Possible role of dopamine in changes in LH and prolactin concentrations after experimentally induced hyperprolactinaemia in rats

Nine-month-old female rats bearing an ectopic pituitary gland (from a litter-mate) under the right kidney capsule since day 30 of life and their sham-operated controls, were treated with a dopamine agonist (lysuride) or antagonist (metoclopramide). Plasma prolactin and LH levels were measured by double-antibody radioimmunoassays. Vaginal smears were taken before and during the treatment periods. Eight months after the operation, a significant (P less than 0.01) increase in basal prolactin levels together with a significant (P less than 0.05) reduction in LH values and permanent dioestrus occurred in the grafted animals when compared with controls. Lysuride treatment resulted in a marked reduction in plasma prolactin levels both in control and grafted rats over the whole 12 days of treatment, together with a partial restoration of plasma LH levels on day 1. From day 7 onwards a depression in LH values was again observed. Oestrous cycles were partially restored at the beginning of the treatment, but after 7 days dioestrus returned. Metoclopramide administration induced a significant (P less than 0.001) increase in basal prolactin levels in both grafted and control rats. Basal plasma LH values were unaffected in controls when compared with vehicle-treated animals. An increase could be seen in hyperprolactinaemic rats after 7 or 12 days of treatment however. The LH response to the administration of LH releasing hormone (LHRH) was greater in the experimental and control metoclopramide-treated rats when compared with vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma and pituitary concentrations of LH, FSH and prolactin in aging mongolian gerbils

Samples of plasma and pituitary homogenates collected from female Mongolian gerbils (3–4, 11–13 and 20–25 month-old) at various stages of the estrous cycle were analyzed by radio-immunoassay for luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (Prl). Plasma and pituitary LH concentrations were similar in all three age groups. Plasma FSH concentrations tended to increase with age while plasma Prl concentrations remained unchanged. Pituitary concentrations of FSH and Prl were variable between the age groups depending upon the stage of the estrous cycle. The inability of older gerbils to produce young appears to result primarily from age-related changes occurring in the uterus rather than from alterations in the hypothalamic-hypophyseal complex.     

The effect of transient dopamine antagonism on thyrotropin-releasing hormone-induced prolactin release in pregnant rats

The effect of transient dopamine (DA) antagonism on the sensitivity of pituitary lactotrophs to the PRL-releasing effect of TRH was investigated in rats on days 3, 9, 15, and 21 of pregnancy. Each animal, bearing an indwelling intraatrial catheter, received injections of either the DA antagonist domperidone (0.01 mg/rat, iv) or saline at 0930 h on the day of the experiment. Five minutes later, all animals were given the DA agonist 2-bromo-alpha-ergocryptine maleate (CB-154; 0.5 mg/rat, iv), followed 60 min later by the administration of TRH (1.0 microgram/rat iv). Plasma samples obtained during the experiment were assayed by RIA for PRL and progesterone (P). The results showed that transient DA antagonism increased the sensitivity to TRH as a PRL-releasing stimulus on the morning of day 3 of pregnancy, but not on days 9 and 15. However, the response was present on day 9 in animals that were hysterectomized (HS) on day 6 of pregnancy. The increase in sensitivity of lactotrophs to TRH after DA blockade was observed on day 21 of pregnancy. Plasma levels of P were high on days 3, 9, and 15, but decreased markedly by day 21. In a second experiment, the anterior pituitary (AP) PRL content was determined on days 3, 9, 15, and 21 of pregnancy. The results demonstrated that AP PRL significantly decreased between days 3 and 9 of pregnancy in both intact and HS animals. However, AP PRL concentrations in animals killed on days 15 and 21 were significantly greater than that on day 9 but were not different from that observed on day 3 of pregnancy. We conclude that the ability to transform AP PRL to a TRH-releasable pool by the transient blockade of DA is present in early and late pregnancy, but is absent in midpregnancy. Since this secretory mechanism is retained on day 9 after hysterectomy on day 6 of pregnancy, it appears that the secretory products of the uterine-placental unit are inhibitory to transformation. Further, this inhibitory effect at midpregnancy cannot simply be the result of decreased AP PRL content or changes in plasma P. Finally, the return of the transformation mechanism on the day before parturition (day 21) may be due to the increase in estrogen secretion that occurs in late pregnancy, since we have previously shown that estrogen can induce this AP secretory mechanism.     

