Suppressed Serum Prolactin Research Articles

Suppressed Serum Prolactin Levels under Topical Treatment with Isoretinoin

Suppressed Serum Prolactin Levels under Topical Treatment with Isoretinoin

Behavioral and hormonal effects of low-dose pergolide in children and adolescents with Gilles de la Tourette's syndrome

Abstract Objective To assess the acute and subacute (≥4 weeks) toxicity of low-dose pergolide in children and adolescents with Gilles de la Tourette's syndrome. Background Pergolide is a mixed dopamine-receptor agonist. At low doses, it may suppress tics in children with Tourette's syndrome. Potential adverse behavioral and hormonal effects of low-dose pergolide in children have not previously been reported. Methods Children with Tourette's syndrome were studied after administration of pergolide for 1 day and for ≥4 weeks. Repeated measurements of serum prolactin and growth hormone levels were performed. Repeated psychologic assessments were performed using the Visual Analogue Mood Scale subscales for happy, drowsy, energized, and tense. Repeated-measures analysis of variance was used for statistical analyses. Results Low-dose pergolide significantly suppressed serum prolactin levels, acutely and chronically. No changes in growth hormone or mood subscales were demonstrated. Conclusions Low-dose pergolide in children with Tourette's syndrome suppresses prolactin but not growth hormone. Its use may not produce the mood-related adverse effects commonly associated with neuroleptic drugs.

Photoperiodic regulation of glutamatergic stimulation of secretion of luteinizing hormone in male Syrian hamsters.

It has been suggested that changes in endogenous glutamatergic stimulation of secretion of luteinizing hormone (LH) induced by photoperiod play a role in regulating seasonal cycles of reproductive activity. The aim of this study was to test the hypothesis that the glutamatergic control of the secretion of LH in the male Syrian hamster is sensitive to photoperiod, by determining whether the glutamate agonist N-methyl-D-aspartate (NMDA) could stimulate LH secretion in this species and, if so, to determine whether the response varied among animals exposed to different daylengths. In the first experiment, adult male hamsters were housed in either short day (8 h light: 16 h dark) for 6 weeks to induce testicular regression, or long days (16 h light: 8 h dark) to maintain testicular function, and the effects of systemic administration of NMDA on serum LH concentrations were determined. In the short-day hamsters, all s.c. doses of NMDA (25-75 mg kg-1 body weight) produced a robust rise in serum LH concentrations within 15 min. In the long-day hamsters, basal LH concentrations were higher than in short-day hamsters, but only the highest dose of NMDA produced a significant increase in LH concentrations, and the magnitude of this increment was less than those observed in short days. In hamsters in long days, the low doses of NMDA that did not significantly alter LH concentrations nevertheless significantly suppressed serum prolactin concentrations, demonstrating the efficacy of the drug. In hamsters in short days, serum prolactin concentrations were at the limit of detection of the assay, so no inhibitory effect of NMDA on prolactin secretion could be determined on this photoperiod. In the second experiment, the effects of a fixed dose of NMDA (50 mg kg-1 body weight) was tested at intervals in hamsters exposed to short days for a prolonged period such that their testes initially regressed, but then became scotorefractory and testicular recrudescence occurred. After 6 and 12 weeks in short days, NMDA stimulated LH secretion. However, after 24 weeks in short days when testicular recrudescence was complete, the response to NMDA was lost. A third experiment determined whether the reduced response to NMDA in hamsters on long days relative to those in short days might result from higher concentrations of circulating testosterone. Hamsters in long days were castrated to remove the influence of gonadal feedback, and the response to NMDA tested 3 weeks later when endogenous LH concentrations had risen to levels characteristic of the chronically castrated condition.(ABSTRACT TRUNCATED AT 400 WORDS)

Involvement of physiological prolactin levels in growth and prolactin receptor content of prostate glands and testes in developing male rats.

