; thus, reproductive aging entails the steady loss of these oocytes through atresia and ovulation, processes that do not necessarily occur at constant rates [36]. Peak fertility in humans occurs in the mid-20s, after which it declines steadily until a steep decrease begins after age 35 [37]. This decline in fertility occurs despite normal hormone secretion by the ovaries of "older" reproductive-age humans, which

In spite of the wide age range at which ovarian dysfunction and reproductive failure occur in these species, the sequence of terminal events is fairly predictable. At the beginning of the process, the menstrual cycle length is shortened due to early follicular development and ovulation [39], which reduces fertility (premenopause). This is followed by disruption of regular menstrual cyclicity (perimenopause) and, finally, complete ovarian failure (menopause). Studies have observed that perimenopause is an indication that the number of remaining ungrown ovarian follicles has dropped below a critical threshold [40]. The period of transition from the reproductive phase to the nonreproductive state is called climacteric. Finally, postmenopause is the period following climacteric and occurs when the hormonal instability that characterizes perimenopause is replaced by the relative stability of the post-reproductive

Declining fertility with age is manifested more commonly in monkeys and apes, to the point that some females cease to reproduce altogether before they die. Some reports on Old World

hormonal changes.

30 A Multidisciplinary Look at Menopause

ally die not long after menopause [1].

continues until 3–4 years prior to menopause [38].

life stage when the reproductive function has ceased [41].

The perimenopause period is also highly variable in human beings, as age at the onset of this period ranges from the mid-1930s to the early 1950s [46]. This wide range impedes gaining a better understanding of the mechanisms that control the onset of menopause in humans. In NHPs, this is even more difficult, since reproductive cessation occurs so late in their life span that relatively few individuals actually live to those ages. However, there are data that support the existence of a perimenopausal in NHPs [33, 47–49], a condition that indicates a transitional stage between fertility and age-associated infertility. Also, it has been reported that patterns of vaginal bleeding and serum hormone profiles of macaques in the third decade of life are similar to those described for peri- and postmenopausal human [29].

Although originally the term menopause was coined in human being context, there are some approaches toward NHPs, which let us build it, considering not only the cessation of menstrual bleeding but also other changes, such as the cessation of perineal swelling, follicular depletion, and hormonal-associated changes. So this term has been adapted focusing in the physiological characteristics of each species. By other hand the life span between species should be considered, because unlike human beings, some species usually transit immediately from the reproductive end to death. Therefore, it is of great importance to know what are the differences between species that could help us identify the age of onset of menopause according to the species of the study, and, since this information, it will depend on whether or not our data can be extrapolated to the human.

### **4. Menopause in nonhuman primates in wild versus captive conditions**

Specific studies over physiological mechanisms that govern the timing of menopause in wild NHPs are scarce [42, 50], because many factors could mask the accuracy of these results, including the ages of subjects—which often must be estimated [51]—predation pressures [52], limited survivability [23], infant mortality [53], food availability and nutrition [54], and social dynamics [55]. Therefore, this information is taken as complementary to data derived from captive animals [1].

### **4.1. Macaques (***Macaca* **spp.)**

Hodgen et al. [29] reported that female rhesus monkeys (*Macaca mulatta*), in captivity and at least 22 years of age, showed true menopause, confirmed by circulating levels of pituitary and ovarian hormones and the pattern of vaginal bleeding. Female rhesus monkeys older than 22 years are considered aged, as the maximum average life span for this species is estimated at 30 years [44, 45]. Hence, these females are close to the end of their life span, compared to humans, who are considered as "aged" at around 75 years.

Graham et al. [8] examined the reproductive history and histology of pigtail macaques (*Macaca nemestrina*) by observing females divided into three age classes (4, 10, and 20 years). They reported that one female over 20 years of age showed functional, hormonal, and morphological characteristics of human menopause (i.e., complete follicular depletion, absence of luteal tissue, amenorrhea, increased LH levels, atrophic uterus, and vagina). Miller et al. [56], meanwhile, reported an age-associated decline in fertility in pigtail macaques, similar to the findings for *Macaca sylvanus* reported by Paul et al. [57].

Walker's study [47], of 15 female *Macaca mulatta* aged 8–34 years, was designed to characterize the endocrine and menstrual changes associated with menopause in this species. Findings indicate that females aged 24–26 years were in transition to menopause, evidenced by elevated LH concentrations consistent with a low E2 concentration and no indication of bleeding menstrual. Also, the histological analysis of their ovaries showed little or no evidence of follicular activity. Finally, the females aged 27–34 years clearly showed a postmenopausal process, marked by high LH concentrations and uniformly low E2 concentrations. This finding was corroborated by Gilardi et al. [48], who suggest that in female rhesus monkeys menopause does not occur until the second half of the third decade of life. Recent studies have also reported that postmenopausal females show low E2 and P4 levels, high indexes of FSH and LH, and a significant decline in the anti-Mullerian hormone and inhibin B. All these findings indicate that these endocrine parameters may be associated with menopause [49]. On the other hand, Johnson and Kapsalis [58] reported a median age >27 years for menopause in free-ranging rhesus monkeys.

Recent studies have concluded that reproductive senescence correlates with overall health [23]. Gore et al. [59], for example, reported that neuroendocrine changes in senescent rhesus monkeys are consistent with those reported in humans [60] and that ovarian changes are related to menopause [61], thus suggesting that these NHPs undergo ovarian changes as a function of aging, similar to humans [40] and chimpanzee [62]. A study of Japanese macaques (*Macaca fuscata*) reported that in free-ranging individuals, fertility rates diminish at around 25 years of age [63], but those normal menstrual cycles continue when they are in captivity, despite a loss of fertility [64]. Finally, recent studies of cynomolgus monkeys (*Macaca fascicularis*) have shown an endocrine pattern similar to that of humans during the postmenopause period [65].

### **4.2. Great apes**

The menstrual cycles, pregnancy, and genital pathology of common chimpanzees (*Pan troglodytes*) were analyzed to determine the extent of perimenopausal changes in females with aged approximately 35–48 years. However, those analyses showed no clear evidence of menopause, because several females continued cycling until death [8]. But the authors did observe a reduced likelihood of conception in those female chimpanzees, even though they did not "run out" of oocytes before the end of the maximum life span. They concluded that female chimpanzees aged 35 years of age or more show increased reproductive senescence that is quite comparable to what is seen during human climacteric.

**4.1. Macaques (***Macaca* **spp.)**

32 A Multidisciplinary Look at Menopause

humans, who are considered as "aged" at around 75 years.

findings for *Macaca sylvanus* reported by Paul et al. [57].

vated LH concentrations consistent with a low E2

reported that postmenopausal females show low E2

free-ranging rhesus monkeys.

**4.2. Great apes**

process, marked by high LH concentrations and uniformly low E2

Hodgen et al. [29] reported that female rhesus monkeys (*Macaca mulatta*), in captivity and at least 22 years of age, showed true menopause, confirmed by circulating levels of pituitary and ovarian hormones and the pattern of vaginal bleeding. Female rhesus monkeys older than 22 years are considered aged, as the maximum average life span for this species is estimated at 30 years [44, 45]. Hence, these females are close to the end of their life span, compared to

Graham et al. [8] examined the reproductive history and histology of pigtail macaques (*Macaca nemestrina*) by observing females divided into three age classes (4, 10, and 20 years). They reported that one female over 20 years of age showed functional, hormonal, and morphological characteristics of human menopause (i.e., complete follicular depletion, absence of luteal tissue, amenorrhea, increased LH levels, atrophic uterus, and vagina). Miller et al. [56], meanwhile, reported an age-associated decline in fertility in pigtail macaques, similar to the

Walker's study [47], of 15 female *Macaca mulatta* aged 8–34 years, was designed to characterize the endocrine and menstrual changes associated with menopause in this species. Findings indicate that females aged 24–26 years were in transition to menopause, evidenced by ele-

ing menstrual. Also, the histological analysis of their ovaries showed little or no evidence of follicular activity. Finally, the females aged 27–34 years clearly showed a postmenopausal

ing was corroborated by Gilardi et al. [48], who suggest that in female rhesus monkeys menopause does not occur until the second half of the third decade of life. Recent studies have also

LH, and a significant decline in the anti-Mullerian hormone and inhibin B. All these findings indicate that these endocrine parameters may be associated with menopause [49]. On the other hand, Johnson and Kapsalis [58] reported a median age >27 years for menopause in

Recent studies have concluded that reproductive senescence correlates with overall health [23]. Gore et al. [59], for example, reported that neuroendocrine changes in senescent rhesus monkeys are consistent with those reported in humans [60] and that ovarian changes are related to menopause [61], thus suggesting that these NHPs undergo ovarian changes as a function of aging, similar to humans [40] and chimpanzee [62]. A study of Japanese macaques (*Macaca fuscata*) reported that in free-ranging individuals, fertility rates diminish at around 25 years of age [63], but those normal menstrual cycles continue when they are in captivity, despite a loss of fertility [64]. Finally, recent studies of cynomolgus monkeys (*Macaca fascicularis*) have shown an endocrine pattern similar to that of humans during the postmenopause period [65].

