Prolactin Production Research Articles

Modulation of Growth Hormone and Prolactin Secretion in Trypanosoma cruzi-Infected Mammosomatotrophic Cells

Objective: In a previous study, we reported an imbalance in the hypothalamus-pituitary-adrenal axis of mice acutely infected with the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Methods: Possible effects of this parasitic infection on the endocrine function of other pituitary cell types were studied, in particular regarding the production of prolactin (PRL) and growth hormone (GH). Results: In the mammosomatotrophic cell line GH3, both GH and PRL secretion were decreased, reflecting the diminished PRL concentrations in the pituitary glands of infected mice. Additionally, expression of extracellular matrix proteins, e.g. laminin, was increased in T. cruzi-infected GH3 cells, which may be related to the diminished secretory function of these cells. Lastly, the expression of Pit-1, a major transcription factor for the PRL and GH genes, is also decreased in T. cruzi-infected cultures. Conclusion: T. cruzi infection downregulates PRL and GH production. Combined with our previous data showing increased glucocorticoid levels following T. cruzi infection, the immunosuppression induced by T. cruzi infection may be partially related to multiple endocrine changes involving the hypothalamus-pituitary axis and corresponding target endocrine glands.

Evo–Devo and the evolution of cancer: A hypothesis for metamorphic therapies for the cancers of prolactin-influenced tumourigenesis: With special reference to glioblastoma multiforme (GBM)

Recalling the remarkable developmental similarities between cancer cells and embryonic tissues, this paper argues that, by the process of retrodifferentiation and heterochronization, stem cells that have become neoplastic could be said to have undergone "cellular heterochrony." It theorizes, therefore, that hormones are the major factor in the non-random regulation of cellular heterochrony in tumourigenesis. Two recent articles confirm that there is low thyroxine and high prolactin in glioblastomas. Thyroxine metamorphoses vertebrates' tissues so as to mature the tissues, e.g., in amphibian metamorphosis. In 1896, thyroxine (horse thyroid extract) was the first successful hormonal product to be used against a fulminating breast cancer. Recent work confirms the important role of prolactin in the induction and progression of mammary, prostate and colorectal tumours. Although the pituitary is the main source of prolactin in vertebrates, there is also placental production of prolactin, and paracrine production of prolactin by tumours themselves. Since tumours produce their own prolactin, shutting down the pituitary source has not proven wholly successful. Research to find prolactin receptor antagonists is ongoing. Therefore, prolactin inhibitors (dopamine agonists), prolactin receptor antagonists, plus thyroxine comprise a plausible metamorphic therapy for shrinking solid tumour mass. By contrast with "differentiation" therapies currently sought by stem cell oncologists, this paper advocates "metamorphic" therapies, to introduce hormonal oncological knowledge of how to modulate signalling pathways that are aberrant in the stem cells that give rise to tumours. Despite subtle differences in these signalling translation pathways and cascades, strategies exist that will allow these evolved populations, going back to their stem precursors, to "metamorphose" or perhaps apoptotically cease proliferation.

Effects of manganese exposure on dopamine and prolactin production in rat

Although manganese (Mn) has been shown to increase prolactin (PRL) by decreasing dopamine (DA) in the hypothalamus, the mechanism of Mn-induced regulation of the hypothalamic-hypophyseal-pituitary axis is unclear. We assessed the effects of inhaled Mn on hypothalamic DA and pituitary PRL production and evaluated the role of pituitary-specific transacting factor 1 (Pit-1), a transacting factor of PRL gene, in Mn-induced changes in PRL secretion in the rat brain. Male rats exposed to Mn for 4 or 13 weeks (1.5 mg/m3, 6 h/day, 5 days/week) showed a progressive and significant decrease in hypothalamic DA, whereas PRL and Pit-1 mRNA levels increased in response to Mn exposure. These results suggest that exposure to Mn decreases hypothalamic DA and promotes the production of PRL in the pituitary and that Pit-1 might be a regulator of DA and PRL.

