Characteristics of pulsatile luteinizing hormone secretion in middle-aged ovariectomized rats

Experiments were performed to characterize the pulsatile patterns of circulating luteinizing hormone (LH) in the middle-aged ovariectomized (OVX) rat. Frequent blood samples were taken from OVX rats at 6, 7-8, and 9-10 mo of age, and LH was measured by radioimmunoassay. Rats had been OVX either 2 wk (STO) or 10-20 wk (LTO) previously. Mean LH levels were significantly lower with increasing age, reflecting effects on both pulse amplitude and pulse frequency. Mean LH levels were higher in LTO than STO groups, reflecting primarily an increase in pulse amplitude, but there was also a small, significant decrease in pulse frequency with increased time following OVX. In a second experiment, a random selection of the rats in the STO groups was tested again 10 wk after OVX. A significantly higher number of 9- to 10-mo-old rats had pulsatile patterns at 10 wk than at 2 wk following OVX. Furthermore, mean plasma LH concentrations were higher in all three groups. We conclude that decreases in several parameters of LH secretion are seen in middle-aged OVX rats, at the time when irregularities are first seen in the estrous cycle in the intact rat.     

Differential changes in the mechanisms controlling luteinizing hormone and prolactin secretion in middle-aged female rats

Serum luteinizing hormone (LH) and prolactin (PRL) concentrations were measured in young (3-4 month old) and middle-aged (10-12 month old) intact female rats on proestrus, in ovariectomized rats after two estrogen injections (estradiol benzoate; EB, 10 micrograms/100 g body weight, s.c.) or after preoptic stimulation in EB-primed ovariectomized rats. Only animals showing regular 4-day estrous cycles were selected for the experiment. The magnitude of proestrous LH surge was significantly smaller in middle-aged than in young rats. Two BE injections, at noon on Days 0 and 3, in ovariectomized middle-aged rats failed to induce surges in LH secretion on Day 4 whereas the same treatment produced LH surges in ovariectomized young rats. The preoptic electrochemical stimulation (50 microA for 60 sec) produced a prompt rise in serum LH levels in ovariectomized EB-primed young but not in middle aged rats. The preoptic stimulation with a larger current (200 microA) induced LH secretin in middle-aged rats. In none of these situations serum PRL concentrations were different between young and middle-age rats. These results suggest differential aging rates in the preoptic mechanisms governing LH and PRL secretion in the rat. The function of the preoptic ovulatory center in responding to the estrogen positive feedback action and inducing LH secretion may become impaired and independent of the PRL control mechanism, even before the regular estrous cycle terminates.     

Diurnal rhythmicity of norepinephrine activity associated with the estradiol-stimulated luteinizing hormone surge: effect of age and long-term ovariectomy on hemispheric asymmetry

The age-related decline in female reproductive capacity in rats is accompanied by an inability to respond positively to estradiol (E2) treatment. This age-related change is associated with a loss in diurnal rhythmicity of norepinephrine (NE) activity in brain areas important in the control of LH. Decreased exposure to ovarian secretions during adulthood delays certain aspects of neuroendocrine aging. We tested the hypothesis that long-term ovariectomy (OVX) would delay the age-related loss of diurnal rhythmicity in NE activity in microdissected hypothalamic nuclei. Intrigued by reports of lateralization of hypothalamic function, we also assayed NE activity in the left and right sides of the hypothalamus separately. Young (2-3 mo) and middle-aged (11-12 mo) rats that exhibited regular estrous cycles were OVX. One week later (Day 0) these short-term OVX animals (Y-ST, MA-ST) plus a group of middle-aged (11-12 mo) rats that were OVX at 3 mo (MA-LT) were treated with E2. On Day 4, the rate constant of NE activity in microdissected hypothalamic nuclei was determined at 0900 h and 1500 h using the alpha-methyl-para-tyrosine method. Rate constants were compared by t-test to determine diurnal rhythmicity. Y-ST rats exhibited a diurnal rhythm in NE activity in the median eminence, which was absent in MA-ST rats. Long-term OVX spared animals this "age-related" loss in rhythmicity since MA-LT rats demonstrated a significant increase in NE activity from morning to afternoon.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation of ovarian steroid levels in young female rats to subsequent estrous cyclicity and reproductive function during aging