We have investigated the role of physiological prolactin levels in the development of prepubertal male rats. Prolactin GH and testosterone levels, as well as body, ventral prostate and testicular weight, have been analysed in both control and bromocriptine-treated rats between 21 and 60 days of life. Furthermore the role of prolactin in the regulation of its own receptors has also been studied during the same period. In control rats, prolactin levels showed a prepubertal peak of secretion at 25 days of age. At this time GH and testosterone levels were low and did not show any significant variation. After this age, prolactin levels increased more gradually; determinations of GH showed great variation with low levels in most of the rats and very high values in the other animals; testosterone levels remained low until day 35 after which they increased. Simultaneously with the serum prolactin peak on day 25, a decrease in prolactin-binding capacity of ventral prostate glands, was observed and a maximum rate of body, prostate and testicular weight gain was obtained. Furthermore, in rats with pharmacologically suppressed serum prolactin levels (lower than 1 microgram/l), prolactin binding to prostate glands as well as the weight of body, ventral prostate and testes were lower than in control animals. When results were expressed in mg prostate or testes/g body weight, testes from 25-day-old treated rats weighed significantly less than controls. The later stages of development, from days 25 to 60, were characterized by an initial decline in serum prolactin levels at 29 days of age which was followed by a continuous increase until adult values were reached. During this period, prostatic prolactin receptors which were at their lowest value at 33 days of age showed a gradual rise parallel with the observed increase in plasma prolactin levels. When testicular tissue was analysed, no changes in prolactin-binding sites caused by sexual maturation were observed. The present results indicate that physiological prolactin secretion has a specific effect on the normal increase in the prostate, testes and body weight and clearly is also implicated in the regulation of its prostatic receptors at the earlier stages of development.

Synthesis and evaluation of N,N-di-n-propyltetrahydrobenz[f]indol-7-amine and related congeners as dopaminergic agonists

An evaluation of 6-[2-(di-n-propylamino)ethyl]indole (4), its rigid analogue N,N-di-n-propyl-5,6,7,8-tetrahydrobenz[f]indol-7-amine (5), and some related congeners, for ability to suppress serum prolactin in reserpinized rats, revealed modest biological activity in this in vivo model of dopaminergic activity. Although the indole N-H in these compounds can be considered to be oriented "meta" with respect to the ethylamine side chain, compounds with the indole N-H located in the other "meta" position (i.e. 4-[2-(di-n-propylamino)ethyl]indole (2) or its rigid benz[e]indole analogue 3) were much more potent dopamine agonists. The results argue for a particular orientation of the indole N-H vector. In addition, relatively potent dopamine agonists also resulted when the pyrrole portion of the indole ring was replaced by a methanesulfonamido function, supporting the idea that the indole N-H serves as a hydrogen-bond donor.

Prolactinomas presenting as primary amenorrhoea and delayed or arrested puberty: response to medical therapy.

Fourteen patients presented with arrested pubertal development associated with prolactin-secreting pituitary tumours; serum prolactin ranged from 4000-104,300 mU/l in the ten females and 920-68,000 in four males. Skull X-ray showed a markedly expanded pituitary fossa in eight patients. CT scan and/or air encephalography showed macroadenomas in nine, of whom seven had large suprasellar extensions to their tumours, yet only five had complained of headache and only two had visual field defects. All were treated with bromocriptine (7.5-60 mg/day) which lowered prolactin substantially in all and into the normal range in 11 (range less than 60-3090, median 105 mU/l). Puberty thereafter progressed spontaneously in 13, but in one patient, whose prolactin did not suppress completely, menarche could be induced only with clomiphene. Anterior pituitary function improved on bromocriptine. In seven patients with macroadenomas, tumour shrinkage into the pituitary fossa was complete and in two others incomplete shrinkage was followed by transsphenoidal hypophysectomy. Seven patients received pituitary irradiation, six after bromocriptine-induced shrinkage and one after transsphenoidal surgery. At follow-up 6 months to 10 years (median 5 years) after presentation, ten remain on bromocriptine with a suppressed serum prolactin, one has a normal prolactin after surgery, and three are off bromocriptine with residual hyperprolactinaemia (418-4680 mU/l). To date, four females have become pregnant and one male has fathered two children. Prolactinomas are an important, albeit rare, cause of arrested puberty and should therefore be sought. Most patients respond well to bromocriptine, with or without pituitary irradiation.

LH subunit mRNA concentrations during LH surge in ovariectomized estradiol-replaced rats.

