A Clinician's Guide to Functional Hypothalamic Amenorrhea.
Ruiz-Zambrana Alvaro,Berga Sarah L
Clinical obstetrics and gynecology
Patients and clinicians alike want to know if stress causes infertility. Stress could impair with reproductive function by a variety of mechanisms, including compromise of ovarian function, spermatogenesis, fertilization, endometrial development, implantation, and placentation. Herein we focus on the pathogenesis and treatment of stress-induced anovulation, which is often termed functional hypothalamic amenorrhea (FHA), with the objective of summarizing the actual knowledge as a clinical guide. FHA is a reversible form of anovulation due to slowing of gonadotropin-releasing hormone pulse frequency that results in insufficient pituitary secretion of gonadotropins to support full folliculogenesis. Importantly, FHA heralds a constellation of neuroendocrine alterations with health concomitants. The activity of the hypothalamic-pituitary-adrenal axis is increased in women with FHA and this observation supports the notion that stress is the cause. The extent of reproductive suppression relates to individual endocrinological and physiological sensitivity to stressors, both metabolic and psychogenic, and chronicity.
10.1097/GRF.0000000000000573
Hormones and depression in the advanced age.
Endokrynologia Polska
INTRODUCTION:In older people, depression and mental disability are more frequently present than in younger subjects. It is found that depressionis a risk factor for dementia, just as dementia is a risk factor for depression. In turn, both disturbances are known to be influenced by hormones. The present study aimed to see whether the hormonal changes in subjects over 75 years old correlate with the symptoms of depression measured using the Geriatric Depression Scale (GDS). MATERIAL AND METHODS:In a group of patients aged over 75 years, concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, testosterone, dehydroepiandrosterone sulphate (DHEAs), and cortisol were measured in serum with the use of chemiluminescence. The symptoms of depression were estimated by GDS, and the mental functions were assessed by the Mini-Mental State Examination (MMSE). The correlations between the obtained results were estimated by Spearman's test. RESULTS AND CONCLUSIONS:A significant correlation between GDS and MMSE scores was observed in the investigated patients. Some statistically significant correlations concerning cortisol and testosterone with GDS were observed in women, but not in men. On the other hand, no significant correlations between concentrations of FSH, LH, DHEAs, and oestradiol with GDS were noticed. Our data support the role of cortisol (possibly secreted during chronic stress) in the risk of depression. The gender difference in the mechanism of depression and stress in older age could be also hypothesized.
10.5603/EP.a2022.0094
GnRH and GnRH receptors in the pathophysiology of the human female reproductive system.
Maggi Roberto,Cariboni Anna Maria,Marelli Marina Montagnani,Moretti Roberta Manuela,Andrè Valentina,Marzagalli Monica,Limonta Patrizia
Human reproduction update
BACKGROUND:Human reproduction depends on an intact hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotrophin-releasing hormone (GnRH) has been recognized, since its identification in 1971, as the central regulator of the production and release of the pituitary gonadotrophins that, in turn, regulate the gonadal functions and the production of sex steroids. The characteristic peculiar development, distribution and episodic activity of GnRH-producing neurons have solicited an interdisciplinary interest on the etiopathogenesis of several reproductive diseases. The more recent identification of a GnRH/GnRH receptor (GnRHR) system in both the human endometrium and ovary has widened the spectrum of action of the peptide and of its analogues beyond its hypothalamic function. METHODS:An analysis of research and review articles published in international journals until June 2015 has been carried out to comprehensively summarize both the well established and the most recent knowledge on the physiopathology of the GnRH system in the central and peripheral control of female reproductive functions and diseases. RESULTS:This review focuses on the role of GnRH neurons in the control of the reproductive axis. New knowledge is accumulating on the genetic programme that drives GnRH neuron development to ameliorate the diagnosis and treatment of GnRH deficiency and