Showing papers on "Prolactin published in 2012"

Mammary gland development

Abstract: The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial–mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development—pubertal growth, pregnancy, lactation, and involution—occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease.

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

Abstract: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

Abstract: Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25–34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists.

Prolactin, neurogenesis, and maternal behaviors.

Abstract: Elevated prolactin during pregnancy increases neurogenesis in the subventricular zone of the lateral ventricle (SVZ) of the maternal brain. Evidence from our laboratory has shown that low prolactin in early pregnancy, and the consequent suppression of neurogenesis in the SVZ in the adult brain, is associated with increased postpartum anxiety and markedly impaired maternal behavior. Daughters of low prolactin mothers also display increased anxiety and a significant delay in the onset of puberty, which is associated with epigenetic changes in neuronal development (see Fig. 1). This suggests that, in rodents, low prolactin in early pregnancy exerts long-term effects that influence maternal mood postpartum, and offspring development. This mini-review aims to summarize the evidence showing that the prolactin-induced increase in SVZ neurogenesis during pregnancy underlies normal postpartum maternal interactions with pups.

Molecular Mechanisms of Prolactin and Its Receptor

Abstract: Prolactin and the prolactin receptors are members of a family of hormone/receptor pairs which include GH, erythropoietin, and other ligand/receptor pairs. The mechanisms of these ligand/receptor pairs have broad similarities, including general structures, ligand/receptor stoichiometries, and activation of several common signaling pathways. But significant variations in the structural and mechanistic details are present among these hormones and their type 1 receptors. The prolactin receptor is particularly interesting because it can be activated by three sequence-diverse human hormones: prolactin, GH, and placental lactogen. This system offers a unique opportunity to compare the detailed molecular mechanisms of these related hormone/receptor pairs. This review critically evaluates selected literature that informs these mechanisms, compares the mechanisms of the three lactogenic hormones, compares the mechanism with those of other class 1 ligand/receptor pairs, and identifies information that will be required to resolve mechanistic ambiguities. The literature describes distinct mechanistic differences between the three lactogenic hormones and their interaction with the prolactin receptor and describes more significant differences between the mechanisms by which other related ligands interact with and activate their receptors.

Prolactin--not only lactotrophin. A "new" view of the "old" hormone.

Abstract: Prolactin (PRL) is a hormone mainly secreted by the anterior pituitary. Recent studies have shown that it may also be produced by many extrapituitary cells. The PRL gene expression is controlled by two independent promoter regions, which may be differentially regulated in the pituitary and extrapituitary organs. Proteolytic modifications of PRL generate variants of the hormone. A16 kDa PRL fragment, acting through a specific receptor, has both an antiangiogenic activity as well as an inhibitory effect on tumor growth. Stimulation of the PRL receptor involves many signal transduction pathways, for example JAK2/STAT, MAPK, c-src and Fyn kinase cascade, and these pathways may vary in different tissues. PRL synthesis and secretion is mainly regulated by the inhibitory influence of dopamine but other hormones are also involved in these mechanisms. The essential biological action of PRL is the stimulation of lactogenesis and galactopoesis. Apart from its classical functions, PRL affects other aspects of human body function including osmoregulation, metabolism and regulation of the immune and the central nervous system. Hyperprolactinemia is a common syndrome affecting both men and women. It is manifested by the presence of galactorrhoea and through the symptoms of hypogonadotrophic hypogonadism. Following on from the fact that PRL has so many pleiotropic tissue specific effects it is not surprising to learn that hyperprolactinaemia is a systemic condition which may predispose to numerous cardiovascular and immune-mediated reactions. The exact effects of PRL on both immune and cardiovascular systems are being currently unraveled and may lead to the introduction of novel therapeutic approaches in the future.

Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements

Abstract: Prolactin (PRL) is a multifunctional signaling molecule best known for its role in regulating lactation in mammals. Systemic PRL is produced by the anterior pituitary, but extrapituitary PRL has also been detected in many tissues including the human endometrium. Prolactin is essential for pregnancy in rodents and one of the most dramatically induced genes in the endometrium during human pregnancy. The promoter for human endometrial Prl is located about 5.8 kb upstream of the pituitary promoter and is derived from a transposable element called MER39. Although it has been shown that prolactin is expressed in the pregnant endometrium of a few mammals other than humans, MER39 has been described as primate specific. Thus, in an effort to understand mechanisms of prolactin regulatory evolution, we sought to determine how uterine prolactin is transcribed in species that lack MER39. Using a variety of complementary strategies, including reverse transcriptase-polymerase chain reaction, 5' rapid amplification of cDNA ends, and whole-transcriptome sequencing, we show that endometrial Prl expression is not a shared character of all placental mammals, as it is not expressed in rabbits, pigs, dogs, or armadillos. We show that in primates, mice, and elephants, prolactin mRNA is transcribed in the pregnant endometrium from alternative promoters, different from the pituitary promoter and different from each other. Moreover, we demonstrate that the spider monkey promoter derives from the long terminal repeat (LTR) element MER39 as in humans, the mouse promoter derives from the LTR element MER77, and the elephant promoter derives from the lineage-specific LINE retrotransposon L1-2_LA. We also find surprising variation of transcriptional start sites within these transposable elements and of Prl splice variants, suggesting a high degree of flexibility in the promoter architecture even among closely related species. Finally, the three groups shown here to express endometrial prolactin-the higher primates, the rodents, and the elephant-represent three of the four lineages that showed adaptive evolution of the Prl gene in an earlier study (Wallis M. 2000. Episodic evolution of protein hormones: molecular evolution of pituitary prolactin. J Mol Evol. 50:465-473), which supports our findings and suggests that the selective forces responsible for accelerated Prl evolution were in the endometrium. This is the first reported case of convergent evolution of gene expression through the independent recruitment of different transposable elements, highlighting the importance of transposable elements in gene regulatory, and potentially adaptive, evolution.

Prolactin Regulates Tuberoinfundibular Dopamine Neuron Discharge Pattern: Novel Feedback Control Mechanisms in the Lactotrophic Axis

Abstract: Balance in the body's hormonal axes depends on feedback onto neuroendocrine hypothalamic neurons. This phenomenon involves transcriptional and biosynthetic effects, yet less is known about the potential rapid modulation of electrical properties. Here, we investigated this issue in the lactotrophic axis, in which the pituitary hormone prolactin is tonically inhibited by tuberoinfundibular dopamine (TIDA) neurons located in the hypothalamic arcuate nucleus. Whole-cell recordings were performed on slices of the rat hypothalamus. In the presence of prolactin, spontaneously oscillating TIDA cells depolarized, switched from phasic to tonic discharge, and exhibited broadened action potentials. The underlying prolactin-induced current is composed of separate low- and high-voltage components that include the activation of a transient receptor potential-like current and the inhibition of a Ca(2+)-dependent BK-type K(+) current, respectively, as revealed by ion substitution experiments and pharmacological manipulation. The two components of the prolactin-induced current appear to be mediated through distinct signaling pathways as the high-voltage component is abolished by the phosphoinositide 3-kinase blocker wortmannin, whereas the low-voltage component is not. This first description of the central electrophysiological actions of prolactin suggests a novel feedback mechanism. By simultaneously enhancing the discharge and spike duration of TIDA cells, increased serum prolactin can promote dopamine release to limit its own secretion with implications for the control of lactation, sexual libido, fertility, and body weight.

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

Abstract: Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten–PI3K–Akt pathway Conditional activation of the PI3K–Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development Surprisingly, we found that mammary differentiation was due to the PI3K–Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)–Jak–Stat5 pathway Consistent with this, Akt-induced mammary differentiation was abrogated in Prl−/−, Prlr−/−, and Stat5−/− mice Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1−/−;Akt2+/− mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production Our findings reveal that PI3K–Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K–Akt pathway

Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals.

Abstract: Breast cells drive bone demineralization during lactation and metastatic cancers. A shared mechanism among these physiological and pathological states is endocrine secretion of parathyroid hormone-related protein (PTHrP), which acts through osteoblasts to stimulate osteoclastic bone demineralization. The regulation of PTHrP has not been accounted for fully by any conventional mammotropic stimuli or tumor growth factors. Serotonin (5-HT) synthesis within breast epithelial cells is induced during lactation and in advancing breast cancer. Here we report that serotonin deficiency (knockout of tryptophan hydroxylase-1) results in a reduction of mammary PTHrP expression during lactation, which is rescued by restoring 5-HT synthesis. 5-HT induced PTHrP expression in lactogen-primed mammary epithelial cells from either mouse or cow. In human breast cancer cells 5-HT induced both PTHrP and the metastasis-associated transcription factor Runx2/Cbfa1. Based on receptor expression and pharmacological evidence, the 5-HT2 receptor type was implicated as being critical for induction of PTHrP and Runx2. These results connect 5-HT synthesis to the induction of bone-regulating factors in the normal mammary gland and in breast cancer cells.

Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

Abstract: Women who experienced amenorrhea during their first antipsychotic treatment for schizophrenia also received metformin, 1000 mg/day, for 6 months in a double-blind placebo-controlled study. Two-thirds of metformin-treated patients, compared to 5% of placebo-treated patients, resumed menstruation. Metformin-treated patients had a mean decrease in body mass index (BMI) of 0.93 and a mean change in insulin resistance index of 2.04. In contrast, placebo-treated patients had a mean increase in BMI of 0.85. Prolactin, luteinizing hormone, and testosterone levels and the ratio of luteinizing hormone to follicle-stimulating hormone decreased significantly with metformin. Metformin had no significant adverse effects.

Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis.

Abstract: Hyperprolactinaemia is a common side effect of antipsychotics; markedly raised levels are less common Higher levels of prolactin result from longer exposure to higher doses, especially with older antipsychotics or with risperidone, sulpiride or amisulpride Galactorrhoea, gynaecomastia, menstrual abnormalities and sexual dysfunction including hypogonadism and fertility problems are consequences of raised prolactin, and in the longer-term bone demineralisation Younger patients may be more susceptible to hyperprolactinaemia Trial reports often fail to state the frequency of raised levels

A pathway map of prolactin signaling

Abstract: Prolactin (PRL) is a pleiotropic polypeptide hormone secreted primarily by the lactotrophic cells of anterior pituitary gland in vertebrates (Freeman et al. 2000). This hormone family includes placental lactogen (PL) and growth hormone (GH) (Corbacho et al. 2002). Prolactin plays a major role in lactation and reproduction and has been shown to have a multitude of effects relating to growth, development, metabolism, immunoregulation and protection (Ben-Jonathan et al. 2006). The prolactin signaling pathway is initiated by the binding of prolactin with the prolactin receptor (PRLR), a member of class I cytokine receptor superfamily (Binart et al. 2000), which is expressed in a variety of tissues. The PRLR comprises of an extracellular ligand binding domain, a transmembrane domain and an intracellular domain. The PRLR lacks intrinsic kinase activity and transduces signal through kinases that interact with its cytoplasmic tail. Three constitutively active variants of the receptor have been reported in humans (Goffin et al. 2010). Though the signaling reactions downstream of the longest isoform of prolactin receptor have been well established, little is known about prolactin signaling initiated by six other isoforms (Bouilly et al. 2011). Studies also indicate that binding affinity of the human prolactin receptor to nonhuman prolactin is lower than human prolactin (Utama et al. 2009). The prolactin receptor also binds to hPL and hGH leading to the activation of downstream pathways. However, we have not considered these reactions in the current study. This study reports only those reactions, which occur upon stimulation of prolactin receptor with prolactin, based on the criteria described previously (Nanjappa et al. 2011). Availability of signaling pathway information is useful to the biomedical research community, especially for systems biology approaches. Considering this, we have developed ‘NetPath’ as a resource of ligand-receptor specific signal transduction pathways (Kandasamy et al. 2010). As a part of this, we have carried out manual annotation of available information from the published literature for ligand-receptor signaling pathways (Raju et al. 2011a; Nanjappa et al. 2011; Telikicherla et al. 2011; Goel et al. 2012). Similarly, in this study, we enriched publicly available information pertaining to prolactin-prolactin receptor dependent signaling pathways and also generated a graphic map depicting the prolactin signaling pathway.

