Version May 2024
INTRODUCTION — This topic will review the basic aspects of ovarian development and the pathogenesis and epidemiology of menopause. The clinical manifestations, diagnosis, and management of menopause are reviewed separately. (See "Clinical manifestations and diagnosis of menopause" and "Treatment of menopausal symptoms with hormone therapy".)
OVARIAN DEVELOPMENT — There are three main steps in ovarian development: germ cell differentiation, continuous follicular growth, and continuous follicular atresia.
Germ cell differentiation — One of the first events of sexual differentiation, occurring as early as the two-cell stage of the zygote, is the random, nearly complete inactivation of one X chromosome in all female somatic cells [1] but not germ cells [2]. Thus, somatic cells have only a few active X chromosome genes, whereas germ cells have two complete X chromosomes [2].
The primordial undifferentiated germ cells then migrate during the fourth to eighth weeks of gestation from the yolk sac to the gonadal ridge, where they are required for development of the ovaries [3]. In the absence of a testicular differentiation factor from the Y chromosome, which directs the production of müllerian-inhibiting substance (MIS) by four to six weeks gestation in males [4], the germ cells differentiate into primitive oogonia, which begin mitosis at approximately six weeks. (See "Typical sex development".)
A quantitative morphologic study of germ cells in 17 normal human fetuses revealed a maximum of seven million germ cells five months after conception [3]; this small study remains the basis of most of our current understanding of oogenesis in humans. The first meiotic division is initiated at approximately 15 weeks, signaling the transformation of oogonia to oocytes. This meiotic division is then arrested at the first prophase until primordial follicles are formed. Medullary structures infiltrate the ovarian cortex and surround the oocytes to invest each one with a single layer of primordial granulosa cells at approximately 20 weeks of gestation, thereby beginning the formation of primordial follicles.
Continuous follicular growth — Follicular and ovarian growth have been studied in late gestational fetuses and prepubertal children, using autopsy [3], laparotomy [5], and ultrasonography [6]. Follicular growth is initiated in the fetus in a continuous pattern that is independent of gonadotropins and is apparently related to both the total mass of follicles and to factors released by atretic follicles [7,8]. Follicles are capable of growth up to the preantral (pre-luminal) stage in the absence of gonadotropins, based upon studies of girls with congenital deficiency of gonadotropin-releasing hormone (GnRH) (Kallmann syndrome) [9] and anencephalic fetuses [10]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
Further follicular development requires follicle-stimulating hormone (FSH) stimulation of granulosa cells and induction of luteinizing hormone (LH) receptors, and therefore responsiveness to LH [11], leading to formation of preovulatory follicles and then to ovulation and formation of the corpus luteum. The ovaries of normal human fetuses, infants, and prepubertal children [12-14] contain larger antral follicles. These follicles are probably formed in response to low levels of pulsatile FSH and LH secretion [14], based upon studies using very sensitive gonadotropin assays [15,16].
Continuous follicular atresia — As soon as primordial follicles are formed in the fetus, before there is detectable follicular responsiveness to FSH, inexorable cycles of follicular growth and subsequent atresia begin. These cycles result in an exponential fall in oocyte number even before birth.
The atresia is a poorly understood process of follicular degradation. It can apparently occur at any point during follicular growth and development and may be associated with re-initiation of meiosis. Studies in both animals and humans suggest that apoptosis is the mechanism responsible for oocyte depletion and follicular atresia [17].
●Suppression of granulosa-cell division by decreasing gonadotropin stimulation can cause atresia [8], whether achieved by decreasing FSH secretion [18] or blocking of FSH action.
●Once a follicle reaches the preovulatory stage, inhibition of theca-cell function can cause atresia by blocking production of the androgen precursors necessary for subsequent aromatization to estrogens during the final stages of follicle differentiation [19].
●In young girls, most, if not all, follicles that reach the preantral (1 mm) stage are already atretic, and the rate of atresia is increased in larger follicles [14].
●There is evidence that human and porcine follicular cells produce a meiosis-inhibiting factor that may arrest atresia by inhibiting the progression of meiosis in oocytes [20,21]. MIS is produced in fetal ovaries and may have a role in regulating meiosis [22-24].
●In a mouse model, Bax and bcl-2, genes expressed in both oocytes and granulosa cells, may play a central role in follicular atresia [25,26]. In a Bax knockout mouse, ovarian lifespan is prolonged when compared with wild-type controls. In contrast, in a bcl-2 knockout mouse, the number of primordial follicles is reduced.
●Follicular depletion in the human fetus may be primarily due to apoptosis of oocytes, while in adult life, granulosa cell apoptosis may play an important role in follicular demise [27].
In contrast to the evidence that the ovary contains a finite number of oocytes that are lost at a steady rate until menopause, a 2004 study of adult mice reported that new oocyte-containing follicles, presumably from stem cells, continue to develop [28]. In a follow-up report by the same investigators, the bone marrow was identified as the possible source of the germline stem cells [29]. However, other investigators have reported that bone marrow cells do not contribute to the formation of mature, ovulated oocytes [30].
