The Effect of Atrazine Administered by Gavage or in Diet on the LH Surge and Reproductive Performance in Intact Female Sprague‐Dawley and Long Evans Rats

Atrazine (ATR) blunts the hormone‐induced luteinizing hormone (LH) surge, when administered by gavage (50–100 mg/kg/day for 4 days), in ovariectomized rats. In this study, we determined if comparable doses delivered either by gavage (bolus dose) or distributed in diet would reduce the LH surge and subsequently affect fertility in the intact female rat. ATR was administered daily to intact female Sprague‐Dawley (SD) or Long Evans (LE) rats by gavage (0, 0.75 1.5, 3, 6, 10, 12, 50, or 100 mg/kg/day) or diet (0, 30, 100, 160, 500, 660, or 1460 ppm) during one complete 4‐day estrous cycle, starting on day of estrus. Estrous status, corpora lutea, ova, and LH plasma concentrations were evaluated. A second cohort of animals was mated on the fourth treatment day. Fertility metrics were assessed on gestational day 20. A higher portion of LE rats had asynchronous estrous cycles when compared to SD rats both during pretreatment and in response to ATR (≥50 mg/kg). In contrast, bolus doses of ATR (≥50 mg/kg) inhibited the peak and area under the curve for the preovulatory LH surge in SD but not LE animals. Likewise, only bolus‐treated SD, not LE, rats displayed reduced mean number of corpora lutea and ova. There were no effects of ATR administered by gavage on mating, gravid number, or fetus number. Dietary administration had no effect on any reproductive parameter measured. These findings indicate that short duration, high‐bolus doses of ATR can inhibit the LH surge and reduce the number of follicles ovulated; however, dietary administration has no effect on any endocrine or reproductive outcomes     

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)     

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.     

Negative feedback as an obligatory antecedent to the estradiol-induced luteinizing hormone surge in ovariectomized pigs

In ovariectomized pigs, estradiol treatment induces a preovulatory-like luteinizing hormone (LH) surge, but only after serum LH concentrations are suppressed for 48 h. This inhibition of LH release is attributable in large part to inhibition of gonadotropin-releasing hormone (GnRH) release. The present report examines the dependency of the estradiol-induced LH surge on this preceding phase of negative feedback. Ten ovariectomized gilts were given an i.m. injection of estradiol benzoate (10 micrograms/kg BW). Beginning at the time of estradiol treatment, 5 of these gilts received 1-microgram GnRH pulses i.v. every 45 min for 48 h, i.e. during the period of negative feedback. The remaining 5 control gilts received comparable infusions of vehicle. Estradiol induced the characteristic biphasic LH response in control gilts. On the other hand, the inhibitory LH response to estradiol was prevented and the ensuing LH surge was blocked in 4 of the 5 gilts given GnRH pulses during the negative feedback phase. These results indicate that suppressing release of GnRH and/or LH is an important antecedent to full expression of the LH surge in ovariectomized pigs. Assimilation of this observation with the existing literature provides novel insights into the neuroendocrine control of LH secretion in castrated and ovary-intact gilts.     

The inhibitory action of corticotropin-releasing hormone on gonadotropin secretion in the ovariectomized rhesus monkey is not mediated by adrenocorticotropic hormone

Earlier observations in our laboratory indicated that i.v. infusion of human/rat corticotropin-releasing hormone (hCRH) suppresses pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in ovariectomized rhesus monkeys. Since cortisol secretion increased significantly as well, it was not possible to exclude the possibility that this inhibitory effect of hCRH on gonadotropins was related to the activation of the pituitary/adrenal axis. The purpose of the present study was to determine the role of pituitary/adrenal activation in the effect of hCRH on LH and FSH secretion. We compared the effects of 5-h i.v. infusions of hCRH (100 micrograms/h, n = 7) and of human adrenocorticotropic hormone (ACTH) (1-24) (5 micrograms/h, n = 3; 10 micrograms/h, n = 3, 20 micrograms/h, n = 3) to ovariectomized monkeys on LH, FSH, and cortisol secretion. As expected, during the 5-h ACTH infusions, cortisol levels increased by 176-215% of baseline control, an increase similar to that observed after CRH infusion (184%). However, in contrast to the inhibitory effect observed during the CRH infusion, LH and FSH continued to be released in a pulsatile fashion during the ACTH infusions, and no decreases in gonadotropin secretion were observed. The results indicated that increases in ACTH and cortisol did not affect LH and FSH secretion and allowed us to conclude that the rapid inhibitory effect of CRH on LH and FSH pulsatile release was not mediated by activation of the pituitary/adrenal axis.     