Differential Actions of Prolactin on Electrical Activity and Intracellular Signal Transduction in Hypothalamic Neurons

Abstract: In many tissues, including brain, prolactin action is predominantly mediated by the Janus kinase/signal transducer and activator of transcription (STAT) signal transduction pathway, leading to changes in gene transcription. However, prolactin can also exert rapid actions on electrical activity of hypothalamic neurons. Here, we investigate whether both responses occur in a single cell type, focusing on three specific populations known to be influenced by prolactin: GnRH neurons, tuberoinfundibular dopamine (TIDA) neurons, and neurons in the anteroventral-periventricular nucleus in female mice. We performed phosphorylated STAT5 (pSTAT5) immunohistochemistry to identify prolactin-responsive neurons after in vivo prolactin treatment. In addition, we carried out in vitro electrophysiology in slices from transgenic mice expressing green fluorescent protein driven by the GnRH or tyrosine hydroxylase promoters as well as from C57BL/6J mice to assess acute electrical responses to prolactin. Approximately 88% of TIDA neurons expressed pSTAT5 in diestrous mice, rising to 97% after prolactin treatment. All TIDA neurons also showed a rapid increase in firing rate after prolactin treatment. In contrast, very few GnRH neurons (11%) showed pSTAT5 in response to prolactin, and none showed a change in electrical activity. Finally, in the anteroventral-periventricular nucleus, most neurons (69%) responded to prolactin treatment with an increase in pSTAT5, but only 2/38 (∼5%) showed changes in electrical activity in response to prolactin. These observations show that prolactin recruits different combinations of electrical and transcriptional responses in neurons depending upon their anatomical location and phenotype. This may be critical in establishing appropriate responses to prolactin under different physiological conditions.

Influence of streptozotocin-induced diabetes and insulin treatment on the pituitary-testicular axis during sexual maturation in rats.

Abstract: Effects of streptozotocin (STZ)-diabetes and insulin treatment on the functioning of pituitary-testicular axis during sexual maturation was studied. Prepubertal (30 days old) and pubertal (50 days old) male Wistar rats were made diabetic by a single injection of STZ. A group of diabetic rats was given insulin (3U/100 g b.wt./day in 2 equally divided doses), 3 days after STZ treatment. Prepubertal and pubertal rats of all groups were killed on postnatal days 51 and 71, respectively. STZ-diabetes caused marked reduction in serum LH, FSH, prolactin, testosterone and testicular interstitial fluid testosterone as well as the activities of Leydig cellular steroidogenic enzymes (3beta-and 17beta-hydroxysteroid dehydrogenases). Insulin treatment to diabetic rats maintained these changes at control range except FSH and prolactin in prepubertal rats. The results indicate that (i) diabetes-induced steroidogenic lesions in Leydig cells represent a direct consequence of dysfunctioning of pituitary-testicular axis, (ii) the adverse effects of diabetes on pituitary-testicular functions are influenced by age of its induction and (iii) optimum insulin level is essential for the acquisition of Leydig cellular steroidogenic efficacy during sexual development.

Growth hormone, prolactin, and sexuality.

Abstract: GH and PRL, although not considered as 'classi cal' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL in crease can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamus-pituitary-gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function.

Oxytocin: an emerging regulator of prolactin secretion in the female rat.

Abstract: In the female rat, a complex interplay of both stimulatory and inhibitory hypothalamic factors controls the secretion of prolactin. Prolactin regulates a large number of physiological processes from immunity to stress. Here, we have chosen to focus on the control of prolactin secretion in the female rat in response to suckling, mating and ovarian steroids. In all three of these states, dopamine, released from neurones in the mediobasal hypothalamus, is a potent inhibitory signal regulating prolactin secretion. Early research has determined that the relief of dopaminergic tone is not sufficent to account for the full surge of prolactin secretion observed in response to the suckling stimulus, launching a search for possible prolactin-releasing factors. This research has subsequently broadened to include searching for prolactin-releasing factors controlling prolactin secretion after mating or ovarian steroids. A great deal of literature has suggested that this prolactin-releasing factor may include oxytocin. Oxytocin receptors are present on lactotrophs. These oxytocin receptors respond to exogenous oxytocin and antagonism of endogenous oxytocin inhibits lactotroph activity. In addition, the pattern of oxytocin neuronal activity and oxytocin release correlate with the release of prolactin. Here, we suggest not only that oxytocin is stimulating prolactin secretion, but also that prolactin secretion is controlled by a complex network of positive (oxytocin) and negative (dopamine) feedback loops. We discuss the available literature and attempt to describe the circuitry we believe may be responsible for controlling prolactin secretion.

Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?

Abstract: Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention.

Prolactin, fatherhood, and reproductive behavior in human males.

