Follicle-stimulating Hormone Pulses Research Articles

Aromatase Inhibition Ameliorates Decreased LH Output Found in Obese Women

In obese ovulatory women, serum luteinizing Hormone (LH) and follicle stimulating hormone (FSH) are lowered compared with normal weight women. This relative hypogonadotropic hypogonadism represents a potential etiology for overall decreased fertility in obesity. The objective was to determine if administration of an aromatase inhibitor (AI) to ovulating obese women would normalize LH and FSH by interrupting estradiol negative feedback. Letrozole (2.5–5 mg) was given daily to 22 women, 12 obese and 10 normal weight, for 7 days. On the last day of administration, 8 h of blood sampling was done every 10 min before and after a bolus of GnRH at 4 h. We obtained data from 21 ovulatory women (10 normal weight and 11 obese) who had undergone a similar protocol of frequent blood sampling but no aromatase inhibitors (AI) treatment. Serum LH and FSH levels and pulse characteristics were measured. Treatment with AI only significantly affected obese women. Further, in women with obesity, LH secretion, prior to the GnRH bolus, was significantly higher in AI treated compared with non-treated (p = 0.011). AI treatment doubled LH pulse amplitude in obese women (p = 0.004). In response to aromatase inhibition, LH secretion in ovulatory women with obesity is increased and similar to levels found in untreated normal weight women. The increase in LH pulse amplitude indicates that the AI effect is mediated at the level of the pituitary. Our results suggest that the hypogonadotropic phenotype of simple obesity is subject to modulation by interruption of estradiol negative feedback.

Intravenous infusion of kisspeptin increased serum luteinizing hormone acutely and decreased serum follicle stimulating hormone chronically in prepubertal bull calves

Kisspeptin (KP) is a hypothalamic neuropeptide that stimulates the secretion of gonadotropin releasing hormone. To determine the acute and chronic effects of KP on serum concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), prepubertal bull calves [12 ± 1 (SD) weeks of age; 96.5 ± 14.5 kg BW] were administered one of four treatments [0.0 (control; CON), 0.125 (L-KP), 0.25 (M-KP), or 0.5 (H-KP) μg of KP/kg BW/hour] by intravenous infusion for 76 h. Blood samples were collected every 15 min for the first (acute; 1–6 h; Day 1) and last (chronic; 71–76 h; Day 4) 6 h of the intravenous infusions. Serum concentrations of LH and FSH were determined by radioimmunoassay. For each day, effects of treatment, time, and interactions on LH and FSH concentrations and pulse parameters were analyzed using procedures for repeated measures with JMP Software (SAS Inst. Inc., Cary, NC). There was a treatment effect (P = 0.002) and a treatment × time interaction during Day 1 (P = 0.02) such that LH concentrations were greatest following administration of all doses of KP when compared to CON. However, there was no treatment effect (P = 0.57) or a treatment × time interaction during Day 4 (P = 0.20) on serum LH concentrations. There was a treatment by day interaction (P = 0.02) on mean serum FSH concentrations. Most notably, on Day 4 mean serum FSH concentrations during intravenous infusion of M-KP and H-KP doses were less than that of CON. There was a treatment by day interaction (P = 0.0054) on FSH pulse amplitude concentrations, such that intravenous infusion of all doses of KP on Day 4 decreased FSH pulse amplitudes. In conclusion, acute infusion of KP increased LH concentrations and chronic infusion of KP decreased FSH concentrations. Despite the potential suppression of the hypothalamic–pituitary–gonadal axis with chronic infusion of KP, there are likely applications of KP, KP analogs, or KP receptor agonists to hasten the onset of puberty in livestock.

Ghrelin Suppresses Secretion of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) in Women

