Gonadotropin-releasing Hormone Challenge Research Articles

Alterations in pituitary gland sensitivity in ram lambs to physiological doses of gonadotrophin-releasing hormone (GnRH), after divergent selection based on the luteinizing hormone response to a pharmacological GnRH challenge

Divergent selection in 10-week-old Finn-Dorset ram lambs was based on the luteinizing hormone (LH) response to a pharmacological dose of GnRH (5 micrograms). After eight generations of selection, the LH responses of the two lines (low and high) to GnRH differed by a factor of five. This study investigates the pituitary sensitivity of the two lines to exogenous GnRH. Initially, two pilot studies were performed: one to determine the range of doses of GnRH which would stimulate LH pulses of similar amplitude to those seen endogenously, and the other to confirm that sodium pentobarbitone prevents pulsatile LH secretion in prepubertal ram lambs. The results indicated that barbiturate anaesthesia suppressed pulsatile LH secretion in castrated and intact ram lambs. A model system was therefore constructed in 18 10-week-old intact ram lambs (high n = 7, low n = 11), whereby endogenous pulsatile LH secretion was prevented by sodium pentobarbitone anaesthesia and the amplitudes of LH pulses produced in response to different doses of exogenous GnRH could be measured. The GnRH dose-response curves demonstrated that there was a five-fold difference in the sensitivity of the pituitary glands of the two lines to stimulation with GnRH. The projected minimum concentration of GnRH required to produce a measurable pulse of LH was 4.75 ng for the high-line animals and 26.6 ng for the low-line animals. The results indicated that the low-line animals required five times more GnRH than the high-line lambs to stimulate LH pulses of similar amplitude (high line 43.67 ng; low line 206.55 ng). These results demonstrate that selection has produced two lines of sheep which differ in the control of LH secretion at the level of the hypothalamus-pituitary gland.

Gonadotropin releasing hormone (GnRH) induced luteinizing hormone (LH) secretion from perifused equine pituitaries

In vitro responsiveness of the horse anterior pituitary (AP) gonadotropes to single and multiple GnRH challenges was examined. The pituitaries were collected from reproductively sound mares in estrus (n=5) and diestrus (n=5). Uniform 0.5 mm AP slices were subdivided using a 3 mm biopsy punch and then bisected for use in the perifusion chamber. Four bisected sections per chamber were perifused at 0.5 ml/min at 37 C for 560 min in Medium 199 saturated with 95% 0 2/5% CO 2. Ten minute fractions were collected after an initial 2 hr equilibration period. Four different treatment regimes of GnRH (10 −10 M) were evaluated: (A) three consecutive 10 min GnRH pulses separated by 80 and 100 min, respectively; (B) a single 120 min GnRH infusion; (C) a 10 min GnRH pulse followed 80 min later by a 120 min GnRH infusion and (D) two 10 min GnRH pulses separated by 60 min followed 80 min later by a 120 min GnRH infusion. Estimated total pituitary LH content was higher in estrous than diestrous mares (p<0.05). The total amount of LH released in response to GnRH tended to be greater in estrus than diestrus (p<0.1), whereas the percentage of LH released in estrus and diestrus was similar. An increase in the area under the LH response curve was noted with each successive 10 min pulse of GnRH during both estrus and diestrus (p<0.05), demonstrating a self-priming effect of GnRH. In addition, a significant increase in the peak LH amplitude (p<0.05) and the slope to peak amplitude (p<0.05) were observed for the 120 min GnRH pulse in regime C and D indicating that prior exposure to short-term pulses of GnRH increased the acute LH secretory response. These results suggest that in the cycling mare (1) the responsiveness of the pituitary (amount of LH released as percent of total LH) is similar in both estrus and diestrus, however, the magnitude of the LH response (total microgram amount of LH released) differs with the stage of the estrous cycle, being highest in estrus, and appears to be related, in part, to pituitary LH content and (2) GnRH self-priming occurs independently of the stage of the estrous cycle. Furthermore, we have demonstrated that the pulsatile mode of GnRH can act directly on the anterior pituitary to dictate the pulsatile release pattern of LH in the cycling mare.