The menstrual cycles, pregnancy, and genital pathology of common chimpanzees (*Pan troglodytes*) were analyzed to determine the extent of perimenopausal changes in females

and P4

concentration and no indication of bleed-

concentrations. This find-

levels, high indexes of FSH and

Other studies of common chimpanzees aged approximately 48–50 years and of bonobos pygmy chimpanzees (*Pan paniscus*)—aged approximately 40 years reported that even though the former were extremely aged, they continued to have menstrual cycles and perineal swelling but with increased cycle length. Also, these aged females continue to secrete GnRH in a pulsatile fashion, although the levels of this hormone are higher than younger females [43]. Recent studies by Lacreuse et al. [66] found that many aged chimpanzees continued to menstruate at age 50 or more, but the length of their cycles increased after age 20. Similar results were reported by Videan et al. [67], who concluded that menopause in *Pan troglodytes* occurs at approximately 35–40 years of age. These data concur with the report on wild chimpanzee by Nishida et al. [50]. These authors reported that the females ceased cycling after 30 years of age. On the other hand, Thompson et al. [68] observed that healthy free-ranging chimpanzees remained reproductively viable well past 40 years. They suggested that in *Pan troglodytes*, menopause occurs as a by-product of ill health, interpreting that the onset of menopause may be delayed in relatively healthy, long-lived animals. Studies of female chimpanzees have shown that reproductive aging is similar to that seen in human females, including higher fetal loss as a function of advancing age [69] and the age-related depletion of ovarian follicles [62]. Thus, these studies showed that *Pan troglodyte* females continued cycling into extreme old age, which distinguishes them from human females in terms of menopause.

Other studies in *Pan paniscus* females, aged at least 40 years, showed no external evidence of menstrual cycling preceding death, and hormone levels consistent with clinically observed amenorrhea, but an exaggerated response to the exogenous GnRH challenge. Histological examination of ovaries showed similar characteristics to those described for senile ovarian tissue in humans [43].

Studies of captive orangutan (*Pongo* ssp.) females have reported the endocrine characteristics of their menstrual cycle and similarities to the human cycle [70]. These reports considered births and inter-birth intervals across the life span and demonstrated an age-specific decline in the fertility of captive female orangutans (*Pongo pygmaeus*; [7]). Other studies with wild female Sumatran orangutans (*Pongo abelii*) failed to document menopause, inferred from increased inter-birth intervals in females of estimated age [51]. Interpreting data from wild animals is difficult because of such countervailing factors as female rank, uncertain age, infant mortality, and food availability [1].

An earlier study that described the reproductive physiology of female gorillas (*Gorilla gorilla*) mentioned a correlation of perineal tumescence with circulating hormones and reported a pattern of cyclic hormone secretion similar to that of humans [71]. Recently, fecal hormone determination in two captive female gorillas aged approximately 40 years showed evidence of the protracted luteal phases that are typical of aging human females [72].

Information related to the occurrence of menopause in baboons (*Papio* ssp.) was based on menstrual cycle length, total cessation of cycling that occurs at 26 years of age in captivity [73]. Similar results were reported by Lapin et al. [74], and other studies of wild baboons have reported increased cyclic variability with age and a complete loss of fertility by the age of 25 years. This suggests that baboons undergo age-linked alterations in reproductive function similar to those of humans.

The living conditions of primates have an impact over the animal life span, so the observations in captivity are not always the same as in wild conditions. Although there are some reports about NHP aging process and menopause, they are scarce. Most of the studies report animal physiology and behavior in captivity, because to follow animals in wild by a long period is a very difficult process due to the NHP living conditions.

### **5. Nonhuman primates as a model to study human being menopause**

Due to the biological similarities between human beings and NHPs, the latter have been studied in the search for an adequate model of menopause. However, it is necessary to clearly delimit the similarities and differences among reproductive characteristics, perimenopausal and menopausal changes, and the average life span of different species [1]. Establishing similarities with humans during this search requires considering the characteristics of menopausal processes when animals are in captivity versus those who are free-ranging, in order to avoid the confusions that have led to the assertion that menopause is a uniquely human event [1]. Walker and Herndon [1] suggested that a comparative analysis of female reproductive senescence should focus on the anatomical, physiological, and biochemical changes that are essential to the cessation of ovarian cyclicity, regardless of the presence of menstrual bleeding. There are few reports on menopause in New World primates compared to Old World monkeys, but studies of the latter have observed declines in sexual activity and decreased birth rates. Also, reports on captive apes suggest a long post-reproductive life span, though this has not been confirmed in the wild [30].

Among the different primate taxa, menopause is manifested along an evolutionary continuum: in some species—such as cercopithecines and apes—it is followed by an extended post-reproductive life span, while in others it may presage death. In terms of NHPs as models for menopause, the species that have most often been employed are baboons and chimpanzees. Studies of these primates have attempted to simulate all the consequences that characterize menopause, namely, hormonal and cognitive changes, cardiovascular alterations, and osteoporosis.

Until recently, the occurrence of reproductive termination in NHPs was widely questioned. However, numerous studies have reported that this does indeed occur in several species of Old World monkeys and great apes. Most of this research has been conducted with *Macaca mulatta* [29, 33, 47–49, 59, 61], but other species also experience menopause, including *Pan troglodytes* [43, 62, 67] and *Gorilla gorilla* [27]. For example, the hormonal profiles of peri- and postmenopausal macaques, chimpanzees, and gorillas [1, 61, 67], as well as the age-related decline in the number of primordial follicle in macaques [61] and chimpanzees [62], share many similarities and occur in a pattern like to that of aging women [40]. On the basis of data from various studies, Fedigan et al. [75] affirmed that "from an endocrinological perspective, reproductive decline may well follow a similar pattern in all primates, and we could use cases of individual post-reproductive monkeys and apes as clinical models of the physiological basis for menopause in human being. However, from an evolutionary perspective, these studies fail to demonstrate similarity between reproductive senescence in NHPs and menopause in the human female. Instead, they highlight the critical differences: female macaques and chimpanzees that cease to cycle very close to age at death, whereas human females cease to cycle in middle age; female macaques and chimpanzees cease to cycle on an idiosyncratic basis, whereas human females universally cease to cycle at the average age of approximately 50 years."

Information related to the occurrence of menopause in baboons (*Papio* ssp.) was based on menstrual cycle length, total cessation of cycling that occurs at 26 years of age in captivity [73]. Similar results were reported by Lapin et al. [74], and other studies of wild baboons have reported increased cyclic variability with age and a complete loss of fertility by the age of 25 years. This suggests that baboons undergo age-linked alterations in reproductive function

The living conditions of primates have an impact over the animal life span, so the observations in captivity are not always the same as in wild conditions. Although there are some reports about NHP aging process and menopause, they are scarce. Most of the studies report animal physiology and behavior in captivity, because to follow animals in wild by a long

**5. Nonhuman primates as a model to study human being menopause**

Due to the biological similarities between human beings and NHPs, the latter have been studied in the search for an adequate model of menopause. However, it is necessary to clearly delimit the similarities and differences among reproductive characteristics, perimenopausal and menopausal changes, and the average life span of different species [1]. Establishing similarities with humans during this search requires considering the characteristics of menopausal processes when animals are in captivity versus those who are free-ranging, in order to avoid the confusions that have led to the assertion that menopause is a uniquely human event [1]. Walker and Herndon [1] suggested that a comparative analysis of female reproductive senescence should focus on the anatomical, physiological, and biochemical changes that are essential to the cessation of ovarian cyclicity, regardless of the presence of menstrual bleeding. There are few reports on menopause in New World primates compared to Old World monkeys, but studies of the latter have observed declines in sexual activity and decreased birth rates. Also, reports on captive apes suggest a long post-reproductive life span, though

Among the different primate taxa, menopause is manifested along an evolutionary continuum: in some species—such as cercopithecines and apes—it is followed by an extended post-reproductive life span, while in others it may presage death. In terms of NHPs as models for menopause, the species that have most often been employed are baboons and chimpanzees. Studies of these primates have attempted to simulate all the consequences that characterize menopause, namely, hormonal and cognitive changes, cardiovascular alterations, and osteoporosis. Until recently, the occurrence of reproductive termination in NHPs was widely questioned. However, numerous studies have reported that this does indeed occur in several species of Old World monkeys and great apes. Most of this research has been conducted with *Macaca mulatta* [29, 33, 47–49, 59, 61], but other species also experience menopause, including *Pan troglodytes* [43, 62, 67] and *Gorilla gorilla* [27]. For example, the hormonal profiles of peri- and postmenopausal macaques, chimpanzees, and gorillas [1, 61, 67], as well as the age-related decline in the number of primordial follicle in macaques [61] and chimpanzees [62], share many similarities

period is a very difficult process due to the NHP living conditions.

this has not been confirmed in the wild [30].

similar to those of humans.

34 A Multidisciplinary Look at Menopause

In light of these data, it is clear that regardless of the age at the onset of menopause, there are numerous physiological similarities between the females of NHPs and human females with respect to the gradual decline and eventual cessation of reproductive capacity. For this reason, several authors of excellent reviews [1, 29, 30] have proposed that NHPs provide the most appropriate animal models available for analyzing menopause in human females and the processes associated with it.

Although NHPs present a rich opportunity to study the process of reproductive senescence or menopause (i.e., the permanent, non-pathological, age-associated cessation of ovulation, [1]) and play a unique role in translational science by bridging the gap between basic and clinical research [76], their use as experimental subjects is limited by the lack of available NHPs that are undergoing the perimenopausal transition and natural menopause, their short menopausal compared to that of human being, high costs, and the strict ethical guidelines that researchers must follow when studying them (see Ref. [33, 76]).