Maternal–neonatal amino acid blood levels in relation to the mode of delivery

To investigate the effect of the mode of delivery on maternal-neonatal amino acid levels as high blood levels of some amino acids are implicated with endurance exercise. Comparative study. Thirty women in normal pregnancy divided into two groups: Group A (n=15) with normal labor and vaginal delivery and group B (n=15) with scheduled cesarean section. Blood was obtained from the mothers pre- versus post-delivery as well as from the umbilical cord. Routine laboratory tests (liver enzymes, muscle enzyme, etc.) and the amino acid blood levels were measured with a clinical chemistry analyzer and tandem mass spectrometry methods, respectively. Routine laboratory tests and the amino acid blood levels were similar in the two groups of mothers pre-delivery. Total antioxidant status levels were reduced, whereas the branched-chain amino acids (BCAAs) and alanine levels were remarkably elevated in the sera of group A post-delivery, whereas they remained unaltered in group B at the same time of study. The mentioned BCAAs and alanine levels were higher in the umbilical cord blood of group A than those in group B. The rest of the amino acids were similar. The increased BCAAs and alanine blood levels in mothers of group A may be related to uterine and skeletal muscle contractions during the vaginal delivery process and the high levels in the umbilical cord blood of their neonates may mirror those of the mothers. The elevation of BCAAs both in mothers of group A and their neonates may exclude or minimize tyrosine and tryptophane levels from entry in the brain resulting in decreased biogenic amine and increased prolactin production in the central nervous system of these mothers and their infants.

Factors affecting plasma prolactin concentrations throughout gestation in high producing dairy cows

The aim of the present study was to investigate possible relationships between plasma concentrations of prolactin and the following factors throughout gestation in lactating dairy cows: photoperiod, season, milk production, Neospora caninum-seropositivity, twin pregnancy, and plasma concentrations of pregnancy associated glycoproteins-1 (PAG-1), progesterone and cortisol. Pregnancy was diagnosed by trans-rectal ultrasonography on Day 40 post-insemination and by palpation per rectum on Days 90, 120, 150, 180 and 210 or until abortion in aborting cows. Blood samples were collected from each animal immediately before each pregnancy diagnosis. The study population was comprised of 73 non-aborting (54 Neospora-seropositive cows) and 20 aborting cows (all Neospora-seropositive) cows. In non-aborting cows, GLM repeated measures of analysis of variance revealed that lactation number and days in milk had no effect on plasma prolactin concentrations throughout gestation, whereas high plasma prolactin concentrations were significantly associated with high plasma levels of cortisol and PAG-1, with Neospora-seropositivity, positive photoperiod (increasing day length), twin pregnancy, and with low plasma progesterone concentrations. An interaction among plasma prolactin, plasma cortisol and milk production was observed in that plasma prolactin concentrations differed significantly throughout gestation and were highest in high-producing cows with high cortisol levels. In Neospora-seropositive non-aborting versus aborting cows, mean prolactin concentrations failed to differ on Days 40, 90, 120, 150 and 180 of pregnancy, whereas prolactin values were significantly lower ( P = 0.03) in aborting animals on Day 210 of pregnancy. Our results indicate that a positive photoperiod and Neospora-infection lead to increased plasma prolactin concentrations throughout gestation. Reduced prolactin concentrations detected in Neospora-seropositive aborting cows compared to non-aborting animals suggests a protective effect of prolactin in N. caninum infection.

Immunization Against Vasoactive Intestinal Peptide and its Effects on Prolactin, Steroid, Luteinizing Hormone and Egg Production During Mid Laying Cycle in Punjab Brown (PB3 ) Birds

Objective of the study is examine the effects of active immunization against chicken Vasoactive Intestinal Peptide (chVIP) on plasma prolactin (PRL) concentration, concentration of luteinizing hormone (LH) profile its interval and duration, Progesterone (P ), Estradiol (E s), intersequence pause days and egg 4 2 production in birds during the later stages of egg production from 48-72 weeks of egg lay in PB3 birds. Twenty-four PB3 birds of same age group were divided into 2 groups of 12 in each. Birds in control group were administered s/c with placebo. Equal volume of chVIP immunogenic protein was administered to treated group from 17 week of age to 36 weeks of age at an interval of 4 weeks. Hormonal profiles of th immunized and control birds were quantified at weekly intervals from 48th to 72nd weeks of age in both the groups for prolactin, LH, estradiol, progesterone. Egg production and pause days were recorded in both the groups. At 59th weeks of age, blood samples from chVIP immunized and control birds were obtained every 4 h for 48 h to study the surges of LH. In immunized PB3 birds (against ch VIP) plasma PRL concentration was lower (p<0.01) with high concentrations of E s, P , LH and its 4 h LH surges in plasma. Significantly 2 4 (p<0.01) higher egg production (13.62%) and less pause days were observed in chVIP immunized birds. It is mainly attributed due to low PRL concentration, associated with high concentrations of LH (with regular interval and duration of LH surges), Es and P concentration required for egg formation and subsequent 2 4 ovulation. In conclusion, chVIP immunization advanced the LH surges, for release of matured oocyte, egg formation and egg lay enabled the birds to lay eggs at regular intervals due to active immunization against chVIP. Results indicate that control of chVIP may lead to more egg production with shorter duration of LH surges.