Nature of gonadotropin-releasing hormone self-priming of luteinizing hormone secretion during the normal menstrual cycle

To investigate further the nature of the gonadotropin-releasing hormone self-priming effect on luteinizing hormone release, we administered two submaximal doses of gonadotropin-releasing hormone 2 hours apart to women at three stages of the menstrual cycle and analyzed the resultant luteinizing hormone secretory episodes with deconvolution analysis. When the characteristics of the secretory episodes associated with the second gonadotropin-releasing hormone challenge were compared with those associated with the first, both an enhanced maximal secretory rate and mass of luteinizing hormone secreted was demonstrable at each phase of the cycle. No differences in the luteinizing hormone secretory event half-duration were detected when the responses to the first and second gonadotropin-releasing hormone doses were compared. These data confirm the gonadal hormone milieu-associated self-priming effect of gonadotropin-releasing hormone on luteinizing hormone release and indicate that it is the rate with which luteinizing hormone molecules are discharged from the pituitary gland, rather than the duration of the secretory episode itself, that provides for the self-priming effect. (Am J Obstet Gynecol 1990;163:1529-34.)

Hypothalamic-Pituitary-Testicular Axis Function in Endurance-Trained Males

The hypothalamic-pituitary-testicular (H-P-T) axis was evaluated in groups of endurance-trained (TRG) and untrained (UNT) males. Each group was subjected to: 1) a 4-h resting hormonal profile [testosterone (T), free-testosterone (FT), estradiol (E2), luteinizing hormone (LH), prolactin (PRL), and cortisol (C)], 2) a dopamine antagonist (DA; 10 micrograms.kg-1 body weight) challenge to the pituitary-testes, and 3) a gonadotropin-releasing hormone (GnRH; 120 micrograms.kg-1 body weight) challenge to the pituitary-testes. Compared to UNT, the TRG resting T (4.8 +/- 0.7 vs 7.1 +/- 1.2 ng.ml-1, p = 0.05) and PRL (3.3 +/- 1.4 vs 7.0 +/- 2.3 ng.ml-1, p = 0.09) were lower while LH was elevated (15.0 +/- 1.8 vs 11.8 +/- 1.5 mIU.ml-1, p = 0.06). The DA challenge produced a greater integrated PRL response in the TRG (2962.7 +/- 265.1 ng +/- ml-1.min) than in the UNT (1735.3 +/- 282.0 ng.ml-1.min; p = 0.01). No significant changes were observed in T following the DA-induced PRL rise. The TRG had a blunted LH response (817.2 +/- 111.6 mIU.ml-1.min) following the GnRH injection as compared to the UNT (1493.7 +/- 213.4 mIU.ml-1.min; P less than 0.02). T levels were significantly (p less than 0.03) increased in both groups by the LH rise after the GnRH challenge (TRG = 9.9 +/- 5.0%; UNT = 8.6 +/- 9.9%, respectively), but no significant between group differences were observed. Results suggest endurance training produces an enhanced PRL and attenuated LH release by the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Testosterone and luteinizing hormone response to GnRH in yearling bulls of different libido

This study was conducted to evaluate pituitary and testicular responsiveness to gonadotropin releasing hormone (GnRH) as measured by luteinizing hormone (LH) assay and by testosterone assay, respectively, in bulls that had previously exhibited either high or low libido based on a libido test. Eighty-four purebred Angus bulls were tested for libido during 1988 and 1989. Blood samples were collected from four bulls that had the highest and lowest libido scores in each year by indwelling jugular cannula at 15 min intervals for 2 h before and for 5 h after GnRH (10 ng/kg body weight, i.v.) administration. The samples were assayed for LH, testosterone and cortisol. Low libido bulls had higher (P<0.05) LH concentrations during the first hour after GnRH treatment than high libido bulls. Testosterone concentrations were higher (P<0.05) in high libido bulls before GnRH administration but were similar afterwards in both years. Cortisol concentrations were higher (P<0.05) during the first hour of sampling in low libido bulls than in high libido bulls. It was concluded that the response to a GnRH challenge as measured by LH or testosterone concentrations was not a useful indicator of libido in bulls.