Despite these difficulties, the use of NHPs as study models has several advantages. Macaques (*Macaca* spp.), including *Macaca mulatta* and *Macaca fascicularis* monkeys, for example, have been particularly useful due to their availability, moderate size, and ability to adapt to laboratory conditions. Also, approximately 95% of the overall genetic coding sequence of macaques is identical to that of humans [77], and many of their physiological systems are comparable. Finally, because they are relatively long lived, they are effective models for studying a number of diseases and conditions that increase in frequency with aging. These factors explain why female macaques have been the preferred model for examining critical health concerns of human beings, including luteal phase deficiencies and hypothalamic amenorrhea [78], obesity and diabetes [79], cardiovascular diseases [80], osteopenia, osteoporosis [81], osteoarthritis [82], cognitive deficits associated with age [76], and—at least potentially—decreased interest in mating [83].

If a single conclusion can be gleaned from this brief summary, it is that a large number of physiological conditions and pathologies that human beings experience during their lifetime appear to be broadly manifested in primate taxa, though information is lacking in other regards, such as the interaction between deficits in cognitive processes and their effect on the modulation of social and sexual interaction.

Primates are mammals distinguished by their large brains, advanced cognitive abilities, flexible behavior, and sophisticated social systems [84]. For example, chimpanzees have the ability to recognize themselves in a mirror [85] and perform tasks involving concept formation [86]. Moreover, the structure and function of human and NHP brains are very similar. In this regard, we can mention nuclear organization, projection pathways, and innervation patterns [87], as well as similar cortical development and organization [88], including visual cortical functional divisions and prefrontal cortex subdivisions [89] that are critical for cognitive processes [90].

In human beings and NHPs, cognitive and reproductive functions decline gradually with advancing age and more precipitously with the loss of circulating estrogen that occurs during menopause. Cognitive deficits in NHPs can be quantified over their life span using a battery of cognitive tests that are similar to, if not the same as, those used with humans [91]. These include the monkey version of the Wisconsin Card Sorting Test (WCST) [92], which is the gold standard for assessing cognitive flexibility in humans. Using a version of WCST (without the numerosity category), executive function deficits have been reported in both middle-aged and older rhesus monkeys [93], as well as in middle-aged menopausal rhesus monkeys [91]. However, the limited availability of animals of adequate age [33] means that studies with monkeys typically involve only a few animals and use premenopausal ovariectomized subjects rather than naturally menopausal females.

Given the dramatic effects of sex steroids on neuronal morphology and brain activity in regions involved in cognition, one might expect that age-related changes in the endocrine milieu will have important consequences for cognitive functions. In effect, data on aged, naturally or surgically menopausal monkeys indicate that estrogen does indeed modulate a broad range of cognitive domains, such as learning and memory. These effects observed appear to be task specific and sensitive to the time that passed without estrogen prior to estrogen replacement. For example, on the delayed response (DR) task—a test of prefrontal functioning—it was noted that performance was impaired in postmenopausal individuals compared to age-matched premenopausal rhesus monkeys [94]. This result suggests that the absence of estrogen, associated with menopause, could be detrimental to prefrontal functioning.

Although the effects of the menstrual cycle, estrogen withdrawal, and estrogen replacement in young monkeys appear limited to non-mnemonic functions, such as attention or aspects of face processing [95], a broad range of cognitive functions, including memory, are sensitive to estrogen deprivation and replacement in older monkeys [92]. Neurobiological data are consistent with such cognitive findings and demonstrate an array of morphological and physiological changes following ovariectomy and/or estrogen replacement in brain areas that are important for cognition.

Although the specific mechanisms through which estrogens may affect cognition remain to be elucidated, it is clear that these hormones have broad effects on areas of the brain that play key roles in cognitive functions [96]. Estrogen receptors are found in the cerebral cortex, hippocampus, and amygdala in both monkeys [97] and human beings [98]. Estrogens alter the neuronal morphology and physiology of some of these areas [99].

NHPs provide valuable animal models that have significantly advanced our understanding of numerous behavioral and biological phenomena in humans and other primates. Their value as models for studying menopause in humans derives from their common ancestry, as well as a series of hormonal, cognitive, and social influences that are similar to those experienced by human beings. The aging process or menopause has been also explored focusing through the neural basis of cognitive functioning, revealing not only alterations over specific neural systems but also differences in the affectation level among brain regions and neurobiological parameters. Therefore, further research into the interactions among hormones and various neurotransmitter systems could potentially produce improved knowledge of the neural and hormonal bases that comprehend the gamma of alterations that human beings suffer before, during, and after menopause.

### **5.1. Anxiety and depression during natural or surgical menopause of nonhuman primates**

to recognize themselves in a mirror [85] and perform tasks involving concept formation [86]. Moreover, the structure and function of human and NHP brains are very similar. In this regard, we can mention nuclear organization, projection pathways, and innervation patterns [87], as well as similar cortical development and organization [88], including visual cortical functional divisions and prefrontal cortex subdivisions [89] that are critical for cognitive processes [90].

In human beings and NHPs, cognitive and reproductive functions decline gradually with advancing age and more precipitously with the loss of circulating estrogen that occurs during menopause. Cognitive deficits in NHPs can be quantified over their life span using a battery of cognitive tests that are similar to, if not the same as, those used with humans [91]. These include the monkey version of the Wisconsin Card Sorting Test (WCST) [92], which is the gold standard for assessing cognitive flexibility in humans. Using a version of WCST (without the numerosity category), executive function deficits have been reported in both middle-aged and older rhesus monkeys [93], as well as in middle-aged menopausal rhesus monkeys [91]. However, the limited availability of animals of adequate age [33] means that studies with monkeys typically involve only a few animals and use premenopausal ovariectomized sub-

Given the dramatic effects of sex steroids on neuronal morphology and brain activity in regions involved in cognition, one might expect that age-related changes in the endocrine milieu will have important consequences for cognitive functions. In effect, data on aged, naturally or surgically menopausal monkeys indicate that estrogen does indeed modulate a broad range of cognitive domains, such as learning and memory. These effects observed appear to be task specific and sensitive to the time that passed without estrogen prior to estrogen replacement. For example, on the delayed response (DR) task—a test of prefrontal functioning—it was noted that performance was impaired in postmenopausal individuals compared to age-matched premenopausal rhesus monkeys [94]. This result suggests that the absence of

estrogen, associated with menopause, could be detrimental to prefrontal functioning.

Although the effects of the menstrual cycle, estrogen withdrawal, and estrogen replacement in young monkeys appear limited to non-mnemonic functions, such as attention or aspects of face processing [95], a broad range of cognitive functions, including memory, are sensitive to estrogen deprivation and replacement in older monkeys [92]. Neurobiological data are consistent with such cognitive findings and demonstrate an array of morphological and physiological changes following ovariectomy and/or estrogen replacement in brain areas that

Although the specific mechanisms through which estrogens may affect cognition remain to be elucidated, it is clear that these hormones have broad effects on areas of the brain that play key roles in cognitive functions [96]. Estrogen receptors are found in the cerebral cortex, hippocampus, and amygdala in both monkeys [97] and human beings [98]. Estrogens alter the

NHPs provide valuable animal models that have significantly advanced our understanding of numerous behavioral and biological phenomena in humans and other primates. Their value

neuronal morphology and physiology of some of these areas [99].

jects rather than naturally menopausal females.

36 A Multidisciplinary Look at Menopause

are important for cognition.

The decrease in ovarian hormones during natural and surgical menopause is associated with a higher incidence of psychiatric disorders, such as anxiety and depression in vulnerable women, where the decrease of hormones—principally E2 and P4 —can induce neural changes that exert affects on both the emotional and affective levels [100]. In this regard, ovariectomies in NHPs have been used as a model of surgical menopause at the experimental level, given that the absence of certain hormones induced by ovariectomy can reproduce the physiological, emotional, and affective change characteristic of menopause.

At the behavioral level, ovariectomized primates may exhibit anxiety and depression-related behaviors. For example, long-term ovariectomy may increase anxiety in Japanese macaques (*Macaca fuscata*), associated with decreases in such behaviors as positive social contact, dominance, and the time spent receiving grooming. Similarly, temperament tests performed on these individuals show an increase in anxiogenic behavior [101]. Furthermore, ovariectomized pigtail macaques (*Macaca nemestrina*) present higher scratching rates [102], a well-established indicator of anxiety in NHPs, while in Japanese macaques, a reduction in locomotion has been observed after ovariectomy [101], in association with depressive behavior. Therefore, these behavioral alterations are probably due to the absence of ovarian hormones, given that after ovariectomy in rhesus (*Macaca mulatta*) and pigtail macaques a reduction in E2 and P4 concentrations is detected, in relation to increased anxiety [102].

The absence of ovarian hormones in NHPs may also generate neural changes in the brain (**Table 1**). Studies of ovariectomized Japanese monkeys have detected downregulation of estrogen receptor beta (ER-β) in the subiculum of hippocampal formation, while postmenopausal monkeys of the same species have shown upregulation of ER-β [103]. On the other hand, in ovariectomized African green monkeys (*Cercopithecus aethiops sabaeus*), a reduction of synaptic plasticity of the hippocampus was detected [104]. Given that the reduced density of dendritic spines and ER-β in the hippocampus is related to an increase in indicators of anxiety and depression in ovariectomized rodents [105], this is probably occurring as well in nonhuman primates that experience surgical menopause. In addition, the long-term absence of ovarian hormones may impact serotonergic activity. For example, it has been demonstrated that ovariectomy in rhesus macaques reduces expression of the mRNA of the tryptophan


**Table 1.** Neural changes related to anxiety and depressive-like behaviors in nonhuman primates with natural or surgical menopause.

hydroxylase-2 (TPH-2) enzyme, increases the expression of MAO-A, and increases DNA fragmentation of serotonin neurons in the dorsal raphe nucleus [106]. These events could lead, on the one hand, to greater serotonin degradation and, on the other, neuronal death and, finally, a malfunction of the serotonergic system.