In cycling rats, pituitary concentrations of luteinizing hormone (LH) beta-subunit mRNA increase two- to threefold before the afternoon proestrus LH surge without a corresponding increase in alpha-subunit mRNA. Estradiol (E2) treatment is known to allow expression of daily LH surges in ovariectomized (OVX) rats, and the timing, magnitude, and duration of LH secretion is similar to the LH surge on proestrus. The present study was conducted to examine whether the regulation of LH subunit mRNAs during the LH surge in OVX-E2-treated rats is similar to that present on proestrus. Female Holtzman rats were OVX and Silastic implants containing E2 were inserted subcutaneously under ether anesthesia. Some animals received bromocriptine (0.6 mg sc, twice/day beginning 1 h before surgery). On the 2nd day after surgery, groups of animals (n = 4-10/group) were decapitated at intervals between 1000 and 2100. LH and prolactin (PRL) levels were measured in trunk blood. LH subunit mRNA concentrations in the pituitaries were measured by dot-blot hybridization assay. In OVX-E2 rats the LH surge occurred at 1830 and was accompanied by a selective twofold increase in alpha-subunit mRNA (from 266 +/- 18 to 459 +/- 61 pg cDNA bound/100 micrograms pituitary DNA) and maximum values were present at 1730. LH beta-subunit mRNA (m = 29 +/- 1 pg cDNA bound/100 micrograms pituitary DNA) was unchanged throughout the day. Bromocriptine treatment resulted in the suppression of serum PRL (m = 23 +/- 2 ng/ml) and the LH surge was delayed by 1-1.5 h and somewhat blunted.(ABSTRACT TRUNCATED AT 250 WORDS)

The intrinsic activities of the partial dopamine receptor agonists (−)-3-PPP and TDHL on pituitary dopamine receptors are lower in female than in male rats

The abilities of the mixed agonists/antagonists on dopamine (DA) receptors, (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((−)-3-PPP) and transdihydrolisuride (TDHL), to suppress serum prolactin levels in acutely hyperprolactinemic male and female rats were investigated. γ-Butyrolactone was used to deplete endogenous DA and raise serum prolactin concentrations. Both (−)-3-PPP and TDHL were found to cause sexually differentiated responses: (−)-3-PPP reduced serum prolactin levels dose dependently and effectively in males but caused only a modest decrease of prolactin release in females. Moreover, (−)-3-PPP antagonized the prolactin-suppressing effects induced by the DA receptor agonist (+)-3-PPP in females. Likewise TDHL decreased prolactin secretion markedly in males while it had only slight effects in females. It can be concluded from these results that the intrinsic activities of the partial DA agonists (−)-3-PPP and TDHL are lower in female than in male rats, suggesting a reduced responsiveness of hypophyseal DA receptors in females. Since DA levels in the pituitary portal circulation are higher in female than in male rats, this study gives further support to the hypothesis claiming an inverse relationship between the intrinsic activity of a mixed agonist/antagonist and the degree of previous stimulation of its receptor.

Suppressed serum prolactin in sinoaortic-denervated rats.

We investigated the effect of arterial baroreceptor deafferentation on serum and pituitary prolactin (PRL) and on catecholamines in median eminence (ME) and anterior and posterior pituitaries. Male Wistar rats were sinoaortic denervated (SAD) or sham operated (SO). Three days after surgery serum prolactin, measured by radioimmunoassay, was suppressed in SAD rats (-54%, P less than 0.05), and dopamine (DA) and norepinephrine (NE) concentrations, measured by radioenzymatic or high-performance liquid chromatography electron capture methods, were significantly reduced in ME of SAD rats (NE, -54% P less than 0.005 and DA, -56% P less than 0.001). Simultaneously, anterior pituitary of SAD rats had significant increases in both catecholamines, whereas posterior pituitary showed no changes. Four hours after surgery serum PRL was also reduced (-40%, P less than 0.05) in SAD rats, but no changes in ME catecholamines were found. Mean arterial pressure (MAP) and heart rate were measured before and after injection of bromocriptine (0.5 mg/kg ip) in SAD and SO rats 3 days after surgery. Bromocriptine markedly suppressed serum PRL in both groups and reduced MAP from 144 +/- 10 to 84 +/- 5 and from 116 +/- 2 to 99 +/- 3 in SAD and SO rats, respectively; heart rate was reduced in SAD rats. We conclude that the SAD rat is a model of hypertension with suppressed serum PRL and that interruption of arterial baroreceptor nerves suppresses PRL secretion probably by modulating tuberoinfundibular turnover of catecholamines.