Changes in LH and prolactin in arteriosclerotic femal breeder rats.

Serum levels of LH and prolactin were measured in repeatedly-bred, arteriosclerotic female rats. Serum LH was abnormally decreased on the afternoon of proestrus and estrus. The extent of the depression of circulating LH levels parallels the severity of the arteriosclerosis. Serum prolactin was significantly increased above normal at proestrus, and the degree of prolactin increase was also correlated with the degree of severity of arteriosclerosis. It is suggested that frequent and repeated pregnancies affect the hypothalamic-pituitary-adrenal-gonadal axis leading to hormonal and metabolic imbalance, which may play a causal role in the pathogenesis of the spontaneous arteriosclerosis which appears in repeatedly-bred rats.     

Estriol affects prolactin and LH secretion in rats

The effects of estriol on serum prolactin (PRL) and LH levels, on the pituitary response to TRH and LHRH and on the synthesis and release of PRL from the anterior pituitary gland were investigated in female rats. The increase of serum PRL levels after estradiol administration was found to be associated with an increase of glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T) in the hypothalamus. Thus, a study was carried out on the effects of estradiol and estriol on PRL secretion and on GAD, GABA-T and gamma-amino butyric acid (GABA) in the hypothalamus and the anterior pituitary. Under basal and TRH-stimulated conditions, estriol increased serum PRL levels, decreased basal serum LH levels, and increased the response to LHRH, in terms of LH release. Estradiol and estriol increased the synthesis and release of 3H-PRL from hemipituitary glands in incubations of pretreated animals. Both estrogens induced hyperprolactinemia, concomitantly with an increase of hypothalamic GAD and GABA-T activity. Estriol increased hypothalamic GABA concentration, but did not modify GABA concentration in the pituitary glands. Our results show that estriol, at relatively high doses, seems to be active in increasing PRL synthesis and release and in decreasing serum LH levels; it can also modify pituitary response to TRH and LHRH stimulation.     

The inhibitory effect of dopamine agonists on LH release in women

Our demonstration of an inhibitory effect of dopamine on LH release prompted us to examine whether a similar action exists for dopamine agonists, such as L-dopa and 2-bromo-alpha-ergocryptine (CB-154). Following the administration of L-dopa (0.5 g, orally) to 6 normal women in the early follicular phase, a significant fall in mean LH levels after 1 h which lasted for 5 h was observed (P less than 0.00005). This was followed by a significant rebound above basal levels between the 7th and 10th h (P less than 0.00005). The expected fall in mean PRL levels which lasted for 4 h (P less than 0.00001) was followed by a significant rebound above basal levels after the 6th h (P less than 0.00001)). There was no significant change in mean FSH levels. Following the administration of CB-154 (2.5 mg. orally) to 6 women with hyperprolactinemic amenorrhea, there was also a significant fall in LH levels (P less than 0.00001) and in FSH levels (P less than 0.00001) from 5 h until the study ended at 10 h. The anticipated PRL suppression was also observed and persisted for the duration of the 10 h study. The demonstration of an inhibitory effect of L-dopa and CB-154 on LH release adds further support to the role of dopaminergic control of pituitary LH secretion.     

L-Dopa effects on serum LH and prolactin in old and young female rats.

