Differential effects of acute DA receptor blockade with domperidone on LH and TSH release in patients with hyperprolactinemia

Since dopamine (DA) has been implicated in the inhibitory control of both TSH and LH, we have compared TSH and LH levels following dopamine (DA) receptor blockade with domperidone in patients with hyperprolactinemia due to presumed prolactinomas. Eight euthyroid patients (aged 19-37 yr) with presumed prolactinomas each received domperidone (10 mg iv) at 11:00 and 23:00 h and tests were separated by at least one week. Basal TSH levels were significantly greater at 23:00 than at 11:00 h (2.7 +/- 0.5 vs 1.7 +/- 0.4 mU/l, mean +/- SE, p less than 0.01) whereas basal LH levels did not differ. All subjects showed clear rises in basal TSH levels following drug administration and these were significantly greater at 23:00 than at 11:00 h (p less than 0.02 at each time point). In contrast there was no alteration in LH levels following drug administration at either time of day. These data suggest that the mechanisms underlying the dopaminergic control of TSH and LH are different in these patients. Furthermore the data argue against an anterior pituitary or median eminence site of action of DA in the inhibition of LH release in hyperprolactinemia since domperidone does not penetrate the blood brain barrier to any appreciable extent.     

DOMPERIDONE: A NOVEL AGENT FOR THE INVESTIGATION OF ANTERIOR PITUITARY FUNCTION AND CONTROL IN MAN

Administration of the novel agent domperidone (10 mg iv), which combines the properties of specific dopamine receptor blockade and inability to cross the blood-brain barrier, leads to acute and significant TSH and PRL release in man. This suggests that the in vivo site of action of endogenous dopamine in the inhibitory control of these two hormones is either the anterior pituitary or median eminence, since these tissues lie outside the blood-brain barrier. This class of drug is of potential value both clinically and experimentally in the investigation of anterior pituitary control mechanisms.     

Effect of dopamine on gonadotropin-releasing hormone-induced gonadotropin secretion in postmenopausal women

Five healthy women who had previously undergone spontaneous menopause and had not received exogenous estrogens were studied with infusions of synthetic GnRH and dopamine to ascertain the site of dopaminergic modulation of pituitary gonadotropin secretion. Infusion of dopamine at 4 micrograms/kg . min for 5 h induced a significant decrease in circulating LH concentrations, but not those of FSH. LH levels returned to baseline concentrations during the postinfusion period. Infusion with synthetic GnRH at 10 micrograms/h for 5 h induced a biphasic change in circulating gonadotropin levels. When dopamine and GnRH were simultaneously infused for 5 h, FSH and LH responses were not statistically different from those observed when GnRH was infused alone. We conclude that in normal postmenopausal women, dopamine modulates pituitary gonadotropin secretion by affecting GnRH-secreting neurons in the median eminence and possibly at other hypothalamic sites.     

Effects of testosterone implants and hypothalamic lesions on luteinizing hormone regulation in the castrated male rat.

The effects of intrahypothalamic and subcutaneous implants of testosterone (T) and those of hypothalamic lesions on resting levels of circulating LH and pituitary responsiveness to exogenous LHRH were studied in castrated male rats to elucidate hypothalamic and pituitary regulation of LH secretion. Two hundred mug implants of testosterone propionate (TP) in the median eminence region suppressed plasma LH titers before evidence of direct inhibition of pituitary function (as indicated by testing with LHRH) was found. Such implants release appreciable amounts of T into the peripheral circulation in the immediate post-operative period, and SC Silastic (constant release) capsules containing T have similar effects. The findings suggest that, regardless of the site of implant, the initial negative feedback inhibition of LH by T is not dependent on direct action at the pituitary levels but rather appears to be a hypothalamic effect. In the days following exposure to hypothalamic or peripheral implantation of T, however, a progressively developing decline in the response to exogenous LHRH was observed. In order to determine whether this effect results from suppression of endogenous LHRH release, the median eminence-arcuate region was destroyed to remove the source of LHRH. In these animals, the suppression of plasma LH was evident on the first day after the lesion, but pituitary responsiveness to LHRH was unaffected until after one week. When Sialastic capsules were implanted SC into lesioned animals, a more rapid (less than 1 week) inhibition of pituitary responsivity ensued. Suprachiasmatic lesions did not affect basal LH secretion or pituitary responses to LHRH. The data provide evidence for a dual feedback action of T on LH in castrated male rats: an initial inhibitory effect presumably due to hypothalamic inhibition (commencing at around 6h after hypothalamic of SC implantation of T), and a subsequent suppression of pituitary responisveness (after one day) presumably due to direct action of T on the pituitary. In addition to these phenomena, findings in rats bearing median eminence-arcurate lesions suggest that the removal of endogenous LHRH by itself leads to an eventual decline in pituitary responsiveness (greater than one week postoperatively).     

