Evidence That GnRH Decreases with Gonadal Steroid Feedback but Increases with Age in Postmenopausal Women (original) (raw)
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Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women
American Journal of Obstetrics and Gynecology, 1998
Our aim was to determine the effect of aging on the hypothalamic-pituitary-gonadal axis function. STUDY DESIGN: We studied 9 women aged 25 to 40 years with well-defined idiopathic premature ovarian failure and compared them with 8 women aged 51 to 70 years who had age-appropriate menopause. All women underwent 24 hours of frequent blood sampling every 10 minutes before and after replacement with transdermal estradiol targeted to achieve serum concentrations of approximately 100 pg/ml. RESULTS: In the absence of estrogen exposure, women with premature ovarian failure demonstrated a greater 24-hour mean luteinizing hormone concentration compared with that in the older women with ageappropriate menopause (32.3 ± 4.3 mIU/ml vs 19.2 ± 2.4 mIU/ml, p = 0.0001). Despite the lesser luteinizing hormone serum levels in the older group, the luteinizing hormone pulse frequency per 24 hours was similar (22.1 ± 3.0 pulses per 24 hours in prematurely menopausal women vs 21.9 ± 2.5 pulses per 24 hours in the older postmenopausal women, p = 0.94). When exposed to estrogen, mean luteinizing hormone concentrations decreased to 11.6 ± 2.7 mIU/ml in prematurely menopausal women versus 4.4 ± 1.0 mIU/ml in older postmenopausal women, p = 0.017. Both groups had suppressed mean luteinizing hormone secretion compared with their paired, non-estradiol-exposed studies, p = 0.0001. Frequency of luteinizing hormone pulsations was reduced to 16.5 ± 3.5 pulses per 24 hours in prematurely menopausal women exposed to estradiol (p < 0.0058, compared with non-estradiol-exposed women). Further reduction was observed in older postmenopausal women (11.5 ± 1.1 pulses per 24 hours, p = 0.0001, compared with nonestradiol exposure, and p = 0.0125, vs prematurely menopausal, estradiol-exposed women). Pulse amplitude was suppressed in both prematurely menopausal women (5.6 ± 0.5 mIU/ml to 2.3 ± 0.5 mIU/ml, p = 0.0001) and older postmenopausal women (3.6 ± 0.4 mIU/ml to 2.3 ±0.6 mIU/ml p = 0.04) in the presence of estradiol. Although luteinizing hormone pulse amplitudes were greater in the women with premature menopause in the absence of estradiol (p = 0.0028) compared with those in older postmenopausal women, pulse amplitudes became similar in the presence of estradiol. Parallel changes in mean follicle-stimulating hormone were observed. Women with premature ovarian failure had a mean follicle-stimulating hormone level of 71.1 ± 9.4 mIU/ml that was suppressed to 18.0 ± 4.1 mIU/ml after estradiol exposure (p = 0.0001); values in older postmenopausal women were 45.9 ± 6.0 and 10.3 ± 2.0, respectively (p = 0.0001). Although the women with premature ovarian failure secreted more follicle-stimulating hormone in the absence and presence of estradiol, only the former situation was statistically significant (p = 0.0008 and p = 0.23, respectively). CONCLUSIONS: These data suggest that there is an age-related decrease in gonadotropin secretion that may be hypothalamic or pituitary in origin. There is less luteinizing hormone secreted in women older than age 50. There is greater suppression of luteinizing hormone and follicle-stimulating hormone secretion by estradiol in aged women. Thus these data indicate that postmenopausal hormone changes involve central hypothalamic-pituitary alterations, as well as ovarian changes. (Am J Obstet Gynecol 1998;178:732-41.) Reproductive aging in women is almost exclusively ascribed to loss of ovarian follicular function. However, in animals, clear-cut hypothalamic-pituitary axis changes occur in the face of adequate ovarian follicular reserve. 1 A phenomenon frequently observed in aging rodents is the inability to achieve a luteinizing hormone (LH) surge in response to a bolus of exogenous estrogen-a feature of middle-aged but not older animals. 1 There is an analogous condition in perimenopausal women, in
Aging Attenuates the Pituitary Response to Gonadotropin-Releasing Hormone
The Journal of Clinical Endocrinology & Metabolism, 2009
Context: Complex changes in GnRH secretion occur with aging in women, but little is known about the effect of aging on the pituitary per se. Objective: The aim of the study was to determine whether pituitary responsiveness to GnRH is attenuated with aging. Design and Setting: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness in Clinical Research Center studies at an academic medical center. Subjects: Subjects were healthy postmenopausal women (PMW) aged 48–57 yr (n = 10) or 70–77 yr (n= 9). Interventions: A suppressive dose of the NAL-GLU GnRH antagonist (150 μg/kg sc) was administered and was followed by GnRH doses of 25, 75, 250, or 750 ng/kg iv every 4 h. Results: The LH response to GnRH was attenuated with aging (P = 0.05) with an interaction between age and dose (P = 0.01) such that the LH amplitude was less in older PMW at the higher doses (250 ng/kg, 50 ± 9 vs. 29 ± 4.9 IU/liter, for young and old PMW, respectively, P = 0.02; and 750 ng/...