consequent delayed or absent puberty. Moreover, a better understanding of the mechanisms controlling the episodic release of GnRH during the onset of puberty and the ovulatory cycle has enabled the pharmacological use of GnRH itself or its synthetic analogues (agonists and antagonists) to either stimulate or to block the gonadotrophin secretion and modulate the functions of the reproductive axis in several reproductive diseases and in assisted reproduction technology. Several inputs from other neuronal populations, as well as metabolic, somatic and age-related signals, may greatly affect the functions of the GnRH pulse generator during the female lifespan; their modulation may offer new possible strategies for diagnostic and therapeutic interventions. A GnRH/GnRHR system is also expressed in female reproductive tissues (e.g. endometrium and ovary), both in normal and pathological conditions. The expression of this system in the human endometrium and ovary supports its physiological regulatory role in the processes of trophoblast invasion of the maternal endometrium and embryo implantation as well as of follicular development and corpus luteum functions. The GnRH/GnRHR system that is expressed in diseased tissues of the female reproductive tract (both benign and malignant) is at present considered an effective molecular target for the development of novel therapeutic approaches for these pathologies. GnRH agonists are also considered as a promising therapeutic approach to counteract ovarian failure in young female patients undergoing chemotherapy. CONCLUSIONS:Increasing knowledge about the regulation of GnRH pulsatile release, as well as the therapeutic use of its analogues, offers interesting new perspectives in the diagnosis, treatment and outcome of female reproductive disorders, including tumoral and iatrogenic diseases.
10.1093/humupd/dmv059
[Role of luteinizing hormone in follicular and corpus luteum physiology].
Hugues J N,Cedrin-Durnerin I
Gynecologie, obstetrique & fertilite
Luteinizing hormone (LH) is an hypophyseal glycoprotein involved in both follicular maturation and corpus luteum function. During the follicular phase, effects of LH must be considered according to the stages of follicular development: in the early follicular phase, LH acts through specific receptors, constitutively present on thecal cells, for stimulating androgen production. Androgens seem to be positively involved in the folliculogenesis in primates. Indeed, a positive correlation has been recently established between androgen receptor expression and follicular cell proliferation. Furthermore, androgens are active through a conversion to estrogens in granulosa cells. Estrogens are needed for achieving pregnancy. Thus, a question remains: what in the minimal amount of endogenous LH required for an optimal production of oestradiol? Several models have been investigated in clinical situations with hypogonadotrophic hypogonadism: WHO type I anovulation or GnRH analog-induced hypogonadisms. A large majority of these studies conclude that the minimal amount of LH needed during the follicular phase is probably low (< 1.5 IU/L of plasma LH level). Recent availability of GnRH antagonist will give a new opportunity for evaluating this minimal LH threshold. During the late follicular phase, LH plays a biphasic role, with a positive effect on steroidogenesis but a negative effect on cell proliferation. As suggested by S. Hillier, this negative effect on cell proliferation may be relevant to control the rate of follicular growth. One study, performed in WHO type I anovulatory patients, seems to confirm this assumption but further evaluation is needed to give support to this concept. Finally, LH is also involved in corpus luteum function. Due to the short half-life of LH as compared to hCG, the role of LH must be evaluated according to the adjunct therapies. For example, following a long-term GnRH aganist administration that constantly induces a profound hypophyseal desensitization, LH administration must be repeated to adequately sustain the corpus luteum function. This conclusion must be reconsidered with the recent introduction of GnRH antagonists. Indeed, according to their short-term effects on LH secretion, it may be presumed that a single injection of LH may be effective to maintain an adequate corpus luteum function.
10.1016/s1297-9589(00)00005-9
New insights into the role of LH in early ovarian follicular growth: a possible tool to optimize follicular recruitment.