In multiparous rats, the incidence of regular estrous cyclicity and fertility decreases markedly at middle age. However, recent studies have shown that repeated pregnancies or progesterone (P) implants can subsequently cause retired breeder females to maintain regular cyclicity for an extended period of time; these results suggest a P-mediated deceleration of reproductive aging. In the present study, we examined the relation of ovarian steroid levels in young virgin females to their subsequent estrous cyclicity and reproductive function during aging as compared to multiparous females. Beginning at 4 mo of age and continuing to 6 mo of age, regularly cyclic virgin rats received either consecutive P implants (n = 41) or no implants (controls, n = 45) for 3 wk, followed by implant removal for 1 wk. Additional females (n = 72) were mated and allowed to undergo repeated pregnancies at 4, 6 1/2, and 8 mo of age. Blood samples were obtained throughout the estrous cycle (virgin females), during pregnancy (multiparous rats), and on Day 11 of successive treatments with P implants (virgins with P implants) for P, estradiol (E2), and testosterone (T) measurements. Subsequently, regularly cyclic females from all three groups were mated with fertile males to undergo term pregnancies at 10 and 12 mo of age. While the virgin controls showed cyclic increases in P, T, and E2 secretion during their estrous cycles, the P-implanted females had persistently low E2 and high P and T levels during treatment, which indicates an inhibition of ovarian E2 synthesis by P.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of day length and endocrine status on luteinizing hormone secretion in intact and ovariectomized adult ferrets

The purpose of this study was to examine the pituitary-ovarian relationship of both estrous and anestrous female ferrets. The endocrine status of the animals was induced by manipulating photoperiod: females in estrus were housed in long days (16L:8D); females in anestrus were housed in short days (8L:16D). For studies of intact animals in both photoperiods, plasma luteinizing hormone (LH) levels were quantified in blood samples collected from adult ferrets at 5-min intervals over a 24-h period. Similar groups of females (estrous and anestrous) were ovariectomized (while remaining in their assigned photoperiods) and blood samples were collected at 5-min intervals for 4-h periods on Days 1, 2, 4, 10, 17, and 35 after ovariectomy. Intact, estrous females exhibited continuously low or undetectable levels of LH with no evidence of episodic secretion. Ovariectomy of these estrous animals resulted in rapid onset (within 24 h) of episodic LH secretion, with pulses occurring in excess of 1 pulse/h. No substantial further change in frequency or amplitude of pulses occurred in these females from 1 to 35 days postovariectomy. In contrast, intact anestrous ferrets exhibited clear episodic LH secretion at a frequency of about 0.4 pulses/h. Removal of ovaries from these females caused no change in LH secretion for 24-48 h, after which LH pulses gradually increased in frequency. By 18 days after ovariectomy, LH patterns were indistinguishable among ovariectomized females in long and short days. These studies suggest a major site of ovarian negative feedback on LH secretion during anestrus is the hypothalamus, whereas the site of the ovarian feedback in estrous females is not yet evident.     

Alterations in the proestrous pattern of median eminence LHRH, serum LH, FSH, estradiol and progesterone concentrations in middle-aged rats

The purpose of the following study was to assess the changes in the proestrous hormone profile in middle-aged cycling rats to better understand the inter-relationship and possible interaction of these hormones during the transition to estrous acyclicity. Median eminence LHRH concentrations and serum LH, FSH, estradiol and progesterone concentrations were measured in young (3-4 months old) and middle-aged (8-10 months old) proestrous rats at 0900, 1200, 1500 and 1800h. The data demonstrate that (1) baseline hormone concentrations prior to the surge at 0900h are the same in middle-aged and young rats; (2) the proestrous gonadotropin surge is temporally delayed in middle-aged rats; (3) this delay is preceded by lower median eminence LHRH concentrations and serum estradiol concentrations at 1200h; (4) serum progesterone concentrations are lower in middle-aged rats during the preovulatory gonadotropin surge (at 1500 and 1800h) probably as a consequence of the delayed LH surge.     

