Showing papers on "Prolactin published in 1991"

Neuroendocrine rhythms and sleep in aging men

Abstract: To delineate the physiological effects of aging on basal levels and temporal patterns of neuroendocrine secretions, the 24-h profiles of cortisol, thyroid-stimulating hormone (TSH), melatonin, prolactin, and growth hormone (GH) levels were simultaneously obtained at frequent intervals in eight healthy, active elderly men, age 67-84 yr and in eight young male adults, age 20-27 yr. The study was preceded by an extended period of habituation to laboratory conditions, and sleep was polygraphically recorded. Mean cortisol levels in the elderly were normal, but the amplitude of the circadian rhythm was reduced. Circulating levels of daytime and nighttime levels of both TSH and GH were greatly diminished in old age. In contrast, prolactin and melatonin concentrations were decreased during the nighttime only. The circadian rises of cortisol, TSH, and melatonin occurred 1-1.5 h earlier in elderly subjects, and the distribution of rapid-eye-movement stages during sleep was similarly advanced, suggesting that circadian timekeeping is modified during normal senescence. Despite perturbations of sleep, sleep-related release of GH and prolactin occurred in all elderly men. Age-related decreases in hormonal levels were associated with a decrease in the amplitude, but not the frequency, of secretory pulses. These findings demonstrate that the normal process of aging involves alterations in the central mechanisms controlling the temporal organization of endocrine release in addition to a reduction of secretory outputs.

Prolactin and growth hormone in the regulation of the immune system.

Abstract: Evidence implicating prolactin (PRL) and growth hormone (GH) in the regulation of the immune system has been reviewed. Hypophysectomized animals have deficiencies in both cell-mediated and humoral immunological functions and either PRL or GH corrects these deficiencies. Animals administered bromocryptine, a drug that specifically blocks PRL release, have impaired immune responses similar to hypophysectomized animals, and again both PRL and GH correct these deficiencies. Genetically dwarf animals, which lack both PRL and GH, are also immunocompromised, and once again PRL and GH can correct the deficiencies. In dwarf animals, however, fewer studies have examined PRL actions. In growth-deficient children, immune function is not dramatically altered and basal secretion of GH has been reported. Very few clinical studies have examined whether PRL secretion is also deficient, and this may explain why a clear loss in immune function is not evident in growth-deficient children. In a number of species, including man, both PRL and GH stimulate thymic function and increase the secretion of thymulin, a thymic hormone. No studies, however, have reported on the effects of PRL and GH on other thymic hormones. A number of studies have reported in vitro effects of PRL and GH on cells involved with immunity, and the presence of high-affinity PRL and GH receptors have been observed on a number of these cells. The action of GH on the proliferative response of cells involved with immunity in vitro appears to be mediated by the production of insulin-like growth factor I. The effect of PRL on insulin-like growth factor I production by these cells has not been examined. One of the most consistent findings from in vitro studies is that prolactin antisera blocked a number of immune reactions. This led to the discovery that cells involved with immunity appear capable of producing PRL and GH, but the physiological significance of these observations have not been explored. There is a great need to identify the cell types responding to PRL and GH and this should be a goal of future investigations. There is also a need for investigators to be aware that both PRL and GH are involved in the regulation of the immune system and to design experiments to elucidate where each functions in the maturation cascade of cells involved with immunity. From the evidence available, it is apparent that PRL and GH have an important function in the immune system and future investigations should be directed toward elucidating their site(s) of action.

Longitudinal assessment of changes in reproductive hormones during normal pregnancy.

Abstract: The concentrations of hormones measured in serum from maternal blood change dramatically during pregnancy. While the relative contributions of sex steroids shift from maternal ovaries and adrenals to the fetoplacental unit, other maternal tissues such as pituitary and liver respond to increasing concentrations of estrogen and secrete increasing amounts of prolactin and sex-hormone-binding globulin. To determine longitudinal changes in circulating maternal hormones, we collected blood from 60 women on three occasions during their pregnancies. We observed a 1.7-fold increase in testosterone concentration in serum; concentrations of sex-hormone-binding globulin in serum rose 5.6-fold. The major increase (6.8-fold) in estradiol in serum occurred within the first 16 weeks, followed by a further 4.8-fold increase by term. Mean concentrations of progesterone, 17-hydroxyprogesterone, and androstenedione in serum increased 11.9-, 3-, and 1.3-fold, respectively, whereas concentrations of dehydroepiandrosterone sulfate (DHEAS) fell by 50%. Mean serum prolactin concentrations increased 3.8-fold during the first trimester and by a similar amount during the final 24 weeks of pregnancy. We used these data, obtained from a cohort of women with uncomplicated pregnancies, to construct reference intervals for hormones in maternal serum.

