Andrea Giannini1, Andrea R. Genazzani1 and Tommaso Simoncini1
(1)
Division of Obstetrics and Gynecology, Department of Experimental and Clinical Medicine, University of Pisa, Via Roma, 67, Pisa, 56126, Italy
Tommaso Simoncini
Email: tommaso.simoncini@med.unipi.it
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].
The impairment of these regulatory and hormonal pathways partially explains why women experiencing hot flushes have a narrower thermoneutral region, so that minimal changes of core body temperature produce thermoregulatory mechanisms such as vasodilation, sweating, or shivering. Declining estrogens and inhibin as well as increasing FSH explain only in part the disturbed thermoregulation, which is associated with changes in different brain neurotransmitters (noradrenaline, beta-endorphin, dopamine, serotonine, NPY) and peripheral vascular reactivity [22]. This unbalance is one of the starting points to determine the onset of sleep disturbances. Mood disorders such as depression and anxiety are not caused by menopause. However, predisposed women may experience their first episode or a relapse during the perimenopausal transition. Muscle and joint pain is also part of the menopausal symptomatology, and it is closely related with hot flushes and depressed mood. Moreover, metabolic changes can occur, leading to increased body fat, which tends to redistribute from the periphery to the trunk, thus resulting in the development of visceral adiposity. In this view, the decline of the HPO axis function has a profound impact on different aspects of women’s life [23–25].
At the time of the menopausal transition, lowered androgen concentrations may play a role in symptoms such as lack of energy and sexual dysfunction and may possibly contribute to long-term development of cognitive, metabolic, and mood disorders. Hypothalamic–pituitary–adrenal (HPA) axis hyperactivity has been demonstrated in depression [26]. The end products of the HPA axis, glucocorticoids (GCs), regulate many physiological functions and play an important role in affective regulation and dysregulation. Despite DHEAS levels which markedly decrease throughout adulthood, an increase in circulating cortisol with advanced age has been observed in human and nonhuman primates [27]. In addition, unlike DHEA(S) concentrations that decline under conditions of chronic stress and medical illness, cortisol concentrations generally either rise or do not change, resulting in a decrease in DHEA(S)-to-cortisol ratios [28–31]. Therefore, it may be important to consider the ratio of both steroids in addition to their absolute concentrations. The resulting decrease in the DHEA-to-cortisol ratio may have drastic implications for many physiological processes, including learning and memory, a view that is supported by the finding that lower DHEA-to-cortisol ratios area associated with greater cognitive impairment [32]. However, the relationship between steroidal concentrations and cognitive impairment is still debated.
In summary, menopausal transition is the consequence of gradual loss of ovarian function. This is the final step in a long and irregular cascade of events taking place both in the brain and in the ovaries. Genetic factors influence the timing of this process, but the key molecular pathways involved are yet unknown. Identifications of such factors would be invaluable to set new strategies to treat reproductive dysfunction and menopause-associated diseases.
References
1.
Brann DW, Mahesh VB (2005) The aging reproductive neuroendocrine axis. Steroids 70(4):273–283CrossRefPubMed
2.
Klein NA, Battaglia DE, Fujimoto VY et al (1996) Reproductive aging: accelerated ovarian follicular development associated with a monotropic folliclestimulating hormone rise in normal older women. J Clin Endocrinol Metab 81(3):1038–1045PubMed
3.
Tom SE, Mishra GD (2013) Current topics in menopause: a life course approach to reproductive aging. Bentham Science Publishers Sharjah, Sharjah/Oak Park
4.
Schoenaker DA, Jackson CA, Rowlands JV et al (2014) Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int J Epidemiol 43:1542–1562PubMedCentralCrossRefPubMed
5.
Nichols HB et al (2006) From menarche to menopause: trends among US Women born from 1912 to 1969. Am J Epidemiol 164:1003–1011CrossRefPubMed
6.
Dratva J et al (2009) Is age at menopause increasing across Europe? Results on age at menopause and determinants from two population-based studies. Menopause 16:385–394CrossRefPubMed
7.
Flint MP (1997) Secular trends in menopause age. J Psychosom Obstet Gynaecol 18:65–72CrossRefPubMed
8.