One month of streptozotocin-diabetes induces different neuroendocrine and morphological alterations in the hypothalamo-pituitary axis of male and female rats

LHRH (median eminence) and LH (pituitary and plasma) from male and female Sprague-Dawley rats were assayed 1 month after streptozotocin injection and compared with values in controls either fed ad libitum or offered a restricted diet. Plasma LH was also assayed after stimulation with exogenous LHRH or naloxone. In diabetic males, the median eminence LHRH content and the plasma LH response to exogenous LHRH were unaltered, pituitary LH was increased, and plasma LH was decreased under basal conditions and after naloxone treatment. In diabetic females, while the median eminence LHRH content and the plasma LH response to exogenous LHRH or naloxone were reduced, pituitary and plasma LH levels were not different. Measurements made in undernourished rats excluded the possibility that the alterations found in diabetic animals were nutrition dependent. In parallel experiments, hypothalami and pituitaries were examined morphologically. In diabetic animals, degenerate axons, mainly of the LHRH type, were found in the arcuate nucleus and median eminence, and LH gonadotrophs were altered and more numerous. Strong differences between control males and females were revealed by morphometry; moreover, diabetic females had higher brain weights and fewer LH gonadotroph changes than diabetic males. These studies indicate that 1) the hypothalamo-pituitary changes that occur early in our streptozotocin-treated rats are unrelated to undernourishment and are possibly caused by insulin deficiency; 2) the LHRH axonal lesions might play a primary pathogenic role in the hypothalamo-pituitary disorder; 3) some anatomical data indicate that the brain and pituitary are less severely affected by diabetes in female than in male animals; and 4) differences between control males and females may account for some of the dissimilarities between the sexes observed under diabetic conditions.     

Atrial natriuretic factor inhibits luteinizing hormone secretion in the rat: evidence for a hypothalamic site of action

The presence of atrial natriuretic factor (ANF) immunoreactivity and receptors for ANF in the median eminence, hypothalamus, and anterior pituitary gland suggests a role for the peptide in the hypothalamic control of anterior pituitary function. In conscious ovariectomized female rats, transient elevation of plasma levels of ANF by volume loading, a stimulus known to release endogenous ANF from the heart, or by bolus iv injection of 0.1, 1.0, or 10 micrograms synthetic ANF failed to result in altered circulating levels of LH or GH. Constant iv infusion of ANF for 30 min, such that 2- to 3-fold elevations in plasma ANF were detected by RIA resulted, however, in significant inhibition of LH release in ovariectomized female rats (0.05 and 0.1 micrograms ANF/kg.min) and orchidectomized male rats (0.1 microgram ANF/kg.min). It was unlikely that this effect was exerted at the level of the anterior pituitary, since ANF failed to alter basal or LHRH-stimulated LH release from cultured anterior pituitary cells in vitro and since iv infusion of 0.1 microgram ANF/kg.min failed to alter pituitary responsiveness in vivo to a 10-ng bolus injection of LHRH. Significant inhibition of LH secretion was also observed after third cerebroventricular injection of 1.0 or 2.0 nmol ANF. As with iv infusion, central administration of ANF failed to significantly alter GH secretion. LHRH release from median eminence explants incubated in vitro in the presence of dopamine (60 or 120 microM) was inhibited by 10(-7) M ANF, suggesting a median eminence site of action of the peptide. Finally, an opiate involvement in the mechanism of ANF's action was suggested, since naloxone (0.5 mg, iv, followed by a 60-min infusion of an additional 1 mg) completely blocked the ability of ANF (0.1 or 0.5 microgram/kg.min, infused over the last 30 min of naloxone administration) to inhibit LH release. These data suggest that ANF can act centrally to alter the hypothalamic control of gonadotropin secretion, possibly by interacting with central dopaminergic and peptidergic systems. They further suggest actions of ANF within the brain unrelated to its previously described effects on fluid and electrolyte homeostasis.     