In a 2009 report, female germline stem cells were isolated from neonatal mice and transplanted into sterile adult mice, who then were able to produce offspring [31]. In a second study, oogonial stem cells were isolated from neonatal and adult mouse ovaries; pups were subsequently born from the oocytes [31]. Further experiments are needed before the implications for humans can be determined.
OVARIAN FUNCTION DURING THE REPRODUCTIVE YEARS — Careful autopsy studies of small numbers of women who died prematurely revealed a steady exponential decline in oocyte number throughout early adult life [3,32,33]; however, only small numbers of older women have been studied (figure 1) [34,35]. Thus, there is uncertainty about the rate of decline in oocyte numbers during these years.
A study evaluated the menstrual cycles, serum hormone concentrations, and oocyte viability in young women and older women who were still having regular menstrual cycles [36]. Oocyte viability declined in older women before they had any measurable decrease in serum or intrafollicular hormone concentrations [36]. These results may explain the gradual decrease in fecundity after age 30 to 35 years in normal women (figure 2) [37]. The isolated increases in serum follicle-stimulating hormone (FSH) concentrations that are found in some normally cycling older women are probably caused by decreasing ovarian production of inhibin (figure 3) [38].
MENOPAUSE — Menopause occurs at a mean age of 51 years in normal women in the United States [39] (see "Clinical manifestations and diagnosis of menopause"). It is associated with a marked decline in oocyte number that is attributable to progressive atresia of the original complement of oocytes (figure 1). However, the evidence for absolute oocyte depletion at this time is limited. Residual oocytes and differentiating follicles have been identified in the ovaries of some postmenopausal women, although the follicles are frequently atretic [34,35].
The decrease in developing follicles is reflected in a parallel decrease in the serum concentration of inhibin B, which is probably the earliest, easily measurable marker of follicular decline (figure 3) [40,41]. The rise in the serum concentration of follicle-stimulating hormone (FSH) in early menopause is also closely related to the fall in inhibin B; this suggests that inhibin B plays an important role in the normal control of FSH secretion [42].
Serum concentrations of müllerian-inhibiting substance (MIS; also known as anti-müllerian hormone [AMH]) may be a useful marker reflecting reproductive aging [43-45]. Low serum AMH concentrations were predictive of a poor ovarian response to exogenous gonadotropin stimulation and may mark a critical juncture in the timing of the menopausal transition [46,47].
Menopausal transition — The menopausal transition, or perimenopause, begins on average four years before the final menstrual period (FMP) and is characterized by irregular menstrual cycles, marked hormonal fluctuations, and menopausal symptoms such as hot flashes. Waxing and waning of ovarian function is common. The Stages of Reproductive Aging Workshop (STRAW) developed a staging system for reproductive aging in women (figure 4). It provides clinical definitions of the menopausal transition, perimenopause, menopause, and postmenopause [48].
●In the early menopausal transition, women begin to experience some menstrual irregularity (figure 4). As noted above, inhibin B and AMH concentrations fall due to a decline in follicular number, and as a result, serum FSH levels begin to rise, with relative preservation of estradiol secretion (normal or high estradiol levels), but with low luteal phase progesterone concentrations (figure 3 and figure 5) [40-42,49,50].
●In the late menopausal transition, cycle variability increases. In addition, fluctuations in serum concentrations of FSH and estradiol may be quite striking; high FSH and low estradiol values may be suggestive of menopause, but soon thereafter FSH and estradiol may return to the normal premenopausal range (figure 4 and figure 6) [51].
The clinical manifestations and endocrinology of the menopausal transition are reviewed in more detail elsewhere. (See "Clinical manifestations and diagnosis of menopause", section on 'Menstrual cycle and endocrine changes'.)
In addition to the decline in follicular number, there may be a decrease in hypothalamic-pituitary sensitivity to estrogen during perimenopause. This was illustrated in a study of 160 perimenopausal women with anovulatory menstrual cycles who collected daily urine samples (across one cycle) for gonadotropin and sex steroid levels [52]. Some cycles were characterized by normal preovulatory levels of estrogen, but no luteinizing hormone (LH) surge, suggesting a failure of estrogen-positive feedback, while in others, normal follicular phase estrogen levels did not suppress LH secretion, indicating a failure of estrogen-negative feedback.
Epidemiology — The average age of menopause, defined as permanent cessation of menses, is age 51 years in normal women. [53]. Clinical menopause is recognized after 12 months of amenorrhea. There is considerable variability around the onset of menopause with 5 percent of women undergoing menopause after age 55 and another 5 percent between ages 40 and 45 years [54,55]. Menopause before age 40 years is considered abnormal and is referred to as primary ovarian insufficiency (formerly called premature ovarian failure). (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Factors affecting age at menopause — A number of factors are thought to play a role in determining an individual woman's age of menopause, including genetics, ethnicity, smoking, and reproductive history.
