Plasma luteinizing hormone and prolactin in normothermic and hyperthermic ovariectomized ewes

The effect of bromocriptine on concentrations of luteinizing hormone (LH) and prolactin (PRL) as well as the rhythmicity of episodic profiles of plasma LH were investigated in twelve ovariectomized ewes exposed to 3-day trials during which ambient temperature/humidity conditions maintained either normothermia or induced an average of 1.4°C increase of rectal temperature (hyperthermia). In 24 of 48 trials, ewes received twice daily subcutaneous injections of 1 mg bromocriptine beginning at 1900 hr on day 1. Plasma PRL and LH were measured at 10-min intervals for 4 hr on days 2 and 3. Bromocriptine significantly decreased plasma PRL (65 ± 6 vs 5 ± 1 ng/ml), mean plasma LH (11.0 ± 0.2 vs 6.5 ± 0.2 ng/ml) and tended (P < 0.1) to decrease LH rhythmicity. In hyperthermic placebo-treated ewes, plasma PRL was increased (65 ± 6 vs 212 ± 20 ng/ml) and mean LH was decreased (11.0 ± 0.2 vs 8.2 ± 0.2 vg/ml) compared to normothermic, placebo-treated ewes, but there was no effect of hyperthermia on LH rhythmicity. Bromocriptine treatment of hyperthermic ewes decreased mean PRL (212 ± 20 vs 32 ± 9 ng/ml) on both days of sampling although mean levels were significantly higher on day 2 than on day 3(54 ± 14 vs 10 ± 6 ng/ml). Perhaps because mean LH was already inhibited in hyperthermic ewes, bromocriptine did not further decrease mean LH (8.2 ± 0.2 vs 6.6 ± 0.2 ng/ml), but LH rhythmicity was decreased (P < 0.01). There was no significant difference in mean LH between normothermic ewes receiving bromocriptine and hyperthermic ewes receiving bromocriptine (6.5 ± 0.2 vs 6.6 ± 0.2 ng/ml). These results indicate that bromocriptine inhibits PRL and LH secretion in normothermic ewes. In hyperthermic ewes, the inhibitory effect of bromoriptine on PRL was even more pronounced, but the effect on LH release was minimal perhaps because LH was already inhibited by hyperthermia.     

Attenuation of the estradiol-induced surge release of luteinizing hormone by antihistamine in ovariectomized ewes

Ovariectomized ewes received intramuscular (i.m.) injections of an H₁-histamine receptor antagonist, diphenhydramine, or saline during the anestrous and breeding seasons to determine if histamine may regulate the estradiol-induced surge release of LH in ewes. In addition, concentrations of histamine and GnRH in hypothalamic regions and histamine and LH in the pituitary gland were determined during the estradiol-induced surge of LH. Pretreatment mean, basal, and estradiol-induced secretion of LH did not differ (P > 0.05) among seasons. However, the quantity of LH (ng) measured during the estradiol-induced surge of LH was less (P < 0.05) in ewes treated with diphenhydramine (411 ± 104) than saline (747 ± 133). Treatment with diphenhydramine did not (P > 0.05) influence steady-state concentrations of histamine in hypothalamic or pituitary gland tissues, hypothalamic concentrations of GnRH, or anterior pituitary concentrations of LH during the estradiol-induced surge of LH. It is concluded that histamine may modulate the estradiol-induced surge release of LH in ewes by affecting the secretion of GnRH.     

Effects of time after ovariectomy, season and oestradiol on luteinizing hormone and follicle-stimulating hormone secretion in ovariectomized ewes.