Mediation of the short-loop negative feedback of luteinizing hormone (LH) on LH-releasing hormone release by melatonin-induced inhibition of LH release from the pars tuberalis.

The pineal hormone melatonin is thought to mediate the effects of the pineal gland on seasonal reproduction by altering the release of gonadotropins. The mechanism by which melatonin controls gonadotropin secretion has been obscure. Recently, labeled 2-iodomelatonin was used to localize melatonin receptors in brain by radioautography. The highest concentration of melatonin receptors was found in the pars tuberalis of the pituitary gland of mammals. Pituitary hormones, in particular luteinizing hormone (LH), have been localized in cells of the pars tuberalis. Consequently, we hypothesized that melatonin might act on its receptors in the pars tuberalis to alter the release of LH. It would then be possible for this LH to diffuse into the overlying median eminence, there to alter the release of LH-releasing hormone (LHRH) from the axons of the LHRH neurons. To evaluate this hypothesis, we incubated median eminence-pars tuberalis tissue from male rats in vitro. After preincubation in Krebs-Ringer bicarbonate buffer for 30 min, test substances were added to fresh medium and the incubation was continued for 30 min. LHRH or LH released into the medium was measured by radioimmunoassay. Melatonin induced a dose-related release of LHRH with the maximum response at the greatest concentration tested (1 microM). This concentration of melatonin also significantly reduced the release of LH into the medium. The increased release of LHRH induced by melatonin (10 microM) was completely blocked by the addition of LH (50 ng/ml), which by itself had no significant effect on LHRH release. Rat LH antiserum (final dilution, 1:1800) significantly elevated LHRH output, whereas normal rabbit serum at a similar dilution had no effect. Finally, LHRH (0.1 microM) induced a significant release of LH from median eminence-pars tuberalis tissue that was completely blocked by melatonin (10 microM). The results support the hypothesis that LH released from the pars tuberalis diffuses to the LHRH terminals in the median eminence to suppress LHRH release. Melatonin acts on its receptors in the pars tuberalis to inhibit LH release, thereby stimulating the release of LHRH from its terminals in the median eminence. The negative short-loop feedback of LH inhibits basal LHRH release in vitro since antiserum against LH increased LHRH release. The results suggest a concept concerning the mechanism by which melatonin can affect the release of pituitary hormones from the pars tuberalis. It is likely that these pituitary hormones diffuse into the median eminence to modify the release of hypothalamic releasing and inhibiting peptides, thereby altering plasma pituitary hormone concentrations.     

Changes in adenohypophysial dopamine related to prolactin release

In order to study whether changes in adenohypophysial dopamine are only related to PRL release or also to the variation of LH or FSH, dopamine (DA) in the pars distalis was measured during the estrous cycle and after castration of both male and female rats. Catecholamines were assayed using a highly sensitive radioenzymatic method. Dopamine and norepinephrine were also measured in the median eminence of the same rats. Adenohypophysial dopamine fluctuates during the estrous cycle, reaching its lowest levels on the afternoon of proestrus. Ovariectomy increases the DA content of the anterior lobe and estrogens reverse this effect. Orchidectomy does not change the amount of DA in the anterior pituitary. DA concentration in the median eminence parallels the changes observed in the pars distalis. We conclude that anterior pituitary dopamine concentration is closely related to PRL release and is not associated with changes in the release of LH or FSH.     