The role of estradiol in adrenal insufficiency and its interaction with corticosterone on hydromineral balance

Estradiol (E2) plays an important role in controlling the homeostasis of body fluids. Several studies have reported the involvement of the hypothalamic pituitary adrenal axis (HPA) in the homeostatic control of hydromineral balance and the influence of estrogens on the modulation of this system. Nevertheless, until now, the physiological relevance of HPA axis activity on the hydromineral balance in females has not yet been fully elucidated. Therefore, the objective of the present study was to evaluate the effects of E2 (20 μg/animal) pretreatment on neuroendocrine and hydroelectrolyte changes induced by adrenalectomy (ADX) with or without glucocorticoid hormone replacement (corticosterone, CORT; 10 mg/kg) in ovariectomized rats (OVX). The results show that sodium appetite, natriuresis and the elevated plasma angiotensin II (ANG II) concentration induced by ADX were attenuated by E2 pretreatment. Additionally, a reduction of AT1 mRNA expression in the subfornical organ (SFO) and an increase in plasma atrial natriuretic peptide (ANP) concentrations by E2 pretreatment were observed. E2 pretreatment reversed the reduction in water intake induced by ADX in ADX CORT-replaced rats. Moreover, E2 pretreatment attenuated corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) induced by ADX. In contrast, E2 pretreatment increased CRF mRNA expression in the PVN in ADX CORT-replaced rats. Taken together, these results suggest that E2 has an important role in the modulation of behavioral and neuroendocrine responses involved in the maintenance of body fluid homeostasis in ADX rats with or without glucocorticoid replacement therapy.     

Role of central epinephrine in regulation of anterior pituitary hormone secretion

Hypothalamic regulation of anterior pituitary hormones is thought to be mediated by the release of stimulatory and/or inhibitory peptides that are, in turn, regulated by catecholaminergic neurons. The recent development of selective epinephrine (EPI) synthesis inhibitors has made it possible to disrupt central EPI neurotransmission without affecting norepinephrine or dopamine. These compounds were used in the present investigation to assess the involvement of brain EPI systems in regulation of GH, LH, and prolactin (PRL) in male and ovariectomized female rats. Inhibition of central EPI synthesis (1) inhibited episodic and morphine-, but not clonidine-induced GH release, and (2) blocked the LH surge induced by estrogen and progesterone, but did not affect episodic LH release in hormonally untreated rats. Inhibition of peripheral (adrenal) EPI synthesis had no effect on these hormones. Results of these studies suggest an excitatory role for EPI in regulation of GH and LH secretion, mediated by stimulation of GH-releasing hormone and LHRH, respectively. EPI does not appear to have a major function in regulation of PRL secretion.     

Influence of hypothalamic-pituitary-adrenocortical hormones on reproductive hormones in gray wolves (Canis lupus).

The release of hypothalamic-pituitary-adrenocortical hormones was studied in intact and neutered gray wolves (Canis lupus) to determine how these hormones interact and affect reproductive hormones. Experiments were performed on adult wolves anesthetized with 400 mg ketamine and 50 mg promazine. Intravenous (i.v.) injections with 50 micrograms ovine corticotropin releasing factor (oCRF) significantly increased adrenocorticotropin (ACTH; P < or = 0.01), cortisol (CORT; P < or = 0.004), and progesterone (P < or = 0.036), but not beta-endorphin (P > or = 0.52). Since neutered wolves demonstrated dose-dependent elevations in response to ACTH, it was concluded that the progesterone was secreted from the adrenal gland. Basal luteinizing hormone (LH) concentrations in neutered wolves were similar before and 60 min after i.v. injection of 1, 5, or 25 IU ACTH (P > or = 0.36) or 2.2 mg/kg cortisol (P = 0.42). Neither 25 IU ACTH (P = 0.55) nor 0.22 mg/kg dexamethasone (P = 0.49) altered the LH response to injection of LH releasing hormone in neutered wolves. Chronic administration of 0.22 mg/kg/day dexamethasone for 3 d did not alter baseline LH concentrations (P = 0.75). Injection of 1.0 mg/kg naloxone (NAL), however, increased LH concentrations relative to baseline values in both intact (P = 0.032) and neutered (P = 0.0005) female wolves, but not in intact (P = 0.19) or neutered males (P = 0.07). These results indicated that in gray wolves (1) oCRF stimulated the release of pituitary and adrenal hormones in a fashion similar to that of other mammals; (2) the adrenal cortex was capable of secreting progesterone into the systemic circulation; (3) exogenous glucocorticoids did not alter LH concentrations; and (4) endogenous opioids may modulate LH secretion in female wolves.     

