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Since the 1970s, clinicians have increasingly become more familiar with hyperprolactinemia (HPRL) as a common adverse effect of antipsychotic medication, which remains the cornerstone of pharmacological treatment for patients with schizophrenia. Although treatment with second-generation antipsychotics (SGAs) as a group is, compared with use of the first-generation antipsychotics, associated with lower prolactin (PRL) plasma levels, the detailed effects on plasma PRL levels for each of these compounds in reports often remain incomplete or inaccurate. Moreover, at this moment, no review has been published about the effect of the newly approved antipsychotics asenapine, iloperidone and lurasidone on PRL levels. The objective of this review is to describe PRL physiology; PRL measurement; diagnosis, causes, consequences and mechanisms of HPRL; incidence figures of (new-onset) HPRL with SGAs and newly approved antipsychotics in adolescent and adult patients; and revisit lingering questions regarding this hormone. A literature search, using the MEDLINE database (1966–December 2013), was conducted to identify relevant publications to report on the state of the art of HPRL and to summarize the available evidence with respect to the propensity of the SGAs and the newly approved antipsychotics to elevate PRL levels. Our review shows that although HPRL usually is defined as a sustained level of PRL above the laboratory upper limit of normal, limit values show some degree of variability in clinical reports, making the interpretation and comparison of data across studies difficult. Moreover, many reports do not provide much or any data detailing the measurement of PRL. Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL. Considering the PRL-elevating propensity of the newly approved antipsychotics, evidence seems to indicate these agents have a PRL profile comparable to that of clozapine (asenapine and iloperidone), ziprasidone and olanzapine (lurasidone). PRL elevations with antipsychotic medication generally are dose dependant. However, antipsychotics having a high potential for PRL elevation (amisulpride, risperidone and paliperidone) can have a profound impact on PRL levels even at relatively low doses, while PRL levels with antipsychotics having a minimal effect on PRL, in most cases, can remain unchanged (quetiapine) or reduce (aripiprazole) over all dosages. Although tolerance and decreases in PRL values after long-term administration of PRL-elevating antipsychotics can occur, the elevations, in most cases, remain above the upper limit of normal. PRL profiles of antipsychotics in children and adolescents seem to be the same as in adults. The hyperprolactinemic effects of antipsychotic medication are mostly correlated with their affinity for dopamine D2 receptors at the level of the anterior pituitary lactotrophs (and probably other neurotransmitter mechanisms) and their blood–brain barrier penetrating capability. Even though antipsychotics are the most common cause of pharmacologically induced HPRL, recent research has shown that HPRL can be pre-existing in a substantial portion of antipsychotic-naïve patients with first-episode psychosis or at-risk mental state.

First-generation somatostatin analogs (SSAs), such as octreotide (OCT), are the first line medical therapy for acromegaly. Pasireotide (PAS), a newly developed SSA, has shown promising results in the treatment of acromegaly. To compare the antisecretory effect of OCT and PAS in primary cultures of growth hormone (GH)-secreting pituitary adenomas (GH-omas). To correlate responses with the adenoma somatostatin receptor (SSTR) profile. The effect of OCT and PAS on GH (and PRL) secretion was tested in 33 GH-oma cultures. SSTR expression was evaluated in adenoma samples. Patients with acromegaly referred to the Erasmus Medical Center (Rotterdam, The Netherlands). OCT and PAS treatment for 72 hours (10 nM). GH (and PRL) concentrations in cell culture media. SSTR expression in adenoma samples. The overall effect of OCT (-36.8%) and PAS (-37.1%) on GH secretion was superimposable. We identified three adenoma groups: PAS+ (PAS more effective than OCT), n = 6; PAS = OCT, n = 22; and OCT+ (OCT more effective than PAS), n = 5. PAS+ adenomas showed lower somatostatin receptor subtype (sst)2 messenger RNA (mRNA) and sst2/sst5 mRNA ratio, compared with the other groups (P < 0.05). PAS inhibited PRL hypersecretion more than OCT (P < 0.01). Overall, OCT and PAS equally reduced GH secretion in vitro. Adenomas with lower sst2 mRNA expression and lower sst2/sst5 mRNA ratio were better responders to PAS compared with OCT. SSTR evaluation in GH-omas may become a tool for tailored SSA treatment in acromegaly.

Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca 2+ signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca 2+ fluxes whereas low-quality embryos caused a heightened and prolonged Ca 2+ response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation.

We have previously shown that soluble factor(s) in conditioned media (CM) from the central and peripheral regions of the anterior pituitary (AP) gland of lactating rats promoted the in vitro dose-related release of prolactin (PRL) from pituitary glands of male rats. In the present experiments we sought to determine whether CM from rats in different physiological states provoked similar effects (like those of lactating rats), and the nature of the factors, whether 23K PRL or other variants of the hormone, were responsible for these effects. Stimulatory effects were induced by CM from pregnant females and steroid-treated castrated males or females, but not from untreated castrated rats, intact males, or by a PRL standard. More potent effects occurred with CM from APs of early- than from mid- or late-lactating rats, and from rats unsuckled for 8 or 16 h than from those unsuckled for 32 h. With respect to the nature of factor(s) responsible for these effects, immunoprecipitation of PRL from the CM of lactating females and of steroid-treated, castrated males eliminated, whereas dephosphorylation or deglycosylation of CM of lactating rats greatly increased its effects upon PRL release. Also, electrophoretic analysis and Western blotting of the CM proteins under native and denaturing conditions revealed a variety of PRL variants, ranging from 14 to <90 kDa, in CM from lactating rats, and the main effects on PRL release were provoked by the 23- to 46-kDa PRL variants. These results indicate that specific effects upon male rat lactotropes may be exerted by PRL variants released from APs of lactating and non-lactating rats.