Prolactin influences autoimmune disease activity in the female B/W mouse.

Abstract: Prolactin, an anterior pituitary hormone, stimulates humoral and cell-mediated immunity. This study investigated effects of manipulating prolactin levels in the autoimmune B/W mouse model of SLE. A group of B/W females was treated with daily injections of the prolactin-suppressing drug, bromocriptine. These mice had delayed elevation of anti-DNA antibodies and serum IgG; longevity was increased compared to control mice. Functioning syngeneic pituitary glands, implanted under the renal capsule, produced prolonged hyperprolactinemia in a separate group of female B/W mice. Hyperprolactinemic animals were characterized by premature albuminuria, elevated circulating gp70IC and IgG, and accelerated mortality. Analyses of thymic and splenic lymphocytes revealed no differences in lymphocyte subpopulations in mice with altered prolactin levels. This is the first report to substantiate an immunomodulatory role for prolactin in B/W mice. Further evaluation of this model may identify specific means of intervening clinically with immunosuppressive hormone-modulating therapy in SLE.

The mammary gland.

Abstract: In vivo studies have shown that the growth of the mammary gland is regulated by a complex synergistic interaction of protein, steroid and thyroid hormones, but it has proved difficult to fully reproduce these effects in vitro. It is becoming apparent that the hormones classically recognized as involved in mammary growth (oestrogen, progesterone, prolactin, GH, adrenal corticoids, triiodothyronine) bring about effects on epithelial cell proliferation at least in part through growth factors produced at distant sites (such as the liver) and also locally by mammary tissue, both parenchyma and stroma. Growth factor receptors can be demonstrated in mammary tissue. Receptor occupancy generates intracellular signals which enable cells to progress through the cell cycle, leading in ways still not understood to DNA synthesis and cell division. Within the mammary gland there probably exists a balance of stimulatory factors (such as IGFs and EGF/TGF-alpha) and inhibitory factors (such as TGF-beta). Interactions between epithelial and stromal cells, involving growth factors and the extracellular matrix, bring about pattern formation. Growth factors may also play some part in mammary differentiation and function, although the evidence here is less clear. Growth factors are also implemented in the failure of growth regulation which neoplastic transformation represents. Breast cancer cells can synthesize and secrete a variety of growth factors which may stimulate tumour growth through local autocrine/paracrine mechanisms. The oestrogen dependence of some breast cancers may involve oestrogen regulation of and interaction with growth factors, progression to hormone independence involving loss of this control. It is significant that the proteins which protooncogenes encode include growth factors and growth factor receptors. Much remains to be learnt about the nature and control of growth factors produced by and acting on the mammary gland. In breast cancer, this research offers the possibility of new methods of diagnosis and treatment.

Function of the homeodomain protein GHF1 in pituitary cell proliferation

Abstract: Mutations that cause pituitary dwarfism in the mouse reside in the gene encoding the transcription factor growth hormone factor 1 (GHF1 or pit1). These dwarf mice (dw and dwJ) are deficient in growth hormone (GH) and prolactin (PRL) synthesis and exhibit pituitary hypoplasia, suggesting a stem cell defect. With antisense oligonucleotide technology, a cell culture model of this genetic defect was developed. Specific inhibition of GHF1 synthesis by complementary oligonucleotides led to a marked decrease in GH and PRL expression and to a marked decrease in proliferation of somatotrophic cell lines. These results provide direct evidence that the homeodomain protein GHF1 is required not only for the establishment and maintenance of the differentiated phenotype but for cell proliferation as well.

Comparison of long and short forms of the prolactin receptor on prolactin-induced milk protein gene transcription

Abstract: The biological activities of long and short forms of the prolactin receptor have been compared. These two receptors expressed in mammalian cells were shown to bind prolactin with equal high affinity. The ability of these different forms to transduce the hormonal message was estimated by their capacity to stimulate transcription by using the promoter of a milk protein gene fused to the chloramphenicol acetyltransferase (CAT) coding sequence. Experiments were performed in serum-free conditions to avoid the effect of lactogenic factors present in serum. An approximately 17-fold induction of CAT activity was obtained in the presence of prolactin when the long form of the prolactin receptor was expressed, whereas no induction was observed when the short form was expressed. The present results clearly establish that only the long form of the prolactin receptor is involved in milk protein gene transcription.