Non-Steroidal Follicular Factors Attenuate the Self-Priming Action of Gonadotropin-Releasing Hormone on the Pituitary Gonadotroph

Pituitary glands of pro-oestrous and oestrous rats were perifused in series with isolated ovarian follicles and the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to gonadotropin-releasing hormone (GnRH) were measured. Pituitary glands from pro-oestrous rats, perifused with the effluent medium from isolated preovulatory follicles, showed a significant reduction in the self-priming effect of GnRH as observed from the typical biphasic LH response to a continuous GnRH challenge. The initial FSH response to GnRH was also reduced. A similar trend was seen in the LH responses of pituitary glands from oestrous rats but results were not significant; there was no parallel reduction in FSH release. It is unlikely that the attenuation of GnRH self-priming was due to the steroids released by the isolated follicles. LH responses of pro-oestrous pituitaries, perifused with medium containing 200 pg oestradiol/ml, 5 ng progesterone/ml or 200 pg testosterone/ml were similar to paired controls as were the responses when all three steroids were added to the perifusing media at identical concentrations. Furthermore, when steroids were charcoal extracted from the effluent medium of perifused isolated follicles the biological activity of this medium in attenuating GnRH self-priming was not destroyed. Finally, the effects of purified bovine inhibin and steroid-free human follicular fluid (hFF) on LH responses were compared. Purified inhibin at a concentration of 20 or 50 ng/ml perifusing medium had no effect on GnRH-stimulated LH release although GnRH-stimulated FSH secretion was significantly reduced toward the end of an extended perifusing period.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadal dysgenesis with X-monosomy in a cynomolgus monkey (Macaca fascicularis).

A 3-year-old female cynomolgus monkey (Macaca fascicularis) was found to have inappropriately high circulating immunoassayable follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels compatible with primary gonadal failure. Hypergonadotropic hypogonadism was confirmed by the findings of persistently high serum gonadotropin levels by both LH bioassay and FSH and LH radioimmunoassays and low levels of serum estradiol. In addition, circhoral gonadotropin pulsatility and an exaggerated response to a gonadotropin-releasing hormone challenge were demonstrated. Both FSH and LH coeluted in a single peak on gel filtration column chromatography. Clinically, the animal showed the following features of Turner syndrome: small body size, sexual underdevelopment, gonadal streaks with absent follicles, and a chromosomal constitution of 41,X. A similar case has been reported previously in a rhesus monkey (Macaca mulatta). Considering the fetal and live birth prevalences in humans of aneuploidy in general and X-monosomy in particular, one would predict that this chromosomal aberration underlies a high number of pregnancy failures in nonhuman primates.

Ovarian cyclicity and serum progesterone and luteinizing hormone in fine-wool ewes supplemented with alfalfa or pinto beans

Effects of season and supplementation on the incidence and rate of ovulation and hormone profiles in multiparous, nonlactating ewes were investigated under range and drylot conditions during anestrus (February through August). Ninety ewes received one of six nutritional treatments: 1) range forage, 2) range forage plus 0.33 kg·hd −1·d −1 pinto beans, 3) 0.45 kg·hd −1·d −1 alfalfa pellets, 4) dry lot plus 1.33 kg·hd −1·d −1 prairie hay only, 5) pinto beans or 6) alfalfa pellets at rates used on the range and prairie hay. Supplemented ewes were heavier (P < 0.05) than ewes fed range forage or prairie hay during most of the study. Seasonality of ovulation, in terms of incidence and rate, was not affected (P > 0.40) by supplementation in range ewes. The ovulation rate tended to be highest in prairie hay plus pinto bean drylot ewes in February (P = 0.21) and in prairie hay plus alfalfa pellet and prairie hay plus pinto bean ewes in March (P = 0.13) compared with prairie hay ewes. Generally, seasonality of ovulation was not influenced by supplementation (P > 0.40). The incidence of ovulation approached zero for drylot ewes in April, May, June and July, while it was 43, 27, 35 and 21% for range ewes, in those same months. Supplementation did not affect serum progesterone during the estrous cycle. Luteinizing hormone (LH) concentrations were similar (P > 0.50) among drylot treatment groups before a 50-ug gonadotropin releasing hormone (GnRH) challenge. Pinto bean supplementation enhanced serum LH response to GnRH (P < 0.10).