The effect of Λ9-tetrahydrocannabinol on the positive and negative feedback control of luteinizing hormone release

The principal psychoactive component of marihuana, Λ⁹-Tetrahydrocannabinol (THC), decreases serum LH levels when given to ovariectomized rats at a dose of 10 mg/kg. This same dose of THC blocks both the estrogen and progesterone mediated positive feed-back release of LH. The steroid-induced LH surge, when blocked by THC, reappears 24 h later. The positive feedback release of LH should serve as a suitable model to study the mechanism of action by which THC blocks the ovulatory LH surge.     

Role of 5 alpha-reduction in progesterone's ability to release FSH in estrogen-primed ovariectomized rats.

In ovariectomized estrogen-primed rats, progesterone as well as 5 alpha-dihydroprogesterone (5 alpha-DHP) are capable of inducing the release of gonadotropins. This study examined the need of 5 alpha-reduction as a prerequisite for the action of progesterone. The 5 alpha-reductase inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide was injected at a 1 or 2 mg dose/rat 2 h prior to an injection of 0.4 or 0.8 mg progesterone/kg body weight at 0900 h to immature ovariectomized, estrogen-primed rats and serum was analyzed for LH and FSH at 1500 h. Pituitary and hypothalamic 5 alpha-reductase activity was measured at the time of progesterone administration and at the time of the surge by incubating tissue homogenates with [3H]progesterone. Substrate, ([3H]progesterone) and product ([3H]5 alpha-DHP), were separated by reverse phase HPLC. The pituitary 5 alpha-reductase activity was not blocked at 1500 h. However, both pituitary and hypothalamic 5 alpha-reductase was blocked at the time of progesterone administration. No effect was seen by acute administration of the 5 alpha-reductase inhibitor upon either the 0.4 or 0.8 mg progesterone/kg-induced release of LH and FSH. There was, however, a specific, significant inhibition of progesterone-induced FSH but not LH release when the 5 alpha-reductase inhibition was sustained throughout the afternoon of the gonadotropin surge. These results indicate a biologically significant role for the irreversible 5 alpha-reduction of progesterone in the modulation of the release of FSH.     

Effects of systemic blockade of nitric oxide synthases on pulsatile LH, prolactin, and GH secretion in adult male rats.

BACKGROUND: Nitric oxide (NO) has emerged as an important neurotransmitter involved in the control of the neuroendocrine function. NO acts at hypothalamic, pituitary, and gonadal levels. Previous data from our laboratory showed that blockade of NO generation, after systemic administration of a NO synthase inhibitor (Nomega-nitro-arginine methyl ester, NAME), increased the luteinizing hormone (LH) secretion in intact and ovariectomized females, whereas a blockade of spontaneous and steroid-induced LH and prolactin surges after NO synthase inhibition has been also described. METHODS AND RESULTS: Adult male rats were implanted with chronic intra-auricular cannulae and 5 days later sampled at 15-min intervals during 6 h (10.00-16.00 h). Administration of NAME (40 mg/kg at 08.00 and 13.00 h) stimulated significantly (p < or = 0.01) the LH secretion, increasing LH pulse amplitude (0.58 +/- 0.14 vs. 0.08 +/- 0.01 ng/ml in controls), mean LH levels (0.64 +/- 0.15 vs. 0.15 +/- 0.03 ng/ml in controls), and area under curve (239 +/- 56 vs. 57 +/- 13 in controls). This effect was blocked by coadministration of sodium nitroprusside (SNP), a NO donor (0.5 mg/kg). The action of NAME was observed 3 h after administration, in contrast to the earlier response detected in female rats, and it appeared selective for LH, as prolactin and growth hormone secretion remained unchanged. Further analysis was carried out to determine whether the effect of NAME on the LH secretion was indirect and mediated by changes in testosterone release. To this end, adult male rats were decapitated 2 h after administration of NAME (40 mg/kg), SNP (0.5 mg/kg), or L-nitro-arginine methyl ester (L-AME), a substrate for NOS (1 g/kg). The serum testosterone concentrations were unchanged after NAME administration, but inhibited by SNP and L-AME. Finally, the effect of NAME and SNP on in vitro testosterone secretion was analyzed. NAME (10 mM) did not affect basal testosterone production, but inhibited the human chorionic gonadotropin stimulated testosterone secretion. CONCLUSIONS: These data strongly suggest that the stimulatory effect of NAME on LH secretion is not due to an inhibition of testosterone release and is exerted at the hypothalamic-pituitary level.     