Ghrelin has been shown to suppress secretion of LH and, less regularly, of FSH in male and female animals and human males. However, no such evidence exists for human females. The aim was to study the effect of ghrelin on secretion of LH and FSH in women. DESIGN/PARTICIPANTS/INTERVENTION: Nocturnal (2000-0700 h) secretion profiles of LH and FSH were determined in six healthy women (age, 25.5±2.9 yr) twice, receiving 50 μg ghrelin or placebo at 2200, 2300, 2400, and 0100 h in this single-blind, randomized, crossover study. LH secretion after ghrelin injection as assessed by the area under the curve (4.01±1.37 mIU/min·ml) was significantly (P=0.031) lower than after placebo injection (5.46±1.33 mIU/min·ml). Also, FSH secretion after ghrelin injection (5.54±0.64 mIU/min·ml) was significantly (P=0.038) lower than after placebo injection (5.87±0.56 mIU/min·ml). LH pulses occurred significantly (P=0.007) less frequently after ghrelin injection (2.3±0.5) than after placebo injection (3.8±0.9). Accordingly, the interval between first and second LH pulse after treatment was significantly (P=0.002) longer after ghrelin injection (300±86 min) than after placebo injection (187±60 min). One of the six women exhibited clear FSH pulses, which overall paralleled LH pulses; two FSH and LH pulses occurred after ghrelin injection, but three occurred after placebo in this woman. This is the first report that ghrelin suppresses the secretion of LH and FSH in women. These findings resemble those in male and female animals and in men.

Physiology of the Canine Anoestrus and Methods for Manipulation of Its Length

Progression from early to late anoestrus is characterized by the appearance of a larger number of gonadotrophin-releasing hormone (GnRH) pulses with a higher amplitude, an increase in the sensitivity of the pituitary to GnRH, an increase in ovarian responsiveness to gonadotrophins, and an increase in basal plasma follicle-stimulating hormone (FSH) concentration. A period of increased luteinizing hormone (LH) pulsatility has been observed shortly before the onset of pro-oestrus. Apart from these changes in the hypothalamus-pituitary-ovary axis, the initiation of a new follicular phase in the bitch is also stimulated by dopaminergic influences other than the accompanying plasma prolactin decrease. Metergoline, a drug which in a low dosage lowers the plasma prolactin concentration via a serotonin-antagonistic pathway, does not shorten the anoestrus; while bromocriptine, in a dosage insufficient to cause a decrease in the plasma prolactin concentration, does prematurely induce a follicular phase. These observations indicate that it is not the decrease in the plasma prolactin concentration, but another dopamine-agonistic influence that plays a crucial role in the transition to a new follicular phase. The dopamine-agonist induced oestrus is associated with a rapid rise in the basal plasma FSH concentration, similar to what is observed during the physiological late anoestrus. Administration of GnRH, eCG and oestrogens may also be used to induce oestrus but with variable results. Oestrus can be prevented surgically or medically, for which purpose progestagens are the most important drugs. The mechanism is still unclear, although it has been demonstrated that with continuing medroxyprogesterone acetate (MPA) treatment the FSH response to GnRH stimulation decreases and changes occur in the pulsatile release of the gonadotrophins. In general, LH pulses coincide with a FSH pulse, but during MPA treatment, LH pulses were observed while there was such a small increase in FSH that it was not recognized as significant FSH pulse.

Pulsatile plasma profiles of FSH and LH before and during medroxyprogesterone acetate treatment in the bitch

The aim of this study was to investigate the effect of medroxyprogesterone acetate (MPA) on pulsatile secretion of gonadotropins in the bitch. Five intact Beagle bitches were treated with MPA in a dose of 10mg/kg body weight subcutaneously at intervals of 4 weeks for a total of 13 injections, starting during anestrus. The 6-h plasma profiles of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined before, and 3, 6, 9, and 12 months after the start of MPA treatment. After 6 months of MPA treatment basal plasma LH concentration was transiently increased significantly. Basal plasma FSH concentration and the area under the curve above the zero level (AUC0) for FSH were significantly higher after 3 months of MPA treatment than before or after 9 and 12 months of treatment. MPA treatment did not significantly affect pulse frequency, pulse amplitude, or AUC above the baseline for either LH or FSH. During treatment 58 significant LH pulses were identified, and although each LH pulse coincided with an increase in plasma FSH concentration, in 17 cases the amplitude of the increase was too small to be recognized as a significant FSH pulse. In conclusion, MPA treatment did not suppress basal plasma gonadotropin levels in the bitches. On the contrary, it caused a temporary rise in the basal concentration of both FSH and LH, which may have been due to a direct effect of MPA on the ovary. In addition, several LH pulses were not accompanied by a significant FSH pulse, suggesting that MPA treatment attenuated the pulsatile pituitary release of FSH.