Furthermore, long-term ovariectomy in Japanese macaques reduces the expression of serotonergic neurons and gene expression of TPH-2, the serotonin reuptake transporter (SERT), and 5HT1A autoreceptors in the dorsal raphe nucleus [109]. This agrees with data showing that in depressed female of *Macaca fascicularis* the binding potential of 5HT1A receptors is reduced in the hippocampus, amygdala, and cingulate cortex [110], three of the structures involved in the pathophysiology of anxiety and depression. In contrast, stress-sensitive female monkeys of the same species decrease levels of Fev (transcription factor that determines whether a neuron is serotonergic), TPH-2, SERT, and 5HT1A mRNAs in the dorsal raphe nucleus [111]. Thus, in the long term, the reduction of TPH-2, which is important for serotonin synthesis, together with determinant markers for serotonergic function, could generate a higher incidence of anxious and depressive behaviors in NHPs with menopause, as occurred in human beings.

On the other hand, exogenous administration of E2 or P4 in ovariectomized primates has the capacity to restore serotonergic neurotransmission [106]. Further, serotonin neurons can express the ER-β protein and ER-β mRNA [112]. And, therefore, estrogens could increase the availability of serotonin in the brain by interacting with its receptor. Thus, the absence of ovarian hormones, such as E2 and P4 , has the ability to induce changes at the level of the the central nervous system in primates [103]. This evidence suggests that neural changes could be related to anxiety and depression behaviors, which could indicate some vulnerability in NHPs that experience natural or surgical menopause or suffer changes in different neurotransmission systems in which ovarian hormones participate, all of which could affect the emotional and affective state of these individuals.

### **6. Conclusion**

Menopause is a natural process that entails the permanent cessation of ovulation. It is associated with physiological and structural changes in aging females. Although it has long been assumed that menopause occurs only in human beings, the search for medical/clinical models to aid in research on this process has revealed that some species of NHPs also exhibit menopause. However, certain differences between human females and NHPs are clear: shorter postmenopausal life spans and variations in the timing of hormonal changes during the menopausal transition. But NHP models allow us to better understand not only several of the processes that occur during human aging—such as cognitive changes, cardiovascular alterations, and osteoporosis—but also similarities among species along the taxonomic scale.

On the other hand, increases in anxiety and depression behaviors may be observed in NHPs that undergo natural or surgical menopause. In a comparative perspective, these findings could improve our understanding of the neurobiological mechanisms that underlie emotional and affective disorders associated with the absence of ovarian hormones, given that experiments have demonstrated that long-term hormonal absence has the ability to affect numerous neurotransmission systems involved in mood disorders. In addition to reproducing various neural changes that can be correlated with depressive and anxious behaviors in NHPs, this might help understand the neurobiological substrate of emotional and affective disorders that can appear in women who experience natural or surgical menopause.

### **Acknowledgements**

hydroxylase-2 (TPH-2) enzyme, increases the expression of MAO-A, and increases DNA fragmentation of serotonin neurons in the dorsal raphe nucleus [106]. These events could lead, on the one hand, to greater serotonin degradation and, on the other, neuronal death and, finally,

**Table 1.** Neural changes related to anxiety and depressive-like behaviors in nonhuman primates with natural or surgical

Furthermore, long-term ovariectomy in Japanese macaques reduces the expression of serotonergic neurons and gene expression of TPH-2, the serotonin reuptake transporter (SERT), and 5HT1A autoreceptors in the dorsal raphe nucleus [109]. This agrees with data showing that in depressed female of *Macaca fascicularis* the binding potential of 5HT1A receptors is reduced in the hippocampus, amygdala, and cingulate cortex [110], three of the structures involved in the pathophysiology of anxiety and depression. In contrast, stress-sensitive female monkeys of the same species decrease levels of Fev (transcription factor that determines whether a neuron is serotonergic),

a malfunction of the serotonergic system.

**Species Natural menopause/**

African green monkeys (*Cercopithecus aethiops* 

38 A Multidisciplinary Look at Menopause

Pigtail macaques (*Macaca* 

Rhesus macaques (*Macaca* 

Rhesus macaques (*Macaca* 

Rhesus macaques (*Macaca* 

Japanese macaques (*Macaca fuscata*)

Japanese macaques (*Macaca fuscata*)

Japanese macaques (*Macaca fuscata*)

Japanese macaques (*Macaca fuscata*)

menopause.

*sabaeus*)

*nemestrina*)

*mulatta*)

*mulatta*)

*mulatta*)

**ovariectomy**

Ovariectomy Reduced density of

Ovariectomy Increased expression

Ovariectomy Decreased expression of

Ovariectomy Increased DNA

dendritic spines in the CA1 layer of the hippocampus

of MAO-A protein and decreased expression of TPH and SERT proteins in the dorsal raphe nucleus

TPH2 mRNA in the dorsal

fragmentation of serotonin neurons in the dorsal raphe

and 5HT1A gene expression in the dorsal raphe nucleus

ER-β immunoreactivity in the subiculum of the hippocampal formation

ER-β immunoreactivity in the subiculum of the hippocampal formation

raphe nucleus

Ovariectomy Not reported Anxiety and

nucleus

Ovariectomy Reduced Fev, TPH-2, SERT,

Natural menopause Upregulation in the

Ovariectomy Downregulation in the

Ovariectomy Not reported Anxiety [102]

**Neural changes Related behavior References**

Not reported [104]

Not reported [107]

Not reported [108]

Not reported [106]

Not reported [109]

Not reported [103]

Not reported [103]

[101]

depression

The authors of the present chapter received support from the following institutions: Sistema Nacional de Investigadores, SNI 60372-0 (AAA-T); Consejo Nacional de Ciencia y Tecnología (CONACyT), 297410 (AP-O); and Universidad Veracruzana, 46392 (BPV-D).

### **Author details**

María de Jesús Rovirosa-Hernández<sup>1</sup> \*, Marisela Hernández González<sup>2</sup> , Miguel Ángel Guevara-Pérez2 , Francisco García-Orduña1 , Abril de los Ángeles Aguilar-Tirado1 , Abraham Puga-Olguín3 and Brisa Patricia Vásquez-Domínguez<sup>4</sup>

\*Address all correspondence to: jrovirosa@uv.mx


### **References**


[10] Fleagle J. Apes and humans. In: Fleagle J, editor. Primate Adaptation and Evolution. 3rd ed. New York, Elsevier; 2013. Pp. 151-168. DOI: 10.1016/B978-0-12-378632-6.0007-0

**Author details**

40 A Multidisciplinary Look at Menopause

Guevara-Pérez2

Puga-Olguín3

**References**

455-464

Reinhold; 1979. 183-202

**10**:43-57. DOI: 10.1002/evan.1013

María de Jesús Rovirosa-Hernández<sup>1</sup>

, Francisco García-Orduña1

\*Address all correspondence to: jrovirosa@uv.mx

and Brisa Patricia Vásquez-Domínguez<sup>4</sup>

2008;**79**:398-406. DOI: 10.1095/biolreprod.108.068536

DOI: 10.1016/j.peptides.2008.05.016

The Belknap Press; 1975. pp. 32-47

1 Instituto de Neuroetología, Universidad Veracruzana, Xalapa, Veracruz, México

3 Posgrado en Neuroetología, Universidad Veracruzana, Xalapa, Veracruz, México 4 Facultad de Medicina, Universidad Veracruzana, Zona-Xalapa, Veracruz, México

[1] Walker ML, Herndon JG. Menopause in nonhuman primates?. Biology of Reproduction.

[2] Rance N. Menopause and the human hypothalamus: Evidence for the role of kissepeptin/neurokinin B neurons in the regulation of estrogen. Peptides. 2009;**30**:111-122.

[3] Hall J. Neuroendocrine changes with reproductive aging in women. Seminars in

[4] Wilson EO. The Relevant Principles of Population Biology: Sociobiology. Cambridge:

[5] Hill K, Hurtado A. Ache life history: The ecology and demography of a foraging people.

[6] Pavelka M, Fedigan L. Reproductive termination in female Japanese monkeys: A comparative life history perspective. American Journal of Physical Anthropology. 1999;**109**:

[7] Caro TM, Sellen DW, Parish A, Frank R, Brown DM, Voland E, Borgerhoff Mulder M. Termination of reproduction in nonhuman and human primate females. International

[8] Graham CE, Kling OR, Steiner RA. Reproductive senescence in female nonhuman primates. In: Bowden DM, editor. Aging in Nonhuman Primates. New York: Van Nostrand

[9] Scott P. Menopause: Adaptation or epiphenomenon?. Evolutionary Anthropology. 2001;

Reproductive Medicine. 2007;**25**:344-351. DOI: 10.1055/s-2007-984740

American Ethonologist. 1996;**26**:531-532. DOI: 10.1525/ae.1999.26.2.531

Journal of Primatology. 1995;**16**:205-220. DOI: 10.1007/BF02735478

2 Instituto de Neurociencias, Universidad de Guadalajara, Jalisco, México

\*, Marisela Hernández González<sup>2</sup>

, Abril de los Ángeles Aguilar-Tirado1

, Miguel Ángel

, Abraham


[38] Hansen K, Thyer A, Sluss P, Bremner W, Soules M, Klein N. Reproductive ageing and ovarian function: Is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women? Human Reproduction. 2005;**20**:89-95. DOI: 10.1093/humrep/deh54

[24] Dukelow W. Reproductive cyclicity and breeding in the squirrel monkey. In: Rosenblum LA, Coe CL, editors. Handbook of Squirrel Monkey Research. NY: Plenum Press; 1985.