Hypothalamic luteinizing hormone-releasing hormone (LHRH) and LH secretion in aging female rats

Age-related changes in hypothalamic luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH) secretion were studied in young (6 months), middle-aged (12 months) and old (18 months) female rats. The LHRH levels in the mid-hypothalamic area were higher in intact middle-aged and old females than in young ones. Additionally, there was no age difference in the hypothalamic LHRH levels in male rats. In order to clarify the significance of this age-related increase in female rats, we examined the effects of progesterone treatment in estrogen-primed ovariectomized young and old rats on the LHRH levels in the median eminence (ME) and on plasma LH levels. We found phasic changes in ME-LHRH and plasma LH levels in estrogen-primed rats following progesterone treatment in rats of both ages, but the progesterone-induced change in ME-LHRH levels tended to be delayed in old rats compared with young females. This delay may correspond to the delayed onset, slow and low magnitude of plasma LH increase in old females. The ME-LHRH levels were generally higher in old rats than in young rats. Nevertheless, we found that the increase in plasma LH in response to progesterone treatment in estrogen-primed ovariectomized females was smaller in old rats than young rats. These results suggest that the LHRH secretory mechanism changes with age in female rats. Such alterations may result in the accumulation of LHRH in the mid-hypothalamic area and an increase in ME-LHRH.     

Early treatment of young female rats with progesterone delays the aging-associated reproductive decline: a counteraction by estradiol

We have recently reported that successive treatments of young virgin rats with progesterone (P) implants produce elevated circulating P and consistently low estradiol (E2) concentrations, and subsequently delay the aging-associated reproductive decline. Inasmuch as E2 has been implicated in causing the loss of regular estrous cyclicity in aging rats, the present study examined if the concomitant presence of moderately increased circulating E2 levels could counteract the effects of P implants on reproductive aging. Starting at 3 1/2 mo and continuing to 8 mo of age, regularly cyclic, virgin rats received either s.c. Silastic implants of P (P-implanted), blank Silastic implants (virgin controls), or P + E2 implants (P + E2-implanted) for 3 wk, followed by implant removal for 1 wk. Each of these implant treatments was repeated in the same female rats 5 times. Blood samples were obtained on different days of the estrous cycle from the control group and on Day 11 of successive treatments with P or P + E2 implants for measurements of serum P and E2 values. At 8 1/2 and 10 mo of age, estrous cyclicity of these same virgin rats was again monitored, and 10-mo-old regularly cyclic females from each treatment group were mated with young fertile males to complete term pregnancies. While virgin controls showed cyclic increases in E2 and P secretion during the estrous cycle, P-implanted virgins exhibited consistently low serum E2 and moderately increased P levels during 5 successive treatments. The latter indicates a potent inhibition of ovarian E2 secretion by P implants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ovarian steroidogenic responsiveness to exogenous gonadotropin stimulation in young and middle-aged female rats

Reproductive aging in the female rat is associated with gradual declines in LH secretion and ovarian progesterone (P) production. This study examined whether the influences of aging on P levels reflect decreased ovarian responsiveness to gonadotropin stimulation, as opposed to changes in gonadotropin release. Young and middle-aged regularly cyclic female rats received sodium pentobarbital to block endogenous proestrous luteinizing hormone (LH) surges, followed by administration of various doses of human chorionic gonadotropin (hCG). Similar treatments were performed in middle-aged acyclic persistent-estrous (PE) females. Injection of hCG resulted in equivalent plasma hCG levels in each treatment group. At the lowest hCG dose tested, a significant rise in plasma P levels was observed in middle-aged cyclic rats, but not in young cyclic or middle-aged PE females. This unexpected finding may reflect accelerated follicular development in middle-aged cyclic females, as suggested by a previous study. At the intermediate dose, young and middle-aged cyclic but not PE rats displayed significantly increased P in response to hCG. At the highest dose tested, all three groups of rats displayed increased P levels after hCG stimulation. However, P concentrations were significantly lower in middle-aged PE than regularly cyclic females. Northern and slot blot hybridization analyses revealed that ovarian mRNA levels for cytochrome P450 side-chain cleavage, the rate-limiting enzyme in P synthesis, were markedly reduced in PE rats following hCG stimulation. These findings indicate that ovarian responsiveness to gonadotropin stimulation is impaired in middle-aged PE, but not regularly cyclic rats, and suggest influences of cycle status on the biochemical and molecular mechanisms regulating ovarian steroid production. Furthermore, these findings reveal that attenuated P production in middle-aged proestrous rats is due to attenuated preovulatory LH surges, rather than decreased ovarian sensitivity to LH.     