Changes in the ovarian dynamics and endocrine profiles in goats treated with a progesterone antagonist during the early luteal phase of the estrous cycle

The aim of the present study was to determine the physiological role of endogenous progesterone in the regulation of ovarian dynamics, gonadotropin and progesterone secretion during the early luteal phase in the goat. Cycling Shiba goats received subcutaneously a vehicle (control group, n = 5) or 50 mg of RU486 (RU486 group, n = 4) daily from 1 to 7 days after ovulation (day 0) determined by transrectal ultrasonography. Ovarian dynamics were monitored by the ultrasonography and blood samples were collected daily until the subsequent ovulation for analysis of progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion. Blood samples were also collected at 10 min intervals for 6 h on day 3 and day 7 for the analysis of pulsatile patterns of LH and FSH. The LH pulse frequency was significantly ( P < 0.05) higher in the RU486 group than in the control group on day 7 (4.8 ± 1.1 pulses/6 h versus 1.2 ± 0.4 pulses/6 h). The shape of the FSH pulses was unclear on day 3 and day 7 in both groups and the overall means of FSH concentration for 6 h on day 3 and day 7 were not significantly different between the RU486 and the control groups. The pattern of daily FSH concentrations showed a wave-like fluctuation in both groups. There was no significant difference in the inter-peak intervals of the wave-like pattern of daily FSH secretion between the RU486 and the control groups (4.1 ± 0.6 days versus 4.5 ± 0.6 days). The maximum diameter of the largest follicle that grew from day 1 to day 7 in the RU486 group tended to be greater than that in control goats (6.4 ± 0.8 mm versus 5.0 ± 0.8 mm, P = 0.050), whereas no significant difference was detected in the size of the corpus luteum and progesterone concentrations between the control and RU486 groups on almost all days during the treatment period. These results indicate that the rise of the progesterone concentration suppresses the pulsatile LH secretion and follicular growth, whereas progesterone has no physiological role in the regulation of FSH secretion and luteal function during the early luteal phase of the estrous cycle in goats.

Secretion patterns of luteinising hormone, follicle-stimulating hormone and 17β-oestradiol during oestrus and the mid-luteal phase of the oestrous cycle in mithun (Bos frontalis)

The present study reports the pulsatile secretion of gonadotrophins and 17beta-oestradiol (OE2) on the day of oestrus and at the mid-luteal phase of the oestrous cycle in mithun (Bos frontalis). The frequency of luteinising hormone (LH) and follicle-stimulating hormone (FSH) pulses was found to be greater (P < 0.05) on the day of oestrus than at the mid-luteal phase. In contrast, the amplitude of the LH and FSH pulses was greater (P < 0.01) at the mid-luteal phase than on the day of oestrus. A synchronised (P < 0.01) LH and FSH secretion pattern was found only at the mid-luteal phase. A pulsatile secretion pattern for OE2 in the peripheral circulation was evident for both phases of the oestrous cycle. The frequency of the OE2 pulses did not differ significantly in different phases of the oestrous cycle. In contrast, the amplitude of the OE2 pulses and the basal OE2 concentration were found to be greater (P < 0.01) at the mid-luteal phase than on the day of oestrus. A synchronised (P < 0.01) LH and OE2 secretion pattern was observed in both phases of the oestrous cycle. In contrast, a synchronised (P < 0.05) FSH and OE2 secretion pattern was found only on the day of oestrus. In conclusion, a different pattern of LH and FSH secretion was observed in both phases of the oestrous cycle, mainly on the day of oestrus, which indicates a differential regulatory mechanism of LH and FSH release. In addition, as in cattle, OE2 exerts a positive feedback on LH and FSH release on the day of oestrus and on LH release at the mid-luteal phase of the oestrous cycle in mithun. Also, as in cattle, the greater basal plasma OE2 concentration and increased amplitude of OE2 pulses exert a negative feedback on FSH release at the mid-luteal phase of the oestrous cycle.