EFFECTS OF GnRH ON LUTEINIZING HORMONE RELEASE AND ONSET OF CYCLIC OVARIAN ACTIVITY POSTPARTUM IN PELIBUEY EWES

Synthetic gonadotropin releasing hormone (GnRH) was administered to Pelibuey ewes to determine its effect on luteinizing hormone (LH) release and on cyclic ovarian activity during the first 3 – 4 wk postpartum. Two GnRH doses were given (10 and 100 μg) on days 4 and 5, 7 and 8, 14 and 15, and 21 and 22, after parturition, respectively. In three trials, 11, 8 and 7 ewes were used. For each trial 5, 3 and 2 ewes were used as controls, respectively; in trial 3, only the 100-μg dose was given once. Results from the three trials indicated that LH release always occurred after GnRH treatment, relative to the saline-treated controls. In trials 1 and 2, the 10-μg dose induced a higher (P &lt; 0.001) LH release than the 100-μg dose; the LH release in response to the 100-μg dose in the three trials was of similar magnitude. Release of LH in response to both doses was lower (P &lt; 0.05) during days 4 – 5 postpartum, than during the following 3 wk. Two types of luteal activity or steroidogenesis were observed in the GnRH-treated ewes, relative to the saline-treated ewes; (1) within 2 – 4 d after each GnRH injection small peaks of progesterone appeared, and (2) within 5 – 15 d after the last GnRH injection there were elevations of progesterone in peripheral plasma to concentrations and of durations characteristic of the luteal phase of the ovine estrous cycle. These results indicate that the pituitary of postpartum Pelibuey ewes regains the ability for maximal release of LH in response to GnRH challenge within 7 d postpartum. Further, treatment with GnRH induces earlier return to cyclic ovarian activity. Key words: Hair sheep, postpartum, GnRH, luteal activity

Effect of Supplemental β-Carotene on Luteinizing Hormone Released in Response to Gonadotropin-Releasing Hormone Challenge in Ovariectomized Holstein Cows

Thirteen lactating Holstein cows were assigned randomly to either a control or β-carotene (600 mg/d) treatment group to determine the effect of long-term β-carotene supplementation on releasable luteinizing hormone in response to gonadotropin-releasing hormone challenge. The experimental period was 28 wk. Milking was terminated at wk 16, ovariectomy performed at wk 20, and response to gonadotropin-releasing hormone determined at wk 27. Serum β-carotene concentrations reflected dietary intake and were higher in the cows fed β-carotene after 2 wk of supplementation and remained higher for the duration of the trial. Feeding supplemental β-carotene had no effect on circulating progesterone concentration, corpora lutea size or corpora lutea progesterone concentration, or basal concentrations of luteinizing hormone, frequency, and amplitude of luteinizing hormone pulses, or the release of luteinizing hormone in response to gonadotropin-releasing hormone. Thus, pituitary responsiveness to exogenous gonadotropin-releasing hormone was not affected by feeding supplemental β-carotene.

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.

Inhibition of gonadotropin-releasing hormone receptors in rat anterior pituitary monolayer cell cultures by danazol

To study possible cellular antigonadotropic effects of danazol, monolayer cultures of anterior pituitary cells from immature female rats were treated with danazol. Measurements of luteinizing hormone release in response to 10−8 mol/L gonadotropin-releasing hormone challenge and iodine 125-labeled gonadotropin-releasing hormone binding activity were done after exposure to increasing concentrations of danazol and for increasing lengths of time. It was found that luteinizing hormone secreted by pituitary cells in response to gonadotropin-releasing hormone was inhibited after danazol treatment in a dose- and time-dependent manner when compared to controls. Also, a 45% decrease in gonadotropin-releasing hormone receptor binding capacity was observed in pituitary cells cultured in the presence of increasing concentrations of danazol in the range of 10−8 to 10−4 mol/L when compared to controls. Furthermore, exposure to danazol for 25 to 96 hours caused a marked decrease in gonadotropin-releasing hormone binding activity (p < 0.005). Under these experimental conditions danazol treatment decreased the pituitary receptors for gonadotropin-releasing hormone in a dose- and time-dependent manner. Scatchard analysis of saturation curves for the binding of gonadotropin-releasing hormone to cellular gonadotropin-releasing hormone receptors indicated that the observed decrease in gonadotropin-releasing hormone binding in the danazol-treated group was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. It is therefore concluded that the antigonadotropic activity of danazol appears to be related to a decrease in gonadotropin-releasing hormone receptors in the pituitary.