Serum LH and prolactin changes in response to an acute systemic L-dopa injection were measured in young (4-6 months) proestrous, estrous and 2nd day diestrous rats, and in aged (23-30 months) constant estrous and pseudopregnant (long diestrous) Long-Evans rats. Serum LH and prolactin were measured by radioimmunoassays in serial blood samples taken before and 15, 60 and 120 min after i.p. injections of 0, 3 or 30 mg of L-dopa. Pretreatment serum prolactin levels were elevated in afternoon samples from young proestrous and estrous rats and in both aged groups. Both the 3- and 30-mg injections caused a reduction in serum prolactin in all groups. The reduction in serum prolactin following 3 mg of L-dopa was less in both the aged groups than in the young rats. The pretreatment serum LH concentration was markedly elevated only on the afternoon of proestrus. The pretreatment serum LH level of the aged constant estrous group was greater than that of either the young estrous or diestrous group. Pretreatment serum LH levels were lower in aged pseudopregnant rats than in young diestrous rats. After the 30-mg L-dopa injection serum LH increased in all groups except the aged pseudopregnant group. Although the increase in LH following L-dopa injection was similar in young estrous and aged constant estrous rats, the increase in serum LH occurred later and lasted longer in the latter group. These data indicate that the hypothalamic-anterior pituitary endocrine control mechanisms are less responsive to acute L-dopa treatment in the aging female rat.     

Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats

The ability of kisspeptins, ligands of the G protein-coupled receptor 54, to potently elicit LH secretion is now undisputed. Yet, most of the pharmacological characterization of their gonadotropin-releasing effects has been conducted after intracerebral administration. In contrast, the effects of peripheral injection of kisspeptin remains less well defined. In this study, dynamic LH secretory responses to iv administration of kisspeptin-10 in different experimental settings are presented, and compared with those evoked by kisspeptin-52, using a protocol of serial blood sampling in conscious, freely moving male rats. LH responsiveness to peripheral administration of kisspeptin appeared extremely sensitive, as doses as low as 0.3 nmol/kg (0.1 microg/rat) evoked robust LH bursts, the magnitude of which was dose-dependent and apparently maximal in response to 3.0 and 30 nmol/kg kisspeptin-10. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved, whereas basal and depolarization-induced GnRH release ex vivo was significantly enhanced. Finally, iv administration of kisspeptin-52 elicited dynamic LH responses analogous to that of kisspeptin-10; yet, their net magnitude and duration was slightly greater. In summary, we present in this study a series of experiments on the effects of systemic (iv) injection of single or repeated doses of kisspeptin upon dynamic LH secretion in conscious male rats. Aside from potential physiologic relevance, our present data might contribute to setting the basis for the rational therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis.     

Effect of naloxone and morphine on LH and prolactin release in androgen-sterilized rats

Many studies suggest that the hypothalamic opiate system modulates the secretion of LH and prolactin (PRL) by its effects on catecholamine release. We previously provided evidence that the LH response to the opiate receptor antagonist naloxone (NAL) may depend upon spontaneous activity in the hypothalamic noradrenergic system at the time the drug is administered. Thus, when NAL is given to rats which have low turnovers of hypothalamic norepinephrine (NE), only small transient rises in LH occur. This is contrasted to the effects of NAL on the LH responses of animals with high rates of NE turnover where marked amplification of phasic LH release is observed. In the present studies, we examined the effects of NAL on LH and morphine on PRL responses in androgen-sterilized rats (ASR). These animals do not respond to the positive feedback actions of estrogen by having LH surges, and hypothalamic NE turnovers do not increase during the afternoon as they do in normal rats. Female rats were given a single injection of testosterone propionate (50 micrograms s.c.) at 5 days of life and ovariectomized (OVX) at 100 days of age. Seven days later (day 0), estrogen capsules were inserted subcutaneously, and on day 2, their responses to NAL or morphine were examined. Comparable estrogen-treated gonadectomized controls also were studied. In control rats, NAL (10 mg/kg s.c.) markedly amplified the phasic secretion of plasma LH. In contrast, NAL had no effect on the basal afternoon secretion of LH in ASR. To determine if neonatal androgen treatment deleteriously affected opiate-tuberoinfundibular dopamine (TIDA)-serotonergic interactions, a second series of studies was performed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute administration of 2-hydroxylated metabolites of oestrogens on LH and prolactin secretion in male and female prepubertal rats