[25] Strassmann BI The evolution of endometrial cycles and menstruation. The Quarterly

[26] Gangestad SW, Thornhill R. Human oestrus. Proceeding of the Royal Society B.

[27] Atsalis S, Margulis SW. Perimenopause and menopause: Documenting life changes in aging female gorillas. In: Atsalis S, Margulis SW, Hof PR, editors. Primate Reproductive

[28] Wise PM. Aging of the female reproductive system. In: Masoro EJ, Austad SN, editors. Handbook of the Biology of Aging. London: Elsevier; 2006. pp. 570-590 . DOI: 10.1016/

[29] Hodgen G, Goodman A, O'Connor A, Johnson D. Menopause in rhesus monkeys: Model for study of disorders in the human climacteric. American Journal of Obstetrics

[30] Atsalis S, Margulis SW. Primate reproductive aging: From lemurs to humans. In: Atsalis S, Marguli S, Hof P, editors. Primate Reproductive Aging. Switzerland: Kargel AC. 2008.

[31] Wright P, King S, Baden A, Jernvall J. Aging in wild female lemurs: Sustained fertility with increased infant mortality. In: Primate Reproductive Aging. Vol. **36**. Chicago, New

[32] Vom Saal FS, Finch CE. Reproductive senescence: Phenomena and mechanisms in mammals and selected vertebrates. In: Knobil E, Neill J, editors. The Physiology of

[33] Bellino FL, Wise PM. Nonhuman primate models of menopause workshop. Biology of

[34] Hawkes K, O'Connell JF, Blurton Jones NG, Alvarez H, Charnov EL. Grandmothering, menopause, and the evolution of human life histories. Proceedings of the National

[35] Hansen K, Knowlton N, Thyer A, Charleston J, Soules M, Klein N. A new model of reproductive aging: The decline in ovarian non-growing follicle number from birth to menopause. Human Reproduction. 2008;**23**:599-708. DOI: 10.1093/humrep/dem408 [36] Soules M, Sherman S, Parrot E, Rebar R, Santoro N, Utian W, Woods N. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Climacteric. 2001;**4**:267-272.

[37] Van Noord-Zaadstra B, Looman C, Alsbach H, Habbema J, te Velde E, Karbaat J. Delayed childbearing: Effect of age on fecundity and outcome of pregnancy. British Medical

Aging. Switzerland: Kargel AC; 2008. pp. 119-146 . DOI: 10.1159/000137704

Gynecology. 1977;**127**:581-584. DOI: 10.1016/0002-9378(77)90352-0

York, Karger Publishers; 2008. pp. 17-28 . DOI: 10.1159/000137677

Reproduction. 2003;**68**:10-18. DOI: 10.1095/biolreprod.102.005215

Reproduction. New York: Raven Press; 1988. pp. 2351-2413

pp. 169-190 . DOI: 10.1007/978-1-4757-0812-7\_7

2008;**275**:991-1000. DOI: 10.1098/rspb.2007.1425

B978-012088387-5/50024-8

42 A Multidisciplinary Look at Menopause

pp. 186-194 . DOI: 10.1159/000137710

Academy of Sciences. 1998:**95**:1336-1339

DOI: 10.1080/cmt.4.4.267.272

Journal. 1991;**302**:1361-1365

Reviex of Biology. 1996;**71**:181-220. DOI: 10.1086/419369


[65] Kavanagh K, Koudy Williams J, Wagner JD. Naturally occurring menopause in cynomolgus monkeys: Changes in hormone, lipid, and carbohydrate measures with hormonal status. Journal of Medical Primatology. 2005;**34**:171-177. DOI: 10.1111/j.1600-0684.2005. 00114.x

[52] Hamilton WD III, Busse C, Smith KS. Adoption of infant orphan chacma baboons.

[53] Teleki G, Hunt EE, Pfifferling JH. Demographic observations (1963-1973) on the chimpanzees of Gombe National Park, Tanzania. Journal of Human Evolution. 1976;**5**:559-

[54] Van Noordwijk MA, Van Schaik CP. Development of ecological competence in *Sumatran orangutans*. American Journal Physical Anthropology. 2005;**127**:79-94. DOI: 10.1002/

[55] Machatschke IH, Wallner B, Dittami J. Impact of social environment on female chimpanzee reproductive cycles. Hormones and Behavior. 2006;**50**:126-131. DOI: 10.1016/j.

[56] Miller PB, Charleston JS, Battaglia DE, Klein NA, Soules MR. Morphometric analysis of primordial follicle number in pigtailed monkey ovaries: Symmetry and relationship

[57] Paul A, Kuester J, Podzuweit D. Reproductive senescence and terminal investment in female Barbary macaques (*Macaca sylvanus*) at Salem. International Journal of

[58] Johnson R, Kapsalis E. Menopause in free-ranging rhesus macaques: Estimated incidence, relation to body condition and adaptive significance. International Journal of

[59] Gore AC, Windsor-Engnell BM, Terasawa E. Menopausal increases in pulsatile gonadotropin-releasing hormone release in a nonhuman primate (*Macaca mulatta*).

[60] Gill S, Sharpless JL, Rado K, Hall JE. Evidence that GnRH decreases with gonadal steroid feedback but increases with age in postmenopausal women. Journal of Clinical

[61] Nichols SM, Bavister BD, Brenner CA, Didier, PJ, Harrison R, Kubisch, HM. Ovarian senescence in the rhesus monkey (*Macaca mulatta*). Human Reproduction. 2005;**20**:79-83.

[62] Jones KP, Walker LC, Anderson D, Lacreuse A, Robson SL, Hawkes K. Depletion of ovarian follicles with age in chimpanzees: Similarities to humans. Biology of Reproduction.

[63] Itogawa N, Tanaka T, Ukai N, Fujii H, Kurokawa T, Ando A, Watanabe Y, Imakawa S. Demography and reproductive parameters of a free-ranging group of Japanese macaques

(*Macaca fuscata*) at Katsuyama. Primates. 1992;**33**:49-68. DOI: 10.1007/BF02382762 [64] Nozaki M, Mitsunaga F, Shimizu K. Reproductive senescence in female Japanese monkeys (*Macaca fuscata*): Age- and season-related changes in hypothalamic-pituitary-ovar-

ian functions and fecundity rates. Biology of Reproduction. 1995;**52**:1250-1257

Endocrinology and Metabolins. 2002;**87**:2290-2296. DOI: 10.1210/jcem.87.5.8508

Animal Behavior. 1982;**30**:29-34. DOI: 10.1016/S0003-3472(82)80233-9

598. DOI: 10.1016/0047-2484(76)90004-X

with age. Biology of Reproduction. 1999;**61**:553-556

Primatology. 1993;**14**:105-124. DOI: 10.1007/BF02196506

Primatology. 1998;**19**:751-765. DOI: 10.1023/A:1020333110918.

Endocrinology. 2004;**145**:4653-4659. DOI: 10.1210/en.2004-0379

2007;**77**:247-251. DOI: 10.1095/biolreprod.106.059634

ajpa.10426

44 A Multidisciplinary Look at Menopause

yhbeh.2006.02.003

DOI: 10.1093/humrep/deh576


[92] Lacreuse A, Chhabra R, Hall M, Herndon J. Executive function is less sensitive to estradiol than spatial memory: Performance on an analog of the card sorting test in ovariectomized aged rhesus monkeys. Behavioural Processes. 2004;**67**:313-319. DOI: 10.1016/j. beproc.2004.05.004

[78] Kaplan JR, Manuck SB. Ovarian dysfunction, stress, and disease: A primate continuum.

[79] Wagner JD, Kavanagh K, Ward GM, Auerbach BJ, Harwood H, Kaplan JR. Old world nonhuman primate models of type 2 diabetes mellitus. ILAR Journal. 2006;**47**:259-271.

[80] Shively CA, Kaplan JR, Clarkson T. Carotid artery atherosclerosis in cholesterol-fed cynomolgus monkeys: The effects of oral contraceptive treatments, social factors and regional adiposity. Arteriosclerosis Thrombosis and Vascular Biology. 1990;**10**:358-366.

[81] Jerome CP, Peterson PE. Nonhuman primate models in skeletal research. Bone. 2001;**29**:1-

[82] Carlson CS, Loeser RF, Purser CB, Gardin JF, Jerome CP. Osteoarthritis in cynomolgus macaques. III: Effects of age, gender, and subchondral bone thickness on the severity of disease. Journal of Bone and Mineral Research. 1996;**11**:1209-1217. DOI: 10.1002/

[83] Wallen K. Sex and context: Hormones and primate sexual motivation. Hormones and

[84] Hartwig W. Primate evolution and Taxonomy. In: Campbell C, Fuentes A, MacKinnon, K, Bearder S Stumpf R, editors. Primates in Perspective. 2nd ed. New York: Oxford

[85] Povinelli DJ, Rulf AB, Landau KR, Bierschwale DT. Self-recognition in chimpanzees (*Pan troglodytes*): Distribution, ontogeny, and patterns of emergence. Journal of Comparative

[86] Thompson R, Oden DL. Categorical perception and conceptual judgements by nonhuman primates: The paleological monkey and the analogical ape. Cognitive Science.