Reproductive biomedicine online
Evidence shows that LH participates in enhancing transition from the early stage to the antral stage of folliculogenesis. It has been demonstrated that functional LH receptors are expressed, albeit at a very low level and even in smaller follicles, during the phase that was traditionally considered to be gonadotrophin independent, suggesting a role for LH in accelerating the rate of progression of non-growing and primary follicles to the preantral/antral stage. Hypogonadotropic hypogonadism, together with other clinical conditions of pituitary suppression, has been associated with reduced functional ovarian reserve. The reduction in LH serum concentration is associated with a low concentration of anti-Müllerian hormone. This is the case in hypothalamic amenorrhoea, pregnancy, long-term GnRH-analogue therapy and hormonal contraception. The effect seems to be reversible, such that after pregnancy and after discontinuation of drugs, the functional ovarian reserve returns to the baseline level. Evidence suggests that women with similar primordial follicle reserves could present with different numbers of antral follicles, and that gonadotrophins may play a fundamental role in permitting a normal rate of progression of follicles through non-cyclic folliculogenesis. The precise role of gonadotrophins in early folliculogenesis, as well as their use to modify the functional ovarian reserve, must be investigated.
10.1016/j.rbmo.2023.103369
Estrogen, synaptic plasticity and hypothalamic reproductive aging.
Hung A J,Stanbury M G,Shanabrough M,Horvath T L,Garcia-Segura L M,Naftolin F
Experimental gerontology
Unlike primates who undergo ovarian failure and loss of sex steroids at the end of reproduction, aging rodents undergo constant vaginal estrus followed by constant diestrus and finally anestrus, which indicates the absence of responsive ovarian follicles. The latter state is analogous to menopause in women. The timing of the appearance of constant estrus is determined by many factors including estrogen exposure in the brain during development and the number of times that the animal gets pregnant. The chief site of this reproductive aging in rat brains is the arcuate nucleus of the hypothalamus. The transition from normal cycles to constant estrus parallels the females' gradually decreased ability to respond to administered estradiol with a cycle of inhibition followed by disinhibition of gonadotrophin-releasing hormone. Evidence has accumulated indicating this to be due to a loss of the rat's ability to respond to markedly elevated estradiol with the usual arcuate nucleus neuro-glial plasticity that supports the estrogen-induced gonadotrophin surge (EIGS). Just as male rats are not capable of an EIGS, aged females loose this ability through repeated EIGS. Experiments indicate that in male rats the hypothalamic synaptology that develops as a result of exposure to testicular androgens in the perinatal period (brain sexual differentiation) is a result of conversion of testosterone from the testes to estrogen in the brain and is therefore due to early estrogen exposure. Aging females appear to reach a synaptology similar to males and constant estrus as a result of repeated exposure to ovarian estrogens during their reproductive careers. The relative role of aging and hormonal factors remains unclear. Morphological evidence is presented that indicates the above effects of estrogen involve changes in hypothalamic arcuate nucleus neurons and glia, including changes in the organization of perikaryal membranes as well as arcuate nucleus synaptology and the load of peroxidase in the astroglia. A possible role for free radicals (reactive oxygen species) in hypothalamic reproductive aging has been proposed. Such a mechanism is supported by evidence that the anti-oxidant vitamin E delays the onset of constant estrus and the accumulation of glial peroxidase in aging female rats. However, since the synaptology and peroxidase load in constant estrus females is independent of the age at which the constant estrus occurs, it appears that the role of (repeated) estradiol exposure is more deterministic of hypothalamic failure than is aging, per se.
Hormonal changes in the menopause transition.
Burger Henry G,Dudley Emma C,Robertson David M,Dennerstein Lorraine
Recent progress in hormone research
The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features of approaching menopause begin. A common initial marker is the onset of menstrual irregularity. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers. Follicle-stimulating hormone (FSH) is an established indirect marker of follicular activity. In studies of groups of women, its concentration, particularly in the early follicular phase of the menstrual cycle, begins to increase some years before there are any clinical indications of approaching menopause. The rise in FSH is the result of declining levels of inhibin B (INH-B), a dimeric protein that reflects the fall in ovarian follicle numbers, with or without any change in the ability of the lining granulosa cells to secrete INH-B. Estradiol levels remain relatively unchanged or tend to rise with age until the onset of the transition and are usually well preserved until the late perimenopause, presumably in response to the elevated FSH levels. During the transition, hormone levels frequently vary markedly - hence, measures of FSH and estradiol are unreliable guides to menopausal status. Concentrations of testosterone have been reported to fall by about 50% during reproductive life, between the ages of 20 and 40. They change little during the transition and, after menopause, may even rise. Dehydroepiandrosterone (DHEA) and DHEAS, its sulphate, on the other hand, decline with age, without any specific influence of the menopause. Symptoms of the menopause can be interpreted as resulting primarily from the profound fall in estradiol, occurring over a 3- to 4-year period around final menses, a fall that presumably contributes importantly to the beginning, in the late perimenopause, of loss of bone mineral density.
