Luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats

Naloxone produces large increases in serum luteinizing hormone (LH) levels in normal males and females, supporting a role for endogenous opioids (EOP) in the tonic inhibition of LH. Since the antagonist apparently exerts no important effects on the pituitary, the reasonable assumption has been made that it elevates gonadotropin levels by affecting the release of LH-releasing hormone (LHRH) from the hypothalamus. However, at present there is no direct in vivo evidence supporting this widely-held view. In an attempt to directly demonstrate that naloxone increases the secretion of LHRH, and thereby elevates serum LH levels, we examined whether a potent synthetic antagonist of LHRH ( [D-p Glu1, D-Phe2, D-Trp3,6]-LHRH, GPT-LHRH) blocked the effects of naloxone in male rats with a normal response to naloxone and in those with a markedly enhanced sensitivity to the drug induced by a brief period of morphine pellet implantation. Our results demonstrated that GT-LHRH antagonized equipotent doses of LHRH (100 ng/kg) and naloxone (0.5 mg/kg) over a similar time course with approximately the same AD50. Most importantly, however, we showed that the GPT-LHRH produced equivalent, parallel shifts to the right in the dose-response curves for LHRH and naloxone, indicative of competitive inhibition. We also found that GPT-LHRH completely abolished the enhanced response to naloxone's effects on LH which occurs in morphine-pretreated rats. Since we observed no competition between LHRH and naloxone for their binding sites in pituitary or brain, the only viable interpretation of our results is that naloxone increases LH by inducing the release of LHRH.     

Augmentation, by naloxone, of the frequency and amplitude of LH-RH pulses in hypothalamo-hypophyseal portal blood in the castrated ram

The effect of naloxone administration on the LH-RH secretion in hypophyseal portal blood and LH secretion in peripheral blood was studied in four short term castrated rams (between 2 to 4 days after castration). For two animals (A and B) given a single naloxone injection, an increase of LH-RH pulse amplitude was observed (A, 22.3 to 80.5 pg/ml and B, 22.5 to 34.5 pg/ml) with only a small (nonsignificant) increase in LH-RH pulse frequency. For animals C and D given four injections of naloxone, both LH-RH pulse amplitudes and LH-RH pulse frequency were increased. Means of LH-RH pulse amplitude increase from 29.3 to 65.1 pg/ml and from 34.6 to 50.8 pg/ml for animals C and D respectively and the number of LH-RH pulses detected during the 3 hrs. before and after the first injection of naloxone were respectively 3 vs. 5 and 3 vs. 7. Whereas all LH pulses were preceded with a LH-RH pulse in animals A and B, after the multiple naloxone injections in animals C and D, a rapid LH-RH pulse frequency was associated with a sustained increment of LH secretion in peripheral blood in such a way that individual LH pulses were not clearly defined. The present report is the first documentation on naloxone increasing the release of LH-RH secretion in hypophyseal portal blood of conscious, unrestrained, short-term castrated rams. The results indicate: (1) that the opiate antagonist naloxone is able to increase both the amplitude and the frequency of LH-RH discharge by the hypothalamus and (2), when the LH-RH pulse frequency exceeds one pulse every 30 min., discrete LH secretory episodes are not observed in peripheral blood.     

Comparison of biological effects of a sustained delivery system and nonencapsulated LH-RH antagonist SB-75 in rats.

Recently, we developed long-acting microcapsules and microgranules of the LH-RH antagonist SB-75. In this study, we compared the inhibitory effects of a single injection of encapsulated and nonencapsulated LH-RH antagonist SB-75 on gonadotropin and testosterone secretion. The resulting serum SB-75 levels were also measured by RIA. Microgranules containing 4% of this antagonist in poly(DL-lactide-co-glycolide) were administered IM at two different doses (30 and 60 mg/rat) to male rats. Other groups of rats were injected SC with equivalent doses of nonencapsulated SB-75 (1.25 and 2.5 mg/rat). The administration of microgranules at a dose of 60 mg/rat produced a significant elevation of serum SB-75 until day 76, and serum testosterone and LH levels were suppressed below the detection limit of the RIA for a period of 70 days. An equivalent dose of nonencapsulated SB-75 acetate (2.5 mg/rat) produced a significant elevation of SB-75 levels for 20 days and decreased testosterone to castration values and LH levels for merely 21 days. In rats treated with 30 mg microgranules of SB-75 or an equivalent dose of SB-75 acetate (1.25 mg/rat), serum testosterone and LH were suppressed to a similar extent, but for only 2 weeks. In another study, the effect of a single SC injection of 1.25 mg/rat of antagonist SB-75 on pituitary LH-RH receptors was determined, 7 and 60 days after administration. SB-75 produced a significant (p < 0.01) downregulation of membrane receptors for LH-RH 7 days after administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation of endogenous opioid peptides and morphine to neuroendocrine functions.

