Inhibition by melatonin of the pituitary response to luteinizing hormone releasing hormone in vivo.

The rate of secretion of 17-oxosteroids by the testes of anaesthetized dogs in vivo was used as an index of LH secretion. Intracarotid injection of luteinizing hormone releasing hormone (LH-RH, 1, 5 or 10 microgram/kg body wt) resulted in an increase in the testicular 17-oxosteroid secretion which was roughly proportional to the dose administered and which reached a maximum 60 min after the injection. Testicular output of 17-oxosteroids was unaffected by administration of melatonin (10 or 100 microgram/kg body wt) into the carotid artery. When LH-RH (5 microgram/kg) was injected into the carotid artery 3 h after intracarotid injection of melatonin (10 or 100 microgram/kg), the testicular response to LH-RH was considerably diminished. Pretreatment with melatonin (100 microgram/kg) did not alter the testicular response to human chorionic gonadotrophin (20 i.u./kg body wt) given i.v. Is is concluded that melatonin may act directly on the anterior pituitary gland in dogs to inhibit the LH-RH-induced release of LH.     

Changes in subcellular distribution of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) after treatment with the LH-RH antagonist cetrorelix.

Treatment with antagonists of luteinizing hormone-releasing hormone (LH-RH) leads to down-regulation of pituitary LH-RH receptors. Thus, the effect of LH-RH antagonists is similar to that of the LH-RH agonists, but the mode of action of antagonists is not completely understood. The aim of this study was to investigate the effects of LH-RH antagonist cetrorelix on the binding characteristics and subcellular localization of receptors for LH-RH in rat pituitaries. Radioligand binding studies, performed after in vitro desaturation, revealed that a single s.c. injection of cetrorelix at a dose of 100 microg per rat significantly decreased the number of pituitary membrane receptors for LH-RH in a time-dependent manner with the nadir occurring at 6 h. In contrast, 2-6 h after cetrorelix treatment, the concentration of binding sites for LH-RH in the nuclei of rat pituitaries was significantly higher (P < 0.01) than in controls. Chronic administration of cetrorelix also decreased the level of membrane receptors for LH-RH by 83% (P < 0.01) after 7 days, and 86% (P < 0.01) after 14 days. The number of LH-RH binding sites in the nuclear pellet was increased 3-fold (P < 0.01) by days 7 and 14 after the initiation of treatment with cetrorelix. A single injection or prolonged treatment with LH-RH antagonist also decreased the mRNA expression of pituitary receptors for LH-RH. Our results demonstrate that the down-regulation of LH-RH receptors on the cell membranes of rat pituitaries after therapy with antagonist cetrorelix is associated with an increase in receptor concentration in the nuclei. These phenomena could be related to the internalization and subcellular translocation of LH-RH receptors.     

Studies with fragments of a highly active analogue of luteinizing hormone releasing hormone.

The minimal structural requirements for gonadotrophin releasing activity were studied with fragments of a highly active analogue of luteinizing hormone releasing hormone (LH-RH), [D-Ser(But)6]LH-RH(1-9)nonapeptide-ethylamide (Hoe 766). All fragments are related to the C-terminal structure of LH-RH and have increased enzyme stability. Ovulation in phenobarbitone-blocked rats was induced with a median effective dose/rat, of 1.9 microgram of the (3-9)-heptapeptide, Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-ethylamide and 6.8, 18.0 and 38.3 microgram for the (4-9), (5-9) and (6-9) fragments respectively. The (3-9)- heptapeptide and (4-9)-hexapeptide induced release of LH and FSH in phenobarbitone-blocked rats with a ratio similar to that of LH-RH. Degradation of LH-RH by enzyme preparations of liver, kidney and hypothalamic or anterior pituitary tissue was not modified by addition of the (3-9)-heptapeptide fragment. The organ distribution of the 125I-labelled (3-9)-heptapeptide fragments was similar to LH-RH, but not to Hoe 766. The peptide accumulated in liver and kidney, but was eliminated from the anterior pituitary gland 15 min after i.v. injection, whereas Hoe 766 showed progressive accumulation in the pituitary gland (tissue:plasma ratio = 6.6 after 60 min). In contrast to C-terminal fragments of LH-RH, the corresponding fragments of nonapeptide analogues retained significant biological activity, and the minimal structural requirements for LH release may be related to the C-terminal sequence of LH-RH.     

Reduced uptake of oestrone and corticosterone by cells from cirrhotic rat liver.