The effects of catechol oestradiol and catechol oestrone on the release of LH and prolactin were investigated in immature male and female Wistar rats. In male rats both catechol oestradiol and catechol oestrone significantly increased the plasma concentration of LH, and catechol oestradiol but not catechol oestrone significantly increased the plasma concentration of prolactin and decreased the pituitary concentration of LH. The parent oestrogens, oestradiol-17 beta and oestrone, had no effect on plasma LH concentrations, but both increased significantly the plasma concentration of prolactin, and oestrone but not oestradiol-17 beta increased the pituitary concentration of LH. In immature female rats, catechol oestradiol inhibited the surge of LH and the increase in uterine weight induced by injecting pregnant mare serum gonadotrophin (PMSG). The injection of oestrone induced an increase in the plasma concentration of LH which was about nine times greater than that produced by oestradiol-17 beta. There were no significant differences in the effects of these steroids on plasma prolactin concentration. These results (i) confirm that in the immature male rat catechol oestrogens can stimulate LH release and show that catechol oestradiol can increase prolactin release, (ii) show that catechol oestradiol can inhibit the stimulatory effects of PMSG on LH release and uterine weight in the immature female rat, and (iii) demonstrate that oestrone can stimulate LH release in the immature female rat.     

Plasma prolactin concentrations in parental male and female rats: effects of exposure to rat young

The effects of pup presentation on the PRL responses in parental male rats were measured and compared with those in parental virgin and lactating female rats. Blood samples were collected from rats through indwelling intraatrial cannulas after a suckling challenge, i.e. presentation of rat young. Lactating rats showed full parental behavior and characteristic large surges in plasma PRL levels within the first 5-10 min on each day that rat young were presented (days 4, 8, and 12 of lactation). When pups were not presented, PRL rises did not occur. In contrast to the pattern of PRL responses shown by lactating mothers, parental ovariectomized nulliparous female and parental intact male rats failed to show specific increases in PRL in response to pup presentation. Plasma PRL levels in these groups, as in nonparental female and male rats, occasionally rose in response to blood collection rather than to pup presentation alone. Treatment of nulliparous female as well as male rats with estradiol and progesterone Silastic implants for 21 days before the initiation of behavioral testing significantly reduced the latencies of both nulliparous females and males to respond to foster young from about 5 to 2 days. The PRL responses of these steroid-primed groups were quite different. The steroid-primed females exhibited a pattern of PRL responses to pups identical to that found in lactating rats. The steroid-primed parental males, in contrast, failed to show specific increases in plasma PRL levels in response to young. These data demonstrate a sex difference in the hormonal, but not behavioral, responses of male and female rats to young and are suggestive of possible sex differences in the hypothalamic and/or peripheral regulation of pup-induced PRL secretion.     

Plasma dopamine concentrations in various types of hypertension

The concentrations of unconjugated plasma dopamine (PDA) were studied in patients with various types of hypertension. Catecholamines were extracted from plasma specimens (1.0-3.0 ml) through an Amberlite CG50 (Li+-form) microcolumn and eluted by a magnesium sulfate - ethanol solution. The elute was then desalinated and deproteinized by the ethanol-treated precipitation procedure and dried in a vacuum oven at 25 degrees C. A fraction of catecholamines was assayed with the modified procedures of the COMT-mediated radio-enzymatic method. This assay system was sensitive enough to permit an accurate measurement of PDA as low as 6.0 pg per ml of plasma without any detectable contamination of the conjugated dopamine. The resting levels of PDA were 10.1 +/- 1.0 pg/ml (mean +/- SEM), 9.5 +/- 1.0 and 13.7 +/- 0.6 in patients with borderline hypertension (BH, n = 25), essential hypertension (EH, n = 22) and renovascular hypertension (RVH, n = 8), respectively. The values in EH patients were significantly smaller than those in age-matched normal controls (13.0 +/- 1.4, n = 14, p less than 0.05). Remarkably increased PDA values were observed in patients with pheochromocytoma (76.5 +/- 25.4, n = 9, p less than 0.01). Significantly raised PDA values were also found in patients with primary aldosteronism (PA, 27.8 +/- 9.0, n = 6, p less than 0.05), while their plasma norepinephrine levels (PNE, 169 +/- 39 pg/ml) tended to be lower than those of normal controls (206 +/- 20), showing an apparent dissociation between the values of PDA and PNE. Upright posture for 15 minutes induced a significant rise in PDA (p less than 0.05) in all subjects except PA patients. The postural changes of PDA, however, were invariably smaller than those of PNE (p less than 0.05). The resting values of PDA in normal, BH and EH patients showed a significant negative correlation with their mean arterial pressures (r = -0.301, n = 61, p less than 0.05) and a positive correlation with those of PNE (r = 0.381, p less than 0.01). There was no correlation between PDA and age in any group studied. These findings indicate that PDA might not be only a precursor fraction of neurotransmitters released from the sympathetic nervous system but could also represent a physiological function of the dopaminergic regulatory system. The varied but distinctive features of PDA status in various types of hypertension suggest the possibility that the peripheral dopaminergic mechanisms play an inherent role in the pathogenesis of hypertension.     