Galanin: a hypothalamic-hypophysiotropic hormone modulating reproductive functions.

Abstract: Galanin (GAL) is widely distributed in the peripheral and the central nervous systems. In the brain, the highest GAL concentrations are observed within the hypothalamus and, particularly, in nerve terminals of the median eminence. This location, as well as GAL actions on prolactin, growth hormone, luteinizing hormone (LH), and LH-releasing hormone (LHRH) secretion, suggest the possibility that GAL may act as a putative hypothalamic-hypophysiotropic hormone. To establish this, GAL and LHRH levels were measured in hypophyseal portal plasma samples using specific radioimmunoassays. Rat galanin (rGAL) concentrations in portal blood were approximately 7-fold higher than those observed in peripheral plasma in male and female (estrus, diestrus) rats, indicating an active secretory process of rGAL into the portal vasculature. Frequent (10 min) sampling revealed that rGAL and LHRH were secreted into the portal circulation in a pulsatile manner with a pulse frequency of one pulse per hour. Interestingly, both hormone series depicted a high degree of coincident episodes. In fact, the probability of random coincidence, calculated by the algorithm HYPERGEO, was less than 0.01. Moreover, the retrograde tracer Fluoro-Gold, when given systemically, was taken up by GAL neurons in the hypothalamus, including a subset of neurons expressing rGAL and LHRH, strengthening the notion of the existence of a GAL neuronal system connected to the hypophyseal portal circulation. These observations reinforce the concept that GAL regulates pituitary hormone secretion. To analyze this in further detail, the effects of rGAL on LH secretion were evaluated under basal and stimulated conditions. rGAL induced a small but dose-dependent increase in LH secretion from cultured, dispersed pituitary cells. Interestingly, rGAL enhanced the ability of LHRH to stimulate LH release. The tight link between GAL and LHRH neuronal systems is strengthened by the observation that during the estrous cycle of the rat, rGAL and LHRH contents in the median eminence show an identical profile (r = 1.00). These data indicate that GAL should be considered as a hypothalamic-hypophysiotropic hormone and as an important neuromodulator of LHRH secretion and action. The colocalization and cosecretion of GAL and LHRH and the cooperative action at the level of the anterior pituitary afford important evidence for the functional significance of coexistence of neurotransmitters in neurons of the central nervous system.

The effect of interleukin-6 on pituitary hormone release in vivo and in vitro.

Abstract: Intravenously administered interleukin-6 (IL-6), a monokine produced by activated monocytes and folliculostellate cells of the pituitary gland, has been recently reported to elevate plasma ACTH level and to stimulate PRL, GH and LH release from cultured pituitary cells. To determine the site(s) of action of IL-6 in the control of pituitary hormone release, we injected human recombinant IL-6 into the third brain ventricle (3V) of freely moving, conscious male rats. Both 0.05 and 0.25 pmol doses of IL-6 were ineffective to change plasma ACTH in comparison to the values in controls. The maximal IL-6 dose tested of 1.25 pmol increased plasma ACTH within 15 min and the response lasted over 180 min. Plasma TSH levels were significantly lowered by a dose of 0.25 pmol IL-6, but neither the lower dose of 0.05 pmol nor the higher dose of 1.25 pmol altered plasma TSH levels throughout the 180 min of the experiment. Plasma PRL and GH levels were not changed by any IL-6 dose tested. In ovariectomized rats plasma LH and FSH levels were also unaltered by IL-6. The effects of IL-6 on plasma ACTH and TSH were only partially paralleled by increased rectal temperature which suggests that hypothalamic temperature regulating centers were independent of these actions. To evaluate a possible direct effect on the pituitary, IL-6 was incubated in vitro with hemipituitaries under an atmosphere of 95% O2/5% CO2. After 1 h of incubation IL-6 failed to cause any change in the secretion of pituitary hormones throughout a concentration range of 10(-15)-10(-9) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal Control of the Surfactant System in Fetal Lung