Kok HS, van Asselt KM, van der Schouw YT et al (2005) Genetic studies to identify genes underlying menopausal age. Human reproduction update 11:483–493CrossRefPubMed
9.
van Asselt KM et al (2004) Heritability of menopausal age in mothers and daughters. Fertil Steril 82:1348–1351CrossRefPubMed
10.
Torgerson DJ, Thomas RE, Reid DM (1997) Mothers and daughters menopausal ages: is there a link? Eur J Obstet Gynecol Reprod Biol 74:63–66CrossRefPubMed
11.
Crame DW, Xu H, Harlow BL (1995) Family history as a predictor of early menopause. Fertil Steril 64:740–745
12.
van Asselt KM et al (2004) Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative trait loci influencing variation in human menopausal age. Am J Hum Genet 74:444–453PubMedCentralCrossRefPubMed
13.
Murabito JM, Yang Q, Fox CS et al (2005) Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study. Fertil Steril 84:1674–1679CrossRefPubMed
14.
Ferrarini E et al (2013) Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. Maturitas 74:61–67CrossRefPubMed
15.
Nelson LM (2009) Clinical practice. Primary ovarian insufficiency. N Engl J Med 360:606–614PubMedCentralCrossRefPubMed
16.
Nejat EJ, Chervenak JL (2010) The continuum of ovarian aging and clinicopathologies associated with the menopausal transition. Maturitas 66:187–190CrossRefPubMed
17.
Broekmans FJ, Soules MR, Fauser BC (2009) Ovarian aging: mechanisms and clinical consequences. Endocr Rev 30:465–493CrossRefPubMed
18.
Burger HG, Hale GE, Robertson DM et al (2007) Review of hormonal changes during the menopausal transition: focus on findings from the Melbourne Women’s Midlife Health Project. Hum Reprod Update 13:559–565CrossRefPubMed
19.
Wise PM (1999) Neuroendocrine modulation of the “menopause”: insights into the aging brain. Am J Physiol 277:E965–E970PubMed
20.
Downs JL, Wise PM (2009) The role of the brain in female reproductive aging. Mol Cell Endocrinol 299:32–38PubMedCentralCrossRefPubMed
21.
Santoro N et al (2003) Impaired folliculogenesis and ovulation in older reproductive aged women. J Clin Endocrinol Metab 88:5502–5509CrossRefPubMed
22.
Archer DF et al (2011) Menopausal hot flushes and night sweats: where are we now? Climacteric 14:515–528CrossRefPubMed
23.
Al-Safi ZA, Santoro N (2014) Menopausal hormone therapy and menopausal symptoms. Fertil Steril 101:905–915CrossRefPubMed
24.
Vivian-Taylor J, Hickey M (2014) Menopause and depression: is there a link? Maturitas 79:142–146CrossRefPubMed
25.
Bay-Jensen AC et al (2013) Role of hormones in cartilage and joint metabolism: understanding an unhealthy metabolic phenotype in osteoarthritis. Menopause 20:578–586PubMed
26.
Labrie F (2004) Adrenal androgens and intracrinology. Semin Reprod Med 22:299–309CrossRefPubMed
27.
Chalbot S, Morfin R (2006) Dehydroepiandrosterone metabolites and their interactions in humans. Drug Metabol Drug Interact 2:21–23
28.
Baulieu EE (1997) Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 5:21–32
29.
Dong Y, Zheng P (2012) Dehydroepiandrosterone sulphate: action and mechanism in the brain. J Neuroendocrinol 24(1):215–224CrossRefPubMed
30.
Bergeron R, de Montigny C, Debonnel G (1996) Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors. J Neurosci 16:1193–1202PubMed
31.
Compagnone NA, Mellon SH (2000) Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 21:1–56CrossRefPubMed
32.
Maurice T, Gregoire C, Espallergues J (2006) Neuro(active)steroids actions at the neuromodulatory sigma1 (sigma1) receptor: biochemical and physiological evidences, consequences in neuroprotection. Pharmacol Biochem Behav 84:581–597CrossRefPubMed