During the breeding season, five groups of three ewes were implanted at ovariectomy with 0.36, 0.5, 1.0 and 6.0 cm oestradiol implants or implants containing no steroid. Eleven days after receiving implants, blood samples were taken every 10 min for 6 h; implants were then removed. Treatments were repeated three times during each of two consecutive breeding seasons and four times during the intervening anoestrus. In ovariectomized ewes without steroid treatment, luteinizing hormone (LH) pulse frequency increased from early to mid-breeding season, decreased to a minimum at mid-anoestrus and increased to reach a maximum at the mid-point of the second breeding season, subsequently declining. LH pulse amplitude was inversely related to frequency. Basal serum LH concentrations decreased gradually from the first breeding season to reach a minimum at mid-anoestrus and gradually increased to reach a maximum at the end of the second breeding season. Mean serum LH and follicle-stimulating hormone (FSH) concentrations were higher at the end of the second breeding season compared with the beginning of the first breeding season. All parameters of gonadotrophin secretion were decreased much more by oestradiol during the anoestrus than during the breeding season. LH pulse frequency was decreased during anoestrus and at high oestradiol concentrations during the first breeding season. Apart from LH pulse amplitude, the decreases in all parameters of gonadotrophin secretion were less during the second compared with the first breeding season. The minimum effective dose of oestradiol required to decrease mean and basal serum concentrations of LH during anoestrus was lower than in the breeding season. The minimum effective dose of oestradiol required to decrease mean serum concentrations of FSH was lower in the first compared with the second breeding season. Oestradiol depression of LH pulse amplitude and mean serum concentrations of LH and FSH showed a dose dependency during the breeding season. During anoestrus dose dependency was seen for basal concentrations of LH and mean serum concentrations of LH and FSH. We conclude that significant chronic changes in gonadotrophin secretion occur in the ewe with time after ovariectomy. Sensitivity to oestradiol also changes, and the effects of oestradiol are not always dose dependent. We suggest that the circannual pattern of LH pulse frequency and basal LH secretion are directly linked to the circannual cycle of photoperiod.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of "stress" on pulsatile luteinizing hormone release in ovariectomized rats.

The effects ov various "stresses" on pulsatile LH release in ovariectomized rats were investigated. Blood was withdrawn through atrial cannulas and replaced with saline at 10 min intervals for 190 min. Plasma LH concentration was suppressed in rats subjected to 30 or 60 min of immobilization during the collection period. On the contrary, sham ovariectomy 4 hr prior to blood collection, leg break or iv injection of ACTH or corticosterone during the collection period did not alter pulsatile patterns in LH release. The results indicate that LH release mechanisms are highly resistant to "stresses" but that immobilization can suppress LH release by an unknown mechanism.     

Effects of oestradiol on LH, FSH and prolactin in ovariectomized ewes

This study was conducted to test the hypothesis that the rate (dose/time) at which oestradiol-17 beta (oestradiol) is presented to the hypothalamo-pituitary axis influences secretion of LH, FSH and prolactin. A computer-controlled infusion system was used to produce linearly increasing serum concentrations of oestradiol in ovariectomized ewes over a period of 60 h. Serum samples were collected from ewes every 2 h from 8 h before to 92 h after start of infusion, and assayed for oestradiol, LH, FSH and prolactin. Rates of oestradiol increase were categorized into high (0.61-1.78 pg/h), medium (0.13-0.60 pg/h) and low (0.01-0.12 pg/h). Ewes receiving high rates of oestradiol (N = 11) responded with a surge of LH 12.7 +/- 2.0 h after oestradiol began to increase, whereas ewes receiving medium (N = 15) and low (N = 11) rates of oestradiol responded with a surge of LH at 19.4 +/- 1.7 and 30.9 +/- 2.0 h, respectively. None of the surges of LH was accompanied by a surge of FSH. Serum concentrations of FSH decreased and prolactin increased in ewes receiving high and medium rates of oestradiol, when compared to saline-infused ewes (N = 8; P less than 0.05). We conclude that rate of increase in serum concentrations of oestradiol controls the time of the surge of LH and secretion of prolactin and FSH in ovariectomized ewes. We also suggest that the mechanism by which oestradiol induces a surge of LH may be different from the mechanism by which oestradiol induces a surge of FSH.     

Effect of adrenalectomy and 5-hydroxytryptophan on phasic release of luteinizing hormone

The effect of 5-hydroxytryptophan (5-HTP) on serum progesterone and the possible role of adrenal progesterone in mediating stimulation by 5-HTP of phasic release of luteinizing. hormone (LH) were investigated in estradiol benzoate (EB)-treated ovariectomized rats. LH surges were induced in long-term (at least two weeks) ovariectomized rats by two injections of EB (20 micrograms/rat, s.c.) with an interval of 72 hrs. Administration of 5-HTP (50 mg/kg, i.p.) at 1000 hr in EB-treated ovariectomized rats resulted in a four-fold increase in serum progesterone within 30 mins, and significantly stimulated the LH surge at 1600 hr. This facilitative effect of 5-HTP on serum LH, but not progesterone, was further potentiated in rats pretreated with P-chlorophenylalanine (PCPA) 72 hrs earlier. Adrenalectomy shortly before 5-HTP administration attenuated the LH surge in saline treated controls, and completely blocked the facilitative effect of 5-HTP on the afternoon surge of LH in rats pretreated with PCPA 72 hrs earlier. On the other hand, chronic adrenalectomy (for 6 days) followed by hydrocortisone (0.2 mg/rat/day) replacement not only had no effect on the LH surge in saline treated controls, but also failed to prevent 5-HTP from facilitating the LH surge in PCPA pretreated rats. On the first day of bleeding, the basal LH value at 1000 hr in sham operated controls was significantly suppressed by PCPA pretreatment 48 hrs earlier. The second dose of 5-HTP administered on the next day failed to potentiate LH surges in either sham operated or adrenalectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of heat stress on plasma concentrations of prolactin and luteinizing hormone in ewes.