Pulsatile secretion of luteinizing hormone and follicle stimulating hormone and their relationship to secretion of estradiol and onset of estrus in weaned sows

The objective of this experiment was to characterise temporal changes in estradiol and pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the interval between weaning and estrus in the sow. Five multiparous sows were sampled at 10-min intervals for 3 h beginning 8 h after weaning and continuing every 12 h until estrus. Interval to estrus was 102 ± 2 h (range 96–108) after litters were weaned, and interval to preovulatory LH and FSH surges was 109 ± 5 h (range 92–116). With the exception of the period of the preovulatory surge, neither average nor basal concentrations of LH or FSH changed over time. Number of LH peaks per 3 h reached a maximum of 2.8 at 48 h before the preovulatory surge, then declined to 0.8 at 12 h before the surge. Peak amplitude for LH and peak frequency and amplitude for FSH also declined with time before preovulatory surges. Relative ranks were computed for individual sows based on the mean concentration of LH or FSH for each bleeding period. Rankings were consistent over the periods, but were not correlated with interval to estrus. Estradiol concentrations peaked (88 ± 7 pg/ml) at 36 h before preovulatory surges, coincident with the decline in peak frequency of LH. We conclude that pulsatile secretion of LH and FSH changes during the interval between weaning and estrus but secretion of these two hormones may be controlled by different mechanisms.     

Effect of gonadotropin-releasing hormone antagonists on serum follicle-stimulating hormone and luteinizing hormone under conditions of singular follicle-stimulating hormone secretion

Previous work has indicated that in long-term ovariectomized rats a potent antagonist to gonadotropin-releasing hormone (GnRH) suppressed serum luteinizing hormone (LH) more successfully than follicle-stimulating hormone (FSH). The present studies examined whether the rise in serum FSH which occurs acutely after ovariectomy, or during the proestrous secondary surge, depends on GnRH. In Experiment A, rats were ovariectomized at 0800 h of metestrus and injected with (Ac-dehydro-Pro1, pCl-D-Phe2, D-Trp3,6, NaMeLeu7)-GnRH (Antag-I) at 1200 h of the same day, or 2 or 5 days later. Antag-I blocked the LH response completely, but only partially suppressed serum FSH levels. Experiment B tested a higher dose of a more potent antagonist [( Ac-3-Pro1, pF-D-Phe2, D-Trp3,6]-GnRH; Antag-II) injected at the time of ovariectomy. The analog suppressed serum LH by 79% and FSH by 30%. Experiment C examined the effect of Antag-II on the day of proestrus on the spontaneous secondary surge of FSH, as well as on a secondary FSH surge which can be induced by exogenous LH. Antag-II, given at 1200 h proestrus, blocked ovulation and the LH surge expected at 1830 h, as well as increases in serum FSH which occur at 1830 h and at 0400 h. Exogenous LH triggered a rise in FSH in rats suppressed by Antag-II. In Experiment D proestrous rats were injected with Antag-II at 1200 h and ovariectomized at 1530 h. By 0400 h the antag had suppressed FSH in controls, but in the ovariectomized rats, a vigorous FSH response occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related alterations in pulsatile luteinizing hormone release: effects of long-term ovariectomy, repeated pregnancies and naloxone

Aging of the female reproductive system may be regulated by changes at the hypothalamic, pituitary, and ovarian levels. Long-term ovariectomy (LT-OVX) and/or multiple pregnancies delay age-related deterioration of several parameters of reproductive potential in rodents. We tested whether long-term suppression of cyclic ovarian hormone release that is normally associated with the 4- to 5-day estrous cycle decelerates age-related decreases in the frequency of luteinizing hormone (LH) pulses to assess whether hormonal milieu influences the rate of aging of the pulse generator. We determined the percentage of rats exhibiting pulsatile LH secretion, mean LH levels, and amplitude and frequency of LH pulses in seven groups of ovariectomized (OVX) rats. Young (3-4 mo), middle-aged (8-10 mo), and old (18-22 mo) virgin rats, ovariectomized 4 wk (4WK-OVX) prior to experimentation, were used to determine the effect of age. The effect of long-term ovarian hormone deprivation was tested by ovariectomizing rats at 2-3 mo of age and using them when they were middle-aged (8-10 months) or old (18-22 mo). The effect of deprivation of cyclic increases in ovarian hormones associated with repeated estrous cycles was tested by using retired breeder (RB) rats that had been ovariectomized 4 wk prior to experimentation. Each rat was implanted with a right atrial cannula and bled the next day at 10-min intervals for 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of naloxone and yohimbine administration on pulsatile LH secretion in luteal phase beef cows

