From pituitary cells to prostate gland in health and disease: direct and indirect endocrine connections

Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 https://doi.org/10.1007/s11154-025-09948-7 Abbreviations ACTH Adrenocorticotropic Hormone AR Androgen Receptor AVP Arginine Vasopressin AVPR1A Arginine Vasopressin Receptor 1A AVPR1B Arginine Vasopressin Receptor 1B AVPR2 Arginine Vasopressin Receptor 2 BPH Benign Prostatic Hyperplasia CRPC Castration Resistance Prostate Cancer DHT Dihydrotestosterone ER Estrogen Receptor FSH Follicle-Stimulating Hormone FSHR Follicle-Stimulating Hormone Receptor GH Growth Hormone GHR Growth Hormone Receptor GHRH Growth Hormone (GH)-Releasing Hormone GnRH Gonadotropin-Releasing Hormone GR Glucocorticoids Receptor IGF1 Insulin-Like Growth Factor 1 LH Luteinizing Hormone LHR Luteinizing Hormone Receptor MCR1 Melanocortin Receptor 1 André Sarmento-Cabral [email protected]g Raúl M. Luque [email protected] 1 Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Avda. Menéndez Pidal s/n., Cordoba 14004, Spain 2 Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba 14014, Spain 3 ReinaSofiaUniversityHospital(HURS),Cordoba 14004, Spain 4 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 5 Board of Governors Regenerative Medicine Institute, CedarsSinai Medical Center, Los Angeles, CA 90048, USA 6 Faculty of Health Sciences, Alfonso X el Sabio University, Villanueva de la Cañada 28691, Spain 7 Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain 8 CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba 14004, Spain Abstract The prostate gland is an endocrine-sensitive organ responding to multiple stimuli. Its development and function are regulated by multiple hormones (i.e. steroids such as androgens, estrogens and glucocorticoids) but also by other key hormonal systems such as those comprised by insulin-like growth factor 1 and insulin, which are sourced by different tissues [e.g. testicles/adrenal-gland/adipose-tissue/liver/pancreas, etc.). Particularly important for the endocrine control ofprostaticpathophysiologyandanatomyarehormonesproducedand/orsecretedbydifferentcelltypesofthepituitary gland [growth-hormone, luteinizing-hormone, follicle-stimulating hormone, and prolactin, oxytocin, arginine-vasopressin andmelanocyte-stimulatinghormone],whichaffectprostateglandfunctioneitherdirectlyorindirectlyunderphysiological and pathophysiological conditions [e.g. metabolic dysregulation (e.g. obesity), and prostate transformations (e.g. prostate cancer)]. This review summarizes the impact of all pituitary hormone types on prostate gland under these diverse conditions including in vivo and in vitro studies. Keywords Prostate · Pituitary · Hormones · Endocrine regulation · Prostate cancer · Obesity Accepted: 27 January 2025 / Published online: 6 February 2025 © The Author(s) 2025 From pituitary cells to prostate gland in health and disease: direct and indirect endocrine connections AndréSarmento-Cabral1,2,3 · Antonio C.Fuentes-Fayos1,2,4,5 · Fernando MataOrdoñez1,2,3,6 · Antonio J.León-González1,2,3,7 · Antonio J.Martínez-Fuentes1,2,3,8 · Manuel D.Gahete1,2,3,8 · Raúl M.Luque1,2,3,8 1 3 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 MCR2 Melanocortin Receptor 2 MCR3 Melanocortin Receptor 3 MCR4 Melanocortin Receptor 4 MCR5 Melanocortin Receptor 5 MSH Melanocyte-Stimulating Hormone OXT Oxytocin OXTR Oxytocin Receptor PCa Prostate Cancer PRL Prolactin PRLR Prolactin Receptor STAT5 Signal Transducer and Activator of Transcription 5 T3 Triiodothyronine T4 Thyroxine TSH Thyroid Stimulating Hormone TSHR Thyroid Stimulating Hormone Receptor 1 Introduction The endocrine system is comprised by multiple glands and organs that produce and secrete a wide variety of regulatory hormones (Fig. 1), which play a critical role in regulating whole-body homeostasis and controlling the development and maintenance of almost all tissues and organsinthebody.Specifically,themostrelevantendocrine organs are the hypothalamus [that produces among others, thyrotropin-releasing hormone, dopamine, growth hormone (GH)-releasing hormone (GHRH), somatostatin, gonadotropin-releasing hormone (GnRH), and corticotropin-releasing hormone [1]], the pineal gland [that produces melatonin [2]], the thyroid gland [that produces triiodothyronine, thyroxine, calcitonin [3]], the pancreas [that produces insulin, glucagon, somatostatin, ghrelin, pancreatic polypeptide, etc [4]], the adrenal glands [that produces glucocorticoids, mineralocorticoids, androgens, adrenaline, noradrenaline, dopamine, etc [5]], the liver [insulin-like growth factor 1 (IGF1), Vitamin D and Angiotensinogen, etc [6]], the adipose tissue [that produces estrogens, multiple adipokines (e.g. leptin, adiponectin, resistin, etc.), etc [7]], the stomach [that secretes somatostatin, ghrelin, etc [8]] or the gonads [that secrete androgens, estrogens, etc [9]]. However, among all endocrine tissues, the pituitary gland is considered as the “master gland” since it produces and secretes a series of key hormones that control the homeostasis and hormonal production of most endocrine organs and tissues [Fig. 2; i.e. GH, adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), thyroid stimulating hormone (TSH), melanocyte-stimulating hormone (MSH), oxytocin (OXT), and arginine vasopressin (AVP) [10]]. 2 The pituitary gland The pituitary gland is a fundamental regulator of a plethora of relevant physiological functions such as growth, reproduction, puberty, lactation, metabolism, stress response, whole-body endocrine homeostasis, etc. This gland is located in a depression in the sphenoid bone, the sella turcica, at the base of the brain, and is comprised of the adenohypophysis (also known as anterior pituitary, which consists of the anterior lobe and intermediate, or pars intermedia) and the neurohypophysis (posterior lobe, or posterior pituitary). Anterior and posterior pituitary lobes are two distinct structures from the morphological and functional point of view, but exhibit a strong developmental and functional interplay [11] (Fig. 2). The posterior pituitary gland is responsible for storing and releasing hormones produced by the hypothalamus [i.e. AVP, with actions on kidneys; and OXT, responsible for contractions of the uterus during labor] (Fig. 2). On theotherhand,theanteriorpituitarycountswithfivedifferent cell types responsible for the synthesis and release of seven fundamental hormones, involved in the development and homeostasis of multiple tissues/organs as well as in the regulation of the plethora of relevant physiological functions (Fig. 2).Specifically:(i)somatotropecellssynthesize and secret GH, essential for somatic growth and tissue development, among other metabolic functions; (ii) gonadotrope cells are responsible for the synthesis and release of FSH and LH, important hormones for the regulation of the reproductive function and the proper prostate function; (iii) lactotroph cells synthesize and secret PRL, essential for mammary gland development and milk production during breastfeeding; (iv) corticotrope cells are the main responsible for the production and release of ACTH and MSH (the last one also secreted by the pars intermedia of the pituitary gland), which are crucial for the regulation of adrenal gland function and skin darkness, respectively; and, (v) finally, thyrotrope cells synthesize and secret TSH, responsible for the proper functioning of the thyroid [extensively reviewed in [12, 13]]. Tofinelyregulatetheproductionandsecretionofthese hormones and to appropriately exert all these functions, the pituitary gland receives, processes and integrates both central (mainly hypothalamic) and peripheral signals produced and secreted by numerous tissues and organs [10, 14]. These central and peripheral regulators signal through specific receptors on the pituitary gland, which comprehensively conveys this information to appropriately control the function of multiple key target organs [extensively reviewed in [12, 14–18]], including the prostate gland. 