Morphine and the endogenous opioid peptides (EOP) exert similar effects on the neuroendocrine system. When adminstered acutely, they stimulate growth hormone (GH), prolactin (PRL), and adrenocorticotropin (ACTH) release, and inhibit release of luteinizing hormone (LH), follicle stimulating hormone (FSH),and thyrotropin (TSH). Recent studies indicate that the EOP probably have a physiological role in regulating pituitary hormone secretion. Thus injection of naloxone (opiate antagonist) alone in rats resulted in a rapid fall in serum concentrations of GH and PRL, and a rise in serum LH and FSH, suggesting that the EOP help maintain basal secretion of these hormones. Prior administration of naloxone or naltrexon inhibited stress-induced PRL release, and elevated serum LH in castrated male rats to greater than normal castrate levels. Studies on the mechanisms of action of the EOP and morphine on hormone secretion indicate that they have no direct effect on the pituitary, but act via the hypothalamus. There is no evidence that the EOP or morphine alter the action of the hypothalamic hypophysiotropic hormones on pituitary hormone secretion; they probably act via hypothalamic neurotransmitters to influence release of the hypothalamic hormones into the pituitary portal vessels. Preliminary observations indicate that they may increase serotonin and decrease dopamine metabolism in the hypothalamus, which could account for practically all of their effects on pituitary hormone secretion.     

Reduced ability of naloxone to stimulate LH and testosterone release in aging male rats; possible relation to increase in hypothalamic met5-enkephalin

Blood luteinizing hormone (LH) and testosterone levels are lower in old than in young male rats. The specific opiate antagonist, naloxone, previously shown to increase serum LH in mature male rats, exhibited relatively little ability to raise serum LH and testosterone levels in old (18–20 mo) as compared to young (4–5 mo) male rats. The brain opiate, met⁵-enkephalin, which depresses LH, was found to be significantly higher in the hypothalamus of old than of young male rats. These observations suggest that hypothalamic opiates may be partially responsible for the lower serum LH and testosterone levels in old male rats, and for reduced release of these hormones in response to naloxone administration.     

Inhibitory control of the pituitary LH secretion by LH-RH in male rats.

Luteinizing hormone-releasing hormone (LH-RH) was administered to prepubertal male rats (intact, castrate or castrate-adrenalectomized, 60 g body weight) for 28 days (1 microgram LH-RH/day, s.c.), at a 10-fold physiological dose, as compared to the minimal FSH-releasing dose of 100 ng/rat s.c. In intact rats, serum LH and weight of androgen-dependent organs (vented prostate, seminal vesicles) were reduced after 14 days of treatment. In castrate rats, the postcastration rise in serum LH was abolished by treatment. Pituitary LH content, FSH secretion and prolactin secretion were not suppressed. Hypothalamic LH-RH was increased at 14 and 21 days. In castrate adrenalectomized male rats, LH secretion was also suppressed by 1 microgram LH-RH s.c. x 28 days. The hypothalamic LH-RH content did not increase. The pituitary LH-RH receptor level was not down-regulated after 14 days treatment either in intact or castrate male rats. Pituitary inhibition (LH release) in rats by a supraphysiological dose of LH-RH given for 28 days indicates that the optimal regime for chronic treatment has to be determined by monitoring LH release at regular intervals. Direct pituitary inhibition by LH-RH may explain some of the unexpected antifertility effects observed with high doses of LH-RH.     

Mode of action of delta-9-tetrahydrocannabinol on hypothalamo-pituitary function in adult female rats.