The melatonin receptors in rat ontogenesis

The development of melatonin receptors in the rat pituitary and median eminence was studied using [125I]melatonin as a ligand. The specific binding was detected in pituitaries of 20-day-old fetuses already. The affinity of the receptor to the ligand (Kd) was in the range 63-133 pM and it did not change significantly during development. The pituitary concentration of [125I]melatonin binding sites was highest in 20-day-old fetuses (Bmax = 31 fmol/mg protein) and then it gradually decreased in the course of postnatal development, until it reached 10% of that value in 29-day-old males. In contrast, the concentration of melatonin receptors in median eminence did not change markedly in the course of development and it was about 15 fmol/mg protein. The marked decrease in the number of the pituitary receptors may be the cause of the reported developmental loss of the melatonin inhibitory effect on LHRH-induced LH release from anterior pituitary.     

Expression of neuropeptide Y precursor-immunoreactivity in the hypothalamic dopaminergic tubero-infundibular system during lactation in rodents.

Evidence from physiological studies in rats shows that neuropeptide Y (NPY) has marked neuroendocrine effects on anterior pituitary function, and especially on LHRH and LH secretions. However, previous immunohistochemical studies in rats have revealed only scarce NPY-axons of medullary origin in the external zone of the hypothalamic median eminence, the common termination site of neuroendocrine adenohypophysiotropic systems. In view of this apparent contradiction, we used light microscopic immunohistochemistry to reassess the distribution of NPY in the hypothalamus of rodents of both sexes under physiological (estrous cycle in rats, pregnancy in rats, and lactation in both rats and mice) and experimental (gonadectomy in rats and adrenalectomy in both rats and mice) conditions with alterations of reproductive functions. We reasoned that such manipulations could induce changes in immunoreactivity in the NPY system involved in neuroendocrine regulation and would thus make it apparent to us. We show here that immunoreactivity for NPY and its carboxyterminal precursor-associated peptide are dramatically increased in the external median eminence of lactating female animals when compared to the other animal groups. This NYP-precursor-immunoreactivity is present, throughout lactation, in the tyrosine hydroxylase-immunoreactive (and therefore possibly dopaminergic) tubero-infundibular system. This immunoreactivity disappears rapidly from the median eminence after pup-removal. These observations suggest a role for NPY-precursor-derived peptides in the control of the suckling-induced PRL secretion and also demonstrate the chemical plasticity of the median eminence during a normal physiological event. Since in nonlactating animals and especially in normal cycling females NPY-precursor-immunoreactivity was detected in the system of medullary origin only, we conclude that, by exclusion, this system might be the one responsible for modulating gonadotropic secretion at the median eminence and/or pituitary levels.     

Effect of infundibular lesions on GnRH and LH release in the frog, Rana temporaria, during hibernation.

The effects of lesions and deafferentations on accelerated hibernatory ovulation and on the concentration of GnRH in blood collected from the hypothalamo-pituitary area along with the blood and pituitary levels of luteinizing hormone (LH) in hibernating female frogs, Rana temporaria, were studied. The lesions to the caudal portion of the nucleus infundibularis ventralis resulted in: (1) an elevation in GnRH concentration in blood collected from the hypothalamo-pituitary area (x +/- SEM = 51 +/- 9.5 and 100 +/- 15 pg/ml in control and lesioned females, respectively), (2) an increase in plasma LH (from 11 +/- 1.3 to 14.7 +/- 2.5 ng/ml in controls to 73.1 +/- 12.0 and 74.2 +/- 15.8 ng/ml in lesioned females at 3 and 7 days), and (3) accelerated ovulations whose onset advanced as the hibernation season progressed. Histological and immunohistochemical analyses of the brains showed that GnRH seems to be stored during hibernation in the median eminence and suggested that the complete disruption of projections to the median eminence is prerequisite for accelerated ovulation. The influence of the hypothalamic inhibitory action on the release of GnRH and the way in which GnRH is transferred to the pituitary gland are discussed.     