Biology of Reproduction, 2004
The present study examined the gonadotropin surge-inducing actions of estradiol (E 2), both alone and with progesterone (P 4), in middle-aged, early persistent-estrous (PE) female rats that had become PE within 35 days. In addition, we also assessed the effect of P 4 on the mating-induced gonadotropin surges in these acyclic animals. Early PE rats were ovariectomized and received E 2 implants (Day 0). On Day 4, an s.c. injection of P 4 (0.5 mg/ 100 g body weight) at 1200 h markedly increased plasma P 4 and elicited both LH and FSH surges, whereas vehicle-treated controls displayed no rise in P 4 or gonadotropins. This observation confirms that at middle age, female rats no longer respond to the positive-feedback stimulation of E 2 on gonadotropin surges whenever the estrous cyclicity ceases. As PE continued, such a surge-inducing action of E 2 plus P 4 became diminished after 75 days of PE and disappeared thereafter. When caged with males, vehicle-treated early PE rats display a mating-induced increase in P 4 from the adrenal along with small gonadotropin surges. The amplitude of these mating-induced gonadotropin surges was enhanced by supplementation with exogenous P 4 in early PE rats. Our findings indicate that during the early phase of PE, the surge-inducing action of E 2 and P 4 remains intact but deteriorates as PE continues. Thus, a deficiency in P 4 secretion during aging may contribute to the diminished gonadotropin surge response in the hypothalamic-pituitary axis and the subsequent cessation of estrous cyclicity.
Altered Neuroendocrine Control of GH Secretion in Normal Women of Advanced Reproductive Age
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 1997
Background. Previous studies have suggested that the neuroendocrine control of growth hormone (GH) secretion changes with increasing age in women with normal menstrual cycles and sex steroid levels. Methods. In order to verify this hypothesis, 8 younger (22-32 years) and 8 older (41-45 years) women with normal menstrual function and gonadal steroid levels were tested with the serotonergic agent sumatriptan (6 mg in a subcutaneous bolus), the GABAergic agonist sodium valproate (800 mg orally), the dopaminergic compound L-Dopa (500 mg orally) and placebos. Furthermore, all women were tested with GH-releasing hormone (GH-RH 1 pg/kg body weight in an intravenous (i.v.) bolus) to determine whether GH secretion in response to its specific releasing factor was preserved. Serum GH levels were recorded over 2 hours in all tests and IGF-I levels in basal samples. Results. Plasma IGF-I concentrations and the GH responses to sumatriptan, sodium valproate and L-Dopa were significantly lower in older than in younger women. Also, the GH-RH-induced GH response was significantly lower in older than in younger subjects. When peak GH responses to releasing stimuli were compared with age, significant negative correlations were found in all tests. Conclusions. These data did not show a specific neurotransmitter change underlying defective GH secretion in older aged reproductive women. On the other hand, the results indicated that age-related changes in the secretory machinery of GH, such as a reduced pituitary sensitivity to GH-RH and/or a reduction in the pituitary GH secretory capacity, affect women during the last years of the reproductive period.
Neuroendocrine control of reproductive aging: roles of GnRH neurons
Reproduction, 2006
The process of reproductive senescence in many female mammals, including humans, is characterized by a gradual transition from regular reproductive cycles to irregular cycles to eventual acyclicity, and ultimately a loss of fertility. In the present review, the role of the hypothalamic gonadotropin-releasing hormone (GnRH) neurons is considered in this context. GnRH neurons provide the primary driving force upon the other levels of the reproductive axis. With respect to aging, GnRH cells undergo changes in biosynthesis, processing and release of the GnRH decapeptide. GnRH neurons also exhibit morphologic and ultrastructural alterations that appear to underlie these biosynthetic properties. Thus, functional and morphologic changes in the GnRH neurosecretory system may play causal roles in the transition to acyclicity. In addition, GnRH neurons are regulated by numerous inputs from neurotransmitters, neuromodulators and glia. The relationship among GnRH cells and their inputs at the c...