Basal concentrations of prolactin but not luteinizing hormone were elevated in ewes by 8--10 h of heat stress given daily during the first 11 days of their oestrous cycle. However, the prolactin and luteinizing hormone responses to thyrotrophin releasing hormone and gonadotrophin releasing hormone were unaffected.     

Genistein-induced pituitary prolactin gene expression and prolactin release in ovariectomized ewes following a series of intracerebroventricular infusions

The aim of the study was to evaluate whether genistein, a phytoestrogen commonly present in feed plants, affects prolactin release and its gene expression in the pituitary gland. In the experimental model, genistein was infused into the third ventricle (IIIv) of the brain in ewes during the short-daylight period (November-December), when the physiological plasma level of prolactin is low. Animals were ovariectomized six weeks before the experiment, to remove the main source of endogenous estrogens, and three weeks later a stainless steel guide cannula was implanted into IIIv. Genistein (10 ng/100 microl/h, n=5) or vehicle (control, n=5) were infused in a series of four one-hour infusions at 30-min intervals (from 16:30 to 22:00). Plasma samples were collected at 15-min intervals from 14:00 to 22:00 through a catheter inserted into the jugular vein and after the experiment ewes were slaughtered. Northern blot analysis revealed that pituitary prolactin mRNA content increased significantly in response to genistein, compared to the vehicle-infused ewes (p<0.05). Prolactin concentration in plasma rose significantly during the periods of genistein infusion, as compared to the values found before infusion (p<0.05-p<0.01) as well as to the values of the concomitant periods in vehicle-infused ewes (p<0.001). Our results show an effective estrogenic action of genistein on prolactin synthesis and release in ovariectomized ewes that might in part be exerted at the central nervous system level.     

Effects of luteinizing hormone on luteal cell populations in hypophysectomized ewes

To examine the effect of purified LH on development and function of luteal cells, 27 ewes were assigned to: (1) hypophysectomy plus 2 micrograms ovine LH given i.v. at 4-h intervals from Days 5 to 12 of the oestrous cycle (oestrus = Day 0; Group H + LH; N = 7); (2) hypophysectomy with no LH replacement (Group N-LH; N = 6); (3) control (no hypophysectomy) plus LH replacement as in Group H + LH (Group S + LH; N = 7); (4) control with no LH treatment (Group S-LH; N = 7). Blood samples were collected at 4-h intervals throughout the experiment to monitor circulating concentrations of LH, cortisol and progesterone. On Day 12 of the oestrous cycle corpora lutea were collected and luteal progesterone concentrations, unoccupied receptors for LH and number and sizes of steroidogenic and non-steroidogenic luteal cell types were determined. Corpora lutea from ewes in Group H-LH were significantly smaller (P less than 0.05), had lower concentrations of progesterone, fewer LH receptors, fewer small luteal cells and fewer non-steroidogenic cells than did corpora lutea from ewes in Group S-LH. The number of large luteal cells was unaffected by hypophysectomy, but the sizes of large luteal cells, small luteal cells and fibroblasts were reduced. LH replacement in hypophysectomized ewes maintained luteal weight and the numbers of small steroidogenic and non-steroidogenic luteal cells at levels intermediate between those observed in ewes in Groups L-LH and S-LH. In Group H + LH ewes, luteal and serum concentrations of progesterone, numbers of luteal receptors for LH, and the sizes of all types of luteal cells were maintained. Numbers of small steroidogenic and non-steroidogenic cells were also increased by LH in hypophysectomized ewes. In Exp. II, 14 ewes were assigned to: (1) sham hypophysectomy with no LH replacement therapy (Group S-LH; N = 5); (2) sham hypophysectomy with 40 micrograms ovine LH given i.v. at 4-h intervals from Day 5 to Day 12 of the oestrous cycle (Group S + LH; N = 5); and (3) hypophysectomy plus LH replacement therapy (Group H + LH; N = 4). Experimental procedures were similar to those described for Exp. I. Treatment of hypophysectomized ewes with a larger dose of LH maintained luteal weight, serum and luteal progesterone concentrations and the numbers of steroidogenic and non-steroidogenic luteal cells at control levels.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of season and lactation on luteinizing hormone secretion in postpartum ewes