This study examined the effects of two specific neurotransmitter receptor antagonists, naloxone (NAL; mu-opioid) and yohimbine (YOH; alpha(2)-adrenergic), on pulsatile luteinizing hormone (LH) release during the luteal phase (Day 10; Day 0 = estrus) of beef cows. Treatments were saline i.m. (C; n = 4); 1mg/kg NAL i.m. followed 3 h later by two 0.5 mg/kg injections spaced 2.5 h apart (N; n = 4); 0.2 mg/kg YOH i.v. (Y; n = 3); or combined N and Y regimens, with Y preceding N by 30 min (NY; n = 4). Blood samples were collected for 8 h before (Period I) and after (Period II) initiation of treatment. Respiration rates of Y cows were similar to C cows during Period II. However, respiration rates of N and NY animals increased 70% within 30 min of the first NAL injection. Acute LH release was not observed in response to either NAL or YOH. Pulsatile LH secretion was unchanged in N, Y and NY cows during Period II when compared with Period I. In contrast, basal and pulsatile LH secretion was inhibited in C cows during Period II. The inhibition of LH secretion in C animals following NAL indicate that the cows were under stress during Period II. Thus, these data suggest that the inhibition of LH release in stressed animals can be overcome by pharmacologic attenuation of inhibitory (N) or accentuation of stimulatory (Y) signals to LHRH-containing neurons.     

Ability of progesterone to reverse anti-androgen (hydroxyflutamide)-induced interference with the preovulatory LH surge and ovulation in PMSG-primed immature rats

In Exp. 1, PMSG was injected to 26-day-old prepubertal rats to induce ovulations. On Day 2 (2 days later, the equivalent of the day of pro-oestrus) they received at 08:00 h 5 mg hydroxyflutamide or vehicle and at 12:00 h 2 mg progesterone or testosterone or vehicle. Animals were killed at 18:00 h on Day 2 or at 09:00 h on Day 3. Progesterone but not testosterone restored the preovulatory LH surge and ovulation in hydroxyflutamide-treated rats. In Exp. 2, 2 mg progesterone or testosterone were injected between 10:30 and 11:00 h on Day 2, to advance the pro-oestrous LH surge and ovulation in PMSG-primed prepubertal rats. Injection of hydroxyflutamide abolished the ability of progesterone to advance the LH surge or ovulation. Testosterone did not induce the advancement of LH surge or ovulation. In Exp. 3, ovariectomized prepubertal rats implanted with oestradiol-17 beta showed significantly (P less than 0.01) elevated serum LH concentrations at 18:00 h over those observed at 10:00 h. Progesterone injection to these animals further elevated the serum LH concentrations at 18:00 h, in a dose-dependent manner, with maximal values resulting from 1 mg progesterone. Hydroxyflutamide treatment significantly (P less than 0.003) reduced the serum LH values in rats receiving 0-1 mg progesterone but 2 mg progesterone were able to overcome this inhibition. It is concluded that progesterone but not testosterone can reverse the effects of hydroxyflutamide on the preovulatory LH surge and ovulation. It appears that hydroxyflutamide may interfere with progesterone action in induction of the LH surge, suggesting a hitherto undescribed anti-progestagenic action of hydroxyflutamide.     

Dose-dependent inhibition of the preovulatory surges of gonadotropins and prolactin by the antiestrogen CI-628: possible sites of action

