madman
Super Moderator
Abstract
The physiological role of prolactin (PRL) in men is still not well defined. The pathological increase is characterized by sexual function impairment along with possible negative consequences in body composition and metabolic profile. Conversely, the clinical significance of reduced PRL levels was only partially investigated or mainly neglected. The present paper aims to summarize and critically discuss possible phenotypes characterizing male subjects with reduced PRL levels. When possible, meta-analytic results were provided. Available data derived from patients seeking medical care for sexual dysfunction as well as from cross-sectional and longitudinal studies showed that low PRL in males is associated with a worse metabolic phenotype (including diabetes mellitus), mood disturbances (including anxiety and depression),and sexual dysfunctions (including psychogenic erectile and ejaculatory dysfunctions). Whether or not these features are direct consequences of reduced PRL levels or whether the latter reflect other pathway impairments such as serotoninergic failure cannot be clarified. The present data, however, emphasize that a deficiency of PRL should be taken into account and need further investigations.
1 Introduction
Prolactin (PRL) is a pleiotropic 23 KDa polypeptide discovered in the early thirties of the last century and produced by many cells throughout the human body, but mainly secreted in the bloodstream from the anterior pituitary [1]. It serves many biological functions, but its main role in mammals is to favor milk production by controlling mammary gland development (mammogenesis), the onset of lactation (lactogenesis), and galactopoiesis [2]. The PRL receptor (PRLR) is a single-pass transmembrane receptor belonging to the cytokine receptor superfamily, acting through Janus Kinase (JAK) and Signal Transducer and Activator of Transcription 5 (STAT5). Although its function in women is well established, the physiological role of PRL in men is still unknown. Unlike other pituitary hormones or hormones from other endocrine glands, a clinical condition characterized by an isolated deficiency of PRL has been scarcely investigated, even in women. Recently, three cases of isolated PRL deficiency have been described in female subjects from one family with post-partum alactogenesis due to a PRL gene mutation [3]. No other phenotype was apparent, and fertility, along with normal menstrual cycling, was preserved [3].The latter finding further corroborates the essential role of PRL in milk production. Recently, several lines of evidence derived from clinical studies, reviewed elsewhere [4–6], recognize an ancillary role of PRL as a metabolic hormone involved in supporting and storing the required substances to favor mammogenesis, lactogenesis, and galactopoiesis during pregnancy and breastfeeding. Pathological excess of PRL in women mimics the scenario of pregnancy and lactation with oligomenorrhea/amenorrhea and galactorrhea, along with hypogonadotropic hypogonadism. Other metabolic correlates of hyperprolactinemia are obesity, hyperinsulinemia and insulin resistance, dyslipidemia, and altered lipolysis [4–6]. Accordingly, hyperprolactinemia was associated with an increased risk of cardiovascular(CV) and overall mortality [7], as also substantiated in a recent meta-analysis [8]. However, in men, clinical symptoms of hyperprolactinemia are scanty and mostly related to hypogonadotropic hypogonadism and sexual dysfunctions,with hypoactive sexual desire (HSD) and erectile dysfunction (ED) being the most specific correlates, as demonstrated also by a recent meta-analysis [9]. In fact, treatment of hyperprolactinemia reverted the sexual complaints [9].
Fifteen years ago, we originally described a male phenotype of hypoprolactinemia in a cohort of 2,531 men consulting for sexual dysfunction selected for being without hyperprolactinemia (PRL>35 ng/mL) or pituitary disorders [10]. The phenotype we described included increased sexual dysfunctions and a worse metabolic and psychological functioning. In this review the aim of the present paper is to critically discuss the male phenotype associated with low PRL in light of subsequent studies including also meta analytic results.
2.1 Hypoprolactinemia and sexual dysfunction
2.2 Hypoprolactinemia and psychological disturbances
2.3 Hypoprolactinemia and metabolic derangements
3 Conclusions
The hypoprolactinemic male phenotype here described is characterized by (i) a worse metabolic phenotype (including DM), (ii) increased psychological disturbances (including anxiety and depression), and (iii) sexual dysfunctions(including psychogenic ED and ejaculatory dysfunctions).These features may be the result of some deficiency in the pleiotropic action of PRL in the peripheral tissues (pancreas, adipose tissue, male accessory glands) or within the CNS. In all these tissues, PRLR was described (reviewed in [4–6, 28]). If this is the case, (over) treatment with dopaminergic medications should induce metabolic derangements, whereas a meta-analysis of trials in prolactinoma demonstrated that they reverse metabolic abnormalities [6]. In addition, in meta-analyses, dopamine agonists in T2DM significantly lowered fasting glucose and triglyceride levels, along with HbA1c, without causing severe negative effects, including CV events [73, 74]. Finally, elevating PRL levels with antidopaminergic medications is not associated with a more favorable metabolic profile, which is even worsened [64]. This evidence argues against the direct role of PRL in the hypoprolactinemic phenotype. Hence, low PRL, at the present time, cannot be considered an useful predictive marker for forthcoming T2DM.