Pulsatile Luteinizing Hormone and Follicle-Stimulating Hormone Secretion and Gonadotropin Subunit mRNA Levels in the Ovariectomized GPR-4 Transgenic Rat

Genetic targeting of the cAMP-specific phosphodiesterase 4D1 (PDE4D1) to gonadotropin-releasing hormone (GnRH) neurons in the GPR-4 transgenic rat resulted in decreased luteinizing hormone (LH) pulse frequency in castrated female and male rats. A similar decrease in the intrinsic GnRH pulse frequency was observed in GT1 GnRH cells expressing the PDE4D1 phosphodiesterase. We have extended these findings in ovariectomized (OVX) GPR-4 rats by asking what effect transgene expression had on pulsatile LH and follicle-stimulating hormone (FSH) secretion, plasma and pituitary levels of LH and FSH, and levels of the α-glycoprotein hormone subunit (α-GSU), LH-β and FSH-β subunit mRNAs. In OVX GPR-4 rats the LH pulse frequency but not pulse amplitude was decreased by 50% compared to wild-type littermate controls. Assaying the same samples for FSH, the FSH pulse frequency and amplitude were unchanged. The plasma and anterior pituitary levels of LH in the GPR-4 rats were significantly decreased by approximately 45%, while the plasma but not anterior pituitary level of FSH was significantly decreased by 25%. As measured by real-time RT-PCR, the mRNA levels for the α-GSU in the GPR-4 rats were significantly decreased by 41%, the LH-β subunit by 38% and the FSH-β subunit by 28%. We conclude that in the castrated female GPR-4 rats the decreased GnRH pulse frequency results in decreased levels of LH and FSH and in the α- and β-subunit mRNA levels.

Hypothalamic control of gonadotropin secretion

Publisher Summary This chapter discusses the hypothalamic control of gonadotropin secretion. The control of gonadotropin secretion is extremely complex as revealed by the research of the past 40 years since the discovery of luteinizing hormone releasing hormone (LHRH), commonly called gonadotropin-releasing hormone (GnRH). This was the second of the hypothalamic-releasing hormones characterized. It stimulates follicle-stimulating hormone (FSH) release, albeit in smaller amounts than luteinizing hormone (LH). For this reason, it was renamed GnRH. Overwhelming evidence indicates that there is a separate follicle-stimulating hormone releasing hormone (FSHRH) because pulsatile release of LH and FSH can be dissociated. In the castrated male rat, roughly half of the FSH pulses occur in the absence of LH pulses, and only a small fraction of the pulses of both gonadotropins are coincident. The hypothalamic areas controlling LH and FSH are separable. Stimulation in the dorsal medial anterior hypothalamic area causes selective FSH release, whereas lesions in this area selectively suppress the pulses of FSH and not LH. Conversely, stimulations or lesions in the medial preoptic region can augment or suppress LH release respectively without affecting FSH release. The putative FSHRH is synthesized in neurons with perikarya in the dorsal anterior hypothalamic area with axons that project to the mid and caudal median eminence to control FSH release selectively.

Influence of dose, frequency, and duration of infused gonadotropin-releasing hormone on secretion of luteinizing hormone and follicle-stimulating hormone in nutritionally anestrous beef cows

Nutritionally induced anovulatory cows were ovariectomized and used to determine the relationships between dose, frequency, and duration of exogenous gonadotropin-releasing hormone (GnRH) pulses and amplitude, frequency, and concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum. In Experiment 1, cows were given pulses of saline (control) or 2 μg of GnRH infused iv during a 0.1-, 1.25-, 5-, 10-, or 20-min period. Concentrations of LH and FSH during 35 min after GnRH infusion were greater than in control cows (P < 0.01), and FSH concentrations were greater when GnRH infusions were for 10 min or less compared with 20 min. In Experiment 2, the effect of GnRH pulse frequency and dose on LH and FSH concentrations, pulse frequency, and pulse amplitude were determined. Exogenous GnRH (0, 2, or 4 μg) was infused in 5 min at frequencies of once every hour or once every 4th hr for 3 d. There was a dose of GnRH × frequency × day effect on LH and FSH concentrations (P < 0.01), indicating that gonadotropes are sensitive to changes in pulse frequency, dose, and time of exposure to GnRH. There were more LH pulses when GnRH was infused every hour, compared with an infusion every 4th hr (P < 0.04). Amplitudes of LH pulses were greater with increased GnRH dose (P < 0.05), and there was a frequency × dose × day effect on FSH pulse amplitude (P < 0.0006). We conclude that LH and FSH secretion in the bovine is differentially regulated by frequency and dose of GnRH infusions.

Median eminence lesions reveal separate hypothalamic control of pulsatile follicle-stimulating hormone and luteinizing hormone release.