Effects of season, postpartum interval and short-term weaning were investigated on luteinizing hormone (LH) secretion in ewes. Blood samples were collected at 10-min intervals for 4 h (basal period). Then gonadotropin-releasing hormone (GnRH) was administered and 10 more blood samples were collected over an additional 4 h period. The effects of day post partum (5, 20 or 40) and short-term weaning (weaned Day 37, tested Day 40 post partum) on basal and GnRH-induced LH secretion were tested. Mean basal concentrations of LH for ewes on Day 5, 20 or 40 post partum ranged from 1.6 to 4.6 ng/ml and did not differ. Mean concentrations of LH during the post-GnRH sampling interval were greater (P<0.01) for ewes bled on Day 20 or 40 post partum (12.3 and 11.8 ng/ml, respectively) than for ewes bled on Day 5 or for unbred control ewes (6.7 and 5.8 ng/ml, respectively). Weaning on Day 37 depressed GnRH-induced LH secretion on Day 40 post partum (8.18 ng/ml; P<0.05). Seasonal changes in LH secretion on Day 20 or 40 post partum in January, March or June lambing ewes were also tested. There was no difference in basal or GnRH-induced LH secretion between Day 20 or 40 post partum among groups in January or March.. In June, ewes had lower (P<0.01) basal and GnRH-induced LH secretion on Day 20 post partum than ewes did on Day 40 post partum. Across month of the year, on Day 20 post partum, ewes lambing in March released more LH in response to GnRH than ewes lambing in January (P=0.07) or June (P<0.05). Response to GnRH on Day 20 post partum was similar for ewes lambing in January or June (P>0.1). Ewes lambing in January released less (P<0.01) LH on Day 40 post partum than ewes lambing in March or June; however, no difference was detected between the latter two groups (P>0.1). Thus, seasonal modifications of the releasable pool of LH may mask or modify the effect of the postpartum interval upon this endocrine response.     

Effects of weaning and naloxone on luteinizing hormone secretion in postpartum ewes

The effects of weaning and naloxone on concentrations of luteinizing hormone (LH) at 20 days postpartum were examined. March-lambing Finnish Landrace x Southdown ewes (n = 20) were bled via jugular venipuncture at 10-min intervals for 4 h. Naloxone (1 mg/kg bodyweight) was administered i.v. at 60, 120, and 180 min. Treatment groups were suckled (S), weaned on Day 17 (W), suckled plus naloxone (SN), and weaned plus naloxone (WN). Mean concentrations of LH were calculated for 0-60, 70-120, 130-180, and 190-240 min time intervals. Analysis of variance indicated a group effect (p = 0.03) and a group x time interaction (p = 0.02). Concentrations of LH followed a cubic pattern in SN (p = 0.03) and WN (p = 0.08) ewes, whereas LH levels decreased (p less than 0.05) in a pattern consisting of linear and quadratic trends in S and W ewes. Concentrations of LH in S and W ewes were similar at 0-60 and 190-240 min. W ewes had lower (p less than 0.05) concentrations of LH than S ewes at 70-120 and 130-190 min. Further analysis revealed that LH was elevated in SN ewes (p = 0.01) and WN ewes (p = 0.07) at 70-120 min, but was not significantly elevated at 130-180 min. At 190-240 min LH was increased in SN ewes (p = 0.03), but LH levels in WN ewes were similar to those of SN ewes as well as to those of S control ewes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Concentrations of luteinizing hormone in ovariectomized ewes and the effect of disturbance, starvation and vascular cannulation

Neither routine experimental procedures, including vascular cannulation and venipuncture, nor starvation or disturbance caused significant fluctuations in luteinizing hormone (LH) concentrations in ovariectomized ewes. Samples obtained at 5-min intervals revealed episodic LH releases occurring every 10-35 min. Hourly sampling over 3 days revealed large LH variations but no distinct diurnal variation.     