[87] Amaral D, Lavenex P. Hippocampal neuroanatomy. In: Anderson P, Morris R, Amaral D, Bliss T, O'Keefe J, editors. The Hippocampus Book. New York: Oxford University

[88] Hutchison RM, Everling S. Monkey in the middle: Why non-human primates are needed to bridge the gap in resting-state investigations. Frontiers in Neuroanatomy. 2012;**6**:1-19.

[89] Uylings HBM, Groenewegen HJ, Kolb B. Do rats have a prefrontal cortex?. Behavioural

[90] Phillips K, Bales K, Capitanio J, Conley A, Czoty P, t Hart B, et al. Why primate models matter. American Journal of Primatology. 2014;**76**:801-827. DOI: 10.1002/ajp.22281 [91] Voytko M, Tinkler G. Cognitive function and its neural mechanisms in nonhuman primate models of aging, Alzheimer disease, and menopause. Frontiers in Bioscience.

ILAR Journal. 2004; **45**:89-115. DOI: 10.1093/ilar.45.2.89

Behavior. 2001;**40**:339-357. DOI: 10.1006/hbeh.2001.1696

2000;**24**:363-396. DOI: 10.1016/S0364-0213(00)00029-X

Press; 2009. DOI: 10.1093/acprof:oso/9780195100273.003.0003.

Brain Research. 2003;**146**:3-17. DOI: 10.1016/j.bbr.2003.09.028

DOI: 10.1093/ilar.47.3.259

46 A Multidisciplinary Look at Menopause

DOI: 10.1161/01.ATV.10.3.358

University Press. 2007. pp. 11-22

Psychology. 1993;**107**(4):347

DOI: 10.3389/fnana.2012.00029

2004;**9**:1899-1914. DOI: 10.2741/1370

jbmr.5650110904

6. DOI: 10.1016/S8756-3282(01)00477-X


## **Psychological and Social Aspects of Menopause**

### Iqbal Afridi

[104] Leranth C, Shanabrough M, Redmond D. Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates. Journal of Comparative Neurology. 2002;**447**:34-42. DOI: 10.1002/

[105] Velázquez-Zamora DA, González-Tapia D, González-Ramírez MM, Flores-Soto ME, Vázquez-Valls E, Cervantes M, González-Burgos I. Plastic changes in dendritic spines of hippocampal CA1 pyramidal neurons from ovariectomized rats after estradiol treat-

[106] Lima FB, Bethea CL. Ovarian steroids decrease DNA fragmentation in the serotonin neurons of non-injured rhesus macaques. Molecular Psychiatry. 2010;**15**:657-668. DOI:

[107] Smith LJ, Henderson JA, Abell CW, Bethea CL. Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of Macaques. Neuropsychopharmacology. 2004;**29**:2035-2045. DOI: 10.1038/

[108] Sanchez RL, Reddy AP, Centeno ML, Henderson JA, Bethea CL. A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques. Molecular Brain Research. 2005;**135**:194-203. DOI: 10.1016/j.

[109] Bethea CL, Smith AW, Centeno ML, Reddy AP. Long-term ovariectomy decreases serotonin neuron number and gene expression in free ranging macaques. Neuroscience.

[110] Shively CA, Friedman DP, Gage HD, Bounds MC, Brown-Proctor C, Blair JB, Henderson JA, Smith MA, Buchheimer N. Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Archives of General Psychiatry. 2006;**63**:396-403. DOI: 10.1001/archpsyc.63.4.396 [111] Lima FB, Centeno ML, Costa ME, Reddy AP, Cameron JL, Bethea CL. Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram. Neuroscience. 2009;**164**:676-691. DOI:

[112] Gundlah C, Lu NZ, Mirkes SJ, Bethea CL. Estrogen receptor beta (ERβ) mRNA and protein in serotonin neurons of macaques. Molecular Brain Research. 2001;**91**:14-22.

2011;**192**:675-688. DOI: 10.1016/j.neuroscience.2011.06.003

ment. Brain Research. 2012;**1470**:1-10. DOI: 10.1016/j.brainres.2012.06.012

cne.10230

48 A Multidisciplinary Look at Menopause

10.1038/mp.2009.97

sj.npp.1300510

molbrainres.2004.12.011

10.1016/j.neuroscience.2009.08.010

DOI: 10.1016/s0169-328x(01)00108-5

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69078

### **Abstract**

Menopause is one of the age-related phases of physiological transition of females. There is robust research and information regarding its biological aspects specially its endocrine base, yet the psychosocial aspect is quite interesting and debatable due to its variability among different cultures and climates. There are certain subthreshold response in form fear and loss of reproductive life to no more ability to reproduce and a feeling of loss of femininity. The period of menstruation simulated to reproductive age or fertility is around half of their lives; therefore, loss of fertility or reproductive life may be a source of stress specially among tribes where long reproductive age period is desired on the cultural belief that this will lead to a large family size that is considered as a symbol of success. Psychological factors such personal or inter-psychic (personality, self-esteem, and coping skills) and intrapsychic (relationship issues and social support) may contribute in the onset, course, and repose to perimenopausal period. There are certain psychiatric conditions such as anxiety, depressive disorder, and premenstrual dysphoric syndrome related to premenopausal period that must be screened. Before embarking on pharmacological treatment, psychosocial intervention especially lifestyle modifications must be offered to avoid complications.

**Keywords:** menopause, psychosocial, women, depression, anxiety

### **1. Introduction**

As female grows old with passing years, she undergoes different phases of life, from childhood to adulthood. Her body keeps on changing at all levels; may it be anatomical, physiological, and hormonal with the years of aging. Menopause is just another phase of life like puberty. It is the time when ovaries stop producing eggs any more.

Menopause is a Latin word where *"Meno"* means month and "*pause*" means to stop. Various terms have been used for menopause in different languages as "*Haiz ka band hona*" in Urdu, "*alssnn yas"* in Arabic.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

It is neither a disease, an illness, a pathology, nor a state of being not well but just a normal physiological phenomenon of aging among females from transition of reproductive life to no more ability to reproduce. It has no impact on sexuality of a female. This transition occurs with some changes in hormones of female endocrine system predominantly estrogen leading to menopausal symptoms.

For women, the menopausal period is considered the climacterium, the middle adulthood; a period in life characterized by decreased biological and physiological functioning and may lead to psychosocial disturbance in form of interpersonal relationships [1]. It may start anywhere from the 40s to the early 50s but generally occurs between 47 and 53 years [1].

Considering the onset of menopausal age, one must keep in mind the difference between days per year in various calendars such as a lunar year of 354 days used by Muslims as compared to the solar year of 365 despite the fact that the later also known as Gregorian calendar is widely in use, but ancient calendars are also used by a significant number of peoples who belong to certain regions and religions, in the form of the Julian calendar, the Islamic calendar, etc.

The menopausal condition has been analog in men as andropause. For men, the climacterium has no clear demarcation; male hormones stay fairly constant through the 40s and 50s and then begin to decline [1].

All women will not experience menopause in the same way in terms of their onset and symptoms. Apart from a normal response or may be a positive feeling in the form of relief from pain or at least the burden of the management of menstruation each month, many premenopausal women have concerns that they will experience mental instability, sudden signs of aging, and diminution of sexuality at this time. Culture, health, previous experience of mood problems, lifestyle, and whether menopause onset is a natural, surgical, or chemotherapyinduced, will all impact on menopausal symptoms. Increased risk for psychiatric morbidity is seen in women who experienced early menopause or surgical menopause [2]. According to study of Bernice Neugarten, the famous American psychologist who is specialized in adult development and the psychology of aging, more than 50% of females described menopause as an unpleasant experience, some believed that their lives had not changed in any significant way, and many women experienced no adverse effects while some reports feeling sexually free after menopause of any worry of becoming pregnant.

### **2. Psychological factors**

### **2.1. Personal psychological vulnerability**

Large epidemiological studies have shown that the years usually associated with natural menopause, that is 45–55, are not associated with increased psychiatric morbidity or more utilization of health services by women [2–5]. Various personal factors of an individual female may affect her menopausal experience. Such as follows:


### **2.2. Life stressors**

It is neither a disease, an illness, a pathology, nor a state of being not well but just a normal physiological phenomenon of aging among females from transition of reproductive life to no more ability to reproduce. It has no impact on sexuality of a female. This transition occurs with some changes in hormones of female endocrine system predominantly estrogen leading

For women, the menopausal period is considered the climacterium, the middle adulthood; a period in life characterized by decreased biological and physiological functioning and may lead to psychosocial disturbance in form of interpersonal relationships [1]. It may start any-

Considering the onset of menopausal age, one must keep in mind the difference between days per year in various calendars such as a lunar year of 354 days used by Muslims as compared to the solar year of 365 despite the fact that the later also known as Gregorian calendar is widely in use, but ancient calendars are also used by a significant number of peoples who belong to certain regions and religions, in the form of the Julian calendar, the

The menopausal condition has been analog in men as andropause. For men, the climacterium has no clear demarcation; male hormones stay fairly constant through the 40s and 50s and

All women will not experience menopause in the same way in terms of their onset and symptoms. Apart from a normal response or may be a positive feeling in the form of relief from pain or at least the burden of the management of menstruation each month, many premenopausal women have concerns that they will experience mental instability, sudden signs of aging, and diminution of sexuality at this time. Culture, health, previous experience of mood problems, lifestyle, and whether menopause onset is a natural, surgical, or chemotherapyinduced, will all impact on menopausal symptoms. Increased risk for psychiatric morbidity is seen in women who experienced early menopause or surgical menopause [2]. According to study of Bernice Neugarten, the famous American psychologist who is specialized in adult development and the psychology of aging, more than 50% of females described menopause as an unpleasant experience, some believed that their lives had not changed in any significant way, and many women experienced no adverse effects while some reports feeling sexually

Large epidemiological studies have shown that the years usually associated with natural menopause, that is 45–55, are not associated with increased psychiatric morbidity or more utilization of health services by women [2–5]. Various personal factors of an individual female

free after menopause of any worry of becoming pregnant.

may affect her menopausal experience. Such as follows:

where from the 40s to the early 50s but generally occurs between 47 and 53 years [1].

to menopausal symptoms.

