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The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level. The genotype profile of 1936 (1931 single nucleotide polymorphisms (SNPs) and 5 copy number variation (CNVs) drug metabolism markers was obtained using the Affymetrix DMET Plus GeneChip microarray platform. Genotypes of SNPs used to test the accuracy of DMET genotype profiling were determined using TaqMan SNP Genotyping Assay kits. Eighty-four patients were selected for the allelic association study after microarray analyses (51 in the normal prolactin group, and 33 in the hyperprolactinemia group). An overlapping allelic association analysis of both analyses discovered five DMET SNPs with a suggestive association (P < 0.05) with risperidone-induced prolactin response. Three UGT1A1 SNPs (UGT1A1*80c.-364C > T, UGT1A1*93 c.-3156G > A, and UGT1A1 c.-2950A > G, showed a suggestive association with the risperidone-induced prolactin response and found to be in complete linkage disequilibrium (D′ value of 1). In this DMET microarray platform, we found three UGT1A1 variants with suggestive evidences of association with the risperidone-induced prolactin response both measured by hyperprolactinemia and by prolactin level. However, due to the lack of validation studies confirmation and further exploration are needed in future pharmacogenomic studies.

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.

Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.

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.

Background Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. Methods We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1 . Results We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. Conclusions Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

Objective To evaluate the frequency, validity, and relevance of statistically significant (P<0.05) sex-treatment interactions in randomized controlled trials in Cochrane meta-analyses.Design Meta-epidemiological study.Data sources Cochrane Database of Systematic Reviews (CDSR) and PubMed.Eligibility criteria for study selection Reviews published in the CDSR with sex-treatment subgroup analyses in the forest plots, using data from randomized controlled trials.Data extraction Information on the study design and sex subgroup data were extracted from reviews and forest plots that met inclusion criteria. For each statistically significant sex-treatment interaction, the potential for biological plausibility and clinical significance was considered.Results Among the 41 reviews with relevant data, there were 109 separate treatment-outcome analyses (“topics”). Among the 109 topics, eight (7%) had a statistically significant sex-treatment interaction. The 109 topics included 311 randomized controlled trials (162 with both sexes, 46 with males only, 103 with females only). Of the 162 individual randomized controlled trials that included both sexes, 15 (9%) had a statistically significant sex-treatment interaction. Of four topics where the first published randomized controlled trial had a statistically significant sex-treatment interaction, no meta-analyses that included other randomized controlled trials retained the statistical significance and no meta-analyses showed statistical significance when data from the first published randomized controlled trial were excluded. Of the eight statistically significant sex-treatment interactions from the overall analyses, only three were discussed by the CDSR reviewers for a potential impact on different clinical management for males compared with females. None of these topics had a sex-treatment interaction that influenced treatment recommendations in recent guidelines. UpToDate, an online physician-authored clinical decision support resource, suggested differential management of men and women for one of these sex-treatment interactions.Conclusion Statistically significant sex-treatment interactions are only slightly more frequent than what would be expected by chance and there is little evidence of subsequent corroboration or clinical relevance of sex-treatment interactions.

Rationale Hyperprolactinemia is a highly prevalent adverse effect of many antipsychotic agents, with potentially serious health consequences. Several guidelines have been developed for the management of this condition; yet, their concordance has not been evaluated. Objectives The objectives of this paper were (1) to review current clinical guidelines; (2) to review key systematic evidence for management; and (3) based on our findings, to develop an integrated management recommendation specific to male and female patients who are otherwise clinically stabilised on antipsychotics. Methods We performed searches of Medline and EMBASE, supplemented with guideline-specific database and general web searches, to identify clinical guidelines containing specific recommendations for antipsychotic-induced hyperprolactinemia, produced/updated 01/01/2010–15/09/2016. A separate systematic search was performed to identify emerging management approaches described in reviews and meta-analyses published ≥ 2010. Results There is some consensus among guidelines relating to baseline PRL screening (8/12 guidelines), screening for differential diagnosis (7/12) and discontinuing/switching PRL-raising agent (7/12). Guidelines otherwise diverge substantially regarding most aspects of screening, monitoring and management (e.g. treatment with dopamine agonists). There is an omission of clear sex-specific recommendations. Systematic literature on management approaches is promising; more research is needed. An integrated management recommendation is presented to guide sex-specific clinical response to antipsychotic-induced hyperprolactinemia. Key aspects include asymptomatic hyperprolactinemia monitoring and fertility considerations with PRL normalisation. Conclusion Further empirical work is key to shaping robust guidelines for antipsychotic-induced hyperprolactinemia. The integrated management recommendation can assist clinician and patient decision-making, with the goal of balancing effective psychiatric treatment while minimising PRL-related adverse health effects in male and female patients.