Ectopic hyperprolactinaemia in a woman with a mesocolic perivascular epithelioid cell tumor (“PEComa”)

Ectopic prolactin secretion remains exceptional and originates mainly from malignant tumors. We report the case of a 47-year-old woman who presented amenorrhea leading to unravel important hyperprolactinaemia (269 ng/mL) with no hypothalamo–pituitary mass on magnetic resonance imaging (MRI). Pelvic imaging revealed the presence of a large pelvic mass that originated from the mesocolon. After complete surgical extraction, histological examination was in favour of a “perivascular epithelioid cell tumor” (PEComa). Prolactin levels normalized after surgical extraction and remained normal after a 3-year follow-up, totally free of tumour recurrence and/or metastasis. This suggests that hyperprolactinaemia was most likely related to the PEComa, despite negative reactions with antiprolactin antibodies at immunohistochemistry. Alternatively to a direct prolactin secretion by the tumor, one could hypothesize that the tumour secreted a prolactin stimulating factor or a dopamine antagonist that could not be identified. In conclusion, in face of an important hyperprolactinaemia without any hypothalamic–pituitary mass, it remains important to search for an ectopic prolactin production, such as a PEComa.

Transgenic Models to Study Actions of Prolactin in Mammary Neoplasia

Transgenic models to explore the role of prolactin and its interactions with other factors in mammary oncogenesis have begun to reveal the dynamic contributions of prolactin to the development and progression of this disease. Targeting prolactin to mammary epithelial cells mimics the local production of this hormone that is prominent in women, and permits studies in the absence of effects on the ovarian steroid milieu. These models have demonstrated that local production of prolactin is sufficient to induce mammary tumors after a long latency. Prolactin also can potentiate actions of other oncogenic stimuli, decreasing tumor latency and increasing incidence in several models. Augmented proliferation, without alteration of apoptosis, is a consistent feature. Pathways in addition to the well-characterized Jak2-Stat5 pathway, including ERK1/2 and Akt1/2, are implicated in these actions. These studies have also revealed a complex relationship with estrogen; while prolactin increases ERalpha expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFalpha, prolactin can contribute to estrogen insensitivity. These studies highlight the utility of these models to decipher the interplay between prolactin and other oncogenic factors in breast cancer, with implications for preventative and therapeutic strategies.

Dose-dependent Effects of a Glucocorticoid on Prolactin Production

Glucocorticoids are known to stimulate growth hormone (GH) production but to suppress prolactin (PRL) production. However, previous data were obtained with rather high doses of corticosterone. In this study we examined the effects of various doses (10 (-12) -10 (-7) M) of corticosterone on GH and PRL production in a rat pituitary somatomammotropic cell line, MtT/SM cells, and found that GH mRNA expression was facilitated by high doses (10 (-7) and 10 (-8) M). In contrast, a biphasic effect of corticosterone on PRL mRNA expression and secretion was observed, i.e., high doses (10 (-7) and 10 (-8) M) suppressed and low doses (10 (-12) -10 (-10) M) facilitated them. In an immunofluorescent staining study, the number of PRL immunopositive cells increased with low doses of corticosterone while it decreased with high doses of it, which corresponded to PRL mRNA expression and hormone secretion, respectively. These effects of corticosterone on PRL production were abolished by a glucocorticoid receptor (GR) antagonist, mifepristone. In addition, co-treatment with low doses of corticosterone (10 (-12) -10 (-10) M) and 17beta-estradiol (E(2), 10 nM) additively increased the number of PRL immunopositive cells. Moreover, a 24 h BrdU incorporation experiment suggested that the increase in the number of PRL immunopositive cells treated with low dose corticosterone was caused by novel synthesis of PRL while, on the other hand, that of those treated with E(2) resulted from PRL cell proliferation. Thus, we concluded that corticosterone biphasically regulates PRL production and the sensitivity of E(2) to different degrees.

What Can We Learn from Rodents about Prolactin in Humans?

Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.

Existe-t-il encore une place pour la dopamine en réanimation pédiatrique ?