The effects of hypothalamic lesions designed to destroy either the anterior median eminence (ME) or the posterior and mid-ME on pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were determined in castrated male rats. In sham-operated animals, mean plasma FSH concentrations rose to peak at 10 min after the onset of sampling, whereas LH declined to a nadir during this time. In the final sample at 120 min, the mean FSH concentrations peaked as LH decreased to its minimal value. In rats with anterior ME lesions, there was suppression of LH pulses with continuing FSH pulses in 12 of 21 rats. On the other hand, in animals with posterior to mid-ME lesions, 3 out of 21 rats had elimination of FSH pulses, whereas LH pulses were maintained. Fifteen of 42 operated rats had complete ME lesions, and pulses of both hormones were abolished. The remaining 12 rats had partial ME lesions that produced a partial block of the release of both hormones. The results support the concept of separate hypothalamic control of FSH and LH release with the axons of the putative FSH-releasing factor (FSHRF) neuronal system terminating primarily in the mid- to caudal ME, whereas those of the LHRH neuronal system terminate in the anterior and mid-median eminence. We hypothesize that pulses of FSH alone are mediated by release of the FSHRF into the hypophyseal portal vessels, whereas those of LH alone are mediated by LHRH. Pulses of both gonadotropins simultaneously may be mediated by pulses of both releasing hormones simultaneously. Alternatively, relatively large pulses of LHRH alone may account for simultaneous pulses of both gonadotropins since LHRH has intrinsic FSH-releasing activity.

The Wisdom of the Body Revisited.

Being selected a Cannon lecturer by the American Physiological Society is a singular honor under any circumstances, but a particularly poignant one for me because of my origins in Cannon’s old Department at the Harvard Medical School. In fact, when I began my career there as an instructor 45 years

Depression of FSH and LH secretion following pulsatile GnRH administration in ovariectomized women.

To investigate the mechanism by which pulsatile administration of gonadotrophin-releasing hormone (GnRH) modifies secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), we studied three groups of five women who had been ovariectomized for non-malignant gynaecological conditions at least 6 months previously, none of whom had received substitutional hormone therapy. Before and after 15 day treatment with subcutaneous pulsatile GnRH (one 20 microg dose every 90 min in group A, one 10 microg dose every 90 min in group B and one 20 microg dose every 120 min in group C), pulsatile secretion of LH and FSH was characterized by determining these hormones in 4 ml blood samples taken every 10 min for 8 h (9.00 a.m. to 5.00 p.m.). For both LH and FSH, mean serum concentration and pulse amplitude were lower after GnRH treatment than before (and in the case of LH the decrease depended upon both the size and frequency of exogenous GnRH pulses) but in no group was there a significant change in LH or FSH pulse frequency. We conclude that exogenous pulsatile GnRH probably acts by partially desensitizing the pituitary rather than by depressing endogenous GnRH secretion. Such partial desensitization would explain reports that exogenous pulsatile GnRH improves ovulation by women with polycystic ovary syndrome.

High-frequency FSH and LH pulses in obese menopausal women.

We studied the pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretory patterns, at early or intermediate years of menopause in seven normal women with different degrees of obesity, taking blood samples every minute for 40 min to 2 h. The hormones were assayed with an immunoradiometric assay (IRMA) system, analyzing with the cluster pulse algorithm. All women showed hormone pulses every 8-10 min. In five of them were found periods of discrete pulses with oscillations of high amplitude alternating with periods of pulses of low amplitude. In two cases, the high-frequency oscillatory pattern with low amplitude was found around low mean levels of 22.8 and 25.7 IU/L. The LH oscillatory pattern also had a high frequency, but at a lower level, giving a high FSH/LH ratio. The coincidence index of FSH with LH peaks was 76.6%. We concluded that at menopause, the frequency of FSH and LH secretion increases with a high FSH/LH ratio. Obese menopausal women may have the same high-frequency oscillatory patterns, but at low levels.