Administration of delta-9-tetrahydrocannabinol (delta 9-THC) to pro-oestrous rats (5 mg/kg and 10 mg/kg, i.p. for 10 days) decreased the hypothalamic LH-RH content. Serum prolactin levels were reduced but serum LH and FSH and pituitary hormone content were similar to values in dioestrous rats. It is suggested that delta 9-THC acts primarily on the hypothalamus.     

Absence of effect of the peptide PHI-27 on LH release in vitro

The effects of PHI-27, a peptide of the glucagon-secretion family, on luteinizing hormone (LH) release and on LH-releasing hormone (LH-RH)- or estradiol-induced LH release were examined in a sequential double chamber perifusion system by perifusing the pituitary alone or in sequence with the mediobasal hypothalamus (MBH) from normal female rats in diestrus. PHI at 10(-7) M had no significant effect on LH release from the pituitary in series with the MBH. Moreover, on perifusion of the pituitary alone with medium containing 10(-7) M PHI, LH release induced by 20 ng/ml LH-RH from the pituitary was not significantly different from that without PHI. Furthermore, PHI had no effect on estradiol-induced LH release from the pituitary in sequence with the MBH. These data indicate that PHI has no effect on LH release in vitro.     

Self-priming effect of LH-RH on pituitary gonadotropins in hyperprolactinemic women

To investigate how various concentrations of serum prolactin (PRL) influence the priming effect of luteinizing hormone releasing hormone (LH-RH) on the pituitary gland, 24 women with various blood PRL concentrations received intravenous injections of 100 micrograms of synthetic LH-RH twice at an interval of 60 minutes and their serum LH and follicle-stimulating hormone (FSH) were measured and analysed. In the follicular phase with a normal PRL concentration (PRL less than 20 ng/ml, n = 6), marked first peaks of the two hormones following the first LH-RH stimulation and enhanced second peaks after the second LH-RH administration were observed, indicating a typical priming effect of LH-RH on gonadotropins, though the second response of FSH was more moderate than that of LH. In hyperprolactinemia, in which the serum PRL concentration was higher than 70 ng/ml (n = 13), the basal concentration of gonadotropins was not significantly changed but the priming effect of LH-RH on LH and FSH was significantly decreased (p less than 0.01). No marked second peaks of LH and FSH were observed, suggesting an inhibitory effect of hyperprolactinemia on the second release of LH and FSH. In contrast, this effect was restored in a group of women whose serum PRL concentration was between 30 and 50 ng/ml (n = 5). Furthermore, enhanced second peaks of both LH and FSH were noted after successful bromocriptine therapy reduced hyperprolactinemia (PRL greater than 70 ng/ml) to less than 25 ng/ml (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal effects of lead acetate in the male rat: mechanism of action

Environmental exposure to toxic levels of lead occurs in a number of industries with potential adverse effects on the reproductive capacity of exposed men. Using a rat model, we previously reported that dietary exposure to lead resulted in suppressed spermatogenesis and testosterone levels without significant changes in luteinizing hormone (LH). In this study, to identify more specifically the site of lead's toxic actions on the hypothalamic-pituitary-testicular axis, the response of lead-treated male rats as compared to control animals to naloxone, gonadotropin-releasing hormone (GnRH), and LH stimulation was studied. Three groups of 52-day-old Wistar rats were allowed access to either deionized distilled water containing no lead acetate or a 0.3% lead acetate solution for 30 days. In each study group, 10 control and 10 lead-treated animals were anesthetized prior to cardiac puncture and collection of serum for the measurement of lead level and baseline LH (Groups I and II) or testosterone levels (Group III). In Group I, 20 min after an i.p. injection of naloxone (1.5 mg/kg/BW), the animals were killed by decapitation, and serum was collected for LH measurement. Thirty minutes after an i.p. injection of GnRH (100 ng/100 gm BW), Group II animals were killed by decapitation, and serum was collected for LH. Sixty minutes after an injection of LH (100 mg/100 mg BW), serum was collected from Group III animals for testosterone measurement. All control animals and lead-treated animals consumed similar volumes of water. Control animals had undetectable levels of lead in their blood. Lead-treated animals had mean blood lead values of 30 micrograms/dl +/- 5 micrograms/dl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulating concentrations of luteinizing hormone, testosterone, and growth hormone after naloxone treatment in sexually mature boars