Effect of N-methyl-d,l-aspartate on luteinizing hormone secretion in ovariectomized ewes in the absence and presence of estradiol

N-methyl-d,l-aspartate (NMA), a potent agonist of the neuroexcitatory amino acids aspartate and glutamate, stimulates release of luteinizing hormone (LH) in rats and nonhuman primates. The objective of the experiments described here was to determine the effect of NMA on LH secretion in ovariectomized ewes, in both the absence and presence of estradiol. In Experiment 1, blood samples were collected from 16 ewes every 12 min for 4 h. At Hour 2, ewes received i.v. injections of either 0, 6, 12, or 24 mg NMA/kg body weight dissolved in 0.9% saline (n = 4 per treatment). Mean LH concentrations were unaltered by any dose of NMA (p greater than 0.3). Immediately after completion of Experiment 1, each ewe received an s.c. Silastic implant designed to maintain circulating concentrations of estradiol of approximately 1 pg/ml. Three weeks later, Experiment 2 was conducted, using the same blood sampling regimen and doses of NMA as Experiment 1. The estradiol implants decreased serum LH concentrations in all animals. Treatment with saline failed to alter mean LH concentrations (p greater than 0.3). In contrast, 6, 12, and 24 mg NMA/kg body weight increased mean LH concentrations by 326% (p less than 0.03), 1125% (p less than 0.02), and 441% (p less than 0.0001), respectively. These results demonstrate that exogenous estradiol suppresses LH release in sheep in a manner antagonized by NMA.     

Studies on a possible pituitary effect of monoamines on luteinizing hormone release in ovariectomized rats

Incubation of anterior pituitaries from ovariectomized rats with LHRH and various concentrations of dopamine, norepinephrine or serotonin indicated that none of these neurotransmitters could decrease pituitary LH secretion in response to the releasing hormone. This indicated that the inhibitions of pulsatile LH release previously observed in our laboratory in ovariectomized rats in response to intraventricularly administered catecholamines or stimulation of brain serotoninergic neurons are due to central rather than pituitary effects of these transmitters.     

Simultaneous measurement of luteinizing hormone-releasing hormone and luteinizing hormone during estradiol-induced luteinizing hormone surges in the ovariectomized ewe

Sequential bleeding and push-pull perfusion of the hypothalamus were used to characterize luteinizing hormone (LH) and LH-releasing hormone (LHRH) release in ovariectomized (OVX) ewes after injection of corn oil or estradiol benzoate (EB). Push-pull cannulae were surgically implanted into the stalk median eminences of 24 OVX ewes. Seven to 14 days later each of 20 animals was given an i.m. injection of 50 micrograms EB. Blood samples and push-pull perfusate were collected at 10-min intervals for 6-12 h beginning 12-15 h after EB injection. Four OVX ewes were given i.m. injections of corn oil 7 days after implantation of push-pull cannulae. Blood samples and push-pull perfusate were collected at 10-min intervals for 4 h between 18 and 22 h after injection of corn oil. Luteinizing hormone remained below 2 ng/ml throughout most of the sampling periods in 9 of 20 EB-treated ewes. In 5 of these 9 LHRH also was undetectable, whereas in 4 LHRH was detectable (1.84 +/- 0.29 pg/10 min), but did not increase with time. Preovulatory-like surges of LH occurred in 11 EB-treated ewes, but LHRH was undetectable in 5. In 4 of 6 ewes showing LH surges and detectable LHRH, sampling occurred during the onset of the LH surge.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of basal and stress-induced prolactin release and stimulation of luteinizing hormone secretion by alpha-melanocyte-stimulating hormone

alpha-MSH and beta-endorphin, both synthesized from a common precursor, have opposite behavioral actions. In order to determine if these peptides have opposite effects on pituitary function, basal LH secretion and basal and stress-induced prolactin release were studied in adult male rats after intraventricular injection of alpha-MSH. Each rat also received intraventricular saline in order to serve as its own control. 18 micrograms alpha-MSH stimulated plasma LH from 16.5 +/- 2.5 (SEM) ng/ml to a peak of 27.2 +/- 4.0 and 26.0 +/- 4.9 ng/ml at 5 and 10 min, and suppressed prolactin from 3.5 +/- 0.7 ng/ml to 1.3 +/- 0.1 and 1.2 +/- 0.1 ng/ml at 15 and 30 min. Intraventricular alpha-MSH also significantly blunted the prolactin rise associated with the stress of swimming. 10 and 20 min after the onset of swimming, prolactin levels in rats pretreated with alpha-MSH were significantly diminished: 7.4 +/- 1.5 and 6.5 +/- 2.0 ng/ml vs 23.8 +/- 3.6 and 15.2 +/- 2.8 after normal saline. Similarly, des-acetyl alpha-MSH which is the predominant form of alpha-MSH in the hypothalamus, diminished the stress-induced prolactin rise from 18.4 +/- 5.3 and 11.2 +/- 3.4 ng/ml at 10 and 20 min to 10.0 +/- 2.4 and 5.5 +/- 1.6 ng/ml. We conclude that centrally administered alpha-MSH stimulates LH and suppresses basal and stress-induced prolactin release in male rats. These actions are opposite to those previously shown for beta-endorphin and suggest that alpha-MSH may antagonize the effects of beta-endorphin on pituitary function.     