An alternative view is that low PRL is not the cause but the consequence of conditions associated with the described phenotype. We originally hypothesized that low PRL is a mirror of events associated with a decrease in serotoninergic tone in the CNS [10–12]. Along with TRH, 5-HT is one of the main releasers of PRL at the hypothalamic level, having a negative action on tuberoinfundibular dopaminergic neurons [42]. A decrease in serotoninergic activity is by far associated with anxiety and mood disturbances [43, 66],which, are all improved by treatment with serotoninergic agents [67]. Similarly, decreased serotoninergic activity is associated with ejaculatory dysfunctions, including premature ejaculation (PE). Serotoninergic medications are considered the first-line treatment for PE [23]. The higher prevalence of psychogenic ED in hypoprolactinemia[10–12] could be the result of the increased level of anxiety, particularly somatoform anxiety [36]. Finally, mood disturbances and decreased central serotoninergic activity per se can be the cause of the worse metabolic profile here described. In the serotoninergic dorsal raphe nucleus, increased activity reduces food intake, while a reduction in 5-HT release increases food intake through a complex interaction with GABA and glutamatergic neurons ( [75, 76] see in [77] for review).
Some limitations to our view of the hypoprolactinemic male phenotype should be recognized. Our view is based mostly on results from a few centers and, in particular,mostly on subjects complaining of sexual dysfunction. In addition, all the associations characterizing the male hypoprolactinemic phenotype here described are of relatively weak magnitude, suggesting that, overall, low PRL has only an ancillary role in their determinism. However, we here propose that, as for other hormones, a deficiency of PRL could suggest to healthcare professionals an underlying phenotype that needs to be further investigated.
The physiological role of prolactin (PRL) in men is still not well defined. The pathological increase is characterized by sexual function impairment along with possible negative consequences in body composition and metabolic profile. Conversely, the clinical significance of reduced PRL levels was only partially investigated or mainly neglected. The present paper aims to summarize and critically discuss possible phenotypes characterizing male subjects with reduced PRL levels. When possible, meta-analytic results were provided. Available data derived from patients seeking medical care for sexual dysfunction as well as from cross-sectional and longitudinal studies showed that low PRL in males is associated with a worse metabolic phenotype (including diabetes mellitus), mood disturbances (including anxiety and depression),and sexual dysfunctions (including psychogenic erectile and ejaculatory dysfunctions). Whether or not these features are direct consequences of reduced PRL levels or whether the latter reflect other pathway impairments such as serotoninergic failure cannot be clarified. The present data, however, emphasize that a deficiency of PRL should be taken into account and need further investigations.
1 Introduction
Prolactin (PRL) is a pleiotropic 23 KDa polypeptide discovered in the early thirties of the last century and produced by many cells throughout the human body, but mainly secreted in the bloodstream from the anterior pituitary [1]. It serves many biological functions, but its main role in mammals is to favor milk production by controlling mammary gland development (mammogenesis), the onset of lactation (lactogenesis), and galactopoiesis [2]. The PRL receptor (PRLR) is a single-pass transmembrane receptor belonging to the cytokine receptor superfamily, acting through Janus Kinase (JAK) and Signal Transducer and Activator of Transcription 5 (STAT5). Although its function in women is well established, the physiological role of PRL in men is still unknown. Unlike other pituitary hormones or hormones from other endocrine glands, a clinical condition characterized by an isolated deficiency of PRL has been scarcely investigated, even in women. Recently, three cases of isolated PRL deficiency have been described in female subjects from one family with post-partum alactogenesis due to a PRL gene mutation [3]. No other phenotype was apparent, and fertility, along with normal menstrual cycling, was preserved [3].The latter finding further corroborates the essential role of PRL in milk production. Recently, several lines of evidence derived from clinical studies, reviewed elsewhere [4–6], recognize an ancillary role of PRL as a metabolic hormone involved in supporting and storing the required substances to favor mammogenesis, lactogenesis, and galactopoiesis during pregnancy and breastfeeding. Pathological excess of PRL in women mimics the scenario of pregnancy and lactation with oligomenorrhea/amenorrhea and galactorrhea, along with hypogonadotropic hypogonadism. Other metabolic correlates of hyperprolactinemia are obesity, hyperinsulinemia and insulin resistance, dyslipidemia, and altered lipolysis [4–6]. Accordingly, hyperprolactinemia was associated with an increased risk of cardiovascular(CV) and overall mortality [7], as also substantiated in a recent meta-analysis [8]. However, in men, clinical symptoms of hyperprolactinemia are scanty and mostly related to hypogonadotropic hypogonadism and sexual dysfunctions,with hypoactive sexual desire (HSD) and erectile dysfunction (ED) being the most specific correlates, as demonstrated also by a recent meta-analysis [9]. In fact, treatment of hyperprolactinemia reverted the sexual complaints [9].