The effects of naloxone, an antagonist of opioid peptides, on circulating concentrations of luteinizing hormone (LH), testosterone, and growth hormone (GH) were determined in sexually mature boars. Blood samples were collected at 15-min intervals for three hr from five crossbred boars. Two hr after initiation of blood sampling, boars received an i.v. challenge of naloxone (1 mg/kg body weight; n=2) or 0.9% saline (n=3). Twenty-four hr later the experiment was repeated, but boars that previously received naloxone received saline and vice versa. A time by treatment interaction (p=0.09) was detected for concentrations of LH in serum, and levels of LH were greater (p<0.03) after treatment with naloxone compared to saline. Concentrations of testosterone in serum were affected by time (p<0.01), but not treatment (p= 0.59) or treatment by time (p=0.74). A treatment by time interaction (p=0.02) was detected for serum GH concentrations. Levels of GH increased in saline-treated boars (p<0.01), but not in boars receiving naloxone (p>0.1). Our results are consistent with the theory that opioid peptides suppress LH secretion and stimulate GH release in sexually mature boars.     

Inhibitory effect of beta-endorphin on gonadotropin-releasing hormone and thyrotropin-releasing hormone releasing activity in cultured rat anterior pituitary cells

To study the effect of human beta-endorphin (beta h-End) on pituitary response to gonadotropin-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) in vitro, we used dispersed rat pituitary cells. When beta h-End (10(-7) M) was simultaneously added along with LH-RH, its stimulatory effect was blocked and naloxone (NAL, 10(-5) M) did not reverse the beta h-End inhibitory effect. NAL alone elicited an increase in LH release, but in the presence of both stimulants (LH-RH and NAL), LH secretion was lower than that observed with LH-RH alone. TRH stimulatory activity of TSH and PRL secretion was blunted by the presence of beta h-End (10(-7) M) and was not reversed by NAL (10(-5) and 10(-3) M). These data suggest that beta h-End directly blocks the LH, TSH- and PRL-secreting activity of both LH-RH and TRH at the pituitary level. This beta h-End effect is not reversed by the specific opiate receptor blocker NAL.     

Lack of correlation between naloxone-induced changes in sexual behavior and serum LH in male rats

Four experiments were conducted to determine whether the action of opiate receptor antagonist drugs on sexual performance in male rats is mediated by the central release of luteinizing hormone releasing hormone (LHRH). First, in Experiment 1 it was demonstrated that administration of naloxone (20 mg/kg) caused a lengthening of postejaculatory intervals and an elevation of serum LH concentrations in gonadally intact male rats. In Experiment 2, manipulation of females' proceptive and receptive behaviors failed to reveal the reductions in ejaculation latencies and in the number of intromissions preceding ejaculation which have been previously reported after administration of naloxone to male rats. Again, the predominant response to treatment with naloxone was an increase in the length of the postejaculatory interval. In Experiment 3, pinching the tails of male rats every 30 sec after ejaculation partially abolished the relative refractory periods of the postejaculatory intervals; naloxone-induced increases in the lengths of these shortened postejaculatory intervals were nevertheless identical to those of control males, suggesting that naloxone acts to lengthen the absolute refractory period. Finally, in Experiment 4 naloxone was given to castrated males implanted with testosterone-filled silastic capsules ranging in length from 2 to 45 mm, which produced a wide range of basal serum LH concentrations. Naloxone caused an increase in postejaculatory intervals; however, this effect was not correlated with the degree to which naloxone stimulated serum LH, suggesting that the effects of naloxone on the postejaculatory interval are not mediated by a drug-induced release of LHRH.     

Occurrence of D-aspartic acid and N-methyl-D-aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release.