REPRODUCTIONREVIEW Neuroendocrine control of reproductive aging: roles of GnRH neurons
2016
The process of reproductive senescence in many female mammals, including humans, is characterized by a gradual transition from regular reproductive cycles to irregular cycles to eventual acyclicity, and ultimately a loss of fertility. In the present review, the role of the hypothalamic gonadotropin-releasing hormone (GnRH) neurons is considered in this context. GnRH neurons provide the primary driving force upon the other levels of the reproductive axis. With respect to aging, GnRH cells undergo changes in biosynthesis, processing and release of the GnRH decapeptide. GnRH neurons also exhibit morphologic and ultrastructural alterations that appear to underlie these biosynthetic properties. Thus, functional and morphologic changes in the GnRH neurosecretory system may play causal roles in the transition to acyclicity. In addition, GnRH neurons are regulated by numerous inputs from neurotransmitters, neuromodulators and glia. The relationship among GnRH cells and their inputs at the c...
Negative Feedback Effects of Gonadal Steroids Are Preserved with Aging in Postmenopausal Women
The Journal of Clinical Endocrinology & Metabolism, 2002
There is now evidence for alterations in the neuroendocrine control of the reproductive axis with aging, but its sensitivity to gonadal steroid negative feedback remains controversial. To examine the independent effect of age and gonadal steroid negative feedback, younger (45-55 yr; n ؍ 7) and older (70-80 yr; n ؍ 6) postmenopausal women (PMW) were studied at baseline on no HRT, after 1 month of transdermal estrogen (50 g/d; E) and again after a further month of E and 7 d of transvaginal progesterone (P) (100 mg bid; E ؉ P). At each admission, blood was sampled every 5 min for 8 h for measurement of gonadotropin free ␣-subunit (FAS), which was used as a marker of GnRH pulse frequency. LH and FSH were measured in pooled samples. Midfollicular and midluteal phase levels of E2 and P were achieved during the E and E ؉ P treatments and were not different between younger and older PMW. There was a negative feedback effect of E and E ؉ P on mean LH (P < 0.0001) and an additional effect of age (P < 0.003), with older women having lower values throughout. Mean FSH was also decreased with E and E ؉ P (P < 0.0001) and was consistently lower in the older women (P < 0.05). Mean FAS levels decreased with hormonal treatment (P < 0.0001) and age (P < 0.001), but the effect of hormonal treatment was attenuated in the older group (P < 0.005). FAS pulse frequency was unchanged with addition of E, but dramatically decreased with E ؉ P (P < 0.002). Both hormonal replacement (P < 0.05) and age (P < 0.005) decreased FAS pulse amplitude, an effect that was attributable entirely to E as there was no additional change with E ؉ P. These studies indicate that: 1) both age and gonadal steroids independently decrease mean LH, FSH, and FAS in PMW; 2) responsiveness to steroid negative feedback on FAS is attenuated with aging in absolute but not relative terms, whereas the effect on mean levels of LH and FSH is clearly preserved; and 3) FAS pulse frequency is unchanged with E2 administration but decreases dramatically with addition of P in both old and young PMW.
Neuroendocrine Modulation and Repercussions of Female Reproductive Aging
Recent Progress in Hormone Research, 2002
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women.
Endocrine, 2000
Reproductive aging in female rats is characterized by profound alterations in the neuroendocrine axis. The preovulatory luteinizing hormone (LH) surge is attenuated, and preovulatory expression of the immediate early gene fos in gonadotropin-releasing hormone (GnRH) neurons is substantially reduced in middleaged compared with young rats. We tested the hypothesis that alterations in GnRH gene expression may be correlated with the attenuation of the LH surge and may be a possible mechanism involved in neuroendocrine senescent changes. Sprague-Dawley rats ages 4 to 5 mo (young), 12-14 mo (middle-aged), or 25 to 26 mo (old) were killed at 10:00 AM or 3:00 PM on proestrus, the day of the LH surge, or diestrus I in cycling rats, and on persistent estrus or persistent diestrus in acyclic rats. RNase protection assays of GnRH mRNA and GnRH primary transcript were performed. GnRH mRNA levels increased significantly with age, whereas GnRH primary transcript levels, an index of GnRH gene transcription, decreased in old compared to young and middle-aged rats. This latter result suggests that an age-related change in GnRH mRNA levels occurs independently of a change in gene transcription, indicating a potential posttranscriptional mechanism. On proestrus, GnRH mRNA levels increased significantly from 10:00 AM to 3:00 PM in young rats. This was in contrast to proestrous middle-aged rats, in which this afternoon increase in GnRH mRNA levels was not observed. Thus, the normal afternoon increase in GnRH mRNA levels on proestrus is disrupted by middle age and may represent a substrate for the attenuation of the preovulatory GnRH/LH surge that occurs in rats of this age, prior to reproductive failure.