Effect of rabbit doe-litter separation on 24-hour changes of luteinizing hormone,follicle stimulating hormone and prolactin release in female and male suckling pups

Background  

The daily pattern of nursing of the rabbit pup by the doe is the most important event in the day for the newborn and is neatly anticipated by them. Such anticipation presumably needs a close correlation with changes in hormones that will allow the pups to develop an appropriate behavior. Although a number of circadian functions have been examined in newborn rabbits, there is no information on 24-h pattern of gonadotropin release or on possible sex-related differences in gonadotropin or prolactin (PRL) release of pups. This study examined the 24-h changes of plasma luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) in 11 days old suckling female and male rabbits left with the mother or after short-term (i.e., 48 h) doe-litter separation.     

Effect of estradiol benzoate and clomiphene on tyrosine hydroxylase activity and on luteinizing hormone and prolactin levels in ovariectomized rats

The effects of estradiol benzoate (EB) on tyrosine hydroxylase (TH) activity in the medial basal hypothalamus (MBH) and on plasma levels of luteinizing hormone (LH) and prolactin were studied in long-term ovariectomized rats. Administration of 10 μg EB produced significant elevation of TH activity on Days 1 and 3 following injection. LH levels were significantly lower than controls throughout the three day treatment period, although there was a significant increase from Day 1 to Day 2. TH activity and LH levels were inversely related throughout the experimental period. Clomiphene (15 μg/rat/day), a purported estrogen antagonist, was administered over a period of three days to control and EB-treated rats to determine whether the effect of EB on plasma LH levels was causally related to changes in TH activity. In rats receiving both EB and clomiphene, TH activity was lower and plasma LH was higher than after EB alone. The results support the hypothesis that the feedback effects of estradiol on LH release involve an action on the tuberoinfundibular dopaminergic (TIDA) neurons of the MBH and that clomiphene can oppose the inhibitory effect of estradiol on LH release by directly inhibiting TIDA neuron activity. Furthermore, EB-induced release of prolactin does not appear to involve detectable changes in the activity of TIDA neurons.     

The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid-primed ovariectomized rats

We have previously reported that leptin, the product of the obese (ob) gene, may play a physiologically relevant role in the generation of estradiol/progesterone-induced luteinizing hormone (LH) and prolactin (PRL) surges in female rats. In the present study, we examined whether the stimulatory effect of leptin on the hormonal surges is mediated through the melanocortin (MC) 4 receptor in the brain, as is leptin's effect on feeding behavior. We also explored whether the MC4 receptor participates in tonic stimulation of steroid-induced LH and PRL surges. Experiments were performed on both normally fed and 3-day starved rats, which were ovariectomized and primed with estradiol and progesterone. At 11:00 h on the day of the experiments, the normally fed rats received an intracerebroventricular administration of artificial cerebrospinal fluid (vehicle), SHU 9119 (a nonselective MC3/MC4 receptor antagonist, 1.0 nmol), or HS014 (a selective MC4 receptor antagonist, 1.0 nmol). The 3-day starved rats were given vehicle, recombinant mouse leptin (0.3 nmol), leptin (0.3 nmol) + SHU9119 (1.0 nmol), or leptin (0.3 nmol) + HS014 (1.0 nmol). From 11:00 to 18:00 h, blood was collected every 30 min to measure LH and PRL. The 3-day starvation completely abolished both LH and PRL surges, but leptin significantly reinstated these hormonal surges. Both SHU9119 and HS014 significantly decreased the magnitude of LH and PRL surges in normally fed rats and also significantly blocked the leptin stimulation of the hormonal surges in starved rats. These results suggest that the MC4 receptor may be the pivotal subtype of MC receptors mediating the leptin stimulation of LH and PRL surges. The data also suggest that endogenous MC(s) may tonically stimulate the hormonal surges in normally fed rats via the MC4 receptor. This is the first report describing a physiological role of a specific MC receptor in regulating the reproductive axis.