The hypothesis that LH-RH induces LH release partly through a protein synthesis dependent step (protein factor) was further investigated using two different experimental designs. First, during incubation of pituitary glands of intact dioestrous female rats with a maximally active concentration of LH-RH, the inhibitor of protein synthesis cycloheximide was added at various times after the beginning of the incubation. The results show that it takes a relatively long time, i.e. more than 1 h of exposure to LH-RH before the amount of the protein factor has increased sufficiently to allow a maximal LH secretion. Secondly, LH-RH was injected iv after which the protein factor was assayed by incubating the pituitary glands with a maximally active concentration of LH-RH in the presence of cycloheximide and measuring LH release in vitro. It was found that 1 h after the injection sufficient protein factor was present to permit an elevated response to LH-RH. This response could be suppressed by injecting cycloheximide prior to LH-RH. When the interval between injection of LH-RH and beginning of the incubation was increased to 2 h, LH release in vitro decreased again. However, ovariectomy immediately before LH-RH injection resulted in maintenance of the elevated response toLH-RH in vitro, indicating a role of the ovaries in this phenomenon.     

Possible priming effect of luteinizing hormone releasing hormone on the anterior pituitary gland in the Japanese quail and the stimulation of secretion of follicle-stimulating hormone.

After the i.m. injection of 10 micrograms synthetic LH releasing hormone (LH-RH) into Japanese quail the levels of LH and FSH in plasma rose significantly within 2 min. The increased level of LH declined rapidly but that of FSH was maintained for the duration of the experiment. To determine whether the anterior pituitary gland is primed by LH-RH a double injection schedule was adopted. It would appear that, while endogenous LH-RH may prime the avian pituitary gland slightly, synthetic LH-RH is ineffective.     

Pituitary apoplexy after leuprolide administration for carcinoma of the prostate

The syndrome of pituitary apoplexy has been reported to occur after the administration of several different medications. We report a case in which pituitary apoplexy developed shortly after the administration of leuprolide in a patient with prostate cancer. Leuprolide is a potent gonadotrophin releasing hormone (GnRH) analogue used to suppress leuteotrophic hormone (LH) and testosterone levels in patients with metastatic prostate cancer. LH and testosterone levels actually rise in the first week after its administration before becoming suppressed. We suspect that this acute stimulating effect of leuprolide is linked to the acute onset of pituitary apoplexy in a patient with a possible gonadotrophoma.     

The effects of LH-RH on the concentration of 3',5'-cyclic AMP and RNA synthesis in rat anterior pituitary.

In an experiment performed to investigate the effect of LH-RH on the anterior pituitary of rats, we studied the changes in the concentration of 3',5'-cyclic AMP in the anterior pituitary and the uridine uptake by the anterior pituitary following the intravenous injection of 100 ng LH-RH. The results obtained are summarized as follows: 1) The tissue level of 3',5'-cyclic AMP in the anterior pituitary reached the highest peak 15 min after the injection of LH-RH. 2) The uridine uptake of the anterior pituitary began to increase 15 min after the LH-RH injection and attained a maximum level (5 to 6 times the normal level) in 30 min. 3) The fact that the uridine uptake was inhibited to a considerable extent by the addition of actinomycin D to the incubation medium suggested that uridine was incorporated into the RNA fraction.     

Pituitary responsiveness to LH-RH in intact and ovariectomized androgen-sterilized rats.

Serum LH changes in response to LH-RH injection were measured in intact and ovariectomized, steroid-treated female rats which were androgenized neonatally with 1,250 microgram testosterone propionate (TP) on day 5. At a dose of 20 ng LH-RH/100 g b.w., serum LH levels in intact rats increased over pre-injection levels, and at a dose of 100 ng LH-RH/100 g b.w., LH concentrations 15 min after injection were higher in nembutal-blocked proestrous rats than in androgen-sterilized rats. However, the ovulation response was not different between the groups. In ovariectomized estradiol benzoate (EB)-treated, androgen-sterilized rats, serum LH concentrations 15 and 60 min after LH-RH injection were lower than in similarly treated control rats. This effect was not secondary to the anovulatory state of the animal, since it also occurred in ovariectomized EB-treated prepuberal rats and in rats ovariectomized prepuberally and treated with EB in adulthood. Also, after treatment with 5alpha-dihydrotestosterone propionate (5alpha-DHTP), pituitary responsiveness to LH-RH in androgen-sterilized rats was lower than in control rats, which suggests that the subnormal response in the estrogen-treated rats was not due to a relative insensitivity to estrogen in the androgen-sterilized rats. The relatively high pituitary responsiveness to LH-RH in intact androgen-sterilized rats is probably due to the high circulating estrogen levels. The subnormal pituitary responsiveness to LH-RH after ovariectomy and estradiol treatment suggests, in addition to an effect on the hypothalamus, also a direct effect of neonatal androgen administration on the pituitary.     