Abstract: The synthesis of surfactant glycerophospholipids and proteins is under multifactorial control and is regulated by a number of hormones and factors, including glucocorticoids, prolactin, insulin, growth factors, estrogens, androgens, thyroid hormones and catecholamines acting through beta-adrenergic receptors, and cAMP. In studies with human fetal lung in organ culture, glucocorticoids, in combination with prolactin and/or insulin, were found to increase the rate of lamellar body PC synthesis and increase the molar ratio of surfactant PG to PI to a value similar to that of surfactant secreted by the human fetal lung at term. Recognition of the potential importance of the surfactant proteins SP-A, SP-B, and SP-C in the reduction of alveolar surface tension and in endocytosis and reutilization of secreted surfactant by type II cells has stimulated rapid advancement of knowledge concerning the structures of these proteins and their genes, as well as their developmental and hormonal regulation in fetal lung tissue. The genes encoding the surfactant proteins are expressed in a lung-specific manner and appear to be regulated independently during fetal development. SP-A gene expression is initiated in fetal lung tissue after 75-85% of gestation is completed in all mammalian species studied to date. In the human fetus, however, expression of the SP-B and SP-C genes is detectable prior to mid-gestation. In situ hybridization studies of human lung tissue indicate that the SP-A gene is expressed only in type II cells, whereas SP-B gene expression is detectable in bronchioalveolar epithelial cells as well. Cyclic AMP and glucocorticoids have pronounced effects on the regulation of SP-A gene expression in human and rabbit fetal lung in culture. In human fetal lung in vitro, the effects of cAMP are primarily at the level of gene transcription. By contrast, glucocorticoids have stimulatory effects on SP-A gene transcription and inhibitory effects on SP-A mRNA stability. Furthermore, the combined effects of cAMP and glucocorticoids on SP-A gene transcription in human fetal lung in vitro are synergistic. Glucocorticoids appear to be of primary importance in the regulation of the genes encoding SP-B and SP-C. Elucidation of the molecular mechanisms involved in the regulation of expression of the surfactant protein genes in developing fetal lung will be of fundamental importance to our understanding of the developmental and tissue-specific regulation of eukaryotic gene expression.

Circadian and sleep-related endocrine rhythms in schizophrenia.

Abstract: Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.

Anterior pituitary hormone control by interleukin 2.

Abstract: Several monokines, proteins secreted by monocytes and macrophages, alter release of hormones from the anterior pituitary. We report here the ability of femtomolar concentrations of interleukin 2 (IL-2), a lymphokine released from T lymphocytes, to alter directly pituitary hormone release. The effects of concentrations of IL-2 ranging from 10(-17) to 10(-9) M on anterior pituitary hormone release were evaluated in vitro. Hemipituitaries were preincubated in 1 ml of Krebs-Ringer bicarbonate buffer (KRB) followed by incubation for 1 or 2 hr with KRB or KRB containing different concentrations of IL-2. This was followed by incubation for 30 min in 56 mM potassium medium to study the effect of pretreatment with IL-2 on subsequent depolarization-induced hormone release. Prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), corticotropin (ACTH), growth hormone (GH), and thyrotropic hormone (TSH) released into the incubation medium were measured by radioimmunoassay. IL-2 stimulated the basal release of PRL at 1 or 2 hr but suppressed the subsequent depolarization-induced PRL release, perhaps because the readily releasable pool of PRL was exhausted. The minimal effective dose (MED) was 10(-15) M. Conversely, IL-2 significantly suppressed the basal release of LH and FSH at 1 or 2 hr, with a MED of 10(-16) M, thus demonstrating a reciprocal action of the cytokine on lactotrophs and gonadotrophs. The subsequent depolarization-induced release of LH and FSH was suppressed, indicative of a persistent inhibitory action of IL-2. IL-2 stimulated ACTH and TSH release at 1 hr and the MEDs were 10(-12) and 10(-15) M, respectively. Conversely, IL-2 significantly lowered the basal release of GH at 1 hr, with a MED of 10(-15) M. The release of GH was not altered at 2 hr. The high potassium-induced release of ACTH, TSH, and GH was not affected. The results demonstrate that IL-2 at picomolar concentrations affects the release of anterior pituitary hormones. This cytokine may serve as an important messenger from lymphocytes exerting a direct paracrine action on the pituitary by its release from lymphocytes in the gland or concentrations in the blood that reach the gland may be sufficient to activate it.

Isolation and characterization of somatolactin, a new protein related to growth hormone and prolactin from Atlantic cod (Gadus morhua) pituitary glands.