Mechanism of anestrus in rats treated with an antihypertensive agent, losulazine hydrochloride

The mechanism of anestrus in rats treated with losulazine, a peripheral sympatholytic antihypertensive agent, was investigated by determining its effect on hypothalamic catecholamines and serum sex hormones and by evaluating the influence of bromocriptine on the reproductive functions of rats treated with losulazine. Groups of six female Upjohn Sprague-Dawley rats were treated orally with 10 mg/kg/day of losulazine and/or 18.75 mg/kg/day of bromocriptine for 15 or 27 days. Six rats were treated with losulazine plus 6.25 mg/kg/day of bromocriptine for 16 days followed by losulazine alone for 11 days. Rats treated with losulazine only were depleted of hypothalamic catecholamines, were hyperprolactinemic, and had interrupted estrous cycles and attenuated vaginal mucosa. Treatment with bromocriptine, a dopamine receptor agonist, resulted in suppression of serum prolactin and normal estrous cycles. Rats reverted back to hyperprolactinemia and anestrus shortly after bromocriptine withdrawal. These results suggest that hyperprolactinemia mediated through hypothalamic dopamine depletion is the mechanism of anestrus in rats treated with losulazine.

Reversal of the delta-9-tetrahydrocannabinol inhibitory effect on prolactin secretion by rostral deafferentation of the medial basal hypothalamus.

The effect of rostral deafferentation of the medial basal hypothalamus (MBH) on delta-9-tetrahydrocannabinol (THC)-induced changes in serum prolactin (PRL) concentrations was investigated in female rats having retrochiasmatic frontal cuts that transected the rostral hypothalamus. Cuts dorsal to the hypothalamus were produced in the same plane in other animals in order to control for possible effects of the surgical procedure or dorsal brain damage. All animals were ovariectomized 28-35 days after stereotaxic surgery to obviate potential confounding effects of differences in ovarian function between groups. Unlesioned rats were ovariectomized to provide a positive control group for THC inhibitory activity. At least 4 weeks after ovariectomy, animals were treated intravenously with THC (0.5 or 1.0 mg/kg body weight) or vehicle at the midpoint of a 110-min experimental period during which blood samples were obtained at 10-min intervals via indwelling atrial cannulae. Serum PRL concentrations were determined by radioimmunoassay and cut locations were confirmed histologically. When administered to ovariectomized animals without brain lesions, THC suppressed serum PRL concentrations from the average treatment level within 30 min (p less than 0.05), and PRL levels remained suppressed for the remainder of the posttreatment sampling period. Treatment with the vehicle alone was without effect. Animals with retrochiasmatic plane cuts that did not transect the rostral hypothalamus similarly displayed PRL suppression in response to THC administration (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine-β-hydroxylase inhibition acutely stimulates rats hypothalamic noradrenaline and dopamine neuronal activity as assessed from metabolic ratios and circulating glucose and ACTH responses

Because central noradrenaline neuronal activity is tonically inhibited by noradrenaline (NA) itself via an action at prejunctional α 2-adrenoceptors, it was hypothesised that the blockade of central NA synthesis following acute dopamine-β-hydroxylase (DBH) inhibition might primarily deplete prejunctional NA levels and result in an increase in central NA neuronal activity through reduced NA autoinhibition. This hypothesis was tested in the rat following the acute administration of the DBH inhibitors diethyldithiocarbamate (DDC) and cysteamine (CSH). Computerised gas chromatography/mass spectrometry was used to precisely measure the hypothalamic levels of NA and dopamine (DA) together with those of their primary neuronal metabolites dihydroxyphenylethyleneglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), respectively. Both DDC (at 4 h) and CSH (at 30 min.) caused approximately a 50% reduction of hypothalamic NA concentrations. However this was associated with marked and highly significant increases in hypothalamic DHPG levels (by 50–100%) and in the hypothalamic ratio DHPG/NA. Also, when measured after CSH, the hypothalamic levels of the DHPG metabolite 3-methoxy-4-hydroxyphenylethyleneglycol were highly significantly increased. Consistent with increased DA neuronal activity, both DBH inhibitors raised DA and DOPAC levels and also the ratio DOPAC/DA in the hypothalami of treated rats and markedly suppressed serum prolactin levels (all p<0.01). The rise in hypothalamic concentrations of DHPG indicates that an increase in hypothalamic NA neuronal activity occurs following DBH inhibition. Significant elevations of blood glucose, corticosterone and ACTH were also observed after DBH inhibition. As we have previously demonstrated that increased central NA activity is associated with elevations of blood glucose, corticosterone and ACTH, these data provide further evidence for a functional increase in central NA activity caused by acute DBH inhibition. It is proposed that the increase in hypothalamic NA activity after DBH inhibition results from a primary depletion of the prejunctional α 2-active autoregulatory pool of NA.