Effects of anterior hypothalamic deafferentation on plasma LH response to LH-RH in the baboon (author's transl)]

We reported previously that a biphasic LH release (within 30 min and 90 approximately 150 min after LH-RH injection) was observed in normal menstruating baboons (non-human primates). Plasma immunoassayable LH-RH reached a maximum within 4 min after injection and was undetectable within 60 min. Plasma estrogen and progestin were elevated within 45 min. No plasma LH release with increment of plasma estrogen and progestin was observed in saline injected baboons. This study was performed to investigate the mechanism of biphasic LH release by LH-RH injection. Synthetic LH-RH (100 microgram) was injected sc into four female retrochiasmatic deafferented baboons. Blood samples collected 30 and 2 min before injection and 5, 10, 15, 30, 45, 60, 90, 120, 150 and 180 min after injection were assayed for LH, estrogen and progestin. In four baboons plasma LH peak was observed within 30 min after injection and plasma estrogen and progestin were elevated within 45 min. However, plasma LH peak within 90 approximately 150 min was not observed. These results infer that exogenous LH-RH exerts an effect on the pituitary to release LH within 30 min after injection. Increased estrogen and progestin exert the effect on the higher brain area (extrahypothalamic area) and the anterior hypothalamus to facilitate release of endogenous LH-RH, which subsequently release LH within 90 approximately 150 min in cooperation with exogenous LH-RH which may be considered to participate LH synthesis in the pituitary. Thus, it seems likely that the extrahypothalamic area (for example; limbic system) and the anterior hypothalamus have an important role in regulating LH-RH secretion and subsequent LH release in the baboon.     

Short-term regulation of LH and FSH secretion in cyclic women. III. Effects of varying doses of two consecutive LH-RH injections on pituitary and ovarian response.

The effects of two consecutive LH-RH injections at 120 min intervals with either a varying first or second LH-RH dose on pituitary gonadotrophin response were investigated in 15 eugonadal women to study pituitary secretory processes. Each volunteer underwent a total of 4 LH-RH double stimulation tests. In group I (n = 8) the first LH-RH dose of each of the 4 tests was fixed at 25 microgram, whereas the second LH-RH dose consisted of either 6, 25, 100 or 400 microgram. In group II (n = 7) the first LH-RH dose varied between 6 and 400 microgram, while the second LH-RH dose was kept constant at 25 microgram. Serum gonadotrophin and serum ovarian steroid levels were determined by radioimmunoassay before and after LH-RH administration. The volunteers in both groups served as their own controls. A linear log-dose response relationship was found between the various doses of LH-RH injected and the corresponding LH and FSH elevations elicited. However, the dose of the first LH-RH injection also significantly influenced the gonadotrophin reaction after the second LH-RH injection in a linear log-dose response relationship. Serum levels of oestradiol, 17-hydroxyprogesterone and progesterone significantly increased in response to the elevated serum gonadotrophin levels after LH-RH stimulation during the 4 h test period, but the rise did not correlate to the LH-RH dose used. The results indicate that LH-releasing hormone stimulates not only the release, but also the synthesis of LH and FSH in a dose-related manner. These findings are consistent with our previously reported concept that the magnitude of LH and FSH response to the first LH-RH injection reflects the "storage capacity", while the increase observed after the second LH-RH injection represents the "synthesis capacity" of the gonadotrophs.     

Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH

The mechanisms through which LH-RH antagonists suppress gonadotroph functions and LH-RH receptor (LH-RH-R) production are incompletely understood. To elucidate these mechanisms, we investigated the effects of Cetrorelix on the mRNA expression of pituitary LH-RH-R and luteinizing hormone (LH) secretion in three experimental systems with different pituitary LH-RH environments. Ovariectomy induced 3.61-fold and 6.34-fold increases in the mRNA expression of pituitary LH-RH-R in rats after 11 and 21 days, respectively. After (5 h) a single injection of 100 microg Cetrorelix, no significant decrease occurred in the mRNA levels of pituitary LH-RH-R in ovariectomized (OVX) rats with high pituitary exposure to LH-RH, but there was a significant 23.2% reduction in cycling rats with normal hypophysial LH-RH environment. Prolonged treatment for 10 days with a Cetrorelix depot formulation releasing 100 microg/day decreased the concentration of mRNA for pituitary LH-RH-R by 72.6% in OVX rats, but only by 32.9% in normal rats. The decline in serum LH was 98.7% in OVX rats and 63.2% in normal rats, resulting in a minimal 0.1--0.2 ng/ml LH concentration in both groups. A continuous exposure of pituitary cells to 100 nM Cetrorelix in the superfusion system, which is devoid of LH-RH, did not cause any significant changes in LH-RH-R mRNA level. These studies demonstrate that prolonged exposure to Cetrorelix in vivo, but not in vitro, down-regulates the mRNA expression of the pituitary receptors for LH-RH. Our findings indicate that LH-RH antagonists exert their inhibitory effects on the gene expression of pituitary LH-RH-R by counteracting the stimulatory effect of endogenous LH-RH.     

Dissociation between LH release and pituitary cyclic nucleotide accumulation in response to synthetic LH-releasing hormone in vivo.

In order to clarify the role of cyclic nucleotides in the mediation of LH-releasing hormone (LH-RH) action on LH release, the effect of LH-RH on LH release and pituitary cyclic AMP and cyclic GMP accumulation was studied in vivo. Pituitary cyclic AMP levels were increased 10 min after the intraveneous injection of 2 mg dibutyryl cyclic AMP (db-cyclic AMP) or 25 mg aminophylline. However, serum LH levels were not altered at 10, 30 or 60 min after the administration of either agent. Synthetic LH-RH (100 ng/rat) increased serum LH levels as measured 10 min after injection, but no effect on either pituitary cyclic AMP or cyclic GMP was seen 1, 5 or 10 min after LH-RH administration. These in vivo results are contradictory to the second messenger hypothesis for either cyclic AMP or cyclic GMP in the mediation of LH-RH-induced LH released and suggest that further work must be done in order to confirm or reject this hypothesis.     

Adenylate cyclase of GH and ACTH producing tumors of human: activation by non-specific hormones and other bioactive substances.

The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE1 and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGE1 and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytroptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing's disease was stimulated by LH-RH, norepinephrine glucagon and MEE but not by TRH. Plasma levels of ACTH, beta-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE1 and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing's syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.     

Relative activity, plasma elimination and tissue degradation of synthetic luteinizing hormone releasing hormone and certain of its analogues.

The abilities of three nonapeptide analogues of synthetic luteinizing hormone releasing hormone (LH-RH) to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anoestrous and cyclic ewes were examined, as were their elimination from the plasma in vivo and degradation by extracts of the hypothalamus, anterior pituitary gland, lung, kidney, liver and plasma in vitro. In all cases, comparisons were made with synthetic LH-RH. When injected i.v. into mature ewes as a single dose, the potencies of the analogues were graded and Des Gly-NH2(10) LH-RH ethylamide was found to be the least potent. It was not possible to demonstrate any significant increase in the potency of this analogue over LH-RH, although a trend was apparent with each parameter examined. [D-Ser(But)6] Des Gly-NH2(10) LH-RH ethylamide had the greatest potency. There were no differences between the responses of anoestrous ewes and those of ewes treated on day 10 of the oestrous cycle. None of the analogues had a rate of elimination from the plasma different from that of LH-RH during either the first or the second components of the biphasic disappearance curve. The incubation of LH-RH with tissue extracts showed that extracts of the hypothalamus and anterior pituitary gland degraded LH-RH to a similar extent. Both the hypothalamic and anterior pituitary gland extracts degraded more LH-RH than did lung extract, which in turn destroyed more LH-RH than did extracts of kidney or liver tissue. The degradative abilities of kidney and liver extracts did not differ from each other. Plasma failed to degrade LH-RH or the analogues. Although LH-RH was rapidly destroyed by hypothalamic extract in vitro, of the analogues, only Des Gly-NH2(10) LH-RH ethylamide was degraded. The anterior pituitary gland and kidney extracts failed to degrade [D-Ser6] Des Gly-NH2(10) LH-RH ethylamide and [D-Ser(But)6] Des Gly-NH2(10) LH-RH ethylamide as rapidly as LH-RH. Extracts of liver and lung were incapable of catabolizing any of the analogues. There was an inverse correlation between the LH- and FSH-releasing potency of an analogue and its rate of degradation by anterior pituitary gland extract. The slower rates of catabolism of certain analogues of LH-RH by the anterior pituitary gland may explain their increased LH- and FSH-releasing potency.     