Ovarian response to active immunization against luteinizing hormone in the cow

Two experiments were conducted to determine whether active immunization against luteinizing hormone (LH) could lead to ovarian cyst development in the cow. In Experiment 1, cyclic beef heifers were randomly assigned to receive bovine LH (bLH) conjugated with ovalbumin (LH-immunized; n=4) or ovalbumin alone (control; n=5). Blood samples were collected at monthly intervals from the LH-immunized heifers to determine antibody titers. Heifers were observed for estrous behavior twice daily. All heifers were slaughtered 4 mo after initial immunization and ovaries examined for follicular status. In Experiment 2, mature dairy cows were immunized with bLH (LH-immunized; n=4) or ovalbumin alone (control; n=3). Weekly blood samples were collected from all cows for 26 wk and ovaries were rectally palpated. Sera from all of the LH-immunized heifers and cows had antibodies to LH. All of the LH-immunized animals stopped cycling 1 mo after immunization. In spite of the fact that serum follicle stimulating hormone levels were unaffected, ovarian cysts could not be found in either the LH-immunized heifers or cows.     

Isolated hypothalami from aging female rats do not exhibit reduced basal or potassium-stimulated secretion of luteinizing hormone-releasing hormone.

Serum LH levels are diminished in middle-aged rats during spontaneous or steroid-induced LH surges and following ovariectomy (ovx). The compromised LH responses are presumed to reflect age-related alterations in LHRH neurosecretion. Direct measurements of LHRH output in middle-aged females are, however, limited. The present study utilizes an in vitro perifusion paradigm to assess basal and stimulated secretory capacity of LHRH neurons in isolated hypothalamic preparations from aging female rats. Individual hypothalamic fragments from middle-aged and young proestrous, ovx, and ovx, estradiol-treated females were perifused for 6 h and effluents were collected continuously at 10-min intervals. After 4 h of unstimulated output, two 10-min depolarizing pulses of KCl were administered. Although stimulated LHRH secretion was comparable in the two age groups, basal LHRH release from aging hypothalami was significantly elevated (pbasal less than 0.001). Furthermore, endocrine influences on LHRH output from aging hypothalami were less pronounced when compared to endocrine influences on LHRH output from young hypothalami, suggesting that steroidal regulation of LHRH secretion may be impaired in middle-aged females. These data demonstrate that LHRH neurons maintain the capacity to respond to a depolarizing stimulus at the time when regular estrous cycles cease and consequently suggest the importance of altered modulation of LHRH neurosecretion to the development of reproductive senescence.     

Influences of age and ovarian follicular reserve on estrous cycle patterns, ovulation, and hormone secretion in the Long-Evans rat