10.1210/rp.57.1.257
The aging reproductive neuroendocrine axis.
Brann Darrell W,Mahesh Virendra B
Steroids
It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.
Effect of age on the response of the hypothalamo-pituitary-ovarian axis to a combined oral contraceptive.
Fitzgerald C,Elstein M,Spona J
Fertility and sterility
OBJECTIVE:To examine the effect of age on the response to treatment with a combined oral contraceptive. DESIGN:Prospective, controlled clinical study. SETTING:Reproductive medicine unit in a tertiary care university medical center. PATIENT(S):Twenty-six healthy female volunteers aged 21-45 years. INTERVENTION(S):After a control cycle, all the women were given a combined oral contraceptive containing 20 microg of ethinylestradiol with 75 microg of gestodene for three cycles. The women were examined through the posttreatment cycle. MAIN OUTCOME MEASURE(S):Pituitary and ovarian activity was assessed with ultrasound and measurement of ovarian steroids. RESULT(S):Follicular activity was observed in all treatment cycles, although ovulation was inhibited. Ovarian suppression was maximal in cycle 1. Mean endogenous E2 levels were lower during cycles 2 and 3 in the older group. Serum FSH levels were higher in the control cycle and on day 28 of the treatment cycles in the older group. Most women ovulated during the posttreatment cycle. CONCLUSION(S):Combined oral contraceptives did not inhibit all ovarian activity; maximal suppression was seen in cycle 1. Less follicular activity was observed in cycles 2 and 3 in the older group. Raised FSH levels with age reflect increasing ovarian resistance to follicular development.
10.1016/s0015-0282(99)00146-6
Endocrine activity of the postmenopausal ovary: the effects of pituitary down-regulation and oophorectomy.
Sluijmer A V,Heineman M J,De Jong F H,Evers J L
The Journal of clinical endocrinology and metabolism
The endocrine activity of the postmenopausal ovary and the effect of pituitary down-regulation were studied in a group of 35 postmenopausal women. All women underwent oophorectomy with or without hysterectomy. Fifteen women received a single dose of a depot GnRH agonist (GnRHa) 2 weeks before operation, whereas 20 women formed the control group. Peripheral venous levels of LH, FSH, estrone, 17 beta-estradiol, testosterone (T), androstenedione (A), sex hormone-binding globulin, and dehydroepiandrosterone sulfate were measured 2 weeks before, during, and 6 weeks after surgery. Ovarian venous blood was sampled during surgery. In the GnRHa and control groups, ovarian venous levels of A and T were significantly higher, and those of dehydroepiandrosterone sulfate and sex hormone-binding globulin significantly lower, compared to the peripheral levels. A significant decrease in T was found in the peripheral and ovarian vein samples during pituitary down-regulation with GnRHa. Six weeks after operation, peripheral T levels were significantly lower than those during surgery in the group that was down-regulated at the time of oophorectomy. We conclude that the postmenopausal ovary produces significant amounts of A and T, although only T contributes significantly to its peripheral serum levels. T production by the postmenopausal ovary is in part stimulated by the high levels of circulating gonadotropins, although pituitary down-regulation does not completely abolish androgenic activity.
10.1210/jcem.80.7.7608272
Aging and reproductive potential in women.