Dopamine is mostly used in patients with cardiogenic or septic shock, but its place in critical care medicine is often questioned. Dopamine, of which pharmacology in children is variable, is prescribed for its inotropic effect, associated with an increase in cardiac output and at a lesser degree blood pressure. Beneficial effects (need for renal replacement therapy and mortality) of low dose in patients at risk of, or with acute renal failure are not demonstrated. Dopamine has numerous potential deleterious effects on local circulations (pulmonary, cerebral, coronary and cutaneous), respiratory function, gastroduodenal motility, endocrine function (further depression of the hypothalamic-pituitary axis induced by stress) and immunity (partially due to decreased production of prolactin). Finally, in shocked adults dopamine infusion might be associated with an increase in mortality rate. Dopamine remains the most prescribed catecholamine, either in adults or children. It still is one of the first line drug included in the recent recommendations for the treatment of septic shock (norepinephrine tends to replace it), cardiogenic shock (dobutamine is the first drug), severe head trauma, and organ donor in cerebral death. In conclusion, if dopamine is today less used, there is no proof that its deleterious effects are associated with an excess of mortality. Thus, dopamine still is part of the stock of drugs that act on the cardiocirculatory system (but for how long?).

Facilitation of decidualization by locally produced ghrelin in the human endometrium

Ghrelin acting via the growth hormone secretagogue receptor (GHS-R) stimulates GH secretion from pituitary glands. Both ligand and receptor are present in the pituitary, hypothalamus and many peripheral tissues including the uterus. This study demonstrates the cyclical expression of GHS-R and ghrelin in human endometrium. mRNA and protein for ghrelin and GHS-R were examined using RT-PCR and immunohistochemistry. Both ghrelin and GHS-R mRNA levels were highest in the secretory phase, with lower levels in the mid-proliferative phase and even lower expression in the menstrual phase. Immunoreactive ghrelin and GHS-R were confined predominantly to glandular epithelial and stromal cells with the greatest intensity of staining in secretory phase samples, consistent with the RT-PCR data. Additionally, we examined ghrelins effect on the decidualization of human endometrial stromal cells (HESCs) combined with sex steroid and cAMP treatments using prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) production as markers of decidualization. Ghrelin administered in combination with sex steroids to HESC, resulted in an increase in PRL and IGFBP-1 production above that obtained with cAMP, or sex steroids alone (P<0.001) whereas ghrelin in combination with cAMP inhibits the action of cAMP. These findings have potential clinical applications for the regulation of fertility.

Differential regulation of thyroid hormone receptor-mediated function by endocrine disruptors

It is well known that endocrine disruptors (EDs) act as anti-estrogenic agents and affect the function of reproductive organ. EDs are also thought to affect thyroid hormone (TH) system which is important for biological functions such as growth, development and metabolism. However, it is still not clear how EDs are able to regulate TH receptor (TR)-mediated functions. In this study, therefore, the modulatory effects of representative EDs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl (Aroclor 1254) and bisphenol A (BPA) were examined using TR-expressing GH3 cells (a rat pituitary gland epithelial tumor cell line) activated by triiodothyronine (T3). EDs tested significantly blocked T3 binding to TR in a dose-dependent manner. Biochemical characterization by Scatchard and Lineweaver-Burk plot analyses indicated that TCDD and aroclor 1254 bound to TH receptors in a competitive inhibitory manner, whereas BPA bound to TH receptors in a non-competitive pattern. The different inhibitory mode of action by EDs was also found in regulating TR-mediated production of prolactin (PRL). Aroclor 1254 exposure for 48 h enhanced T3-mediated PRL production, but BPA down-regulated. These results suggest that the EDs (TCDD, Aroclor 1254 and BPA) could differentially bind to TR and distinctly regulate the action of TR function, even though EDs are structurally similar.