This study examined the influences of aging and reduced ovarian follicular reserve on estrous cyclicity, estradiol (E(2)) production, and gonadotropin secretion. Young virgin and middle-aged (MA) retired breeder female rats were unilaterally ovariectomized (ULO) or sham operated (control). Unilateral ovariectomy of young rats reduced the ovarian follicular reserve by one-half, to a level similar to that found in MA controls. Unilateral ovariectomy of MA females reduced the follicular pool further, to one half of MA controls. The incidence of regular cyclicity was significantly lower in MA ULO females than in young controls, with intermediate cycle frequency in young ULO and MA controls. Among cyclic rats, the magnitude of the proestrous LH surge was highest in young controls, intermediate in young ULO rats and MA controls, and lowest in MA ULO females. Similarly, ovulation rates were highest in young controls, intermediate in young ULO rats and MA controls, and lowest in MA ULO females. While young ULO rats exhibited augmented secondary FSH surges on estrous morning, middle-aged ULO females displayed secondary FSH levels comparable to young controls. The effects of age and reduced follicle number on estrous cyclicity and gonadotropin secretion were not due to altered E(2) secretion, as preovulatory E(2) levels were similar among all groups. Thus, experimental reduction in the follicular reserve exerts acute effects on the preovulatory LH surge, ovulation rate, and estrous cyclicity in both young and MA rats. However, decreased follicle number increases FSH levels only in young rats, indicating aging-related alterations in the feedback regulation of FSH.     

Effectiveness of estradiol and progesterone in inducing LH release in different stages in rat estrous cycles

The effectiveness of estradiol (E2) and progesterone (P4) in inducing the release of the luteinizing hormone (LH) in the acutely ovariectomized (OVx) rats was studied. Female rats were Ovx in different stages of the estrous cycles and received a series of injections of E2 and P4. LH dynamic changes in the blood were examined in the afternoon of the following day after Ovx. Intact rats treated with oil vehicle or E2 and P4 were used as controls. The surgical operation and oil treatment did not interfere with the normal reproductive rhythm and LH secretion, but treatment with E2 and P4 did facilitate the LH release in some intact rats. E2 and P4 were very effective in inducing LH release in Ovx rats as compared with controls. Results indicated that E2 and P4 are essential substances in eliciting the LH surge, but their efficacies are dependent on the stage in the estrous cycles.     

Delayed anovulatory syndrome induced by estradiol in female C57BL/6J mice: age-like neuroendocrine, but not ovarian, impairments

These studies describe induction of a delayed anovulatory syndrome (DAS) by estradiol (E2) in female C57BL/6J mice. Six days after birth, female mice were injected s.c. with 0.1 micrograms estradiol benzoate or oil. Over 90% of the oil-injected controls exhibited estrous cycles from 2 to 9 mo of age. In contrast, 60% of the E2-injected mice exhibited estrous cycles at 2 mo of age but were acyclic by 9 mo; these mice were considered to have exhibited a DAS, and had longer cycles than controls. At 12 mo, ovarian impairments were assessed by examining 1) ovulation after s.c. injection of 5 IU human chorionic gonadotropin (hCG), and 2) estrous cycles after grafting into young (3-mo-old) hosts. Simultaneously, neuroendocrine impairments were assessed by examining 1) the surge of luteinizing hormone (LH) induced by E2 implants after ovariectomy, and 2) estrous cycles after receiving ovarian grafts from 3-mo-old mice. Ovaries from DAS and control mice ovulated equally in response to hCG. Ovaries from DAS mice grafted into young ovariectomized hosts supported 30% more cycles, of shorter period, compared with ovaries from control donors. However, the E2-induced LH surge was 50% smaller in DAS mice than in controls. Ovariectomized DAS hosts with ovarian grafts from young mice supported 70% fewer estrous cycles, of longer period, compared with ovariectomized control hosts with young grafts. We conclude that the E2-induced DAS in female mice is not due to ovarian impairments, but seems to result from neuroendocrine impairments.     

Prolongation and cessation of estrous cycles in aging C57BL/6J mice are differentially regulated events