Short-term regulation of LH and FSH secretion in cyclic women. I. Altered pituitary response to a second of two LH-RH injections at short intervals.

The effects of two iv 25 microgram LH-RH injections (180 tests) at different intervals (30 min to 24 h) on radioimmunoassay serum LH and FSH levels were investigated in 30 women in the midfollicular or midluteal phase of the menstrual cycle. The pituitary LH and FSH response to the second LH-RH injection at time-intervals of 30 and 360 min was significantly lower than the response elicited after the first injection. The second response was significantly higher at 60 to 180 min intervals. The maximum increment occurred at 120 min. No significant differences between the two pituitary responses to LH-RH were found at intervals of 240 min and 24 h. A theory with regard to intracellular processes of hormone synthesis and degradation is proposed to explain these time-dependent differences in the pituitary LH and FSH response.     

Estradiol positive feedback on the rat anterior pituitary gland in vitro

LH surges can be elicited by estradiol (E2). The mechanism could be either by induction of a surge of hypothalamic LH-RH or by directly increasing the responsiveness of the pituitary gland to hypothalamic LH-RH without an LH-RH surge. In order to study the positive feedback of E2 on the anterior pituitary gland, without any possible influence of an LH-RH surge, we utilized long-term in vitro superfusion of the anterior pituitary gland. The E2 concentration was 100 pg/ml and 10(-8) M LH-RH was pulsed every 30 min for 3 min. LH and FSH surge was detected about 21 h after the beginning of the E2 infusion in all three repeated experiments. No surge was detected in any other channels, i.e. control, E2 superfusion alone or LH-RH stimulation alone. This study demonstrates that in the rat the induction of the preovulatory LH peak can be accomplished by a direct effect of E2 upon the anterior pituitary gland, provided it is being stimulated by constant pulses of LH-RH.     

Inhibition of growth of a prolactin and growth hormone-secreting pituitary tumor in rats by D-tryptophan-6 analog of luteinizing hormone-releasing hormone.

The effect of long-term administration of analogs of luteinizing hormone-releasing hormone (LH-RH) and somatostatin on the growth of the growth hormone (GH)- and prolactin (PRL)-secreting rat pituitary GH3 tumor was investigated. Daily administration of [D-Trp6]LH-RH (50 micrograms/day), early after inoculation of the GH3 tumor, inhibited tumor growth by more than 90% as compared to controls. Similarly, in two experiments, a single once-a-month injection of long-acting [D-Trp6]LH-RH microcapsules (in a dose calculated to release about 25 micrograms/day for 30 days) inhibited the growth of GH3 pituitary tumor by more than 50% 6 or 13 wk after transplantation, when the tumors were fully developed. Serum GH and PRL levels also were reduced markedly by treatment with [D-Trp6]LH-RH. On the other hand, the administration of an antagonistic analog of LH-RH, N-Ac-[D-Phe(4Cl)1,2, D-Trp3, D-Arg6, D-Ala10]LH-RH, did not significantly reduce the growth of this tumor, and the treatment with two different analogs of somatostatin, cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) and D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr NH2, appeared to enhance it. These results are in agreement with previous findings of growth inhibition of 7315a pituitary tumors with different hormone-secreting characteristics by agonistic analogs of LH-RH. The collective data from experimental work with rat pituitary tumor models support the contention that the use of [D-Trp6]LH-RH might be considered for the treatment of some patients with pituitary tumors who failed to respond to conventional therapy.     

The effect of synthetic chicken LH-RH on the release of LH and FSH and ovulation in rats (a comparative study of synthetic mammalian LH-RH and chicken LH-RH)