Hypogonadism, presenting with low libido, erectile dysfunction, and gynecomastia, frequently occurs in men with hyperprolactinemia, typically characterized by elevated serum prolactin, suppressed gonadotropins, and low testosterone. However, we identified a rare subset of patients who presented with normal testosterone levels, but whose clinical profiles were poorly defined. A retrospective analysis of medical records was conducted on 23 men diagnosed with idiopathic hyperprolactinemia and normal testosterone levels between 01/07/2019 and 01/12/2024. Baseline clinical characteristics, hormone levels, pituitary gland dimensions (as measured by MRI-derived pituitary height), and responses to medical treatments (bromocriptine or cabergoline) were evaluated. The mean age at diagnosis was 30.91 ± 7.66 years (range: 20-50). Mean serum prolactin at presentation was 38.22 ± 30.68 ng/mL (range: 20.00-170.93), and mean pituitary height was 6.40 ± 0.97 mm. Primary complaints at diagnosis included low libido, gynecomastia, impotence, and erectile dysfunction. Eighteen patients received bromocriptine, whereas five patients received cabergoline. After an average treatment duration of 7.83 ± 6.97 months (range: 1-29 months), prolactin levels normalized in all patients, pituitary height was significantly reduced to 4.39 ± 1.37 mm, and most patients reported notable clinical improvements, particularly in sexual function. Idiopathic hyperprolactinemia-associated hypogonadism can occasionally present with normal testosterone levels, emphasizing the importance of clinical vigilance beyond standard hormonal assessments. Pituitary height reduction may serve as an important diagnostic marker and indicator of treatment effectiveness. Medical treatment, including bromocriptine or cabergoline, with a possible preference for cabergoline based on clinical considerations, can effectively normalize hormone levels and significantly improve clinical symptoms.

Purpose Non-functioning pituitary adenomas (NFPAs) are often associated with hyperprolactinemia, which is known as the “stalk effect”. However, the relationships between hyperprolactinemia and the radiographic characteristics of the tumor that affects the pituitary stalk have not been well characterized. We aimed to identify the differences in the clinical and radiographic characteristics of patients with NFPA, with and without hyperprolactinemia. Methods We enrolled 107 patients with NFPA and allocated them to hyperprolactinemia and non-hyperprolactinemia groups using two different cut-off values: (1) the upper limit of the normal reference range, adjusted for sex and menopausal status, and (2) the upper quartile across the cohort, and compared their clinical and radiographic characteristics. These analyses were conducted to clarify the relationship between the “stalk effect” and the postoperative change in antidiuretic hormone secretion. Results The specific radiographic characteristics of the patients included the presence of a cystic or hemorrhagic tumor and the presence of pituitary stalk deviation, which were more frequent in the patients with hyperprolactinemia. Interestingly, the incidence of postoperative transient diabetes insipidus was statistically significantly higher in the hyperprolactinemia group (≥40 ng/mL) and in the group with radiologic evidence of stalk deviation, which were shown to be independent risk factors on multivariate analysis. Conclusion The presence of a “stalk effect” was associated with a higher risk of postoperative transient diabetes insipidus, reflecting perioperative pituitary stalk dysfunction following NFPA surgery, especially in patients with serum prolactin concentrations ≥40 ng/mL and radiologic evidence of stalk deviation.

Objective Transsphenoidal surgery for lactotroph pituitary neuroendocrine tumor (PitNET) lowers serum prolactin concentrations, occasionally below the normal range. However, the clinical significance of postoperative hypoprolactinemia is still unclear. In this study, we retrospectively reviewed the female patients with lactotroph PitNET who were treated with transsphenoidal surgery to elucidate the influence of postoperative hypoprolactinemia on regular menstruation restoration and endocrinological remission. Results The serum prolactin levels in all thirty three participating females had decreased following surgery. Serum prolactin levels in seven patients had decreased below the lower limit of normal ranges (hypoproactinemia group) and in the remaining twenty six patients, it was within the normal range (non-hypoproractinemia group). In hypoprolactinemia group, regular menstruation was restored in all patients with only lactotroph axis deficiency. Nine patients from the non-hypoprolactinemia group experienced re-elevation of serum prolactin concentration (27%). No patient in hypoprolactinemia group experienced the relapse of hyperprolactinemia. These data suggest that early postoperative hypoprolactinemia after transsphenoidal surgery for lactotroph PitNET is not only a good predictive factor for endocrinological remission but also no unfavorable effects on regular menstruation restoration.