The relative contributions of ovarian failure and hypothalamic-pituitary dysfunction to the prolongation and cessation of estrous cycles were assessed by measuring the ability of acutely ovariectomized (OVX) middle-aged (12 mo) mice to cycle after receiving grafts (under the renal capsule) of ovaries from young (2 mo) mice. The potentially disruptive effect of the acyclic state on the cycling response to grafted, young ovaries was avoided restricting grafting to middle-aged hosts that were still cycling. The effect of chronic exposure to ovarian secretions before the cessation of cyclicity on age-related hypothalamic-pituitary dysfunction was also assessed. The cycling ability of long-term OVX middle-aged mice (i.e., OVX at 3 mo) bearing grafts of young ovaries was compared to that of age-matched acutely OVX controls. Grafted young ovaries extended the cycling lifespan of acutely OVX middle-aged hosts by 60%. The length of this extended cycling lifespan, however, was only 80% of that achieved by young hosts bearing grafts of young ovaries. Young ovaries in middle-aged mice markedly lowered the incidence of long cycles (greater than 5 days), shifting the modal cycle length to 5 days. However, young ovaries in middle-aged mice failed to increase the incidence of 4-day cycles, the modal cycle of young controls. Middle-aged ovaries grafted into young hosts lengthened their cycles and shortened their cycling lifespan to middle-aged values. Long-term ovariectomy failed to increase the cycling lifespan of middle-aged hosts bearing grafts of young ovaries beyond that achieved in acutely OVX mice. Long-term ovariectomy did shorten the modal cycle length of middle-aged mice to 4 days, although the duration of 4-day cycling was only one-third (2 mo) that of young controls. These results indicate that the relative contributions of ovarian and neuroendocrine factors to three major events of reproductive aging vary with each event. Whereas the hypothalamic-pituitary unit appears to play an important role in the initial shift from 4- to 5-day cycles, the aging ovary plays the major role in the subsequent shift to longer cycles and in the ultimate cessation of cyclicity. Although chronic exposure to ovarian secretions during the period of cyclicity does not play a major role in the cessation of cyclicity, it appears to contribute to the hypothalamic-pituitary changes responsible for the initial shift from 4- to 5-day cycles.     

Pulsatile patterns of gonadotropins and ovarian steroids during estrus and pseudopregnancy in the rabbit

Consecutive daily plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol-17 beta (E2), progesterone (P4) and 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OHP) were monitored in estrous rabbits and in these same doses during pseudopregnancy (PSP); these daily hormone levels, as well as the immediate post-coital changes in gonadotropin secretion, were similar to those in previous reports. To examine the pulsatile patterns of the gonadotropins and ovarian steroids, sequential, 10-min plasma samples were collected for 6 h from estrous does and on Days 3, 10, and 17 of PSP. All five hormones were measured in the serial samples from estrous and PSP Day 10 does; LH and FSH only were assayed in the remaining sequential samples. The amplitude and frequency of FSH pulses did not differ between any of these stages. In marked contrast, LH pulse amplitudes, and even pulse frequencies in Day 17 does, were profoundly increased during PSP above those in estrous does. Progestin secretions, both P4 and 20 alpha-OHP, also were sharply elevated in PSP Day 10 does as compared with those in estrous rabbits; the pulse amplitudes of both progestins were severalfold higher during PSP. P4 pulse frequencies were also increased at this time. Conversely, the parameters of E2 secretion did not differ between estrous and PSP Day 10 animals. In PSP Day 10 does, high amplitude pulses of both P4 and 20 alpha-OHP occurred simultaneously with high amplitude LH pulses. Simultaneous E2 and P4 pulses were evident in these same sequential plasma samples, and this E2-P4 pulse association was greater than that of 20 alpha-OHP pulses with E2 pulses. Our findings failed to identify conclusively the trophic stimulus for the progestin pulse patterns, but the mechanism may involve the coordinated action of LH and E2. The results do demonstrate that each gonadotropin and ovarian steroid is secreted in a pulsatile manner in both estrous and pseudopregnant rabbits. There are altered profiles in LH and progestin pulses, without major changes in FSH and E2 patterns, between the stages of estrus and PSP. The causes and consequences of these divergent endocrine shifts cannot be deduced from these data.     