Steroid hormone feedback on LH in prepubertal holstein heifers

A significant dose-response relationship between gonadotropin-releasing hormone (GnRH) and time to luteinizing hormone (LH) peak, peak serum LH and total serum LH was obtained in prepubertal Holstein heifers (28 weeks of age) (Experiment 1). For the second experiment, the effect of steroid feedback on the anterior pituitary was determined. A steady infusion of saline, estradiol-17β or progesterone was maintained for 24 h while GnRH, in various schemes, was administered 8 h after the beginning of steroid infusion. Estradiol-17β infusion (2.08 μg/h), although it did not affect peripheral concentrations of estrogen, caused an LH release 24 to 30 h later in 37.5% of the heifers. This amount of exogenous estrogen did not affect the LH response to a single GnRH (4 μg) challenge. When the same GnRH dosage (4 μg) was administered 6 times at hourly intervals, the heifers infused with estradiol had a lower response after the first 2 injections of GnRH and a greater response after the last 4 injections than heifers infused with saline. When GnRH was infused (4 μg/h) for 6 h, beginning 8 h after steroid infusion, estradiol infusion caused a significantly higher peak LH and total LH release than an infusion of either saline or progesterone (7.3 μg/h). The progesterone infusion had no effect on the GnRH-stimulated LH release. We conclude that prepubertal dairy heifers have an anterior pituitary capable of responding to the feedback effect of estrogen in a positive manner.

Estradiol potentiation of gonadotropin-releasing hormone responsiveness in the anterior pituitary is mediated by an increase in gonadotropin-releasing hormone receptors

In order to investigate the mechanism by which 17β-estradiol potentiates the action of gonadotropin-releasing hormone on the anterior pituitary in vitro, cultured pituitary cells from immature female rats were used as the model system. Cultures exposed to estradiol at concentrations ranging from 10−10 to 10−6 mol/L exhibited a significant augmentation of luteinizing hormone release in response to a 4-hour gonadotropin-releasing hormone (10 μmol/L) challenge at a dose of 10−9 mol/L compared to that of control cultures. The estradiol augmentation of luteinizing hormone release was also dependent on the duration of estradiol exposure. When these cultures were incubated with tritium-labeled l-leucine, an increase in incorporation of radiolabeled amino acid into total proteins greater than that in controls was observed. A parallel stimulatory effect of estradiol on iodine 125-labeled d-Ala6 gonadotropin-releasing hormone binding was observed. Cultures incubated with estradiol at different concentrations and various lengths of time showed a significant increase in gonadotropin-releasing hormone binding capacity and this increase was abrogated by cycloheximide. Analysis of the binding data showed that the increase in gonadotropin-releasing hormone binding activity was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. These results suggest that (1) estradiol treatment increases the number of pituitary receptors for gonadotropin-releasing hormone, (2) the augmentary effect of estradiol on luteinizing hormone release at the pituitary level might be mediated, at least in part, by the increase in the number of binding sites of gonadotropin-releasing hormone, and (3) new protein synthesis may be involved in estradiol-mediated gonadotropin-releasing hormone receptor induction.

Effect of follicular fluid treatment on follicle-stimulating hormone, luteinizing hormone and compensatory ovarian hypertrophy in prepuberal gilts.