Using two specific and sensitive fluorometric/HPLC methods and a GC-MS method, alone and in combination with D-aspartate oxidase, we have demonstrated for the first time that N-methyl-D-aspartate (NMDA), in addition to D-aspartate (D-Asp), is endogenously present as a natural molecule in rat nervous system and endocrine glands. Both of these amino acids are mostly concentrated at nmol/g levels in the adenohypophysis, hypothalamus, brain, and testis. The adenohypophysis maximally showed the ability to accumulate D-Asp when the latter is exogenously administered. In vivo experiments, consisting of the i.p. injection of D-Asp, showed that D-Asp induced both growth hormone and luteinizing hormone (LH) release. However, in vitro experiments showed that D-Asp was able to induce LH release from adenohypophysis only when this gland was co-incubated with the hypothalamus. This is because D-Asp also induces the release of GnRH from the hypothalamus, which in turn is directly responsible for the D-Asp-induced LH secretion from the pituitary gland. Compared to D-Asp, NMDA elicits its hormone release action at concentrations approximately 100-fold lower than D-Asp. D-AP5, a specific NMDA receptor antagonist, inhibited D-Asp and NMDA hormonal activity, demonstrating that these actions are mediated by NMDA receptors. NMDA is biosynthesized from D-Asp by an S-adenosylmethionine-dependent enzyme, which we tentatively denominated as NMDA synthase.     

Changes in hypothalamic LH-RH content and blood levels of LH-RH, gonadotropin and estradiol during the preovulatory stage of rat estrous cycle.

In order to investigate the sequence of events concerning gonadotropin surge, serum LH, FSH and estradiol concentrations were measured during the rat estrous cycle as well as hypothalamic and blood levels of LH-RH in the preovulatory stage. Normally cyclic female Wistar rats kept on 12 hr light (from 22.00 hr to 10.00 hr) and 12 hr dark were killed at different times of day during each stage of the cycle. The hypothalamus was quickly dissected out, divided into 3 portions (the anterior, middle and posterior) and extracted in 90% methanol. Blood LH-RH was extracted by affinity chromatography prior to radioimmunoassay. The content of LH-RH in the anterior and middle hypothalamus started to decrease between 1.00 hr-3.00 hr, reached its nadir at 6.00 hr on proestrus and recovered to its previous values on estrus. Almost simultaneously blood LH-RH concentration showed an increase of 18.3 pg/ml-8.8 pg/ml between 1.00 hr-3.00 hr, and then fell to less than 1.0 pg/ml at 6.00 hr. On the other hand, serum estradiol level began to elevate on diestrus II followed by its peak at 6.00 hr on proestrus, while the peaks of serum LH and FSH were observed at 8.00 hr and 10.00 hr, respectively. These studies indicate that the elevation of serum estradiol was followed by the release of LH-RH from the hypothalamus and the LH-RH may be responsible for the preovulatory discharge of gonadotropin.     

Sexual differentiation of the luteinizing hormone response of neonatal rats to the narcotic antagonist naloxone: critical role of estrogen receptors

Administration of the narcotic antagonist naloxone results in an elevation of serum luteinizing hormone (LH) levels in 10-day-old female, but not male, rats. Previous studies from this laboratory indicated a role for neonatal gonadal steroids in the development of this sex-specific response. In this study, the estrogen receptor antagonist OH-Tamoxifen or the androgen-receptor antagonist flutamide were injected on Days 1 or 9 of life, and the LH responses of male and female pups to naloxone were assessed on Day 10. Flutamide did not produce a response different from that seen in vehicle-treated pups, discounting a role for androgen receptors. OH-Tamoxifen on Day 9 caused an increase in basal levels of LH; neither sex showed a response to naloxone. However, OH-Tamoxifen treatment of 1-day-old males resulted in an enhanced release of LH upon challenge with naloxone on Day 10 of life; similar treatment of 1-day-old females resulted in a normal female-type response to the opioid antagonist. These results show that blockade of estrogen receptors in males during the "critical period" of sexual differentiation results in a female phenotypic response to naloxone. Therefore, estrogen receptors play a critical role in the sexual differentiation of the LH response to naloxone in neonatal male rats.     

Naloxone enhances LH but not FSH release during various phases of the estrous cycle in the ewe

Suffolk x whiteface ewes were infused with 0.5 mg/kg/hr naloxone hydrochloride (NAL) for 6 hrs during the early, mid and late luteal and early follicular phases of the estrous cycle. Basal serum luteinizing hormone (LH) concentration was increased by NAL during each trial in the luteal phase and LH pulse amplitude was proportionately increased by 158%, 164% and 350% during the early luteal, mid luteal and early follicular phases, respectively. The apparent NAL induced increase (92%) in LH pulse amplitude during the late luteal phase was not significant. NAL only affected LH pulse frequency during the early follicular phase, when it was decreased. Mean serum follicle stimulating hormone (FSH) concentration was not affected by NAL. The results of this study indicate that endogenous opioid peptides (EOPs) may partially mediate the suppressive influence of estradiol-17 beta (E2) on LH pulse amplitude and also the stimulatory effect of E2 on LH pulse frequency in the early follicular phase. The data may suggest that NAL enhances the amplitude of pulses of gonadotropin releasing hormone (GnRH) by counteracting E2 inhibitory effects on LH release at the level of the pituitary. Alternately, some component of E2 feedback may be an EOP mediated component at the level of the hypothalamus.     