Abstract: The characterization of cod somatolactin (SL), a new pituitary protein belonging to the growth hormone/prolactin family, is described. Cod SL has a molecular weight of 26 kDa and consists of 209 amino acids, of which eight are Cys. The protein has three disulfide bonds between residues Cys5-Cys15, Cys65-Cys181, and Cys198-Cys206. The Cys residues at positions 42 and 180 are not involved in disulfide bonding. The positions of these disulfide bonds are homologous to those found in prolactin and growth hormone. Cod SL has two possible N-glycosylation sites, but only one appears to have carbohydrate units attached. Chemical analysis showed the following sugars to be present: galactose, mannose, N-acetylneuramic acid, and glucosamine. A smaller variant (23 kDa) of SL has been isolated, which is believed to be deglycosylated. Sequence comparison revealed cod SL to be similarly related to both GH and PRL, but slightly higher identity was observed to the tetrapod hormones (27-33%) than to the teleost hormones (21-27%).

d-fenfluramine/prolactin response throughout the menstrual cycle: evidence for an oestrogen-induced alteration.

Abstract: The prolactin (PRL) response to fenfluramine (FEN), a serotonin (5-HT) releasing agent, is used as an index of 5-HT sensitivity in studying disorders associated with central 5-HT abnormality. Plasma oestrogen levels are known to augment PRL responses to a variety of stimuli. In order to examine the effect that ovarian steroids have on this response nine, healthy women were tested twice at three time points in the menstrual cycle: early follicular, mid-cycle and late luteal phase with either d-FEN, a more specific 5-HT agent than the racemic mixture, or placebo. Responses to d-FEN were maximal at mid-cycle, lowest during the early follicular phase, with responses premenstrually being intermediate between the two. Responses to placebo did not vary. Plasma oestradiol levels fluctuated in parallel with neuroendocrine responses to d-FEN. The possible mechanisms are discussed, including an effect that oestradiol may exert at central serotonin sites.

Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue.

Abstract: Hypophysectomy of Fischer 344 rats of both sexes led to a rapid involution of the thymus and spleen which was associated with a profound decrease in spontaneous DNA synthesis in these organs. The proportion of B lymphocytes in the spleen, of T cells and their subsets (CD4+/CD8+) in spleen and thymus, and the histological structure of the involuted organs remained normal. Treatment of hypophysectomized animals with growth hormone (GH) or prolactin (PRL) stimulated the expression of the c-myc proto-oncogene and DNA synthesis and reversed the involution in these organs. Replacement doses of adrenocorticotrophic hormone, follicle-stimulating hormone, luteinizing hormone, or thyroid-stimulating hormone had no influence on thymus or spleen size and DNA synthesis. A rapid expression of c-myc was also observed in thymuses and spleens of intact rats after the injection of GH or PRL. In vitro physiological concentrations (2.5 ng/ml) of either ovine or rat PRL or GH stimulated the incorporation of [3H]thymidine by thymus and spleen cells. These results indicate that GH and PRL regulate lymphocyte growth. This regulatory role is likely to serve as the principal mechanism of immunoregulation by these hormones.

Hypophysectomized rats depend on residual prolactin for survival.

Abstract: Hypophysectomized (Hypox) female Fischer 344 rats had 10-20% lactogenic activity in their serum when compared to controls by the Nb2 lymphoma proliferation assay. If such animals were treated daily with a rabbit antirat PRL serum, their serum lactogenic activity diminished further; severe anemia and immunological anergy developed; and death occurred within 8 weeks. In contrast, untreated Hypox animals increased gradually their serum lactogenic activity, starting on the 7th week after pituitary removal, which rose up to 50% of control levels by week 9. Hypox animals showed normochromic normocytic anemia, a grossly reduced immunocompetence, decreased body, thymus, spleen, adrenal, and ovary weights, and decreased DNA and RNA synthesis in the thymus, spleen, and bone marrow. However, the condition of Hypox animals did not deteriorate further over the 9-week experimental period. All the hematological deficiencies and decrease in organ weights observed in Hypox rats were normalized after grafting with syngeneic pituitaries (SPG). These effects of SPG could be inhibited by additional treatment with antirat PRL serum. Treatment of Hypox animals with ovine PRL had a restoring effect similar to SPG, which was not inhibited by additional antirat PRL serum treatment. Rat and ovine PRL and GH and human placental lactogen all stimulated the incorporation of 3H-thymidine by rat bone marrow cells in vitro. These results indicate that PRL has a multiple trophic effect and is capable of maintaining vital bodily functions for long periods of time.

Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus.

