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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 -
Endocrine Reviews Apr 2020Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and... (Review)
Review
Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in "normal" breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.
Topics: Breast Neoplasms; Estrogens; Female; Humans; Progesterone; Receptors, Progesterone
PubMed: 31512725
DOI: 10.1210/endrev/bnz001 -
International Journal of Molecular... Dec 2021Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of... (Review)
Review
Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored in this context. This is interesting since it has long been appreciated clinically that excessive GH serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and prominent HF defects. The outer root sheath keratinocytes have recently been shown to express functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to inhibit female human scalp HFs' growth ex vivo, likely via stimulating the expression of the catagen-inducing growth factor, TGF-β2. These limited available data encourage one to systematically explore the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core neurohormone in human skin physiology.
Topics: Female; Hair Follicle; Human Growth Hormone; Humans; Receptors, Somatotropin; Skin
PubMed: 34948002
DOI: 10.3390/ijms222413205 -
Endocrine Reviews Apr 2019The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice... (Review)
Review
The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.
Topics: Aging; Animals; Dwarfism, Pituitary; Growth Hormone; Humans; Laron Syndrome; Longevity
PubMed: 30576428
DOI: 10.1210/er.2018-00216 -
Psychotherapy and Psychosomatics 2017The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term... (Review)
Review
The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.
Topics: Antipsychotic Agents; Brain; Dopamine; Dopamine D2 Receptor Antagonists; Humans; Psychoses, Substance-Induced; Receptors, Dopamine D2
PubMed: 28647739
DOI: 10.1159/000477313 -
Nature Communications May 2020The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with...
The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1 mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.
Topics: Adult; Female; Humans; Male; Mutation; Phosphoproteins; Progression-Free Survival; Prolactin; Prolactinoma; RNA Splicing Factors; Receptors, Estrogen; Transcription Factor Pit-1; Young Adult
PubMed: 32427851
DOI: 10.1038/s41467-020-16052-8 -
Molecular Cancer Therapeutics Mar 2023Most antibody-drug conjugates (ADC) approved for the treatment of cancer contain protease-cleavable linkers. ADCs that traffic to lysosomes traverse highly acidic late...
Most antibody-drug conjugates (ADC) approved for the treatment of cancer contain protease-cleavable linkers. ADCs that traffic to lysosomes traverse highly acidic late endosomes, while ADCs that recycle to the plasma membrane traffic through mildly acidic sorting and recycling endosomes. Although endosomes have been proposed to process cleavable ADCs, the precise identity of the relevant compartments and their relative contributions to ADC processing remain undefined. Here we show that a METxMET biparatopic antibody internalizes into sorting endosomes, rapidly traffics to recycling endosomes, and slowly reaches late endosomes. In agreement with the current model of ADC trafficking, late endosomes are the primary processing site of MET, EGFR, and prolactin receptor ADCs. Interestingly, recycling endosomes contribute up to 35% processing of the MET and EGFR ADCs in different cancer cells, mediated by cathepsin-L, which localizes to this compartment. Taken together, our findings provide insight into the relationship between transendosomal trafficking and ADC processing and suggest that receptors that traffic through recycling endosomes might be suitable targets for cleavable ADCs.
Topics: Humans; Immunoconjugates; Antibodies; Cancer Vaccines; Endosomes; ErbB Receptors
PubMed: 36861363
DOI: 10.1158/1535-7163.MCT-22-0414 -
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 -
Future Science OA Oct 2021Migraine is an incapacitating neurological disorder that predominantly affects women. Sex and other hormones (e.g., oxytocin, and prolactin) may play a role in sexual... (Review)
Review
Migraine is an incapacitating neurological disorder that predominantly affects women. Sex and other hormones (e.g., oxytocin, and prolactin) may play a role in sexual dimorphic features of migraine. Initially, prolactin was recognized for its modulatory action in milk production and secretion; later, its roles in the regulation of the endocrine, immune and nervous systems were discovered. Higher prolactin levels in individuals with migraine were found in earlier studies, with a female sex-dominant trend. Studies that are more recent have identified that the expression of prolactin receptor in response to neuronal excitability and stress depends on sex with a dominant role in females. These findings have opened up potentials for explanation of sex-related pathophysiology of migraine, but have left some unanswered questions. This focused review examines the past and present of the link between prolactin and migraine, and presents open questions and directions for future experimental and clinical efforts.
PubMed: 34737888
DOI: 10.2144/fsoa-2021-0047