Effects of chronic exposure to estradiol on ovarian cyclicity in C57BL/6J mice: potentiation at low doses and only partial suppression at high doses

Long-term exposure to ovarian hormones contributes to age-related changes in estrous cyclicity in rodents. Estrogens are implicated in this process, but the concentration of estrogen required to exert these effects is not well established. Also, although estrogens are presumed to alter vaginal cyclicity by affecting the hypothalamic-pituitary axis, they may also impair the ability of the vaginal epithelium to cornify. To address these issues, young and middle-aged ovariectomized (ovx) C57BL/6J mice were exposed for 7-10 wk to plasma levels of estradiol (E2) at one of three ranges (30-40, 50-80, or 120-160 pg/ml). Ovaries from young mice were then transplanted under the renal capsule, and vaginal cyclicity was monitored for 4 mo. Mice exposed to the lowest level of E2 not only failed to stop cycling, but had a higher monthly frequency of estrous cycles than did controls (nearly 1 extra cycle/mo). Mice exposed to the intermediate level of E2 showed no impairment in cyclicity. Although mice exposed to the highest concentrations of E2 showed no vaginal cyclicity, they continued to ovulate as evidenced by fresh, albeit reduced, numbers of corpora lutea. These results indicate that, in ovx mice, (1) chronic exposure to relatively low concentrations of E2 potentiates cyclicity, (2) very high levels of E2 are required to induce acyclicity, and (3) this acyclicity reflects vaginal as well as neuroendocrine alterations. The results also indicate that vaginal acylicity may be a poor indicator of ovulatory acyclicity in mice that have been chronically exposed to E2.     

Why do some adult birds skip breeding? A hormonal investigation in a long-lived bird

Skipping reproduction is often observed in long-lived organisms, but proximate mechanisms remain poorly understood. Since young and/or very old snow petrels (Pagodroma nivea) commonly skip breeding, we tested whether they are physiologically able to breed during the pre-laying stage. To do so, we measured the ability of known-age (11-45 years old) petrels to release luteinizing hormone (LH, a crucial driver for breeding), by injecting exogenous gonadotropin-releasing hormone (GnRH). Although young petrels exhibited low baseline LH levels, they were able to elevate LH levels after a GnRH challenge. Moreover, young and very old petrels showed a stronger decrease in LH levels after the 10 min post-GnRH injection compared with middle-aged petrels. Birds that skipped breeding were as able as breeders to release LH after a GnRH challenge, indicating that they had functional pituitaries. However, the decision to skip reproduction was linked to a strong LH decrease after the 10 min post-GnRH injection. Our result suggests that the youngest and the oldest petrels fail to maintain elevated baseline LH levels, thereby do not initiate reproductive activities. Skipping reproduction in long-lived birds probably results from age-related changes in the dynamics of the hypothalamic-pituitary-gonadal (HPG) axis function.     

A Mathematical Model for the Actions of Activin,Inhibin, and Follistatin on Pituitary Gonadotrophs

The timed secretion of the luteinizing hormone (LH) and follicle stimulating hormone (FSH) from pituitary gonadotrophs during the estrous cycle is crucial for normal reproductive functioning. The release of LH and FSH is stimulated by gonadotropin releasing hormone (GnRH) secreted by hypothalamic GnRH neurons. It is controlled by the frequency of the GnRH signal that varies during the estrous cycle. Curiously, the secretion of LH and FSH is differentially regulated by the frequency of GnRH pulses. LH secretion increases as the frequency increases within a physiological range, and FSH secretion shows a biphasic response, with a peak at a lower frequency. There is considerable experimental evidence that one key factor in these differential responses is the autocrine/paracrine actions of the pituitary polypeptides activin and follistatin. Based on these data, we develop a mathematical model that incorporates the dynamics of these polypeptides. We show that a model that incorporates the actions of activin and follistatin is sufficient to generate the differential responses of LH and FSH secretion to changes in the frequency of GnRH pulses. In addition, it shows that the actions of these polypeptides, along with the ovarian polypeptide inhibin and the estrogen-mediated variations in the frequency of GnRH pulses, are sufficient to account for the time courses of LH and FSH plasma levels during the rat estrous cycle. That is, a single peak of LH on the afternoon of proestrus and a double peak of FSH on proestrus and early estrus. We also use the model to identify which regulation pathways are indispensable for the differential regulation of LH and FSH and their time courses during the estrous cycle. We conclude that the actions of activin, inhibin, and follistatin are consistent with LH/FSH secretion patterns, and likely complement other factors in the production of the characteristic secretion patterns in female rats.