Abstract: Although humans are considered un- usual among mammals for the intensity of care that fathers often provide offspring, little is known about the hormonal architecture regulating human paternal invest- ment. Prolactin has important reproductive functions in both female and male mammals and other taxa, making it a candidate regulator of human paternal behavior. Notably, prolactin is higher during periods of offspring care in some species, but it is unknown if this pattern occurs in human fathers. We draw on a sample of men (n 5 289; age 21-23 at baseline) from Metropolitan Cebu City, Philippines to evaluate relationships between prolac- tin, assayed from dried blood spots, and components of reproductive behavior and relationship status. In this sample, fathers had higher prolactin than nonfathers (P 5 0.006), and fathers of infants had borderline higher prolactin than fathers of older children (P 5 0.054). Among single nonfathers at baseline (2005), baseline pro- lactin did not predict who transitioned to fatherhood by follow-up 4.5 years later. Among nonfathers, men with greater prolactin reported more lifetime sexual partners (P 5 0.050) as well as more sexual activity in the month before sampling (P 5 0.060). Our results suggest that fathers in Cebu have higher prolactin than nonfathers, with hormone levels highest among fathers of young infants. Although these findings are generally consistent with evidence from other species for pronurturing effects of prolactin, evidence for positive relationships between the hormone and measures of sexual behavior at Cebu point to likely complexities in the hormone's involvement in male reproductive strategy. Am J Phys Anthropol 148:362-370, 2012. V C 2012 Wiley Periodicals, Inc.

Role of p53-dependent placental apoptosis in the reproductive and developmental toxicities of caffeine in rodents.

Abstract: Summary The aim of the present study was to evaluate the role of placental apoptosis in mediating the reproductive and developmental toxicity of caffeine in rodents. Female Kunming mice were treated with caffeine (60, 120 and 240 mg/kg per day) before and during pregnancy. The conception rate, maternal bodyweight gain, placental weight and indices of fetal developmental, including the rate of intrauterine growth retardation (IUGR; i.e. the actual number of fetuses exhibiting IUGR as a percentage of the total number of fetuses), were determined on gestational day (GD) 18. Female Wistar rats were treated with caffeine (20, 60 and 180 mg/kg per day) from GD11 to GD20. The IUGR rate, maternal plasma angiotensin (Ang) II and prolactin concentrations, placental pathology, expression of angiotensin AT1 and AT2 receptors and apoptosis-related proteins were measured on GD20. In mice, caffeine treatment dose-dependently reduced the total conception rate, delayed conception and decreased maternal bodyweight gain, placental weight, fetal bodyweight and fetal body and tail lengths, whereas the IUGR rate was increased. In rats, caffeine treatment dose-dependently decreased placental weight and fetal bodyweight and increased the IUGR rate. Abnormal placental structures and decreased maternal plasma prolactin concentrations were observed following 180 mg/kg per day caffeine treatment, which resulted in increases in renin–angiotensin system (RAS) activity, including maternal plasma AngII concentrations and placental AT1B and AT2 receptor expression, and Bax and p53 expression, but decreases in placental Bcl-2 expression. On the basis of the results of the present study, it appears that caffeine ingestion has detrimental effects on the reproductive system and fetal development in rodents that are associated with chronic activation of the maternal and placental RAS, and induction of p53-dependent placental apoptosis.

The role of hypothyroidism in male infertility and erectile dysfunction

Abstract: Purpose: To evaluate the effect of hypothyroidism on erectile function and sperm parameters. Materials and Methods: This study was conducted on 24 patients with hypothyroidism and 66 normal individuals. Serum levels of hormones, including thyroid stimulating hormone (TSH), thyroxin (T4), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone, were measured and semen analysis was done in all the participants. Erectile function was evaluated using International Index of Erectile Function (IIEF-5) questionnaire. Results: The mean IIEF-5 total score was 11.75 [95% confidence interval (CI): 9.70 to 13.79) and 20.81 (95% CI: 20.02 to 21.6) for hypothyroid group and normal subjects, respectively ( P = .005). Furthermore, serum concentrations of PRL and seminal parameters were significantly different between two groups ( P < .001). Conclusion: Hypothyroidism adversely affects erectile function and sperm parameters, including sperm count, morphology, and motility. In patients with sperm abnormalities and erectile dysfunction, measurement of thyroid hormones is recommended.