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Frontiers in Endocrinology 2022Over the last years, the metabolic role of PRL has emerged. PRL excess is known to promote weight gain, obesity, metabolic syndrome, and impairment in gluco-insulinemic... (Review)
Review
Over the last years, the metabolic role of PRL has emerged. PRL excess is known to promote weight gain, obesity, metabolic syndrome, and impairment in gluco-insulinemic and lipid profiles, likely due to the suppression of physiologic dopaminergic tone. Prolactin receptors and dopamine receptors type 2 have been demonstrated to be expressed on both human pancreatic β- cell and adipocytes, supporting a key role of prolactin and dopamine in peripheral metabolic regulation. Medical treatment with the dopamine agonists bromocriptine and cabergoline has been demonstrated to decrease the prevalence of metabolic syndrome and obesity, and significantly improve gluco-insulinemic and lipid profiles. In hyperprolactinemic men with concomitant hypogonadism, correction of hyperprolactinaemia and testosterone replacement has been proven to restore metabolic impairment. In turn, low prolactin levels have also been demonstrated to exert a detrimental effect on weight gain, glucose and lipid metabolism, thus leading to an increased prevalence of metabolic syndrome. Therefore, PRL values ranging from 25 to 100 mg/L, in absence of other recognizable pathological causes, have been proposed to represent a physiological response to the request for an increase in metabolic activity, and nowadays classify the so-called HomeoFIT- PRL as a promoter of metabolic homeostasis. The current review focuses mainly on the effects of hyperprolactinemia and its control by medical treatment with DAs on the modulation of food intake, body weight, gluco-insulinemic and lipid profile. Furthermore, it provides the latest knowledge about the metabolic impact of hypoprolactinemia.
Topics: Bromocriptine; Cabergoline; Dopamine; Dopamine Agonists; Glucose; Humans; Hyperprolactinemia; Lipids; Male; Metabolic Syndrome; Obesity; Prolactin; Receptors, Dopamine; Receptors, Prolactin; Testosterone; Weight Gain
PubMed: 36237192
DOI: 10.3389/fendo.2022.1015520 -
Nature Reviews. Endocrinology Jun 2019The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the... (Review)
Review
The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.
Topics: Animals; Female; Genetic Pleiotropy; Health Status; Homeostasis; Humans; Hyperprolactinemia; Osteoporosis; Prolactin; Receptors, Prolactin
PubMed: 30899100
DOI: 10.1038/s41574-019-0194-6 -
Molecular and Cellular Endocrinology Feb 2020Prolactin is pleotropic in nature affecting multiple tissues throughout the body. As a consequence of the broad range of functions, regulation of anterior pituitary... (Review)
Review
Prolactin is pleotropic in nature affecting multiple tissues throughout the body. As a consequence of the broad range of functions, regulation of anterior pituitary prolactin secretion is complex and atypical as compared to other pituitary hormones. Many studies have provided insight into the complex hypothalamic-pituitary networks controlling prolactin secretion patterns in different species using a range of techniques. Here, we review prolactin secretion in both males and females; and consider the different patterns of prolactin secretion across the reproductive cycle in representative female mammals with short versus long luteal phases and in seasonal breeders. Additionally, we highlight changes in the pattern of secretion during pregnancy and lactation, and discuss the wide range of adaptive functions that prolactin may have in these important physiological states.