Effect of two dopamine agonists, TL-99 and 3-PPP, on prolactin secretion in the rat

TL-99 and 3-PPP, two putative dopamine autoreceptor agonists, effectively suppressed serum prolactin (PRL) concentrations in rats treated with α-methyltyrosine. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by TL-99 and 3-PPP. These findings are supportive of the view that TL-99 and 3-PPP exert a dopamine agonist action at dopamine receptors in the anterior pituitary gland.

Variation of serum prolactin-releasing activity in women with the galactorrhea-amenorrhea syndrome after bromocriptine treatment

Serum methanol extracts were obtained from nine women with the galactorrhea-amenorrhea syndrome, 24 pregnant women in the third trimester, and 18 normal men and women. The serum extract released prolactin (PRL) in significant amounts from rat anterior pituitary in vitro. The extracts from patients with galactorrhea-amenorrhea released PRL in large quantities. A significant positive correlation was observed between the PRL-releasing activity and serum PRL levels in individual samples from the pregnant women and normal subjects but not from the patients with galactorrhea-amenorrhea. Bromocriptine therapy suppressed serum PRL levels of five patients without tumors but increased the PRL-releasing activity in three out of five patients after treatment for 1 or 2 months. Apparently hypothalamic regulation of PRL secretion was disrupted in these three patients after bromocriptine therapy.

Suppression of Prolactin Secretion in Normal Young Women by 2-Hydroxyestrone

The nonuterotropic natural estrogen 2-hydroxyestrone administered to normal young women results in a prompt and profound suppression of serum prolactin in most of the subjects. With the exception of dopamine, this is the only endogenous material known to strongly inhibit prolactin secretion, and its action suggests that the physiological regulation of prolactin by estrogens in the human is dual in nature, consisting of stimulation by estradiol and inhibition by its catechol estrogen metabolite.

Suppression of serum prolactin by naloxone but not anti-β-endorphin antiserum in stressed and unstressed rats

The role of endogenous opioids in the regulation of tonic and stress-induced prolactin secretion was studied in male rats. Animals with chronically indwelling intra-atrial catheters were used and served as their own controls. Intravenous injection of a potent rabbit anti-β-endorphin antiserum produced no change in either baseline serum prolactin or in the rise induced by swimming for 15 minutes at 20 C. Naloxone, 0.5 mg/kg intravenously, produced a small but statistically significant lowering of baseline serum prolactin levels, as well as a mild blunting of the stress-induced serum prolactin rise. The failure of anti- - endorphin antiserum to affect serum prolactin may be explained either by failure of the antiserum to gain access to hypothalamic prolactin regulating loci, or to lack of involvement of β-endorphin in the control of serum prolactin. The suppression of prolactin secretion seen with naloxone indicates that endogeneous opioids are involved in prolactin regulation, though the relatively small magnitude of the changes observed suggests that their role under physiological conditions may be a minor one.

Response of Serum Prolactin to Catechol Estrogen in the Immature Rat

The response of serum prolactin to the catechol estrogens, 2-hydroxyestrone (2-OH E1) and 2-hydroxyestradiol (2-OH E2) and their primary estrogens, estrone (E1) and estradiol (E2), was studied in 35-day-old male rats. The subcutaneous administration of 50 microgram of 2-OH E1 or 2-OH E2 significantly suppressed serum prolactin concentrations, but they were not significantly altered by the administration of 50 microgram of E1 or E2.

