Short-term Hyperprolactinemia Research Articles

Short-Term Hyperprolactinemia Reduces the Expression of Purinergic P2X7 Receptors during Allergic Inflammatory Response of the Lungs

Purpose: We have previously shown that domperidone-induced short-term hyperprolactinemia reduces the lung’s allergic inflammatory response in an ovalbumin antigenic challenge model. Since purinergic receptor P2X7R activity leads to proinflammatory cytokine release and is possibly related to the pathogenesis of allergic respiratory conditions, the present study was designed to investigate a possible involvement of purinergic and prolactin receptors in this phenomenon. Methods: To induce hyperprolactinemia, domperidone was injected intraperitoneally in rats at a dose of 5.1 mg × kg^–1 per day for 5 days. P2X7 expression was evaluated by lung immunohistochemistry while prolactin receptor expression in bronchoalveolar lavage leukocytes was analyzed through flow cytometry. Results: Previous reports demonstrated that rats subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, especially granulocytes. Here, it is revealed that hyperprolactinemia promotes an increased expression of prolactin receptors in granulocytes. Also, increased expression of purinergic P2X7R observed in allergic animals was significantly reduced by hyperprolactinemia. Conclusions: Both purinergic and prolactin receptor expression changes occur during the anti-asthmatic effect of hyperprolactinemia.

Short-term hyperprolactinemia decreases allergic inflammatory response of the lungs.

Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1mg·kg(-1) per day, i.p., for 5days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in lung explants supernatants were measured and interferon gamma (IFN-γ) in bronchiolar lavage cells suspensions (BAL) was measured. The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-α and IFN-γ expression. Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients.

Short-term hyperprolactinemia decreases allergic inflammatory response of the lungs

The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung’s allergic inflammatory response.To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1 mg kg -1 per day, i.p., for 5 days. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated microscopically. Enzyme-linked immunosorbent assays were performed to measure serum corticosterone and prolactin levels and interleukin-4 (IL-4), IL-6, IL-10, and TNF- alpha expression in lung explants.The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, and TNF-alpha expression. Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients. Authors wish to gratefully acknowledge the following grants: 09/51886-3 and 13/01610-7 from Sao Paulo Research Foundation (FAPESP) and 5984-11-4 from the Coordination for the Improvement of Higher Education (CAPES).

Acute and Chronic Stress and the Inflammatory Response in Hyperprolactinemic Rats

Background/Aim: Prolactin (PRL), a hormone produced by the pituitary gland, has multiple physiological functions, including immunoregulation. PRL can also be secreted in response to stressful stimuli. During stress, PRL has been suggested to oppose the immunosuppressive effects of inflammatory mediators. Therefore, the aim of the present study was to analyze the effects of short- and long-term hyperprolactinemia on the inflammatory response in rats subjected to acute or chronic cold stress. Methods: Inflammatory edema was induced by carrageenan in male rats, and hyperprolactinemia was induced by injections of the dopamine receptor antagonist domperidone. The volume of inflammatory edema was measured by plethysmography after carrageenan injection. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. Results and Conclusion: Five days of domperidone-induced hyperprolactinemia increased the volume of inflammatory edema. No differences in serum corticosterone levels were observed between groups. No significant differences were found among 30 days domperidone-induced hyperprolactinemic animals subjected to acute stress and the inflammatory response observed in chronic hyperprolactinemic animals subjected to chronic stress. The results suggest that short-term hyperprolactinemia has pro-inflammatory effects. Because such an effect was not observed in long-term hyperprolactinemic animals, PRL-induced tolerance seems likely. We suggest that short-term hyperprolactinemia may act as a protective factor in rats subjected to acute stress. These data suggest that hyperprolactinemia and stress interact differentially according to the time period.