Abstract: We performed prospective hormonal studies in 9 patients (5 active and 4 inactive) with systemic lupus erythematosus (SLE) during pregnancy (Weeks 10 to 37) Nine healthy pregnant women and 5 patients with rheumatoid arthritis (RA) were used for comparison Serum prolactin (PRL), testosterone and estradiol (E2) levels were determined by RIA The patients with SLE showed higher serum PRL levels, the difference being statistically significant at Week 20, and reaching the highest levels at Weeks 30 to 40 (p = 005 when compared to healthy pregnant women) The 5 patients with active SLE had the highest serum PRL levels; one of these had fetal wastage In active SLE the serum testosterone and E2 levels were decreased significantly from Weeks 10 to 30 compared with controls (p = 0001) In patients with RA serum PRL levels, although higher than in controls, did not differ significantly, nor did the lower testosterone and E2 levels We conclude that gonadal hormones and PRL changes observed in SLE are present also during pregnancy and may be related to fetal wastage and reactivation of disease

Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo.

Abstract: TheN-methyl-N-nitrosurea (NMU) model of hormone-responsive rat mammary carcinogenesis was used to address the hypothesis that melatonin (Mel), the principle hormone of the pineal gland, inhibits tumorigenesis by acting as an anti-promoting rather than an anti-initiating agent. Daily late-afternoon injections of Mel (500 μg/day), restricted to the initiation phase of NMU mammary tumorigenesis, were ineffective in altering tumor growth over a 20-week period. When Mel treatment was delayed for 4 weeks after NMU and then continued through the remainder of the promotion phase, only tumor number was significantly lower than in controls. However, when Mel injections encompassed the entire promotion phase, both tumor incidence and number were significantly lower than in the controls. Although elimination of the endogenous Mel signal via pinealectomy promoted tumor growth, the effect was not statistically significant. Serum levels of estradiol and tumor estrogen receptor content were unaltered by either Mel or pinealectomy. While Mel treatment failed to affect circulating prolactin levels, pinealectomy caused a two-fold increase in serum prolactin. The estradiol-stimulated recrudescence of tumors following ovariectomy was completely blocked by either 20, 100 or 500 μg Mel/day or tamoxifen (20 μg/day). Thus, Mel appears to be an antipromoting hormone that may antagonize the tumor-promoting actions of estradiol in this model of mammary tumorigenesis.

Endocrine and reproductive dysfunction following fractionated total body irradiation in adults.

Abstract: The endocrine and reproductive sequelae of total body irradiation for haematological malignancy have been studied in 21 patients (11 male) who were treated with 10 Gy in five fractions or 12 or 13.2 Gy in six fractions over 3 days. Eighteen patients (eight male) aged 16-49 years underwent dynamic tests of the hypothalamic-pituitary axis with insulin hypoglycaemia, thyrotrophin releasing hormone (TRH) and gonadotrophin releasing hormone stimulation and basal measurement of prolactin, sex steroids and thyroid hormones. Growth hormone responses (mean peak 64 +/- 36 mU/l, range 21-146 mU/l) and cortisol responses (mean peak 831 +/- 122 nmol/l, range 626-1105 nmol/l) were all within the normal range. Two patients had minimally elevated serum prolactin levels (445 and 588 mU/l, normal less than 350 mU/l). Serum thyroxine levels (57-133 nmol/l) were normal but six patients had elevated basal thyrotrophin (TSH) levels (6-9 mU/l) and seven had an exaggerated TSH response to thyrotrophin releasing hormone, indicating radiation-induced damage to the thyroid. Amenorrhea developed within 3 months of irradiation in all females and oestradiol levels were low, at 37-108 pmol/l (mean 58 +/- 22 pmol/l). Severe oligospermia or azoospermia was noted in men tested 5-70 months after irradiation and testicular volume was below the normal adult range in five of seven men assessed. Serum testosterone levels (12.4-35 nmol/l) were normal. Gonadotrophin-releasing hormone-stimulated gonadotrophin levels were elevated in all patients. However, two men have fathered two children each; one has refused semen analysis, but the other has a sperm count of 7 x 10(6)/ml (60 per cent motile, 20 per cent abnormal forms) 70 months after irradiation. When given by the above fractionated regimens, the endocrine sequelae of total body irradiation are limited to gonadal failure requiring oestrogen replacement in women and severe impairment of fertility in men. Subclinical thyroid dysfunction has been seen in 39 per cent of patients there is no evidence of direct damage to the hypothalamic pituitary axis.