Prolactin (PRL) secretion is quantifiable as mean, peak and nadir PRL concentrations, degree of irregularity (ApEn, approximate entropy) and spikiness (brief staccato-like fluctuations). Distinct PRL dynamics reflect relatively distinct (combinations of) subject variables, such as gender, age, and BMI. Clinical Research Unit. Seventy-four healthy adults aged 22-77 yr (41 women and 33 men), with BMI 18.3-39.4 kg/m(2). Immunofluorometric PRL assay of 10-min samples collected for 24 hours. Mean 24-h PRL concentration correlated jointly with gender (P<0.0001) and BMI (P = 0.01), but not with age (overall R(2) = 0.308, P<0.0001). Nadir PRL concentration correlated with gender only (P = 0.017) and peak PRL with gender (P<0.001) and negatively with age (P<0.003), overall R(2) = 0.325, P<0.0001. Forward-selection multivariate regression of PRL deconvolution results demonstrated that basal (nonpulsatile) PRL secretion tended to be associated with BMI (R(2) = 0.058, P = 0.03), pulsatile secretion with gender (R(2) = 0.152, P = 0.003), and total secretion with gender and BMI (R(2) = 0.204, P<0.0001). Pulse mass was associated with gender (P = 0.001) and with a negative tendency to age (P = 0.038). In male subjects older than 50 yr (but not in women) approximate entropy was increased (0.942±0.301 vs. 1.258±0.267, P = 0.007) compared with younger men, as well as spikiness (0.363±0.122 vs. 0463±2.12, P = 0.031). Cosinor analysis disclosed higher mesor and amplitude in females than in men, but the acrophase was gender-independent. The acrophase was determined by age and BMI (R(2) = 0.186, P = 0.001). In healthy adults, selective combinations of gender, age, and BMI specify distinct PRL dynamics, thus requiring balanced representation of these variables in comparative PRL studies.

Hyperprolactinemia is often attributed to pituitary adenomas; however, primary hypothyroidism is an important and often overlooked secondary cause. We report the case of a 36-year-old woman who presented with giddiness, fatigue, menstrual irregularity, and markedly elevated serum prolactin levels 339 ng/mL (SI: 339 µg/L); reference range, 5-25 ng/mL (SI: 5-25 µg/L) with normal pituitary imaging. Biochemical evaluation revealed severe primary hypothyroidism with significantly elevated thyroid-stimulating hormone levels. Treatment with levothyroxine alone resulted in clinical and biochemical improvement, confirming the diagnosis of hypothyroidism-induced hyperprolactinemia. This case highlights the importance of evaluating thyroid function in patients with hyperprolactinemia to avoid misdiagnosis and unnecessary treatment.

Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. GH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.

Cadmium (Cd) is a heavy metal of considerable occupational and environmental concern affecting wildlife and human health. Recent studies indicate that Cd, like other heavy metals, can mimic effects of 17β-estradiol (E2) involving E2 receptor (ER) activation. Lactotrophs, the most abundant cell type in anterior pituitary gland, are the main target of E2, which stimulates cell proliferation and increases prolactin secretion through ERα. The aim of this work was to examine whether Cd at nanomolar concentrations can induce cell proliferation and prolactin release in anterior pituitary cells in culture and whether these effects are mediated through ERs. Here we show that 10 nM Cd was able to stimulate lactotroph proliferation in anterior pituitary cell cultures from female Wistar rats and also in GH3 lactosomatotroph cell line. Proliferation of somatotrophs and gonadotrophs were not affected by Cd exposure. Cd promoted cell cycle progression by increasing cyclins D1, D3 and c-fos expression. Cd enhanced prolactin synthesis and secretion. Cd E2-like effects were blocked by the pure ERs antagonist ICI 182,780 supporting that Cd acts through ERs. Further, both Cd and E2 augmented full-length ERαexpression and its 46 kDa-splicing variant. In addition, when co-incubated Cd was shown to interact with E2 by inducing ERα mRNA expression which indicates an additive effect between them. This study shows for the first time that Cd at nanomolar concentration displays xenoestrogenic activities by inducing cell growth and stimulating prolactin secretion from anterior pituitary cells in an ERs-dependent manner. Cd acting as a potent xenoestrogen can play a key role in the aetiology of different pathologies of the anterior pituitary and in estrogen-responsive tissues which represent considerable risk to human health.

Mammary morphogenesis is orchestrated with other reproductive events by pituitary-driven changes to the systemic hormone environment, initiating the formation of a mammary ductal network during puberty and the addition of secretory alveoli during pregnancy. Prolactin is the major driver of development during pregnancy via regulation of ovarian progesterone production (in many species) and direct effects on mammary epithelial cells (in all species). Together these hormones regulate two aspects of development that are the subject of intense interest: (1) a genomic regulatory network that integrates many additional spatial and temporal cues to control gene expression and (2), the activity of a stem and progenitor cell hierarchy. Amalgamation of these two aspects will increase our understanding of cell proliferation and differentiation within the mammary gland, with clear application to our attempts to control breast cancer. Here we focus on providing an over-view of prolactin action during development of the model murine mammary gland.

Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both “stalk effect” hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the “stalk effect” pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.