The functional life of human ovaries is determined by a complex and yet largely unidentified set of genetic, hormonal, and environmental factors. Women undergo menopause when follicles in their ovaries are exhausted. However, the clinical manifestations experienced by women approaching menopause are the result of a dynamic interaction between neuroendocrine changes that take place in the brain with the reproductive endocrine axis governing the function of ovaries.

Although menopause is ultimately defined by ovarian follicular exhaustion, evidence in humans and animals now suggests that dysregulation of estradiol feedback mechanisms and hypothalamic-pituitary dysfunction contribute to the onset and progression of reproductive senescence, independent of ovarian failure [1, 2].

Understanding the mechanisms that propel women into menopause may offer opportunities for interventions that delay menopause-related increases in disease morbidity and thus improve the overall quality of life for aging women.

Results from epidemiologic studies give a median age of natural menopause (ANM) of 48–52 years among women in wealthy nations [3]. In a more recent meta-analysis of 36 studies spanning 35 countries, the overall mean ANM was estimated at 48.8 years (95 % CI: 48.3, 49.2), with significant variation by geographical region. ANM was generally earlier among women in African, Latin American, and Middle-Eastern countries (regional means for ANM: 47.2–48.4 years), while in Europe and Australia, ANM is later (ANM 50.5–51.2 years), and it presents increasing trend for women in wealthy nations over the twentieth century; however, the interplay of biological and environmental factors behind regional differences and historical trends in the timing of menopause remains far from clear [4–7].

The timing of the ANM reflects a complex interplay of factors from genetic and epigenetic, to socioeconomic and lifestyle factors. Heritability in menopausal age is estimated to range between 30 and 85 % [8, 9]. Women whose mothers or other first-degree relatives were known to have early menopause have been found to be 6- to 12-fold more likely to undergo early menopause themselves [10, 11].

Linkage analysis studies pinpoint areas in chromosome X (Xp21.3 region) that are associated with early (<45 years) or premature (<40 years) menopause. A region in chromosome 9 (9q21.3) contains a gene that encodes for a protein of the B-cell lymphoma 2 (BCL2) family. BCL2 is involved in apoptosis and may thus be relevant in determining menopause through follicular depletion [12]. Other linkage analysis studies have identified a region in chromosome 8 that is associated with age at menopause. Interestingly, near this identified DNA sequence is the gene encoding for gonadotropin-releasing hormone (GnRH) [13]. Other genes specific to ovarian function such as the follicle-stimulating hormone (FSH) and inhibin receptors have been shown to be associated with early and premature menopause [14]. Women who are carriers of the fragile X mutation and have an intermediate number of CGG repeats in their fragile X mental retardation 1 (FMR1) gene on their X chromosome have been observed to undergo premature and early menopause [15].

Candidate gene association studies, looking at possible association between genes encoding with factors involved in reproductive pathophysiology and menopause, have been disappointing, and most of them failed to identify associations or failed to be confirmed in replication tests.

One of the starting points of deterioration of the HPO axis function is the exhaustion of ovarian gametes, which are the key players in determining the timing of menopause, but it is not the exclusive determinant of female reproductive senescence.

The number of follicular cells is pre-set before birth, when oocytes expand to a maximum of six million to seven million at mid-gestation. Afterwards, a rapid loss of oocytes starts because of apoptosis, leading to a population of 700,000 at birth and of 300,000 at puberty. The continuing apoptotic loss, along with the use of oocytes during the 400–500 cycles of follicular recruitment taking place in a normal reproductive life, combined with the recruitment of multiple follicles per cycle, leads to final exhaustion of these cells at midlife, determining menopause between 45 and 55 years [16].

In this view, lifespan of the ovaries is only marginally influenced by ovulation, while it mostly depends on the extent and rapidity of the apoptotic process of its oocytes, and molecular mechanisms regulating this process are still unknown.

Findings from previous studies support the hypothesis that the specialized granulosa and theca steroid-secreting cells, and not the oocytes, determine the coordinated processes driving the menstrual cycle. Follicular cells are regulated by pituitary gonadotropins as well as by locally produced hormones. Loss of sensitivity to stimulating factors by follicular cells is thought to have a key role in ovarian function decline [17].

In this view, the most relevant endocrine modification throughout the menopausal transition is the progressive decline in inhibin B and anti-mullerian hormone (AMH), marking the decrease in follicle quantity and/or functionality and explaining why fertility is impaired in women before any dysregulation in menstrual cyclicity is seen [18].

During the menopausal transition, the HPO axis undergoes significant modifications, which are in part secondary to the declining ovarian function and that are partially directly related to hypothalamic functional changes [19].

To this extent, increases of FSH concentrations can be detected in middle-aged women before estrogen declines or cycle irregularities are observed. Similarly, in this period, LH pulses secretion patterns are broader and less frequent.

Findings from experimental work in rat models suggest that an age-related desynchronization of the neurochemical signals involved in activating GnRH neurons happens before modifications in estrous cyclicity. Several hypothalamic neuropeptides and neurochemical agents (glutamate, norepinephrine, vasoactive intestinal peptide) that regulate the estrogen-mediated GnRH/LH surge seem to diminish with age or lack the precise temporal coordination required for a specific pattern of GnRH secretion [20]. Disruption of this hypothalamic biological clock would lead to progressive impairment in the timing of the pre-ovulatory LH surge, which would add to the poor ovarian responsiveness typical of this reproductive phase.

Thus, it becomes clear that the endocrine modifications of perimenopausal period depend on the interplay of dysfunction of the ovaries and of the hypothalamus. A shortened follicular phase associated with elevation of FSH plasmatic concentrations is common for the early menopausal transitional period during which patients typically experience shorter cycle intervals and others menstrual irregularities.

Several experimental studies affirm that shortened follicular phases are associated with accelerated ovulation, happening at smaller follicle size. The most plausible explanation of this phenomenon is the loss of inhibin B production, leading to higher FSH release and therefore to an “overshoot” of estrogen production. This would facilitate and accelerate the achievement of the LH surge.

Throughout the menopausal transition, the age-related hypothalamic modifications determine a reduction in estrogen sensitivity and the LH surge becomes more erratic. Follicles also become less sensitive to gonadotropins, thus leading to luteal phase defect (LPD), anovulatory cycles and, therefore, to the first menstrual irregularities. Hypothalamic insensitivity to estrogens also explains why menopausal symptoms, such as hot flushes and night sweats, commonly appear at this stage, when women have rather high levels of estrogens, as well as why exogenous estrogens are effective in reducing the symptoms [21].