Prepuberal 130-day-old gilts were treated with 10 ml of charcoal-stripped porcine serum (PS), whole porcine follicular fluid (WpFF) or charcoal-stripped pFF (CpFF) twice daily beginning the day before and continuing 8 days after unilateral ovariectomy (ULO). Follicle-stimulating hormone (FSH) declined for the first 14 h after ULO in WpFF and CpFF gilts and then by 24 h returned to values observed at or before ULO, whereas FSH was increased nearly twofold at 14 h in PS gilts. At 8 days after ULO the remaining ovaries from PS-treated gilts were heavier than ovaries from follicular fluid-treated gilts. In a second experiment, ovariectomized 130-day-old gilts were assigned to either a group infused with PS, a group infused with 5 ml CpFF, or a group infused with 10 ml Cpff at 18 and 2 h before a gonadotropin-releasing hormone (GnRH) challenge. Porcine follicular fluid had no effect on luteinizing hormone (LH) response to GnRH, depressed the FSH response to a 10-micrograms challenge of GnRH, but had no effect on FSH response to a 50-micrograms challenge of GnRH. In a third study, gilts were subjected to sham ovariectomy (Sham) or ULO at 130 days of age. GnRH (10 micrograms) was given on Days 1, 2 or 8 after surgery. The response to GnRH in ULO versus Sham gilts did not differ for FSH or LH on any day.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of clomiphene citrate on pituitary responsiveness to gonadotropin releasing hormone in rams and wethers

The objective of this study was to determine the effect of clomiphene citrate (clomid) on pituitary responsiveness to gonadotropin releasing hormone (GnRH) in rams and wethers. Doses of 200 mg clomid per ram and 1 μg GnRH per 50 kg body weight were used in studies on 12 rams and 4 wethers. The experimental design involved bleeding each animal at 15-minute intervals for 6.5 hours. At the end of the first hour, GnRH was injected IV. The second GnRH challenge was administered 0.5 hours after an injection of clomid or vehicle (4.5% sorbitol solution) which was given on the third hour. The relative response to clomid or vehicle was calculated as the mean increase in concentration of LH during the two-hour period after the second GnRH injection. Each treatment (clomid and vehicle) was given to all animals with a 14-day recovery period between treatment days. The relative response for the rams receiving vehicle (1.80 ± 0.65) was greater (P < 0.05) than the response during clomid treatment (0.34 ± 0.22). This suppression of LH response by clomid was observed in 10 of the 12 rams. In contrast to the rams, the concentrations of LH in wethers after the second GnRH injection were lower than those observed after the first GnRH injection. Similar to the rams, the relative response following clomid treatment of wethers (0.04 ± 0.04) was less than the relative response (P > 0.05) following vehicle (0.40 ± 0.16). The results suggest that clomid at this dosage inhibits GnRH-induced release of LH from the pituitary of rams but not of wethers.

Human menopausal gonadotropin stimulation in monkeys: Blockade of the luteinizing hormone surge by a highly transient ovarian factor

Women and monkeys treated with human menopausal gonadotropin (hMG) often fail to demonstrate timely luteinizing hormone (LH) or follicle-stimulating hormone (FSH) surges despite serum estradiol (E 2 ) levels sufficient to elicit positive feedback of LH and FSH secretion. Here we explored the mechanism of this blockade of estrogen-mediated positive feedback by hMG and the duration of this effect in acutely ovariectomized monkeys. Cycling cynomolgus monkeys ( n =14) were administered hMG (22.5IU, intramuscularly) daily beginning on cycle day 3. Three monkeys received an E 2 -benzoate challenge on day 10, resulting in peak E 2 levels of 892±313pg/ml, without subsequent LH or FSH surges. Four monkeys underwent bilateral ovariectomy on day 12, followed within 60 to 90minutes by gonadotropin-releasing hormone (GnRH) administration (15 μ g, intravenously). Five intact monkeys underwent a similar GnRH challenge. LH response to GnRH in the intact monkeys was significantly suppressed in comparison with the ovariectomized group. None of the animals manifested an FSH response to GnRH administration. Two additional monkeys did have a spontaneous LH surge during hMG administration. We conclude that hMG stimulates the production of an ovarian factor(s) which blocks the pituitary LH response to GnRH. This blockade of GnRH action on the pituitary may be the mechanism by which hMG stimulation prevents estrogen-mediated positive feedback of LH secretion. The putative ovarian factor(s) has a relatively short circulatory half-life and/or binding time, resulting in loss of its blocking activity within 90minutes after bilateral ovariectomy. Evidence is presented to suggest that this factor(s), designated gonadotropin surge-inhibiting factor, belongs to an amorphous group of nonsteroidal ovarian hormones that remain to be further characterized.