Development of Prolactin Receptor Antagonists: Same Goal, Different Ways

Hyperprolactinemia is an endocrine pathology resulting from over-production of prolactin (PRL) by pituitary adenomas, and leading to various reproductive disorders. In addition, there is increasing evidence that PRL acts as a growth-promoter of breast and prostate tumors. Classical drugs blocking pituitary PRL production are not necessarily efficient in these pathological situations, which has encouraged the search for alternative ways of inhibiting the undesirable actions of PRL. Prolactin receptor (PRLR) antagonists, acting at the level of receptor activation rather than PRL production, are the most promising strategy. Based on the protein core of human (h)PRL or growth hormone (hGH), the other natural hPRLR ligand, a series of new variants have been engineered within the past couple of years, leading to various patent applications. Modifications of amino acid sequences involve single/multiple substitutions, truncations, or generation of fusion proteins. Three mechanisms of action have been reported for these PRLR antagonists: 1) inhibition of PRLR signaling by competition with endogenous PRL for receptor binding, 2) activation of specific PRLR signalling pathways resulting in actions opposite to those of wild-type hPRL, and 3) engineering of chimeric ligands targeting more than one receptor/cell type, in order to improve tumor-growth inhibition. Since none of these patented molecules is yet in clinical trials, their efficacy to treat PRL-dependent pathologies remains to be demonstrated in humans. Keywords: Breast cancer, prostate cancer, hyperprolactinemia, growth hormone, G129R-hPRL, Δ1-9-G129R-hPRL, G129RhPRL, S179D-hPRL, induced-fit

Prolactin inhibition in dams during lactation programs for overweight and leptin resistance in adult offspring

Maternal malnutrition during lactation reduces prolactin (PRL) and milk production, alters milk composition, and programs the body weight of the offspring. Our study aimed to evaluate the long-term effects of maternal hypoprolactinemia at the end of lactation on food ingestion, body weight, amount of retroperitoneal white adipose tissue (RPWAT), leptinemia, and anorectic leptin effect in the adult offspring. Lactating rats were treated with bromocriptine (BRO), a PRL inhibitor, 1 mg twice a day, or saline (C - control) for the last 3 days of lactation. The body weight and food intake were monitored, and after sacrifice at 180 days, the RPWAT was weighted. In a second experiment, the anorectic leptin effect was tested on 180-day-old animals. Adult offspring whose mothers were BRO-treated showed higher body weight (10%), higher amount of RPWAT (2 x 3 times), higher total body fat (+39%), and hyperleptinemia (2 x 9 times) when compared with C, although food intake did not alter. After injection of leptin, the food ingestion at 2, 4 and 6 h was unaffected in BRO animals, confirming a resistance to the anorectic effect of leptin. Since the maternal PRL inhibition during lactation programs, a higher body weight with no alteration of food ingestion, we suggest a hypometabolic state. The leptin anorectic resistance can be due to the hyperleptinemia. We suggest that PRL changes during lactation can regulate body weight during adulthood.

Decidual Prolactin Silences the Expression of Genes Detrimental to Pregnancy

Although the main role of prolactin (PRL) in pregnant rodents is to sustain progesterone production by the corpus luteum, progesterone treatment of PRL or PRL receptor (PRL-R) null mice is unable to prevent fetal loss. We have previously shown that the rat decidua is a site of PRL production and action. In this report, we examined the hypothesis, using PRL null mice and rat decidual cell culture, that the absence of this hormone leads to the expression in the decidua of genes detrimental to pregnancy. The results show that decidual growth is normal in PRL null mice treated with PRL, progesterone, or their combination. However, the decidua of mice treated with progesterone starts expressing IL-6 and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), two proteins absent from the decidua of wild-type mice and involved, respectively, in inflammation and progesterone catabolism. The expression of both IL-6 and 20alpha-HSD is prevented by PRL treatment. Our results further suggest that PRL inhibition of 20alpha-HSD expression is at the level of transcription and that decidual PRL (dPRL) inhibits 20alpha-HSD promoter activity. Inhibitors of Janus kinase 2 (Jak2) but not other kinases prevent dPRL down-regulation of the 20alpha-HSD promoter. Furthermore, cotransfection of the 20alpha-HSD promoter with expression vectors of constitutively active PRL-R, Jak2, or signal transducer and activator of transcription 5b (Stat5b) leads to substantial inhibition of promoter activity. Taken together, our investigation provides an explanation for the inability of progesterone to sustain pregnancy in PRL null mice and suggests that dPRL plays an important role in pregnancy by repressing the expression of IL-6 and 20alpha-HSD in the decidua. The study also demonstrates that PRL signals through the Jak2/Stat5 pathway to down-regulate 20alpha-HSD expression in the decidua.