The present series of experiments was conducted in an attempt to correlate previously reported dose-dependent and site-selective inhibitory effects of an antiestrogen, CI-628, on 17 beta-estradiol (E2)-receptor interactions in the anterior pituitary gland (AP) and hypothalamus with its effects on the preovulatory surges of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. The effects of CI-628 on the response of the AP to luteinizing hormone-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) also were examined. In the first study, rats exhibiting 4-day estrous cycles were injected with various doses (0.02, 0.20, 2.0, and 20 mg/kg) of CI-628 or vehicle at 0900 h on diestrus-2 and proestrus. The preovulatory LH surge and both preovulatory and secondary FSH surges were marginally affected by 0.02 mg/kg CI-628, but were completely abolished by higher doses. In contrast, a dose of 0.20 mg/kg only delayed the prolactin surge; however, higher doses were effective in extinguishing cyclic prolactin release. In a second experiment, CI-628 in rats treated on diestrus-2 and proestrus exerted a dose-dependent suppression of the AP LH response to an initial injection of LHRH on proestrous afternoon in rats whose endogenous LH surges were blocked by phenobarbital. However, AP LH responses to a second LHRH injection to assess the self-priming capacity of LHRH were attenuated only in rats given 0.20, 2.0, and 20 mg/kg CI-628. Contrastingly, the AP prolactin response to TRH was suppressed only in rats given 0.20 mg/kg CI-628.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of adrenalectomy and corticosterone on cocaine-induced sensitization in rats.

Effects of adrenalectomy (ADX) and corticosterone (CORT) on the development and expression of sensitization to the locomotor effect of cocaine (COC) were studied in rats. Sensitization was evoked by 5 daily injections of COC (10 mg/kg) and measured after a challenge dose of the drug (10 mg/kg) after a 5-day withdrawal (on day 10 of the experiment). ADX, performed before the start of COC administration, completely blocked the manifestation of COC-induced sensitization. In contrast, ADX performed on animals already sensitized to COC did not affect the sensitized locomotor activity response to a challenge dose of COC (on day 18). Pretreatment with CORT, 10 mg/kg, but not 5 mg/kg, before each of the 5 daily COC injections facilitated the development of COC sensitization, tested after a 5-day withdrawal. When pretreated with CORT alone (10 mg/kg), the challenge dose of COC administered on day 10 induced cross-sensitization to CORT. CORT (10 mg/kg) injected acutely before COC on day 10, potentiated the expression of COC sensitization. When given alone, on day 10 CORT (5-10 mg/kg) induced an increase in the locomotor activity of rats pretreated daily (5 injections) with COC. No drug treatment induced conditioned locomotion, as measured after saline challenge on day 8. Our results indicate that CORT facilitates the development and expression of COC sensitization, while ADX blocks the initiation of the behavioral phenomenon only. Moreover, there takes place cross-sensitization between CORT and COC, which indicates a close relationship between the drug-related mechanism and behavioral sensitization.     

Capability of ovarian steroids in inducing LH surges in acutely ovariectomized rats.

The capability of estradiol (E2) or E2 and progesterone (P4) in inducing luteinizing hormone (LH) surge in acutely ovariectomized (Ovx) rats was studied. In group I, rats were Ovx on estrus and were implanted with E2 capsules and atrial cannulae immediately after operation for blood samplings. In group II, rats were also Ovx on estrus but were implanted with E2 capsules and sampling cannulae the next day (the expected diestrus day 1, D1). In group III, rats were Ovx on D1, and were implanted E2 with capsules and atrial cannulae immediately after operation. All surgical operations were done around 1000h in the morning. On the expected diestrus day 2(D2) at 0930h, one half of the rats in each group received an oil vehicle or 2mg of P4 subcutaneously. Blood samples were taken from the indwelled cannulae at 1300, 1500, and 1700hrs in the afternoon. Results showed that P4 treatment amplified LH release in all three groups of rats primed with E2, and that the oil vehicle did not assist in LH release in E2 primed rats of group I and group II, but it did in 8 out of 10 rats in group III in the late afternoon of D2. Results suggested that the estradiol alone was capable in inducing LH surge on the expected D2 afternoon, and that under estradiol-primed conditions, P4 can trigger neural initiators to advance LH surge, but that the internal hormonal milieu at the time of ovariectomy may affect the influence of ovarian steroids in inducing LH release.     

Effects of ovariectomy and estradiol replacement on naloxone induced LH secretion in the female rabbit

The effects of an opioid antagonist, naloxone, on the secretion of gonadotrophins were investigated in the long term ovariectomized rabbit. In the intact and acutely ovariectomized rabbit (2 days p.o.) naloxone at 10 mg/kg induced an increase of 260-300% in LH secretion at 40 min post-injection. From days 33-66 post-surgery naloxone at 10 mg/kg caused significant elevations in LH release even when animals were treated with estradiol benzoate 24 h previously. By contrast, treatment with oestradiol benzoate 3 h before naloxone abolished the LH increase. An LH surge could be elicited in these rabbits with GnRH treatment. These studies indicated that long term ovariectomy in the female rabbit does not completely remove the opioid control of GnRH release and that the LH response to naloxone is influenced by circulating estradiol levels.