50 A Multidisciplinary Look at Menopause

Islamic calendar, etc.

then begin to decline [1].

**2. Psychological factors**

**2.1. Personal psychological vulnerability**

They may include the following:


### **2.3. Interpersonal relationships**

Social interpersonal relationships also have their impact on a person's life and general wellbeing. They constitute a major social support in a woman's life and help her in managing stressors and problems in life with influencial effect on psychological health. They may include the following:


Menopause could be a stressful transition due to various beliefs related to fertility and a gradual diminishing role or role shifts in society. Depression at menopause has been attributed to the *Empty Nest Syndrome.* A phenomenon observed with depression that occurs in some men and women when their youngest child is about to leave home. Many women, however, report an enhanced sense of well-being and enjoy opportunities to pursue goals postponed because of child rearing [1].

### **3. Social factors**

Education and socioeconomic statuses are also important factors found to influence the intensity and symptoms of menopause [8]. The influence of psychological factors, lifestyle, body image, interpersonal relationships, role, and sociocultural factors in predicting levels of depression and anxiety in the menopause cannot be ignored.

Role, social factors, and culture have a great impact on menopausal symptoms, as few studies have shown rates of depressive symptoms and hot flashes or sweats were significantly lower among Japanese women than females of American and Canadian population [9]. Such variations across cultures may reflect differences in


In developing countries where there is low literacy rate, it has been observed that females expect conception even after menopause, and this may be because the success of woman was considered to be related to production of more children, particularly males.

The factors that must be considered while dealing with menopausal women are the following:


As reproductive life could vary significantly among the various countries, we may consider average menarche age as 13 years and age of menopause as 51 years, and on calculating the reproductive period of women in developing country with average life expectancy of 50 years, they would have reproductive life that is 74% of their total life in comparison to women of developed country with life expectancy of 86 years who would have reproductive life constituting only 44% of their life from birth.

With the above fact, the period of menstruation is simulated to reproductive age or fertility is around half of their lives; therefore, loss of fertility or reproductive life may be a source of stress specially among tribes, where long reproductive age period is desired on the cultural belief that this will lead to a large family size that is considered as a symbol of success.

### **4. Secondary effects on mood/psychiatric morbidity and menopause**

Popular psychiatric nosology such as the WHO International Classification of Diseases (ICD-10) and Diagnostic and Statistical Manual of Mental *Disorders* (DSM-5) is also ambiguous about this condition; therefore, insurance for its management need to be addressed. ICD-10 has a variety of coding for menopause and related menopausal disorders as shown in **Figure 1**.

Menopause is not a time of high risk for psychiatric illness but may be a time of psychological stress for women. Some women will experience psychological symptoms during the perimenopausal years [10]. Since mild emotional symptoms occur in many women during


**Figure 1.** ICD-10 coding for menopause and related disorders.

Role, social factors, and culture have a great impact on menopausal symptoms, as few studies have shown rates of depressive symptoms and hot flashes or sweats were significantly lower among Japanese women than females of American and Canadian population [9]. Such varia-

In developing countries where there is low literacy rate, it has been observed that females expect conception even after menopause, and this may be because the success of woman was

The factors that must be considered while dealing with menopausal women are the following:

**1.** The variation in reproductive period, i.e., from onset of menses (also termed "menarche)"

**2.** Variation in life expectancy among different countries, e.g., life expectancy of woman is as

As reproductive life could vary significantly among the various countries, we may consider average menarche age as 13 years and age of menopause as 51 years, and on calculating the reproductive period of women in developing country with average life expectancy of 50 years, they would have reproductive life that is 74% of their total life in comparison to women of developed country with life expectancy of 86 years who would have reproductive life con-

With the above fact, the period of menstruation is simulated to reproductive age or fertility is around half of their lives; therefore, loss of fertility or reproductive life may be a source of stress specially among tribes, where long reproductive age period is desired on the cultural belief that this will lead to a large family size that is considered as a symbol of success.

**4. Secondary effects on mood/psychiatric morbidity and menopause**

Popular psychiatric nosology such as the WHO International Classification of Diseases (ICD-10) and Diagnostic and Statistical Manual of Mental *Disorders* (DSM-5) is also ambiguous about this condition; therefore, insurance for its management need to be addressed. ICD-10 has a variety of coding for menopause and related menopausal disorders as shown in **Figure 1**. Menopause is not a time of high risk for psychiatric illness but may be a time of psychological stress for women. Some women will experience psychological symptoms during the perimenopausal years [10]. Since mild emotional symptoms occur in many women during

considered to be related to production of more children, particularly males.

low as 50.8 years in Sierra Leone and as high as 86.8 years in Japan.

tions across cultures may reflect differences in

• Sensitivity to specific symptoms

52 A Multidisciplinary Look at Menopause

to menopause.

• Biology, diet, and health behaviors

stituting only 44% of their life from birth.

• Status and roles of women in a particular society

• Beliefs and expectations regarding menopause and aging

the perimenopausal years, it is important to establish whether the symptoms are of sufficient severity and duration to constitute major depression, generalized anxiety disorder, or panic disorder. Psychological distress is usually seen more in females with disturbed sleep [11]. Sleep could be disturbed in midlife due to psychosocial stressors of life or as a result of symptoms of menopause like hot flushes (also termed as "flashes") and night sweats. Female reproductive hormones and rapid changes in their levels may influence neurotransmitters in the brain, particularly the serotonin and gamma amino butyric acid systems. Estrogen modulates serotonin to increase serotonin presynaptic reuptake, modulates norepinephrine levels, decreases monoamine oxidase levels, affects dopamine turnover, increases brain excitability, affects endorphin levels, and possibly interacts with gamma amino butyric acid [12]. Progesterone is found to increase monoamine oxidase levels. In high doses, progesterone has an anesthetic effect and may decrease brain excitability through an interaction with the gamma amino butyric acid system [12]. The drop in estrogen levels during perimenopause and menopause can lead to hot flashes that disturb sleep. This can lead to anxiety, fears, and mood swings [1].

The greater frequency of symptoms during the years prior to the end of the menses and the reduction of symptoms once menopause has occurred suggest that emotional symptoms are related to changing hormone levels rather than low hormone levels [12].

Research has shown that reproductive hormones produced during menopause contribute to mood alterations, such as depression [13]. Menopausal status, however, remains an independent predictor of depressive symptoms [14]. Some women experience anxiety and depression, but women who have a history of poor adaptation to stress are more predisposed to the menopausal syndrome [1].

The two most common psychiatric conditions are anxiety and depression. Therefore, all the general physicians and gynecologists must ask two screening questions for each of these conditions from women of perimenopausal age, as suggested by experts, given in **Figures 2** and **3** (\*in Urdu—for developing countries where Urdu language is medium of communication).

**Figure 2.** Screening questions for depression among perimenopausal cases (Urdu).

**Figure 3.** Screening questions for anxiety among perimenopausal cases.

### **4.1. Depression and the menopause**

The changes that occur in hormone levels along with general health, shifts, and stresses of family life in a woman's menopausal years as a whole effect the onset of depression among them [15]. According to a study at Harvard on Moods and Cycles constituting premenopausal women aged 36–44 years with no history of major depression with a follow-up of these women for 9 years to detect new onsets of major depression. Clinically significant depressive symptoms likely to develop among perimenopausal women were twice as common than women who had not yet gone under menopausal transition [16].

Typical symptoms of depression include depressed mood, anhedonia, and fatigue. Reaching diagnosis of Depressive Disorder, two internationally recognized criteria are of ICD-10 and DSM-5. Symptoms should be there for at least 2 weeks and leading to poor social or occupational functioning and condition should not be due to any substance use. Presence of at least two typical expressions with two common symptoms constitutes the criteria of Major Depressive Disorder (F32) according to International Classification of Diseases version 10 (ICD-10), while presence of at least one typical and five or more common symptoms constitute criteria to diagnose Depressive Disorder in Diagnostic and Statistical Manual (DSM). List of Symptoms is shown in **Figure 4**.

### **4.2. Anxiety and the menopause**

Women who are more anxious experience greater extent of menopausal symptoms. Many of the symptoms of anxiety and menopause coincide like sweating, palpitations (increased heart rate), restlessness, sleep disturbance, which may confuse some. But no correlations have been found in between hormonal changes during menopause with incidence of anxiety disorder. Other psychosocial factors may contribute in development of anxiety among females of midlife.


**4.1. Depression and the menopause**

54 A Multidisciplinary Look at Menopause

The changes that occur in hormone levels along with general health, shifts, and stresses of family life in a woman's menopausal years as a whole effect the onset of depression among them [15]. According to a study at Harvard on Moods and Cycles constituting premenopausal women aged 36–44 years with no history of major depression with a follow-up of these women for 9 years to detect new onsets of major depression. Clinically significant depressive symptoms likely to develop among perimenopausal women were twice as common than

women who had not yet gone under menopausal transition [16].