Localization of interleukin-1 receptor antagonist mRNA in rat brain.

Abstract: Interleukin-1 (IL-1) is an inflammatory peptide hormone, with potent neuroendocrine effects. IL-1 stimulates the central nervous system production of corticotropin-releasing hormone (CRH), growth hormone (GH), thyroid-stimulating hormone (TSH), and somatostatin, and inhibits the secretion of prolactin and luteinizing hormone (LH). Interleukin-1 receptor antagonist (IL-lra) is a novel cytokine, recently purified, characterized, and cloned. IL-lra is a pure endogenous antagonist of IL-1: IL-1 function is modulated not only by local levels of IL-1, but also by the levels of IL-lra. We have localized by in situ hybridization histochemistry IL-lra mRNA in rat brain, in areas of importance to neuroendocrine function, such as the para ventricular nucleus (PVN) of the hypothalamus, hippocampus, as well as cerebellum. These findings indicate that IL-lra is produced in brain in areas of relevance to the regulation of neuroendocrine function and suggest that IL-lra may modulate the neuroendocrine effects of IL-1.

The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine.

Abstract: Several lines of evidence suggest that the anterior pituitary hormone prolactin has a stimulatory role on immune function and that pharmacological suppression of prolactin secretion with the dopamine-agonist bromocriptine suppresses both humoral and cellular immunity. Here, we describe the effects of prolactin-suppression on the course of experimental allergic encephalomyelitis in female Lewis rats. Initiation of continuous bromocriptine treatment before immunization reduced both the severity and incidence of clinical signs of acute experimental allergic encephalomyelitis. Experimental allergic encephalomyelitis-immunized rats experienced a threefold rise in basal prolactin levels on day 4 after immunization and maintained elevated prolactin levels on day 10, before the onset of neurological signs of experimental allergic encephalomyelitis. Bromocriptine treatment reduced prolactin levels to those of sham-immunized rats. In vivo bromocriptine pretreatment inhibited splenic lymphocyte proliferative responses in vitro to the immunizing antigen and to concanavalin A. Moreover, bromocriptine therapy was protective when initiated 1 week after the initial immunization and was also effective in suppression of late disease. These results indicate that (1) prolactin levels are elevated after immunization and before the onset of experimental allergic encephalomyelitis, (2) bromocriptine inhibits both prolactin secretion and the severity of acute experimental allergic encephalomyelitis, and (3) inhibition is also present when treatment is begun after sensitization, suggesting an effect of prolactin on the effector limb of the immune response during experimental allergic encephalomyelitis.

Cortisol rapidly reduces prolactin release and cAMP and 45Ca2+ accumulation in the cichlid fish pituitary in vitro

Abstract: During in vitro incubation, prolactin release is inhibited in a dose-related manner by cortisol. This action is mimicked by the synthetic glucocorticoid agonist dexamethasone but not by other steroids tested. Perifusion studies indicate that the inhibition of [3H]prolactin release by cortisol occurs within 20 min. Cortisol (50 nM) also inhibits cAMP accumulation and reduces 45Ca2+ accumulation in the tilapia rostral pars distalis within 15 min. Cortisol's action on prolactin release is blocked in the presence of either the Ca2+ ionophore A23187 or a combination of dibutyryl cAMP and 3-isobutyl-1-methylxanthine, which increase intracellular Ca2+ and cAMP, respectively. Taken together, these findings suggest that cortisol may play a physiologically relevant role in the rapid modulation of prolactin secretion in vivo. Our studies also suggest that the inhibition of prolactin release by cortisol is a specific glucocorticoid action that may be mediated, in part, through cortisol's ability to inhibit intracellular cAMP and Ca2+ metabolism.

Free alpha molecules from pregnancy stimulate secretion of prolactin from human decidual cells: a novel function for free alpha in pregnancy.