Modulation of luteinizing hormone subunit gene expression by intracerebroventricular microinjection of gonadotropin-releasing hormone or beta-endorphin in female rats

The effects of gonadotropin-releasing hormone (GnRH), beta-endorphin and its antagonist naloxone on the expression of luteinizing hormone (LH) subunit genes and LH secretion were examined in ovariectomized and/or cycling female rats through their direct microinjection into the third cerebral ventricle, in the proximity of the hypothalamus-pituitary complex. GnRH (1 nM) induced a significant augmentation of the pituitary content of alpha mRNA when administered 15, 30 or 60 min intervals over 5 h to ovariectomized rats whereas only the 30 and 60 min intervals were effective in increasing LHbeta mRNA, and the 60 min intervals for LH release. This was in agreement with the established concept of a pulse-dependent regulation of gonadotropin synthesis and release. Hourly pulses of GnRH also increased alpha and LHbeta mRNA levels when microinjected in female cycling rats during proestrus or diestrus II. Using this model we observed a marked negative influence of hourly intracerebral microinjections of beta-endorphin on LH mRNA content and LH release in ovariectomized rats while naloxone had no effect. This suggests that endogenous beta-endorphin was unable to exert its negative action on beta-endorphin receptors that were present and responded to the ligand. The present approach would be valuable for the exploration of the mechanisms of action of beta-endorphin or other substances on the functions of the gonadotrophs.     

The roles of endogenous opioids in the inhibitory action of the hippocampus on preovulatory luteinizing hormone in rats

Whether endogenous opioid peptides were involved in the inhibitory action of the hippocampus (HPC) on luteinizing hormone (LH) release was studied examining the effect of naloxone, an opioid antagonist, on the inhibitory action of electrical stimulation of the HPC and also by examining the effect of metenkephalin administration in the HPC, on preovulatory release of LH in proestrous rats. In rats treated with saline at 13:00 h, either sham stimulation or electrical stimulation of the dorsal HPC, which was performed acutely under ether anesthesia, significantly inhibited the afternoon rise in serum LH. In animals treated with naloxone at a dose of 2.0 mg/kg body weight, the afternoon rise in LH appeared smaller than that in the control group. However, statistical analysis showed no significant difference in LH values compared to the control group. Direct administration of met-enkephalin at a dose of 10 micrograms at 13:00 h through a chronically implanted cannula in the HPC did not induce any significant change in the afternoon rise in LH, regardless of whether it induced behavioral seizures or not. The results suggest that opioid peptides in the HPC do not play a significant role in the inhibitory action of HPC on LH release. Opioids existing in areas other than the HPC may play a certain, but small role.     

Opioidergic control of luteinizing hormone secretion in the female rabbit: influence of age on the response to naloxone

To examine the role of opioid neurons on luteinizing hormone (LH) secretion in the female rabbit, we determined LH release at timed intervals after naloxone administration to rabbits aged 25-150 days. The LH response to naloxone (10 mg/kg) was not significantly elevated until day 43 when LH rose 76-113% above basal levels at 40-80 min. In 56-day-old females the corresponding increase was 160% at 15 min and in 65- to 67-day-olds it was 154%. From 70 to 80 days of age the LH response was blunted and no significant elevations could be elicited. By contrast, naloxone-induced LH increases were again evident when rabbits were older than 100 days. At all ages no significant change in FSH concentrations was observed. In the adult females, naloxone at 2.5, 5, and 10 mg/kg caused increases in LH secretion which occasionally were high enough to induce ovulation as exemplified by elevated serum progesterone 4 days later. These data suggest that opioid peptides may be involved in the prepubertal rise in LH and in the normal inhibition of adult secretion in the female rabbit.