Genetics — Women with a family history of early menopause are at higher risk for undergoing an earlier than average menopause themselves [56]. Additional evidence that genetic factors play a role in the normal variation in age at natural menopause include the following:
●Genome-wide association studies have identified a number of regions associated with age at menopause [57-61]. One meta-analysis points to genes regulating immune function and DNA repair [59].
●Genetic variation in the estrogen receptor gene may be another determinant of the age of menopause, as illustrated in a study of 900 postmenopausal women in the Netherlands; the mean age at menopause varied by 1.1 year among women with different alleles at the same locus of the estrogen receptor gene [62].
●The fragile X messenger ribonucleoprotein 1 (FMR1) premutation has been associated with premature ovarian failure and an earlier age of menopause by up to seven years [63,64]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Ethnicity — Ethnicity and race may also affect the age of menopause. In two prospective, multiethnic, cohort studies, natural menopause occurred earlier among Hispanic women [65] and later in Japanese American women [65,66] when compared with White women.
Smoking — The age of menopause is reduced by approximately two years in women who smoke [39,67-69]. Passive smoking may also be associated with earlier age of menopause [70,71].
Other — Other factors that may be associated with earlier menopause include galactose consumption [54,72], the presence of a variant form of galactose-1-phosphate uridyl transferase [54,73], a history of type 1 diabetes mellitus [74], and in utero exposure to diethylstilbestrol (DES) [75].
Night shift work, which is known to have a number of adverse effects on reproductive health, may also impact the age at menopause. In a prospective cohort study of over 80,000 women followed for 22 years, those who worked rotating night shifts more than 20 months in the previous two years had an increased risk of earlier menopause compared with women without night shift work (multivariable-adjusted hazard ratio [MV-HR] 1.09, 95% CI 1.02-1.16) [76]. This risk was stronger among women undergoing menopause under age 45 years (MV-HR 1.25, 95% CI 1.08-1.46). It is not known if the impact of night shift work on menopausal age is related to circadian disruption or to the fatigue and stress associated with the demanding work schedules.
Hysterectomy with ovarian conservation — Hysterectomy appears to alter ovarian function over the long term, even if the ovaries are conserved. This effect is incompletely understood. Observational data have shown that women who undergo hysterectomy develop menopausal symptoms and menopausal hormone profiles earlier than controls who were not exposed to this surgery, possibly due to impairment of the ovarian blood supply or other yet unknown mechanisms. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Surgical alternatives to oophorectomy for ovarian cancer risk reduction'.)
Ultrasound findings — Newer techniques of ovarian ultrasonography have revealed small (1 to 3 mm) cysts in the ovaries of women many years after the menopause [34,35]. These cysts probably represent secondary follicles, because a primordial follicle cannot begin to grow and mature unless it contains a viable oocyte, and follicles are the major cystic structures in the ovaries. It is not clear how long an intact oocyte must be present for follicular growth to occur and antral fluid to accumulate, and ultrasonography cannot detect follicular atresia. As a result, the importance of these small cysts in postmenopausal women is currently unknown.
Neuroendocrine changes — Aging is associated with changes in hypothalamic-pituitary, as well as ovarian, function. The FSH and LH secreted by postmenopausal women contain more carbohydrate, and the serum half-lives of the hormones are prolonged, as compared with young women [77]. The prolonged half-life contributes to the high serum FSH and LH concentrations found in older women. In addition, the FSH and LH secreted by older women may be less biologically active [78].
Thus, some of the decline in ovarian function at the time of the menopause may be due to changes in the quantity or quality of the hormones secreted by the hypothalamus and pituitary or the pattern of their secretion, rather than to a primary loss of ovarian responsiveness [79]. However, the poor response to exogenous administration of gonadotropins in older women undergoing in vitro fertilization argues against this possibility.
SUMMARY
●Follicular growth is initiated in the fetus in a continuous pattern that is independent of gonadotropins and is related to both the total mass of follicles and to factors released by atretic follicles. (See 'Ovarian development' above.)
●Cycles of follicular growth and subsequent atresia begin before birth and continue throughout the reproductive years. (See 'Ovarian development' above.)
●Oocyte viability declines in older women of reproductive age before they have any measurable decrease in serum or intrafollicular hormone concentrations. (See 'Ovarian function during the reproductive years' above.)
●Menopause is associated with a marked decline in oocyte number that is attributable to progressive atresia of the original complement of oocytes. However, the evidence for absolute oocyte depletion at this time is limited. (See 'Menopause' above.)
●The average age of menopause, defined as permanent cessation of menses, is age 51 years in normal women. A number of factors appear to be associated with age at menopause. (See 'Menopause' above and 'Factors affecting age at menopause' above.)
●Revised nomenclature, referred to as the Stages of Reproductive Aging Workshop (STRAW) staging system, is now used to describe the stages of reproductive aging (figure 4). (See 'Menopausal transition' above and "Clinical manifestations and diagnosis of menopause", section on 'Menstrual cycle and endocrine changes'.)
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