The effects of light exposure on plasma concentrations of melatonin, LH, FSH and prolactin in women

The effects of light exposure on plasma concentrations of melatonin, LH, FSH and prolactin were studied in 11 normal cycling women during their follicular phases. Blood samples were obtained via an indwelling venous catheter every 10 min. for 2.5 hours starting at 9:30 and 21:30h. For the blood samplings taken at night, six women were kept in a dark room and were permitted to sleep. Their blood samples were obtained using a flashlight (5-10 lux) without their rest being disturbed. However, the other five women were exposed to light (3,000 lux at eye level) and awakened from 22:40 to 24:00h. Plasma melatonin concentrations in the morning decreased from 48.7 +/- 11.6 pg/ml at 9:30h to 24.7 +/- 4.0 pg/ml at 12:00h. On the other hand, plasma melatonin concentrations at night increased from 65.4 +/- 9.6 pg/ml at 21:30h to 138.2 +/- 28.6 pg/ml at 24:00h. The pulsatile LH secretion was changed from the type of "high frequency, low amplitude" in the morning to the type of "low frequency, high amplitude" at night. Nocturnal FSH concentrations were lower than diurnal ones, but nocturnal prolactin concentrations were higher than diurnal ones. Nocturnal concentrations of melatonin were suppressed 40 min. after the light exposure (from 117.4 +/- 11.4 pg/ml at 22:40h to 74.6 +/- 13.9 pg/ml at 23:20h). On the the other hand, the light exposure increased plasma prolactin concentrations from 10.9 +/- 4.1 ng/ml at 22:40h to 17.0 +/- 4.4 ng/ml at 22:50h, maintained those higher levels for 20 min. and decreased them gradually after 23:20h. With the light exposure, mean values of nocturnal LH concentrations were increased from 11.9 +/- 1.5 mIU/ml before exposure to 14.2 +/- 1.8 mIU/ml after exposure, and those of FSH were also increased from 5.9 +/- 0.4 mIU/ml to 6.3 +/- 0.4 mIU/ml. These results showed that the secretion of melatonin, as well as LH, FSH and prolactin had daily rhythms and that melatonin and prolactin showed different responses to light exposure, suggesting different control mechanisms for the secretion of those two hormones.     

The influence of oestrogen administration in vivo on in vitro prolactin release. Interaction between dopamine and thyrotrophin releasing hormone.

The influence of oestrogen administered to the ovariectomized rat on the interaction between dopamine (DA) and thyrotrophin releasing hormone (TRH) on the release of radioimmunoassayable (RIA) and [3H]leucine incorporated into prolactin ([3H]PRL) was examined in vitro. Dopamine had a more marked suppressing effect on newly synthetized PRL (80%), as determined [3H]PRL, than on total PRL (50%), as determined by RIA-PRL. The administration of 5 micrograms of oestradiolbenzoate (OeB) for 7 days resulted in blocking the suppressing effect of DA when RIA-PRL was measured but not when [3H]PRL was measured. The administration of 5 micrograms of OeB enabled TRH to partially override the suppressing effect of DA and the degree of response was more marked when RIA-PRL was measured than when [3H]PRL was measured. The administration of 50 micrograms of OeB for 3 days enabled TRH to override the DA blockade of prolactin release to levels comparable to that of the control when RIA-PRL was measured but had little to no effect on [3H]PRL. The results are discussed in relation to the two storage pools of PRL in the pituitary and the data suggest that DA acts predominantly to suppress the newly synthetized, rapidly releasable pool. Oestrogen acts to block DA action on the older more stable PRL pool. The ability of TRH to override the DA blockade of PRL release depends upon the presence of oestrogen; here TRH acts predominantly on the older more stable pool of PRL. Oestrogen's action on disrupting the DA suppression of PRL release appears to be related to the time of day the hormone is administered subsequent to when the pituitary is exposed to DA in vitro.     