Fitzgerald C,Zimon A E,Jones E E
The Yale journal of biology and medicine
Reproductive potential in women declines with age. Age-related changes in the ovary account for most of this loss of reproductive function. Oocytes, all of which are present at birth, decline in number and quality with age. The endocrine function of the ovary also declines with age, and the ovary becomes unable to sustain its normal function in the neuroendocrine axis. The neuroendocrine axis may be further affected by primary changes occurring in the hypothalamus and pituitary during aging, although this has not been established in humans. Aging also affects the function of the uterus as the endometrium loses its ability to support implantation and growth of an embryo. Diminished uterine function during aging may be due to changes in the uterine vasculature or to changes in the hormone-dependent development of the endometrium. Finally, aging increases a woman's risk of developing medical, gynecologic or obstetric conditions that may impair her fertility. Knowledge of these affects of aging on a woman's reproductive function is essential to advise and treat the growing number of women seeking pregnancy at advanced reproductive age.
The role of the brain in female reproductive aging.
Downs Jodi L,Wise Phyllis M
Molecular and cellular endocrinology
In middle-aged women, follicular depletion is a critical factor mediating the menopausal transition; however, all levels of the hypothalamic-pituitary-gonadal (HPG) axis contribute to the age-related decline in reproductive function. To help elucidate the complex interactions between the ovary and brain during middle-age that lead to the onset of the menopause, we utilize animal models which share striking similarities in reproductive physiology. Our results show that during middle-age, prior to any overt irregularities in estrous cyclicity, the ability of 17beta-estradiol (E(2)) to modulate the cascade of neurochemical events required for preovulatory gonadotropin-releasing hormone (GnRH) release and a luteinizing hormone (LH) surge is diminished. Middle-aged female rats experience a delay in and an attenuation of LH release in response to E(2). Additionally, although we do not observe a decrease in GnRH neuron number until a very advanced age, E(2)-mediated GnRH neuronal activation declines during the earliest stages of age-related reproductive decline. Numerous hypothalamic neuropeptides and neurochemical stimulatory inputs (i.e., glutamate, norepinephrine (NE), and vasoactive intestinal peptide (VIP)) that drive the E(2)-mediated GnRH/LH surge appear to dampen with age or lack the precise temporal coordination required for a specific pattern of GnRH secretion, while inhibitory signals such as gamma-aminobutyric acid (GABA) and opioid peptides remain unchanged or elevated during the afternoon of proestrus. These changes, occurring at the level of the hypothalamus, lead to irregular estrous cycles and, ultimately, the cessation of reproductive function. Taken together, our studies indicate that the hypothalamus is an important contributor to age-related female reproductive decline.
10.1016/j.mce.2008.11.012
The endocrinology of the menopause.
Burger H G
Maturitas
Changes in the endocrinology of the pituitary-ovarian axis first become manifest at about the age of 40, a selective rise in serum follicle stimulating hormone (FSH) levels occurring at about the same time as a marked acceleration in the loss of primordial follicles from the ovary. FSH levels gradually increase with increasing age in women who continue to cycle regularly. During the menopausal transition, initiated when changes in cycle frequency or in menstrual flow are first observed, both gonadotrophins, oestradiol and inhibin show a marked degree of variability with abrupt changes from typical post-menopausal patterns to those characteristic of the reproductive age group. Within 1-2 years after the final menstrual period or menopause, FSH levels are markedly elevated, luteinizing hormone (LH) levels moderately so, while oestradiol and inhibin levels are low or undetectable. Post-menopausally, adrenal androstenedione is the major source of oestrogen and serum testosterone levels fall moderately, with oophorectomy leading to a further significant fall. Serum sex hormone binding globulin levels fall to a small degree post-menopausally. Areas of persisting controversy include the question of whether oestradiol levels fall with increasing age prior to the onset of the menopausal transition, the relative roles of oestradiol and inhibin in the selective rise of serum FSH and the role of serum androgens post-menopausally.
HPG-axis hormones during puberty: a study on the association with hypothalamic and pituitary volumes.