Fifteen years ago, we originally described a male phenotype of hypoprolactinemia in a cohort of 2,531 men consulting for sexual dysfunction selected for being without hyperprolactinemia (PRL>35 ng/mL) or pituitary disorders [10]. The phenotype we described included increased sexual dysfunctions and a worse metabolic and psychological functioning. In this review the aim of the present paper is to critically discuss the male phenotype associated with low PRL in light of subsequent studies including also meta analytic results.
2.1 Hypoprolactinemia and sexual dysfunction
2.2 Hypoprolactinemia and psychological disturbances
2.3 Hypoprolactinemia and metabolic derangements
3 Conclusions
The hypoprolactinemic male phenotype here described is characterized by (i) a worse metabolic phenotype (including DM), (ii) increased psychological disturbances (including anxiety and depression), and (iii) sexual dysfunctions(including psychogenic ED and ejaculatory dysfunctions).These features may be the result of some deficiency in the pleiotropic action of PRL in the peripheral tissues (pancreas, adipose tissue, male accessory glands) or within the CNS. In all these tissues, PRLR was described (reviewed in [4–6, 28]). If this is the case, (over) treatment with dopaminergic medications should induce metabolic derangements, whereas a meta-analysis of trials in prolactinoma demonstrated that they reverse metabolic abnormalities [6]. In addition, in meta-analyses, dopamine agonists in T2DM significantly lowered fasting glucose and triglyceride levels, along with HbA1c, without causing severe negative effects, including CV events [73, 74]. Finally, elevating PRL levels with antidopaminergic medications is not associated with a more favorable metabolic profile, which is even worsened [64]. This evidence argues against the direct role of PRL in the hypoprolactinemic phenotype. Hence, low PRL, at the present time, cannot be considered an useful predictive marker for forthcoming T2DM.
An alternative view is that low PRL is not the cause but the consequence of conditions associated with the described phenotype. We originally hypothesized that low PRL is a mirror of events associated with a decrease in serotoninergic tone in the CNS [10–12]. Along with TRH, 5-HT is one of the main releasers of PRL at the hypothalamic level, having a negative action on tuberoinfundibular dopaminergic neurons [42]. A decrease in serotoninergic activity is by far associated with anxiety and mood disturbances [43, 66],which, are all improved by treatment with serotoninergic agents [67]. Similarly, decreased serotoninergic activity is associated with ejaculatory dysfunctions, including premature ejaculation (PE). Serotoninergic medications are considered the first-line treatment for PE [23]. The higher prevalence of psychogenic ED in hypoprolactinemia[10–12] could be the result of the increased level of anxiety, particularly somatoform anxiety [36]. Finally, mood disturbances and decreased central serotoninergic activity per se can be the cause of the worse metabolic profile here described. In the serotoninergic dorsal raphe nucleus, increased activity reduces food intake, while a reduction in 5-HT release increases food intake through a complex interaction with GABA and glutamatergic neurons ( [75, 76] see in [77] for review).
Some limitations to our view of the hypoprolactinemic male phenotype should be recognized. Our view is based mostly on results from a few centers and, in particular,mostly on subjects complaining of sexual dysfunction. In addition, all the associations characterizing the male hypoprolactinemic phenotype here described are of relatively weak magnitude, suggesting that, overall, low PRL has only an ancillary role in their determinism. However, we here propose that, as for other hormones, a deficiency of PRL could suggest to healthcare professionals an underlying phenotype that needs to be further investigated.