Topics: Animals; Female; Humans; Lactation; Luteal Phase; Male; Pregnancy; Prolactin
PubMed: 31843563
DOI: 10.1016/j.mce.2019.110679 -
Pharmacology & Therapeutics Jul 2023Women experience chronic pain more often than men with some pain conditions being specific to women while others are more prevalent in women. Prolactin, a neuropeptide... (Review)
Review
Women experience chronic pain more often than men with some pain conditions being specific to women while others are more prevalent in women. Prolactin, a neuropeptide hormone with higher serum levels in women, has recently been demonstrated in preclinical studies to sensitize nociceptive sensory neurons in a sexually dimorphic manner. Dysregulation of prolactin and prolactin receptors may be responsible for increased pain especially in female predominant conditions such as migraine, fibromyalgia, and pelvic pain. In this review, we focus on the role of prolactin in endometriosis, a condition characterized by pelvic pain and infertility that affects a large proportion of women during their reproductive age. We discuss the symptoms and pathology of endometriosis and discuss how different sources of prolactin secretion may contribute to this disease. We highlight our current understanding of prolactin-mediated mechanisms of nociceptor sensitization in females and how this mechanism may apply to endometriosis. Lastly, we report the results of a systematic review of clinical studies conducted by searching the PubMed and EMBASE databases to identify association between endometriosis and blood levels of prolactin. The results of this search strongly indicate that serum prolactin levels are increased in patients with endometriosis and support the possibility that high levels of prolactin may promote pelvic pain in these patients and increase vulnerability to other comorbid pain conditions likely by dysregulating prolactin receptor expression. Targeting of prolactin and prolactin receptors may improve management of pain associated with endometriosis.
Topics: Female; Humans; Endometriosis; Prolactin; Receptors, Prolactin; Pelvic Pain; Chronic Pain
PubMed: 37169264
DOI: 10.1016/j.pharmthera.2023.108435 -
Cell and Tissue Research Jan 2019Among the more than 300 biological actions described for prolactin, its role in the neurogenic capacity of the hippocampus, which increases synaptogenesis and neuronal... (Review)
Review
Among the more than 300 biological actions described for prolactin, its role in the neurogenic capacity of the hippocampus, which increases synaptogenesis and neuronal plasticity, consolidates memory and acts as a neuronal protector against excitotoxicity-effects mediated through its receptors are more recently known. The detection of prolactin in the hippocampus and its receptors, specifically in the Ammon's horn and dentate gyrus, opened up a new field of study on the possible neuroprotective effect of hormones in a structure involved in learning and memory, as well as in emotional and behavioral processes. It is currently known, although controversial, that prolactin may be related to sex and age and that the hormone could be synthesized in the hippocampus itself. However, the regulatory mechanisms of changes in prolactin or in its hippocampal receptors still remain unknown. This review introduces the reader to general aspects concerning prolactin and its receptors and to what is currently known about the role prolactin plays in the brain and, in particular, in the hippocampus.
Topics: Animals; Brain; Hippocampus; Humans; Neuroprotection; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 29806058
DOI: 10.1007/s00441-018-2858-2 -
Hormone and Metabolic Research =... Apr 2019Prolactin is a peptide hormone known to have multiple functions. However, the role of prolactin has been extensively studied only in female physiology and its function... (Review)
Review
Prolactin is a peptide hormone known to have multiple functions. However, the role of prolactin has been extensively studied only in female physiology and its function in male reproduction still remains majorly unexplored. Studies in rodents and humans have demonstrated the presence of prolactin and its receptor in testes, thereby suggesting a possible role during spermatogenesis. Experimental evidences from prolactin and prolactin receptor deficient male rodent models as well as studies done in hypo- and hyper-prolactinemic males hint at neuroendocrine and reproductive abnormalities. Nonetheless, there still remains a lot of ambiguity on the exact role of prolactin and its receptor in male reproduction. This review summarizes in depth on the role of prolactin in spermatogenesis.
Topics: Animals; Humans; Male; Models, Animal; Prolactin; Receptors, Prolactin; Reproduction; Signal Transduction; Testis
PubMed: 30840999
DOI: 10.1055/a-0859-1144 -
International Journal of Molecular... Oct 2016The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at... (Review)
Review
The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.
Topics: Bone Neoplasms; Bone and Bones; Breast Neoplasms; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Mammary Glands, Human; Neoplastic Cells, Circulating; Osteoblasts; Osteoclasts; Osteolysis; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 27782069
DOI: 10.3390/ijms17101764 -
Molecular Pharmaceutics Jun 2018Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and...
Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and assessing pharmacodynamic effects of drug interventions. Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy. We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine B or labeled with I-131/I-124. In vitro determination of the half-maximal inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878, and iodinated REGN2878 was performed by examining the effect of the increasing amounts of these on uptake of trace-labeled I-131 REGN2878. REGN1932, a non-PRLR binding antibody, was used as a control. Imaging and biodistribution studies were performed in mice bearing tumor xenografts with various expression levels of PRLR, including MCF-7, transfected MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines. The specificity of uptake in tumors was evaluated by comparing Zr-89 REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878 uptake in tumor xenografts with and without prior injection of 2 mg of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878 at ratios of 3.53-5.77 DFO per antibody showed IC50 values of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive xenografts at delayed times of 189 h (presented as mean ± 1 SD, percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL). In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0 ± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89 REGN2878 has excellent antigen-specific targeting in various PRLR tumor xenograft models. We estimated, using image-based kinetic modeling, that PRLR antigen has a very rapid in vivo turnover half-life of ∼14 min from the cell membrane. Despite relatively modest estimated tumor PRLR expression numbers, PRLR-expressing cells have shown final retention of the Zr-89 REGN2878 antibody, with an uptake that appeared to be related to PRLR expression. This reagent has the potential to be used in clinical trials targeting PRLR.
Topics: Animals; Antibodies, Monoclonal; Cell Line, Tumor; Female; Humans; Immunoconjugates; Mice; Mice, Nude; Molecular Imaging; Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Prolactin; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 29684277
DOI: 10.1021/acs.molpharmaceut.7b01133 -
Journal of Ovarian Research Nov 2023The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout...
The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.
Topics: Humans; Female; Animals; Mice; Polycystic Ovary Syndrome; Receptors, Prolactin; Prolactin; Diabetes Mellitus, Type 2; Infertility; Hyperandrogenism
PubMed: 37993904
DOI: 10.1186/s13048-023-01280-5 -
Pain Jun 2023Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we...
Repeated stress produces hyperalgesic priming in preclinical models, but underlying mechanisms remain uncertain. As stress engages kappa opioid receptors (KORs), we hypothesized that repeated administration of KOR agonists might mimic, in part, stress-induced hyperalgesic priming. The potential contribution of circulating prolactin (PRL) and dysregulation of the expression of PRL receptor (PRLR) isoforms in sensory neurons after KOR agonist administration was also investigated. Mice received 3 daily doses of U-69593 or nalfurafine as a "first-hit" stimulus followed by assessment of periorbital tactile allodynia. Sixteen days after the first KOR agonist administration, animals received a subthreshold dose of inhalational umbellulone, a TRPA1 agonist, as the second-hit stimulus and periorbital allodynia was assessed. Cabergoline, a dopamine D2 receptor agonist, was used to inhibit circulating PRL in additional cohorts. Prolactin receptor isoforms were quantified in the V1 region of the trigeminal ganglion after repeated doses of U-69593. In both sexes, KOR agonists increased circulating PRL and produced allodynia that resolved within 14 days. Hyperalgesic priming, revealed by umbellulone-induced allodynia in animals previously treated with the KOR agonists, also occurred in both sexes. However, repeated U-69593 downregulated the PRLR long isoform in trigeminal neurons only in female mice. Umbellulone-induced allodynia was prevented by cabergoline co-treatment during priming with KOR agonists in female, but not male, mice. Hyperalgesic priming therefore occurs in both sexes after either biased or nonbiased KOR agonists. However, a PRL/PRLR-dependence is observed only in female nociceptors possibly contributing to pain in stress-related pain disorders in females.
Topics: Male; Mice; Female; Animals; Hyperalgesia; Prolactin; Receptors, Opioid, kappa; Cabergoline; Pain; Protein Isoforms
PubMed: 36625833
DOI: 10.1097/j.pain.0000000000002835