Alteration of hormone and neurotransmitter production in cultured cells by high and low frequency electrical stimulation

HFS has become a widely used method in functional neurosurgery. However, its mechanism is not well understood, and its cellular and molecular effects have not yet been investigated. The aim of the study was to understand which cellular events, unrelated to the network organization of cells or neurons, participate in the mechanism of action of HFS. In vitro cellular effects of high (HFS) and low (LFS) frequency electrical stimulation on prolactin secretion in GH3 cell lines (prolactinoma), as well as the catecholaminergic secretion on PC12 cells (pheochromocytoma) were investigated. Cells were cultured in dishes with integrated electrodes to deliver stimulation at the same parameters as those used in clinical conditions to treat advanced forms of Parkinson's disease. Prolactin production was measured in GH3 using a Radio-Immuno-Assay. Dopamine, epinephrine and norepinephrine were measured in PC12 using Enzymo-immuno-assays. HFS for 24 hours reduced prolactin secretion by 40.3%, dopamine by 32.7%, epinephrine by 18.1% (non significant) and norepinephrine by 27.0%. LFS did not induce significant changes. These results suggest that HFS has an inhibitory impact on the cellular machinery responsible for hormone and neurotransmitter production. In this model of isolated cultured cells, network interactions and particularly presynaptic actions are discarded. HFS has inhibitory effects on cellular mechanisms responsible for the production and release of molecules participating in intercellular communication. This HFS-induced inhibition might participate in the lesion-like effect of therapeutic HFS in the basal ganglia during various movement disorders.

Acute myeloid leukaemia presenting as galactorrhoea

The clinical presentation of acute myeloid leukaemia is variable. We report a 40-year-old woman who presented with a 1-month history of galactorrhoea with an elevated prolactin level. The blood counts were normal, but she was found to have acute myeloid leukaemia with monocytic differentiation. The serum prolactin level normalized after chemotherapy. In the absence of evidence of CNS involvement, the hyperprolactinaemia is presumed to be a paraneoplastic phenomenon. We discuss the potential mechanism of prolactin production in this case.

Increased apoptosis of lactotrophs in streptozotocin-induced diabetic rats is followed by increased proliferation

Poorly controlled diabetes mellitus can result in decreased prolactin production and thus problems with lactation, reproduction, and other physiological processes. This may be due to a loss of lactotrophs, as we have previously shown that long-term (8 weeks) poorly controlled streptozotocin-induced diabetes results in increased death of lactotrophs and that this most likely occurs through the activation of caspase-8 and the extrinsic cell death cascade. However, cell proliferation is also increased in the anterior pituitary at this time, although the cell type undergoing this proliferation and whether it is a response to the increased cell death remains unknown. In order to determine the time-course of increased cell death and proliferation in the anterior pituitary and if this is related to changes in tumor necrosis factor (TNF)-alpha, a cytokine involved in the activation of the extrinsic cell death pathway, rats were killed at 1, 4, 6, and 8 weeks after the induction of diabetes. Cell death was significantly increased after 4 weeks, as was caspase-8 activation, although circulating levels of TNF-alpha were increased as early as 1 week. Pituitary levels of TNF-alpha did not change significantly until 8 weeks after diabetes onset. Similarly, Western-blot analysis of proliferating cell nuclear antigen showed that anterior pituitary cell proliferation increased significantly 8 weeks after diabetes onset, with the majority of proliferating cells, as detected by BrdU incorporation, corresponding to lactotrophs. These results suggest that the increased death of lactotrophs in poorly controlled diabetic rats is followed by increased proliferation of this cell type, even when no treatment is given.

Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?

Prolactin is a polypeptide hormone whose major biological actions are related to normal lactation and reproduction. Abnormally high prolactin levels, referred to as hyperprolactinemia, can result in various reproductive disorders. Currently, therapeutic management of hyperprolactinemia relies on dopamine agonists, since dopamine is the primary physiological suppressor of pituitary prolactin production. Epidemiologic studies have shown that prolactin levels in the high-normal range, as well as medications that interfere with dopamine action (e.g. certain antipsychotic drugs), might correlate with increased breast cancer risk. In addition to circulating prolactin, it is now well established that prolactin is also produced locally within various tissues, including breast and prostate. Increasing evidence, mainly from animal studies at present, suggests that excess locally produced prolactin may promote the growth of breast and prostate tumors via an autocrine or paracrine mechanism. These findings have renewed the interest in finding alternative strategies to suppress prolactin actions when dopamine agonists are ineffective. Our studies of the relationship between prolactin structure and function have resulted in the development of pure prolactin-receptor antagonists. These molecules prevent endogenous prolactin from exerting its actions via a competitive mechanism for receptor binding. In this review, we discuss the possible future therapeutic utility of this novel class of compounds.