Patterns of luteinizing and follicle-stimulating hormone pulsatility in menopausal women: Correlation with plasma testosterone level and vasomotor instability episodes

OBJECTIVE: The purpose of this study was to test the hypothesis that subtle differences among postmenopausal women can be detected by careful analysis of plasma luteinizing hormone and follicle-stimulating hormone pulses. STUDY DESIGN: Twelve postmenopausal women not receiving estrogen therapy were admitted for continuous blood withdrawal at the rate of 1 ml/min. Aliquots of 3 ml of pooled blood were collected every 3 minutes for 3 hours for the measurement of plasma luteinizing hormone and follicle-stimulating hormone. Estradiol, estrone, free testosterone, androstenedione, and dihydrotestosterone were measured from pooled specimens. Concomitantly, continuous recordings of peripheral blood flow and peripheral temperature from the opposite arm were obtained to detect vasomotor instability episodes. RESULTS: Analysis of gonadotropin pulses revealed a single pattern of plasma follicle-stimulating hormone but two distinct patterns of luteinizing hormone frequency and amplitude. One group of six women had a low mean (±SEM) interpulse interval frequency of 0.8 ± 0.26 ( p < 0.005) and a high mean amplitude of 18.4 ± 1.8 IU/L ( p < 0.05). The second group of six women had a high mean interpulse interval frequency of 3.5 ± 0.34 and a low mean amplitude of 12.2 ± 1.8 IU/L luteinizing hormone pulses. Women with this pattern had more inter-vasomotor instability episode intervals (3.5 ± 1.6) than did women with low frequency and high amplitude (1.3 ± 0.5, p < 0.001). Women with low frequency and high amplitude pulses had higher plasma levels of estrone (266 ± 33 nmol/L), testosterone (2.3 ± 0.7 mmol/L), and free testosterone (8.0 ± 0.1 pmol/L, p < 0.05). CONCLUSION: There are subgroups of postmenopausal women with different patterns of luteinizing hormone pulsatility. This difference can be explained by higher steroid levels in women with low frequency and high amplitude pulses.

Endocrinology: Evidence suggesting an additional control mechanism regulating episodic secretion of luteinzing hormone and follicle stimulating hormone in pre-pubertal children and post-menopausal women

The possible differential regulation of pulsatile follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertal children and in post-menopausal women was investigated. Children were studied for 4 h and post-menopausal women for 6 h; blood samples were taken every 10 min. Post-menopausal women were studied before and 21 days after administration of a single i.m. dose of gonadotrophin-releasing hormone (GnRH) analogue. Eight post-menopausal women and 18 children (nine boys and nine girls) were enrolled. The children were divided into two groups: A, at Tanner stages 0-1 (four boys and three girls); B, at Tanner stage 2-3 (five boys and six girls). Plasma LH and FSH concentrations were determined using an immunofluorimetric assay. Time series were analysed and the specific concordance (SC) index was computed to determine the degree of concordance between episodes of LH and FSH secretion. While children of group A had LH concentrations below the minimal detectable dose of 0.1 IU/l, group B showed measurable LH plasma concentrations (1.4 +/- 0.3 IU/l, mean +/- SEM). Plasma FSH concentrations were detectable in both groups. Group A showed FSH plasma concentrations significantly lower than those of group B (0.75 +/- 0.2 and 1.95 +/- 0.4 IU/l respectively; P < 0.05), but FSH pulse frequency was higher in group A (P < 0.05). Children of group B showed significant concomitance of LH and FSH secretory events at time 0 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Does the gonadotropin pulsatility of postmenopausal women represent the unrestrained hypothalamic—pituitary activity?

Ovarian sex steroids profoundly modulate the gonadotropin pulsatile secretion in women. A gonadotropin pulsatility determined in the absence of any considerable ovarian sex steroid feedback, as in postmenopausal women (PMW), may thus represent the unrestrained activity of the hypothalamic-pituitary axis. We hypothesized that increases in the gonadotropin pulse frequencies and amplitudes during sex steroid replacements may be limited by those determined in the hypogonadal state of PMW. To address this assumption, we investigated the unstimulated the gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in PMW before and during sequential ovarian sex steroid treatments. Seven PMW (mean age 59.4 years) were studied initially during unreplaced conditions (control studies), then on the last day of a 21-day course of oral estradiol valeriate (E2) administrations (2 mg daily) and, finally, on the last day of a 21-day course of oral estradiol-progesterone (E2/P4) replacements (2 mg of E2 and 200 mg of micronized P4 daily). On all study occasions, blood was drawn at 10-min intervals for 10 h and GnRH (25 micrograms iv) was administered 8 h after initiation of blood collections. Compared to control conditions, the basal serum estrogen (estrone and E2) and progesterone (P4) concentrations markedly increased (p < 0.001) following oral E2 or E2/P4 treatments. As determined by Cluster pulse algorithm, LH and FSH were found to be released episodically during each study condition. Mean LH and FSH release rates declined (P < 0.05 or less) during E2 and E2/P4 regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrinology of aging in humans: attenuated sensitivity to sex steroid feedback in elderly postmenopausal women.