Effects of Short‐term Hyper‐ and Hypoprolactinaemia on Hormones of the Pituitary, Gonad and ‐Thyroid Axis and on Semen Quality in Male Beagles

Effects of a short-term hyper- and hypoprolactinaemia on serum concentrations of LH, testosterone and semen quality in six male Beagles were investigated. Blood samples were collected at 3-day intervals for 12 weeks. The time span was divided into five 3-week periods: pre-treatment, metoclopramide (MCP) treatment (0.2 mg/kg orally three times daily), cabergoline (CAB) treatment (5 microg/kg orally once daily), post-treatment 1 and post-treatment 2. In the latter, only semen characteristics were evaluated. Semen parameters were analyzed once per week during the whole 15-week investigation time. At the end of each period, the effects of a single intravenous injection of thyrotropin-releasing hormone (TRH; 10 microg/kg) on the secretion of prolactin (PRL), LH, testosterone, thyroid-stimulating hormone and thyroxine (T4) were investigated. Pre-treatment serum PRL concentration increased under MCP (p < 0.05), followed by a decrease under CAB administration (p < 0.05). Luteinizing hormone and testosterone concentrations were not affected. Except for straight-line sperm velocity, semen quality did not differ between collection periods. A single iv TRH injection induced a significant PRL increase at 20 min in all experimental periods except during CAB treatment. Luteinizing hormone and testosterone did not show clear TRH-related changes. Basic T4 levels were significantly reduced after CAB treatment (p < 0.05). The results of the present study demonstrate that MCP-induced short-term hyperprolactinaemia in male beagles does not seriously affect the hypothalamo-pituitary axis and semen quality.

Inhibition of human chorionic gonadotropin-induced ovulation and steroidogenesis by short-term hyperprolactinemia in female rabbits.

To clarify the possible direct effects of hyperprolactinemia on the ovulatory process, we experimentally established hyperprolactinemia in female rabbits with 4 daily injections of sulpiride (SLP) at different doses and induced ovulation with human chorionic gonadotropin (hCG). Plasma levels of prolactin (PRL) were increased significantly before hCG injection in each SLP-treated group compared with the corresponding values for the controls. The ovulation rates at 14 h after hCG were significantly reduced in the 16 and 24 mg/kg/day SLP-treated groups. An inverse correlation (r = -0.74, P less than 0.001) was found between the ovulation rate and the increasing in plasma PRL measured just prior to hCG injection. The increase in peripheral as well as ovarian venous progesterone and 20 alpha-hydroxypregn-4-en-3-one(20 alpha-OHP) at 4 and 14 h after hCG injection in inhibited ovulation groups was much less than in the control group. However, the estradiol, androstenedione and testosterone concentrations were comparable with the control values. These results indicate that hypersecretion of PRL induced by SLP has a direct effect on ovary by inhibiting follicular rupture induced by hCG and this inhibitory effect was partly due to the suppression of progesterone secretion during the course of ovulation. This may be one of the causes leading to hypogonadism during hyperprolactinemia.

Hyperprolactinemia and estrogen-induced rhythms in LH and prolactin release in the ovariectomized rat.

Short-term (9 days) hyperprolactinemia induced by pituitary grafts reduced basal plasma LH levels in ovariectomized rats whereas long-term (31 days) grafts increased basal LH levels. Although long-term grafts inhibited estradiol-induced prolactin surges, hyperprolactinemia had no effect on the LH surge. It is concluded that the estrogen-treated ovariectomized rat is not suitable for studying the effects of hyperprolactinemia on LH release.

Prolactin and sexual behavior: A review

Despite the large body of evidence showing that prolactin (PRL) can suppress sexual behavior in humans and rodents, it is still unclear how this hormone affects sexual capacity of male subjects. Few studies have been performed on the effects of PRL on female sexual behavior. Short-term hyperprolactinaemia seems to facilitate some elements of sexual behavior in male rats. Furthermore, contrasting findings exist on the effects of drug-induced hyperprolactinaemia on sexual capacity of male animals. The possible mechanisms of action (on peripheral organs, endocrine, central) of PRL on male sexual behavior are discussed in details.