**Figure 3.** Screening questions for anxiety among perimenopausal cases.

**Figure 2.** Screening questions for depression among perimenopausal cases (Urdu).


Symptoms of anxiety include the following:


The symptoms of anxiety and depression may sometimes coincide and may be present simultaneously so if asked what are the defining symptoms of anxiety and depression? The clear difference and presentation of symptoms have been described in **Figure 5** with various differences and the similarities of anxiety and depressive disorder.


### **4.3. Other psychiatric conditions**

Symptoms of anxiety include the following:

• apprehension • irritability • impatience • fearfulness • restlessness

• difficulty concentrating • trouble falling asleep

56 A Multidisciplinary Look at Menopause

• hyperventilation

• muscle tension

• increased frequency of urination

• sweating, especially in the palms

ences and the similarities of anxiety and depressive disorder.

**Figure 5.** Features that differentiate anxiety and depression.

The symptoms of anxiety and depression may sometimes coincide and may be present simultaneously so if asked what are the defining symptoms of anxiety and depression? The clear difference and presentation of symptoms have been described in **Figure 5** with various differApart from anxiety and depressive disorder, the other psychiatric conditions that have been linked to menopause are premenstrual dysphoric syndrome and surprisingly a rare condition Trichotillomania discussed as under.

*Premenstrual dysphoric syndrome*: it is a condition of changing mood with changes in hormone levels every month before menstruations.

Anecdotally, many cases as they approach to menopause report that their symptoms of premenstrual dysphoric syndrome worsen at onset of perimenopause and alleviate with menopause [17].

*Trichotillomania* (hair-pulling disorder) symptoms may worsen at perimenopause [17].

### **5. Biopsychosocial aspects in management of symptoms of menopause**

The art of assessing menopausal symptoms and menses may be threatening in some culture; therefore, reaching this condition needs proper working and skills which are less cumbersome because in general females are sensitive about aging process and loss of fertility.

### **5.1. Pharmacological interventions**

### *5.1.1. Hormone replacement therapy*

Estrogen and androgen alone or in combination of both is found to be more effective in improving symptoms in nonclinically depressed perimenopausal and menopausal women according to meta-analysis [18] of various studies on effects of hormone replacement therapies on mood. Progesterone had a much smaller effect, and when combined with estrogen, reduced the positive effects of the estrogen. The most robust effect was noted with androgen, either alone or in combination with estrogen.

Studies have shown that combined estrogen-progestin drugs (e.g., premarin) cause small increases in breast cancer, heart attack, stroke, and blood clots among menopausal women. Studies of the effects of estrogen alone in women who have had hysterectomies (because estrogen alone increases the risk for uterine cancer) are ongoing [1].

### *5.1.2. Antidepressants*

Depression during perimenopause and menopause is treated in much the same way as depression that strikes at any other time.

Although symptoms of depression are relieved by a majority of antidepressants including SSRIs such as Fluoxetine, Paroxetine, SNRIs, e.g., venlafaxine, des-venlafaxine, and TCA as amitriptyline, but desvenlafaxine (the dual serotonin and norepinephrine reuptake inhibitor) is used popularly, off label, for symptoms of depression with menopause despite the fact that the US Food and Drug Administration (FDA) has denied an application for its use for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes associated with menopause.

A meta-analysis shows that desvenlafaxine was associated with a statistically significant reduction in the number and severity of daily moderate-to-severe hot flashes. The number of nighttime awakenings because of hot flashes was also significantly decreased. However, the rate of desvenlafaxine treatment discontinuation because of adverse events was significantly higher than placebo-treated women and the risk ratios of adverse events such as asthenia, hypertension, anorexia, constipation, diarrhea, dry mouth, nausea, dizziness, insomnia, somnolence, and *mydriasis* (the dilation of the pupil) were very high [19].

### **5.2. Nonpharmacological interventions**

### *5.2.1. Lifestyle modifications*

A healthy lifestyle can help to reduce symptoms of menopause


Phytoestrogens are estrogen-like substances found in some cereals, vegetables, legumes (including soy), and herbs. They might work in the body like a weak form of estrogen. The first widely attributed health benefit of phytoestrogen consumption was relief from vasomotor perimenopausal symptoms, including hot flushes and night sweats. Moderation is a likely key and the incorporation of real foods, as opposed to supplements or processed foods to which soy protein is added, is probably essential for maximizing health benefits [21]. Consumption of 30 mg/day of soy isoflavones reduces hot flashes by up to 50% [22].

• Ensure enough calcium and vitamin D intake on regular basis

	- Caffeine

is used popularly, off label, for symptoms of depression with menopause despite the fact that the US Food and Drug Administration (FDA) has denied an application for its use for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes associated with

A meta-analysis shows that desvenlafaxine was associated with a statistically significant reduction in the number and severity of daily moderate-to-severe hot flashes. The number of nighttime awakenings because of hot flashes was also significantly decreased. However, the rate of desvenlafaxine treatment discontinuation because of adverse events was significantly higher than placebo-treated women and the risk ratios of adverse events such as asthenia, hypertension, anorexia, constipation, diarrhea, dry mouth, nausea, dizziness, insomnia, som-

• Exercise has beneficial effects on hot flashes, well-being, Body Mass Index (BMI) and Coro-

• Activities that stimulate the brain can help rejuvenate memory such as doing crossword

• A healthy diet, low in fat, high in fiber, with plenty of fruits, vegetables, and whole-grain

Phytoestrogens are estrogen-like substances found in some cereals, vegetables, legumes (including soy), and herbs. They might work in the body like a weak form of estrogen. The first widely attributed health benefit of phytoestrogen consumption was relief from vasomotor perimenopausal symptoms, including hot flushes and night sweats. Moderation is a likely key and the incorporation of real foods, as opposed to supplements or processed foods to which soy protein is added, is probably essential for maximizing health benefits [21]. Consumption of 30 mg/day of soy isoflavones reduces hot

nolence, and *mydriasis* (the dilation of the pupil) were very high [19].

A healthy lifestyle can help to reduce symptoms of menopause

• Being physically active helps with hot flushes, stress, and mood

puzzles, longhand mathematics, and reading books.

• A nutritious diet helps with fatigue and moodiness.

• Ensure enough calcium and vitamin D intake on regular basis

**5.2. Nonpharmacological interventions**

nary Heart Diseases risks [20]

• Intake of foods with phytoestrogen.

flashes by up to 50% [22].

*5.2.1. Lifestyle modifications*

**1.** Exercise

**2.** Diet

foods.

menopause.

58 A Multidisciplinary Look at Menopause


### **Author details**

### Iqbal Afridi

Address all correspondence to: driqbalafridi@yahoo.com

1 Department of Psychiatry & Behavioural Sciences, JPMC (Jinnah Postgraduate Medical Centre), Karachi, Pakistan


5 JPMC, Pakistan

### **References**


[20] Dennerstein L, Lehert P, Guthrie JR, et al. Modeling women's health during the menopausal transition: A longitudinal analysis. Menopause: Journal of the North American Menopause Society. 2007;**14**(1):53-62

[5] Nicol-Smith L. Causality, menopause, and depression: A critical review of the literature.

[6] Ayers B, Forshaw M, Hunter MS. The impact of attitudes towards the menopause on women's symptom experience: A systematic review. Maturitas. 2010 Jan;**65**(1):28-36 [7] RosemeierHP, Schultz-ZehdenB. Psychological aspects of menopause. In: FischlFH, ed. Menopause-Andropause: Hormone Replacement Therapy Through The Ages. Gablitz:

[8] Dennerstein L. Wellbeing, symptoms and the menopausal transition. Maturitas. 1996;**23**:

[9] Avis N, Kaufert PA, Lock M, McKinlay SM, Vass K. The evolution of menopausal symp-

[10] Diana C. Depression and emotional aspects of the menopause. BCMJ. 2001 Oct:**43**(8);

[11] Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: A multiethnic community study. American Journal of Public Health. 2001 Sep;

[12] Pearlstein TB. Hormones and depression: What are the facts about premenstrual syndrome, menopause, and hormone replacement therapy? American Journal of Obstetrics

[13] Gordon JL, Girdler SS, Meltzer-Brody SE, Stika CS, Thuston RC, Clark CT, et al. Ovarianhormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: A novel heuristic model. American Journal of Psychiatry. 2015 Mar;

[14] Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE, Gold EB, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: Results from the Study of Women's Health Across the Nation (SWAN).

[15] Kaufert PA, Gilbert P, Tate R. The Manitoba project: A reexamination of the link between

[16] Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: The Harvard study of moods and cycles. Archives of

[17] American Psychiatric Association. Diagnostic and statistical manual of mental disorders

[18] Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormone replacement therapy

[19] Berhan Y, Berhan A. Is desvenlafaxine effective and safe in the treatment of menopausal vasomotor symptoms? A meta-analysis and meta-regression of randomized doubleblind controlled studies. Ethiopian Journal of Health Sciences. 2014 Jul;**24**(3):209-218

toms. Baillieres Clinical Endocrinology and Metabolism. 1993;**7**:17-32

BMJ. 1996;**313**:1229-1232

60 A Multidisciplinary Look at Menopause

147-157.

463-466

**91**(9):1435-1442

**172**(3):227-236.

Krause & Pachernegg GmbH. 2001

and Gynecology. 1995;**173**:646-653

General Psychiatry. 2006;**63**:385-390

Archives of General Psychiatry. 2010 Jun;**67**(6):598-607

menopause and depression. Maturitas. 1992;**14**:143-155

(5th ed.). Arlington, VA: American Psychiatric Publishing. 2013

upon depressed mood. Psychoneuroendocrinology. 1997;**22**:189-212