LH and FSH (basal values and pituitary responses to GnRH) in hyperthyroidism

Gonadotropin behaviour (basal plasma values and pituitary responses to GnRH) in hyperthyroid patients was studied. LH values (both basal and pituitary responses) higher than the controls were documented. Thyroid hormones seem to modulate pituitary response to GnRH for LH only in hyperthyroid patients of both sexes. In order to explain the mechanism of the action of thyroid hormones, rather than the possibility of peripheral effect on binding capacity of the proteins for circulating steroids, a central interaction at medial eminence level is suggested.     

Implication of dopaminergic systems on GnRH and GnRHR genes expression in the hypothalamus and GnRH-R gene expression in the anterior pituitary gland of anestrous ewes.

We examined by Real-time PCR how prolonged inhibition of dopaminergic D-2 receptors (DA-2) in the hypothalamus of anestrous ewes by infusion of sulpiride into the third cerebral ventricle affected GnRH and GnRH-R gene expression in discrete parts of this structure and GnRH-R gene expression in the anterior pituitary. Blockaded DA-2 receptors significantly decreased GnRH mRNA levels in the ventromedial hypothalamus but did not evidently affect GnRH mRNA in the preoptic/ anteriorhypothalamicarea. Blockaded DA-2 receptors led to different responses in GnRH-R mRNA in various parts of the hypothalamus; increased GnRH-R mRNA levels in the preoptic/anterior hypothalamic area, and decreased GnRH-R mRNA amounts in the ventromedial hypothalamus stalk/median eminence. An infusion of sulpiride into the III-rd ventricle increased GnRH mRNA levels in the anterior pituitary gland and LH secretion. It is suggested that the increase of GnRH gene expression in the anterior pituitary gland and LH secretion in sulpiride-treated ewes are related with an increase of biosynthesis GnRH with concomitant decreased biosynthesis of GnRH-R protein in the ventromedial hypothalamus/stalk median eminence allowing to an increase of GnRH release.     

Ovarian steroid effects on gonadotrophin output, and on the incorporation of 35S from methionine into protein of discrete brain areas and the anterior pituitary.

The effects of various ovarian hormones administered on the morning of pro-oestrus on gonadotrophin levels and the incorporation of 35S from methionine into protein of discrete areas of the brain and the anterior pituitary were investigated at 15.00 h of the same day in female rats. The hormones which were investigated in this study could be divided in general into two groups according to their actions. The first group, consisting of oestradiol-17 beta and progesterone, tended to advance the pre-ovulatory surge of luteinizing hormone (LH) by 3-6 h from 18.00-21.00 h, together with the peaks of [35S]incorporation in the median eminence area and the anterior pituitary which normally accompany the LH surge. The second group, consisting of the LH-stimulated reduced progesterone metabolites, 5 alpha-pregnane-3,20-dione (pregnanedione) and 20 alpha-hydroxy-pregn-4-en-3-one (dihydroprogesterone), tended to inhibit serum gonadotrophin levels as well as inhibiting the pro-oestrous increase of [35S]incorporation in the median eminence area and in the amygdala, but not in the preoptic area and the anterior pituitary. On the afternoon of pro-oestrus in intact animals, luteinizing hormone-releasing hormone or LH administration had the same effect on [35Si1incorporation in the brain as did the progesterone metabolites, though this effect was not observed if the animals had been ovariectomized a few hours beforehand. It is suggested that certain ovarian hormones are involved in the neural events which induce the pre-ovulatory LH surge, while others are associated with neural events which terminate the stimulus for the LH surge.     