Catecholamine utilization in specific rat brain nuclei after short-term hyperprolactinaemia

Endogenous hyperprolactinaemia was induced in intact male rats by transplantation of pituitaries under the kidney capsule. Five days later the utilization of noradrenaline (NA) and dopamine (DA) in individual brain nuclei and changes of plasma prolaction (PRL) were measured. Inhibition of catecholamine synthesis by α-methyl- ptyrosine (α-MPT) was used to measure utilization. Hyperprolactinaemia increased the utilization of NA in the locus coeruleus, the cell-body region of the dorsal noradrenergic bundle (DNB), but decreased it in some terminal projections of the same pathway (e.g. the cingulate gyrus). DA utilization was increased by hyperprolactinaemia in the eminentia mediana. In the nigrostriatal DA-ergic projection, hyperprolactinaemia decreased the utilization of DA in the cell-body region (substantia nigra) and increased it in the terminal projection (nucleus caudatus). In the ventral tegmental area (mesolimbic DA-ergic projection), hyperprolactinaemia decreased the utilization of DA. It is concluded that hyperprolactinaemia affects neurotransmission in the hypothalamus and also in specific extrahypothalamic pathways (e.g. DNB, nigrostriatal and mesolimbic DA-ergic projections) and that these changes may correlate with some behavioural effects of the pituitary hormone.

Effects on short-term hyperprolactinemia on the endocrine reproductive system in male rabbits

We have systematically studied the effects of short-term hyperprolactinemia on reproductive function in male rabbits. Purified ovine prolactin (PRL) was administered intravenously, as bolus injections or by constant infusion, to unanesthetized animals bearing two chronically implanted Silastic catheters; blood samples were obtained via the second catheter. Short-term hyperprolactinemia did not modify serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations in either castrated or intact rabbits. However, in spite of no changes in LH and FSH, short-term PRL administration lowered the serum testosterone (T) in intact animals. Furthermore, while PRL had no effect on the LH and FSH response to gonadotropin-releasing hormone, it did inhibit the testicular secretion of T in response to the increased endogenous LH. PRL also inhibited human chorionic gonadotropin-stimulated T secretion by the testes. All of these studies indicate that PRL interferes with the testicular response to LH. The fact that LH and FSH did not rise in response to the lowered T in intact animals suggested that PRL also altered the steroid feedback control of LH and FSH secretion. To assess this, PRL or saline was repeatedly injected after castration. PRL prevented the postcastration rise in LH and FSH. These studies indicate that PRL acts at at least two sites in the reproductive system in rabbits: (1) directly at a gonadal level by interfering with gonadotropin action and (2) at a hypothalamic-pituitary central level by preventing the expected rise in gonadotropins in response to low gonadal steroids.

Effect of metoclopramide induced hyperprolactinaemia on the gonadotrophic response to oestradiol and LRH.

Abstract. The effect of oral metoclopramide 10 mg three times daily during the follicular and periovulatory period on Prl, LH, FSH, oestradiol and progesterone was determined in 6 regularly menstruating women. During a control cycle and a treatment cycle the gonadotrophic response was measured after 1 mg oestradiol benzoate given im on the 8th day and after LRH 25 μg iv on the 8th and 11th day of the menstrual cycle. Prl, LH and FSH were also measured in 7 post-menopausal women either during short-term or long-term treatment with metoclopramide. Compared to a control cycle metoclopramide significantly (P &lt; 0.01) increased serum Prl, but a sustained hyperprolactinaemia was not obtained in 2 women. Treatment significantly (P &lt; 0.02) increased the LH and FSH responses to LRH and augmented the negative feedback of oestradiol on both LH and FSH (P &lt; 0.05). A major gonadotrophin surge occurred in those 2 women where a sustained hyperprolactinaemia was not achieved. Oestradiol benzoate caused a significant increase of the LH (P &lt; 0.01) and FSH (P &lt; 0.05) responses to LRH after 72 h during the control cycle, but failed to increase either LH or FSH responses significantly during treatment. Short-term hyperprolactinaemia in post-menopausal women was not associated with any consistent alteration in either LH or FSH levels or pulsatility, but chronic treatment resulted in a significant reduction in serum FSH (P &lt; 0.02), without any alteration in LH levels or pulsatility. LH and FSH responses to LRH increased in all. There was no effect on serum DHAs, urinary androgens or follicular phase serum progesterone levels. These data show that moderate drug induced moderate hyperprolactinaemia is associated with an increased responsiveness of both LH and FSH to LRH, and has a more pronounced effect on the negative feedback compared to the positive feedback of oestradiol on gonadotrophin secretion. It is suggested that hypersecretion of Prl impairs periodic LH release, mainly through an altered feedback mechanism, but also has a direct inhibitory effect on FSH secretion.