Plasma patterns of LH, FSH and prolactin in rats with a polycystic ovarian condition induced by oestradiol valerate

The patterns of plasma LH, FSH and prolactin concentrations were investigated in rats with a polycystic ovary condition (PCO). The condition was induced by treatment with oestradiol valerate 9 weeks before blood sampling. Serial blood samples were taken at 10-min intervals for 4 h from ten rats with PCO. All samples were assayed for LH, those from five animals for FSH and those from the remaining five animals for prolactin. In addition, five control animals with normal oestrous cycles were sampled during oestrus and the samples assayed for LH. Mean concentrations of LH, FSH and prolactin in rats with PCO were 140 ng/l, 76 micrograms/l and 7.6 micrograms/l respectively. All three hormones exhibited an episodic pattern. The mean peak amplitudes of LH, FSH and prolactin were 120 ng/l, 25 micrograms/l and 3.5 micrograms/l respectively. All three hormones exhibited a similar mean frequency of four or five episodes per 4 h. The LH and FSH patterns were closely synchronized; nearly all FSH peaks coincided with LH peaks. The prolactin pattern did not, however, correlate with that of the gonadotrophins. Despite the persistent oestrous condition of the animals with PCO, it was clear that their pattern of LH did not resemble that of cyclic animals in normal oestrus; in the normally cyclic animals in oestrus the pulse period was nearly twice as long and the pulse amplitude was more than sixfold greater than those in animals with PCO. We conclude that the unique episodic patterns of gonadotrophins are more important than mean blood concentrations of these hormones in establishing and maintaining the polycystic ovary syndrome.     

The effect of ACTH administration on serum estrogens, LH, and FSH in the aged.

The effect of administration of long acting ACTH on serum levels of estrogens, LH and FSH was studied in aged subjects. Nine women and 5 men between 66 and 90 years of age were examined. One milligram of long-acting synthetic ACTH was given in every 12 h for 2 days. Significant increases in serum estrone and estradiol levels were induced in parallel with serum cortisol at 24 hours and no further change was observed at 48 hours. The estrone/estradiol ratio increased from a control value of 3.0 to 4.0 at 24 hours and to 4.7 at 48 hours (P less than 0.02) compared to control values.     

Effect of reserpine on the inhibition of prolactin released from different pituitary constructs in vitro by dopamine, bromocriptine and apomorphine.

Hourly release of Prolactin by pituitary constructs 1 whole pituitary (PI), adenohypophysis (P-N) and pituitary-hypothalamus co-incubate (PHC) were compared. Adenohypophysis secreted significantly more prolactin than PI and PHC, while PHC secreted significantly less than PI. Co-incubation of (P-N) with posterior pituitary reduced the elevated secretion of prolactin. Addition of dopamine (10(-7) M), bromocriptine (10(-7) M) and apomorphine (5 x 10(-8) M) to these constructs did not affect the release of prolactin from PI but inhibited the same from (P-N) and PHC. Treatment with reserpine increased serum prolactin levels but intrapituitary prolactin contents were decreased. Hourly release of prolactin from pituitary constructs derived from reserpine-treated rats was significantly reduced as compared to ascorbic acid--treated controls. Inclusion of dopamine (10(-7) M), bromocriptine (10(-7) M) and apomorphine (5 x 10(-8) M) in these constructs inhibited prolactin secretion further. In vitro addition of perphenazine stimulated the release of prolactin by PHC but was without any effect on PI and (P-N). The data are interpreted to suggest that dopamine in posterior pituitary may be an important determinant of hypothalamic modulation of prolactin secretion.