Studies in experimental animals have shown that the sensitivity of the hypothalamic-pituitary system to ovarian sex steroid feedback declines while aging progresses. Since similar observations are lacking in humans, we studied the gonadotropin secretion of postmenopausal women (PMW) of different ages before and following a 7-day course of oral clomiphene citrate (CC, 100 mg daily). For serial determinations of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, blood was sampled frequently from 5 younger PMW (mean age 55.2 years) and 6 older PMW (mean age 80.3 years) for 10 h. Eight hours after initiation of blood sampling, gonadotropin-releasing hormone (GnRH, 25 micrograms) was administered. Compared to untreated conditions, CC administration did not significantly change the serum concentrations of the estrogens (estrone, estradiol) and androgens (testosterone; androstenedione, dehydroepiandrosterone sulfate). However, CC increased the sex hormone-binding globulin levels in both younger and older PMW, suggestive of the estrogenic effects of this compound. In the unstimulated secretory profiles of younger PMW, mean LH levels decreased (p < 0.05) in response to CC, presumably a consequence of decreased (p < 0.05) pulse frequencies, but not pulse amplitudes. Likewise, by virtue of decreased (p < 0.05) FSH pulse amplitudes, FSH levels declined (p < 0.05) in younger PMW. In contrast, both the LH and FSH levels and their pulsatility remained virtually unaltered following CC administrations to older PMW. The GnRH-mediated gonadotropin release was uneffected by CC administrations in either group of PMW.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotrophin releasing hormone pulse generator activity before and during sexual maturation in girls: new insights.

The activity of the gonadotrophin releasing hormone (GnRH) pulse generator during pubertal transition was investigated in 40 healthy girls 7-18 years of age. Ten were pre-pubertal, seven were in early puberty, and 23 were post-menarcheal. Serum concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured with immunofluorimetric assays, which have a sensitivity approximately 100-fold that of radioimmunoassay, in samples taken at 10-min intervals for 24 h during basal conditions, during Nal-Glu antagonist suppression, and in response to GnRH stimulation (10 micrograms). Serum levels of androstenedione, testosterone and oestradiol were measured by radioimmunoassay. Our data show that the GnRH pulse generator is functionally active in prepubertal girls with selective expression of LH and FSH pulses after the onset of sleep. The onset of puberty is associated with a greater increase in LH pulse amplitude than frequency. These overall changes are punctuated by a switch of wake/sleep activities of GnRH pulse generator with a progressive increase in day-time pulsatility and a gradual reduction of sleep-entrained amplification. While LH pulsatility appears to be highly GnRH dependent at all ages, a remarkable decrease in the predominance of GnRH regulation of FSH pulsatility occurs in conjunction with ovarian activation.

Elevated inhibin concentration in the follicular fluid of dairy cows with chronic cystic ovarian disease

This study compared serum and follicular fluid inhibin and gonadotropin profiles between chronic cystic ovarian diseased (CCOD) and normal cyclic dairy cows. Blood samples and follicular fluid were collected from CCOD cows (n=15) and cyclic cows in the follicular phase of the estrous cycle (control, n=6) and analyzed for inhibin, follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations. There was a significant increase in inhibin and a decrease in FSH and LH concentrations in the follicular fluid of CCOD cows compared with those of cyclic cows (P < 0.05). Mean serum inhibin, FSH and LH concentrations between CCOD and cyclic cows were not differnt (P > 0.05), however, there was a tendency for serum inhibin to be higher and FSH to be lower in CCOD cows compared to cyclic animals (P < 0.1). The FSH pulse frequency also was lower in CCOD cows than in cyclic cows (P < 0.05). These data suggest that increased production of inhibin from cystic follicles of CCOD cows alters pituitary FSH secretion and subsequently reduces the concentration of FSH in follicular fluid. As a result, decreased FSH stimulation at the ovarian level could ultimately lead to the reduction in follicular LH and FSH receptor concentrations, resulting in abnormal follicular steroidogenesis in CCOD dairy cows.