Peper Jiska S,Brouwer Rachel M,van Leeuwen Marieke,Schnack Hugo G,Boomsma Dorret I,Kahn René S,Hulshoff Pol Hilleke E
Psychoneuroendocrinology
OBJECTIVE:During puberty, the hypothalamus-pituitary-gonadal (HPG) axis is activated, leading to increases in luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex steroids (testosterone and estradiol) levels. We aimed to study the association between hypothalamic and pituitary volumes and development of pubertal hormones in healthy pubertal children. METHOD:Hormone levels of LH, FSH, estradiol (measured in urine) and testosterone (measured in saliva) were assessed in 85 healthy children (39 boys, 46 girls) between 10 and 15 years of age. Hypothalamic and pituitary gland volumes were segmented on high resolution structural MRI scans. Since sex hormone production is regulated in a sex-specific manner, associations between hormones, hypothalamus and pituitary were analyzed in boys and girls separately. RESULTS:LH, estradiol and testosterone levels all increased with age in both sexes, whereas FSH level did not. Pituitary volume also increased with age and explained 12%, 10% and 8% of the variance in female estradiol, testosterone and LH levels respectively. Corrected for age, pituitary volume explained 17% of FSH level in girls (not boys). Hypothalamic volume did not change with age and did not significantly explain variance in any hormonal level. DISCUSSION:Our study suggests that a larger pituitary volume is related to higher FSH production, but this association seems independent of pubertal development. The positive association between estradiol, LH and testosterone and pituitary volume is related to age-related pubertal development. With respect to the hypothalamus, we did not find convincing evidence for a larger structure to be involved in elevated hormonal production.
10.1016/j.psyneuen.2009.05.025
Aging of the hypothalamo-pituitary-ovarian axis: hormonal influences and cellular mechanisms.
Nelson J F,Bergman M D,Karelus K,Felicio L S
Journal of steroid biochemistry
Longitudinal studies employing heterochronic ovarian grafts and long-term ovariectomy indicate that there is no single pacemaker of reproductive aging. Neuroendocrine dysfunction, the declining follicular reserve, and ovarian secretions all contribute to reproductive decline, and their relative importance to the different stages of reproductive aging varies markedly. Moreover, although ovarian secretions during adulthood potentiate certain aspects of the reproductive aging process, their behavior does not fit a simple model of cumulative steroidal damage incurred over the lifespan. Current data are more consistent with temporally distinct windows of steroidal vulnerability for the events affected: cycle lengthening is affected by ovarian secretions during the period of cyclicity, and post-cyclic neuroendocrine failure is potentiated by ovarian secretions during the peri- and post-cyclic period of the lifespan. Recent examination of estradiol receptor dynamics reveals multiple, albeit selective, changes during aging that may contribute to the age-related impairments of tissue sensitivity to estrogen. These changes vary qualitatively and quantitatively among target tissues. Thus, aging of the hypothalamo-pituitary-ovarian axis at the cellular level mirrors, in its multifactorial nature, aging at the organismic level.
Neuroendocrine aspects of aging in women.
Hall J E,Gill S
Endocrinology and metabolism clinics of North America
In women, the loss of ovarian function at menopause is associated with marked changes in hypothalamic and pituitary function. In addition, the steady decline in serum levels of LH, FSH, and FAS with age following menopause provides clear evidence for age-related neuroendocrine changes independent of the changes occurring owing to loss of ovarian feedback on the hypothalamic and pituitary components of the reproductive axis. An increase in the overall amount of GnRH secreted occurs despite a 30% decrease in GnRH pulse frequency with aging. This observation implies that the amount of GnRH secreted with each secretory bolus is greater in older postmenopausal women when compared with younger postmenopausal women. Thus, there may be a prominent pituitary component to the age-related decline in gonadotropin secretion. Recent studies indicate that the response to estrogen negative feedback at the hypothalamic level is preserved with aging, whereas the response to estrogen positive feedback may decrease with reproductive aging; however, the response to estrogen positive feedback in women has not been investigated with respect to aging, per se. It will be important to determine whether these age-related changes in hypothalamic-pituitary function contribute to reproductive senescence in normal women, as has been suggested for similar changes in animal models.
10.1016/s0889-8529(05)70205-x