Abstract: Free alpha molecules isolated from pregnancy, as well as highly purified reference preparations of hCG alpha subunit (CR119 or CR123), stimulated the release of prolactin from human decidual cells in culture. The amount of prolactin secreted during a 24 h incubation was concentration-dependent over a range of increasing doses of alpha from 0.2 to 20 ng/ml with an ED50 of about 1.6 ng/ml. These concentrations are well within the physiologic maternal serum free alpha levels which average 350 ng/ml during the third trimester of pregnancy. Incubation of decidual cells with a reference preparation of intact hCG (CR123) at a concentration of 260 ng/ml resulted in stimulated secretion of prolactin, however, the observed stimulation could be attributed to contamination of the preparation with free alpha or dissociated hCG alpha subunit. Purified hCG beta subunit had no stimulatory activity on the decidual cell culture. The effect of alpha subunit on the stimulated release of prolactin was not due to a generalized stimulation of protein synthesis and secretion since no increase was observed in the release of 35S-labeled proteins compared to controls. In addition, the observed increase in prolactin secretion was not due to a toxic effect of the alpha subunit since there was no visible effect on cell viability, and the cellular enzymes, LDH and alkaline phosphatase, were not detected in the culture medium. Addition of exogenous hCG alpha subunit to primary cultures of human trophoblast cultures did not result in stimulated release of human placental lactogen. We conclude that free alpha molecules of pregnancy stimulate release of prolactin from human decidual cells in culture. These results suggest a novel role for free alpha in the paracrine regulation of decidual prolactin secretion.

The relationship between pituitary-gonadal function and sexual behavior in healthy aging men.

Abstract: Few studies have assessed the role of pituitary and gonadal hormones on age-related changes in sexual behavior in healthy men We conducted a retrospective and prospective evaluation of sexual function and behavior in 77 healthy married men aged 45 to 74 years The subjects were studied in the sleep laboratory for four nights with the last night devoted to sequential blood sampling every 20 minutes Significant age-related decreases in sexual desire, sexual arousal and activity, and increases in erectile problems were noted Aging was negatively correlated with bioavailable testosterone (bT), was positively correlated with luteinizing hormone (LH), and was not related to total testosterone, estradiol, and prolactin Bioavailable testosterone, and the ratio of bT over LH showed a close association with several sexual behavior dimensions while total testosterone, estradiol, and prolactin demonstrated few or no behavioral relationships The age-related effect of bT was, however, a more important determinant of the reported behavioral differences than were the effect of bT independent of age There was no evidence that changes in circulating hormones contribute to erectile disorders in healthy aging men

Effect of dopamine agonist medication on prolactin producing pituitary adenomas. A morphological study including immunocytochemistry, electron microscopy and in situ hybridization.

Abstract: Conventional light microscopy, immunocyto-chemistry, electron microscopy and in situ hybridization were used to evaluate the effect of dopamine agonists (bromocriptine-LAR and bromocriptine) on the morphology of surgically removed prolactin (PRL)-producing pituitary adenomas. Dopamine agonist therapy resulted in decrease of serum PRL, clinical improvement and tumour shrinkage. Using light and electron microscopy cellular atrophy, interstitial and perivascular fibrosis were noted; in several tumours connective tissue accumulation was pronounced. The cellular response was not uniform. In some adenomas populations of large cells and small cells were distinguished. The large cells contained immunoreactive PRL and expressed the PRL gene indicating resistance to dopamine agonists. It appears that these cells retained the potential to secrete PRL and proliferate despite exposure to dopamine agonists. In the small cells, PRL immunoreactivity and PRL gene expression decreased providing evidence that both PRL release and synthesis were blocked. Small cells can persist in tumours after discontinuation of dopamine agonist medication suggesting these small cells are irreversibly suppressed and are not capable of regaining their endocrine function and proliferative capability. The formation of irreversibly suppressed PRL cells may explain why some PRL-producing adenomas do not recur after withdrawal of dopamine agonists.

A pilot study of the social correlates of levels of urinary cortisol, prolactin, and testosterone in wild long-tailed macaques ( Macaca fascicularis )

Abstract: Urine samples were collected from individuals in a wild population of Sumatran long-tailed macaques (Macaca fascicularis), and the levels of cortisol, immunoreactive prolactin, and (for males) testosterone were determined. The amount of foraging during the 2 hr preceding urine collection were found to affect the levels of urinary cortisol, but not those of the other hormones. Immigration into a new group and having one's infant kidnapped led to increased levels of cortisol. Levels of cortisol and testosterone were correlated both within and between individuals, whereas prolactin varied independently. The effects of age, reproductive status, and social rank on the mean values of individuals were also examined. Lactating females had higher prolactin levels than non-lactating ones; reproductive state interacted with the age effect on prolactin and possibly cortisol. No effects of social status were found in spite of a small, but consistent effect of rank on birth rate in this population. Among males, age and rank are strongly linked. The low ranking old males had increased levels of cortisol, even though the younger high-ranking males were involved in the fiercest conflicts.