Neuroendocrine studies in hyperprolactinaemic male mice

In several species, including man and the rat, hyperprolactinaemia is associated with suppression of gonadotrophin release and male sexual behaviour. However, in the hyperprolactinaemic male mouse, plasma LH and FSH levels and copulatory behaviour are increased rather than suppressed. In an attempt to identify mechanism(s) which may be responsible for these effects of hyperprolactinaemia in the mouse, we have examined the effects of two ectopic pituitary isografts on several indices of hypothalamic and pituitary function in adult DBA/2J males. Animals with pituitary grafts had markedly increased plasma concentrations of prolactin, LH and FSH and enlarged seminal vesicles, whereas testicular and pituitary weights were not affected. Content of LHRH receptors and activity of aromatase in the pituitary, as well as dopamine-beta-hydroxylase activity in the hypothalamus were nearly identical in pituitary-grafted and sham-operated males. Biosynthesis of dopamine and turnover of noradrenaline in the median eminence were significantly increased in grafted males. We suggest that the increase in the activity of hypothalamic noradrenergic neurones may mediate stimulatory action of hyperprolactinaemia on LH and FSH release in the mouse. Comparison of these results with those obtained previously in the rat suggests that species differences in the effects of prolactin on gonadotrophin release may be related to its divergent effects on noradrenaline turnover.     

Galanin-like immunoreactivity is influenced by estrogen in peripubertal and adult rats.

Galanin gene expression in the anterior pituitary is potently stimulated by estrogen in adult rats. To evaluate the influence of estrogen on galanin during the peripubertal period 30- to 32-day-old female rats were treated with pregnant mare serum gonadotropin (PMSG, 10 IU s.c., 10.00 h). Galanin-like immunoreactivity (galanin-LI) in hypothalamic and pituitary tissues was evaluated 1, 2 or 3 days after PMSG treatment between 17.00 and 19.00 h. The PMSG treatment stimulated 17 beta-estradiol secretion, which induced a midafternoon LH surge 2 days after the PMSG treatment. Concentrations of galanin-LI at the time of this LH surge were elevated 82% in the anterior pituitary and 58% in the hypothalamus (without the median eminence) when compared to saline-treated female rats. On the 3rd day after the PMSG injection, galanin-LI was increased 236% in the anterior pituitary, 88% in the neurointermediate lobe and 39% in the median eminence compared to saline-treated female rats. These changes in galanin-LI were not observed in similarly aged male rats or ovariectomized rats treated with PMSG. In adult male rats, daily injections with 17 beta-estradiol valerate (10 micrograms/daily s.c.) for 1 week increased galanin-LI in the median eminence and neurointermediate lobe to an extent similar to that seen in juvenile female rats following PMSG treatment. In contrast, the high serum levels of 17 beta-estradiol achieved after 17 beta-estradiol valerate treatment increased galanin-LI in the anterior pituitary 65-fold. These studies indicate that galanin-LI is influenced by estrogen in peripubertal and adult rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neural grafts and the restoration of pituitary and gonadal function in hypogonadal (HPG) mice

The hypogonadal mouse is a mutant deficient in the hypothalamic gonadotrophic hormone releasing hormone (GnRH) with a consequent extreme depletion in pituitary luteinising hormone (LH) and follicle stimulating hormone (FSH) and a failure of post-natal gonadal growth. Grafting late foetal-early neonatal preoptic area (POA) tissue into the third ventricle of adult hpg mice resulted in increased GnRH receptors in the pituitary, increased synthesis and secretion of LH and FSH, and full stimulation of spermatogenesis in the male and folliculogenesis in the females. Although the POA grafts in the female stimulated ovarian and uterine growth and vaginal opening, so far there has been no evidence of ovarian cyclicity and the females did not ovulate spontaneously. However the increased ovarian steroidogenesis stimulated full female mating behaviour and a high percentage of the females became pregnant. The evidence suggests that these females must have ovulated reflexly upon mating, raising the question as to where in the graft the mating response was transduced. Over 90% of GnRH positive axons ended up innervating the median eminence, suggesting that even in adult mice this region of the brain retains its trophic capacity. In male hpg mice treated with testosterone there was no evidence of a negative feedback upon the graft induced elevation of pituitary LH and FSH content, suggesting that a site of androgen negative feedback may be at a CNS site removed from the GnRH neurone.     

Neuropeptide Y affects secretion of luteinizing hormone and growth hormone in ovariectomized rats.