Differential sensitivity of prolactin release to dopamine and thyrotrophin-releasing hormone in intact and pituitary stalk-sectioned rhesus monkeys.

The effects of dopamine and thyrotrophin-releasing hormone (TRH) on prolactin release was studied in 14 intact and six pituitary stalk-sectioned (SS) female rhesus monkeys (Macaca mulatta). Baseline prolactin values were ninefold higher in SS animals (149+/-16 ng/ml) than in intact animals (16+/-1 ng/ml). Prolactin release after intravenous administration of TRH in doses of 0, 125, 250, 500 and 1000 ng revealed that SS monkeys were more sensitive to the prolactin-releasing activity of this tripeptide than were intact animals. A significant (P less than 0.05) increment in serum prolactin was observed in SS animals after injection of 125 ng TRH whereas 250 ng was required to raise prolactin levels in the circulation of intact animals significantly (P less than 0.05). Furthermore, at each comparable dose level of TRH, the increment in serum prolactin was distinctly greater in SS animals than in intact monkeys. Infusion of dopamine at the rate of 10 microgram/kg body weight per min significantly (P less than 0.05) lowered prolactin levels within 60 min in intact animals and no further decline was observed with 20 or 40 microgram dopamine. Serum prolactin concentrations were not affected by saline infusion or by 5 microgram dopamine. Infusion of dopamine at the rate of 10 microgram/kg body wt per min also resulted in significant (P less than 0.01) suppression of serum prolactin in SS animals. This prolactin decrease was apparent within 40 min. Prolactin release after 500 ng TRH was less in these dopamine-treated SS monkeys than after an infusion of saline. Higher doses of dopamine (20 and 40 microgram) did not cause a further decrease in basal serum prolactin concentrations, but these two dopamine treatments blocked the increase in prolactin elicited by 500 ng TRH. The results suggest that the removal of hypothalamic influence, possibly related to the effects of dopamine, renders the pituitary gland more sensitive to the prolactin-releasing action of TRH.

Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats

In the present study we compared the ability of amphetamine and methylphenidate to antagonize the elevation of serum prolactin produced by reserpine because of the differences in the actions of amphetamine and methylphenidate on brain dopamine turnover. Groups of male rats were treated with either methylphenidate (10 mg/kg) or amphetamine (5 mg/kg) alone or in combination with reserpine (5 mg/kg). The reserpine treatment was given 4 hours before methylphenidate or amphetamine, and the rats were killed 5 hours after reserpine. Neither amphetamine nor methylphenidate alone was able to suppress serum prolactin. Amphetamine but not methylphenidate was able to block the increase of serum prolactin in response to reserpine. Amphetamine lowered brain DOPAC in control and reserpine-treated rats, but methylphenidate elevated brain DOPAC in control rats and had no effect in reserpine-treated rats. These results indicate that the methylphenidate group of CNS stimulants can be differentiated on the basis of their neuroendocrine effects from the amphetamine group of stimulants.

Ultrastructural alterations in mammary glands of pregnant rats after ovariectomy and hysterectomy: Effect of adrenal steroids and prolactin

Pregnant rats were subjected to oophorectomy and hysterectomy (O–H) on the seventeenth day of pregnancy, a time when serum levels of prolactin, estrogen, and corticosterone are not substantially greater than the respective levels in nonpregnant rats. At 32 hours after O–;H, serum prolactin and corticosterone both rose more than threefold, and lactose appeared in the mammary glands. Biopsies of mammary tissue obtained at 8 hour intervals after O–H showed a progressive secretory response over 16 hours, similar to that previously shown to occur within a period of about 4 hours on the last day of pregnancy. Suppression of serum prolactin by ergocriptine administration and adrenalectomy 24 hours before O–H each prevented the secretory response. However, some differences in the effects of deprivation of the two types of hormones were evident. After cortisol acetate administration at O–H, mammary tissue responded rapidly despite adrenalectomy 24 hours earlier. It is concluded that simple withdrawal of progesterone is not sufficient to initiate lactation in the pregnant rat; glucocorticoids must be present continuously during progesterone withdrawal, and prolactin elevation and other factors present at parturition may be required as well.