Recently, Miyamoto et al and King et al, independently isolated chicken LH-RH and determined its chemical structure as [Gln8] LH-RH. In this report, the in vivo effect of synthetic chicken LH-RH on the release of LH and FSH and ovulation in rats was investigated. A single i.v. injection of chicken LH-RH, as well as mammalian LH-RH, induced a significant increase of plasma LH levels at 15 min after injection in adult male rats. Plasma LH levels then declined at 30 min to 60 min and returned to basal levels at 120 min. The biological potency of chicken LH-RH estimated from plasma LH levels at 15 min after injection in adult male rats by parallel line assay was 4.1% of that of mammalian LH-RH. It was likely that the activity of chicken LH was shorter in duration on the LH secretion as compared with that of mammalian LH-RH because of quickly decreased plasma LH levels. Plasma FSH levels were also increased, but the increment of FSH was not so obvious as compared with that of LH. Plasma FSH levels reached a plateau at 15 min and did not return to basal levels at 120 min in either the chicken LH-RH injection groups or the mammalian LH-RH injection groups. The chicken LH-RH was able to induce an increase of plasma LH and FSH and ovulation in pentobarbital-blocked, proestrous female rats. The biological potency of chicken LH-RH estimated from plasma LH levels at 15 min after injection in pentobarbital-blocked, proestrous female rats was 2.2% that of mammalian LH-RH. The ovulation-inducing potency of chicken LH-RH estimated from ED50 was about 2.1% of that of mammalian LH-RH. It is noteworthy that chicken LH-RH has a LH and FSH releasing and ovulation inducing-activity on rats in vivo, but its biological potency is weaker and of shorter duration compared with that of mammalian LH-RH, although the chemical structure of chicken LH-RH is different from that of mammalian LH-RH.     

Suppression of the luteinizing hormone releasing effect of luteinizing hormone releasing hormone by arginine-vasotocin.

The concentrations of 17-oxosteroids in the spermatic venous blood of anaesthetized dogs were used as an index of LH release to assess the effects of arginine-vasotocin on the response of the canine pituitary gland to exogenous luteinizing hormone releasing hormone (LH-RH). When injected into the carotid artery, arginine-vasotocin (1.0 microgram/kg body wt) caused no significant alterations in the testicular output of 17-oxosteroids. The administration of LH-RH (5 microgram/kg body wt, a standard dose) into the carotid artery produced typical stimulation of testicular 17-oxosteroid secretion. Administration of arginine-vasotocin (0.01, 0.1 or 1.0 microgram/kg body wt) into the carotid artery 3 h before the administration of a standard dose of LH-RH inhibited the testicular secretion of 17-oxosteroids normally induced by LH-RH. However, pretreatment with arginine-vasotocin (1.0 microgram/kg body wt) did not affect the testicular response to i.v. administration of human chorionic gonadotrophin (5 i.u./kg body wt). These results indicate that in the dog, arginine-vasotocin inhibits the LH-RH-induced release of LH by acting acting directly on the anterior pituitary gland.     

The effect of systemic administration of dopamine and apomorphine on Plasma LH and prolactin concentrations in conscious rats.

The effect of systemic administration of various doses of dopamine (DA) and apomorphine (APM) on plasma gonadotropin and prolactin (Prl) concentrations in ovariectomized (OVX) as well as in ovariectomized, estrogen-progesterone (OEP)-primed rats bearing indwelling jugular venous catheters was evaluated. Intravenous (i.v.) infusion or pulse injection of 0.9% NaCl had no significant effect on plasma titers of LH or Prl. I.v. infusion of DA at 4 micrograms/kg-b.w./min induced a progressive increase in circulating LH concentration in OEP rats while infusion at a similar dose in OVX animals had no effect on plasma LH. I.v. injection of 100 micrograms DA or APM significantly increased LH at 15 min in OVX rats. Similarly, in OEP rats 100 micrograms of DA elevated plasma LH at 30 and 90 min while APM induced a significant elevation of plasma LH at 15 min after injection. In OVX rats injection of DA i.p. at a dose of 5 mg/kg-b.w. did not alter plasma LH levels, but a dose of 50 mg/kg-b.w. produced a significant reduction in plasma LH concentration. APM injected i.p. at either 5 or 50 mg/kg-b.w. doses was nearly equally effective in lowering plasma LH and the suppressive effect was significantly greater than with similar doses of DA. A single injection of LH-RH (100 ng in 0.2 ml of 0.9% NaCl) in animals pretreated 15 min earlier with an effective dose of APM (5 mg/kg-b.w.) produced a peak increase in LH titers 15 min after injection. The increment in plasma LH following LH-RH in APM-treated rats was comparable to that in rats which had received saline instead of APM. Prl levels were significantly lowered by each dose of DA and APM in OVX as well as in OEP rats. There was no significant change in plasma FSH titers induced by either drug in any of the experiments. It is concluded that DA may have different actions depending upon the dose and the endocrine state of the animal. Thus, i.v. infusion of low doses of DA in OEP animals or by pulse injection in both OVX and OEP rats can elevate plasma LH by activating the release of LH-RH from the hypothalamus, while large doses of DA in OVX animals may suppress the release of LH-RH.