Neuropeptide Y (NPY) has recently been localized in the rat hypothalamus. We have evaluated the effects of NPY on hypothalamic and pituitary function by injecting NPY into the third ventricle in vivo and by examining its action on perifused pituitary cells in vitro. Injections of NPY into the third ventricle of conscious ovariectomized rats led to a dramatic and highly significant reduction in plasma luteinizing hormone (LH) relative to pretreatment levels in these animals or to those of controls injected with physiological saline. Significant inhibition was obtained with doses ranging from 0.02 to 5.0 micrograms (4.7-1175 pmol) of NPY. These inhibitory effects on LH release were dose dependent and lasted for at least 120 min after injection of 5.0 micrograms of NPY. Intraventricular injection of NPY also significantly decreased plasma growth hormone; however, the threshold dose was 2.0 micrograms (470 pmol), a dose 100-fold greater than the lowest dose that inhibited LH release. Plasma follicle-stimulating hormone was unaffected by injection of NPY. NPY (10(-6) and 10(-7) M) stimulated secretion of LH, growth hormone, and follicle-stimulating hormone from perifused anterior pituitary cells loaded in a Bio-Gel P-2 column. These results indicate that NPY acts on structures adjacent to the third ventricle to inhibit the secretion of LH and growth hormone but not follicle-stimulating hormone, whereas it can directly stimulate the secretion of all three hormones from the cells of the anterior pituitary in vitro. Since NPY has been found in the hypothalamus and median eminence, it is quite likely that it plays a physiologically significant role at both hypothalamic and pituitary sites: influencing secretion of pituitary hormones.     

Inhibition by prolactin of post-castration rise in LH.

Castration of male and female rats resulted in a marked rise in serum LH. The rise in serum LH was partially or completely prevented by injection of prolactin (Prl), by implantation of a small amount of Prl in the median eminence (ME), by grafting 2 anterior pituitaries (APs) underneath the kidney capsule, or by transplantation of a Prl-secreting pituitary tumor underneath the skin. The larger pituitary tumor transplants secreted more Prl and were more effective in reducing LH release than the smaller tumors which secreted less Prl. Suppression of LH release generally was greater during the earlier than in the later phases of the different treatments. The pituitary LH response to synthetic LH-RH was the same in ovariectomized rats with or without pituitary grafts, and the decrease in hypothalamic LH-RH after orchidectomy was prevented by pituitary grafts. These results indicate that Prl can depress LH release after castration and that these effects are mediated via the hypothalamus.     

Negative feedback effects of progesterone correlated with changes in hypothalamic norepinephrine and dopamine turnover rates, median eminence luteinizing hormone-releasing hormone, and peripheral plasma gonadotropins

Progesterone (P) amplifies and advances gonadotropin surges when administered to estradiol (E2)-treated ovariectomized rats. While daily rhythmic LH surges continue to occur in E2-treated rats, they are extinguished in E2- and P (E2P)-treated animals 24 h after P treatment. We examined whether this negative feedback effect on P affect catecholamine activity within the median eminence, medial preoptic nucleus, arcuate nucleus, and suprachiasmatic nucleus and also the changes which occur in median eminence LHRH concentrations. Twenty-four hours after P exposure, LH and FSH surges in E2P-treated rats are extinguished, and the magnitude of the PRL surge is reduced. In E2-treated rats, there is an increase in medial preoptic nucleus, suprachiasmatic nucleus, and median eminence NE turnover rates from 1000--1200 to 1500--1700 h, but these changed in NE activity do not occur in E2-treated rats which received P 24 h earlier. Rather, such E2P-treated animals have markedly elevated medial preoptic nucleus, arcuate nucleus, and median eminence DA turnover rates during the period that plasma gonadotropin levels are suppressed. No differences in median eminence LHRH concentrations in E2- or E2P-treated rats were detected. P may exert its negative feedback action in suppressing LH, FSH, and PRL release by blocking activation of the hypothalamic noradrenergic system and by increasing dopaminergic activity within the tuberoinfundibular system.