Human menopausal gonadotropin stimulation in monkeys: blockade of the luteinizing hormone surge by a highly transient ovarian factor

Women and monkeys treated with human menopausal gonadotropin (hMG) often fail to demonstrate timely luteinizing hormone (LH) or follicle-stimulating hormone (FSH) surges despite serum estradiol (E2) levels sufficient to elicit positive feedback of LH and FSH secretion. Here we explored the mechanism of this blockade of estrogen-mediated positive feedback by hMG and the duration of this effect in acutely ovariectomized monkeys. Cycling cynomolgus monkeys (n = 14) were administered hMG (22.5 IU, intramuscularly) daily beginning on cycle day 3. Three monkeys received an E2-benzoate challenge on day 10, resulting in peak E2 levels of 892 +/- 313 pg/ml, without subsequent LH or FSH surges. Four monkeys underwent bilateral ovariectomy on day 12, followed within 60 to 90 minutes by gonadotropin-releasing hormone (GnRH) administration (15 micrograms, intravenously). Five intact monkeys underwent a similar GnRH challenge. LH response to GnRH in the intact monkeys was significantly suppressed in comparison with the ovariectomized group. None of the animals manifested an FSH response to GnRH administration. Two additional monkeys did have a spontaneous LH surge during hMG administration. We conclude that hMG stimulates the production of an ovarian factor(s) which blocks the pituitary LH response to GnRH. This blockade of GnRH action on the pituitary may be the mechanism by which hMG stimulation prevents estrogen-mediated positive feedback of LH secretion. The putative ovarian factor(s) has a relatively short circulatory half-life and/or binding time, resulting in loss of its blocking activity within 90 minutes after bilateral ovariectomy. Evidence is presented to suggest that this factor(s), designated gonadotropin surge-inhibiting factor, belongs to an amorphous group of nonsteroidal ovarian hormones that remain to be further characterized.

Regulation of tonic gonadotropin release in prepubertal female hamsters.

Basal serum gonadotropin levels were monitored weekly in female hamsters from birth to 10 weeks of age. Hamsters raised on three different photoperiods presented uniform pre- and postpubertal patterns of serum LH and FSH, suggesting that gonadotropin release in the young hamster occurs independently of ambient photoperiod. In all groups, serum LH levels increased gradually in animals up to 4 weeks of age, after which levels plateaued at 50--100 ng/ml. Serum FSH was markedly elevated in 2- and 3-week-old hamsters (800--1200 ng/ml), but remained at 200--400 ng/ml in all other groups. We next examined the change in the responsiveness of the pituitary to exogenous gonadotropin-releasing hormone (GnRH) challenge. Female hamsters 2 days of age failed to respond to any dose (0.025--1000 ng) of GnRH, while 10-day old females responded in typical dose-dependent fashion. GnRH-stimulated LH release first occurred in 6-day-old hamsters and was maximal by day 9, whereas FSH release first occurred on day 8 and was maximal by day 9. The prepubertal pattern of gonadotropin release can, in part, be explained on the basis of the development of pituitary GnRH sensitivity, which occurs independently of photoperiod.

Gonadotropin release after administration of GnRH in depressed patients and healthy volunteers

Considerable attention has been paid to studies of hormonal response abnormalities in depressed patients, and functional changes have been demonstrated in a number of neuroendocrine axes. The findings from the present study extend the results of previous investigations but demonstrate a functionally intact HPG axis in depressed patients. A number of statements can be made concerning the gonadotropin-releasing hormone (GnRH) strategy: (1) Previous studies utilizing GnRH challenge have been limited in number and poorly controlled. (2) We chose to utilize our own normative data because standard gonadotropin response ranges to GnRH have not previously been established in studies with depressed patients. Moreover, hormonal responses may be affected by age, sex, mentrual status, dose, and method and rate of GnRH administration. The assessment of the hormonal responses to GnRH in depressed patients and healthy controls studied under identical conditions provides the most accurate basis for comparison. (3) The incidence of abnormal LH and FSH release in depressed subjects was similar to controls, in contrast to response abnormalities found with other neuroendocine axes. (4) Alterations in gonadotropin were limited to FSH, were sporadic, and did not differ significantly from controls. This finding is of interest and suggests that neuroendocrine alterations in depression do not necessarily affect all neuroendocrine axes.