HCG‐STIMULATION OF TESTICULAR STEROIDOGENESIS DURING INDUCED HYPER—AND HYPOPROLACTINAEMIA IN MAN

In order to elucidate the role of prolactin in the regulation of testicular steroidogenesis in man, hyper- and hypoprolactinaemia were induced by sulpiride (group 2) and bromocriptine (group 3) administration in eight and nine young adults, respectively, and the responses of testosterone and six other steroids to a single dose of 5000 iu hCG were compared with those obtained under basal conditions (group 1) in eight men. During hyperprolactinaemia (group 2) the responses of pregnenolone, progesterone, 17-hydroxyprogesterone, testosterone and 5 alpha-dihydrotestosterone tended to be greater than in the control and hypoprolactinaemia groups, but these changes were not statistically significant. In contrast to the behaviour of these steroids, oestradiol showed diminished peak values at 24-36 hCG in the sulpiride-treated group and the response was significantly smaller (P less than 0 . 01) than during hypoprolactinaemia. These findings suggest that testicular aromatization is modulated by prolactin and thus the partial inhibition of oestradiol production, observed during short-term hyperprolactinaemia, may result in a better androgen response to hCG.

Pituitary sensitivity to gonadotrophin releasing hormone after hyperprolactinaemia induced with neuroleptics and domperidone in the rat.

The effect of hyperprolactinaemia induced by dopamine-antagonist drugs on pituitary responsiveness to gonadotrophin releasing hormone (Gn-RH) and on plasma LH levels has been investigated in intact and ovariectomized rats. The animals were pretreated with haloperidol, pimozide or domperidone and the sensitivity of isolated pituitary glands to pulses of Gn-RH were tested using a perifusion system. Trunk blood, collected at the time of killing, was assayed for plasma LH and prolactin. In addition, a direct effect of the drugs on pituitary responsiveness to Gn-RH was investigated by perfusing pituitary glands taken from untreated, pro-oestrous rats in medium containing the dopamine antagonists. The pituitary responsiveness was significantly impaired in intact rats after treatment with each of the drugs whereas no effect was observed in pretreated ovariectomized rats. None of the drug treatments altered levels of circulating LH. High concentrations of the drugs present in the perifusion medium also inhibited pituitary responsiveness although it is not known whether the concentrations of the drugs present in the pretreated animals would exert a similar effect. The results suggest that short-term hyperprolactinaemia impairs pituitary responsiveness through a modulation of ovarian steroid secretion and that Gn-RH release is not altered. Treatment with domperidone exhibited similar effects on the parameters measured here to those caused by the two neuroleptics, indicating that this novel anti-dopaminergic drug is acting in a similar manner.

Failure of short-term hyperprolactinaemia to increase the number of gonadotrophin receptors in the ram testis.

Hyperprolactinaemia was induced during March in 2-year-old rams which had regressed testes. Five animals were intravenously infused with prolactin for 3 days at a rate that raised concentrations of prolactin in plasma to levels equivalent to those generally found in summer. Five untreated animals acted as controls. The treatment did not change plasma levels of LH and FSH and had no effect on testicular content of LH and FSH receptors. These results indicate that prolactin is not directly involved in the acute regulation of gonadotrophin receptors in the ram testis.

Short-term endogenous hyperprolactinaemia and sexual behavior of male rats

Sexual behavior of male rats was studied in a short-term endogenous hyperprolactinaemic condition. Hyperprolactinaemia was induced by grafting two pituitary glands under the kidney capsule. Five days after operation homografted animals, as compared to the sham operated, displayed an enhancement of several parameters of copulatory behavior. In particular, significant reductions in the mount and intromission latencies were observed. The stimulation of sexual behavior of male rats by short-term hyperprolactinaemia might be due to an enhancement of dopaminergic transmission in specific brain areas by prolactin (PRL).