1 3 188 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 3 Prostate gland as a component of the endocrine system The prostate is an oval-shaped gland located between the bladder and the penis and with the size of a walnut (approximately 4 cm wide and 3 cm thick), which is part of the male reproductive system. This gland is responsible for the production and secretion into the urethra, during ejaculation, of afluidthatnourishesandprotectsthesperm[19, 20]. In the endocrine context, the prostate has been classically considered an exocrine gland that depends on other hormones (i.e. steroids) to maintain its size and normal secretory function. However, it is becoming evident that the prostate can also act as an endocrine, paracrine, and autocrine organ producing a variety of regulatory factors (i.e. hormonessuchasandrogensandestrogens)thatcaninfluence the growth and function of the prostate itself, but also of other organs [21, 22]. In fact, prostate gland development and function are regulated by multiple hormones [i.e. steroids hormones such as androgens, estrogens and glucocorticoids [19–21, 23, 24]] producedbydifferenttissues[e.g.testicles,adrenalgland, Fig. 1 Main endocrine system comprised by glands and organs, which produce and/or secrete a wide variety of hormones. ACTH - Adrenocorticotropic Hormone; ADR - Adrenalin; As - Androgens, AVP - Arginine Vasopressin; CRH - Corticotropin Releasing Hormone; DA - Dopamine; FSH - Follicle Stimulating Hormone; GCs - Glucocorticoids; GH -Growth Hormone; GHRH - Growth Hormone Releasing Hormone; GHRL - Ghrelin; GLUC - Glucagon; GnRH - Gonadotropin Releasing Hormone; IGF1 - Insulin-Like Growth Factor 1; IGFBPs - Insulin-Like Growth Factor Biding Proteins; INS - Insulin; LH - Luteinizing Hormone; MCs - Mineralocorticoids; MSH - Melanocyte Stimulating Hormone; NA - Noradrenaline; OXT - Oxytocin; PRL - Prolactin; SST - Somatostatin; T3 - Triiodothyronine; T4 - Thyroxine; TRH - Thyrotropin Releasing Hormone; TSH - Thyroid StimulatingHormone.ThisfigurewascreatedwithBioRender.comandwith Microsoft PowerPoint 365 1 3 189 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 estrogens, and glucocorticoids exert their actions at the prostate level via binding their cognate nuclear receptors (AR, ER and GR, respectively), thus regulating prostate function [29–32]. Hence, although the physiological role of glucocorticoids as regulators of prostatic biology is still unclear [33], the actions of androgens (mainly produced by the testicles) and estrogens (mainly produced in the adipose tissue) are crucial for prostate development, growth, and function [Fig. 3 [20, 34, 35]]. However, novel information from both human prostatic pathologies and animal models indicates that the endocrine control of prostatic pathophysiology is not as simple and straightforward as originally envisioned and might involve a wide variety of factors produced by other endocrine organs (e.g. adipose tissue, liver, pancreas, etc.) such asinsulin,IGF1,differentadipokinesandmicroRNAs,and adipose tissue, etc [25, 26]; Fig. 3]. In this regard, androgens are classically considered to be the most important hormones controlling prostate gland homeostasis, development, and function. The control of androgens production is highly complex since it is the result of a crosstalk between the hypothalamus, the pituitary gland, and the testicles (responsible for the production of 95% of the testosterone) [25, 27], but also with the participation of the adrenal glands, which, besides being the main source of glucocorticoids, also produce additional androgenic hormones as androstenedione and dehydroepiandrosterone [26]. In this sense, the majority of estrogens present in men are derived from the peripheral conversion, mainly in the adipose tissue, of androstenedione and testosterone to estrone and estradiol [28], however, estrogens have been also reported to be produced in the testicles [29]. As a result, androgens, Fig. 2 Representative model summarizing anatomy of pituitary gland andmain(well-known)whole-bodyactionsofthedifferenthormones synthetized and/or secreted by the anterior and posterior pituitary gland. ACTH - Adrenocorticotropic Hormone; AVP - Arginine Vasopressin; FSH - Follicle Stimulating Hormone; GH -Growth Hormone; LH - Luteinizing Hormone; MSH - Melanocyte Stimulating Hormone; OXT - Oxytocin; PRL - Prolactin; TSH - Thyroid StimulatingHormone.ThisfigurewasgeneratedusingServierMedicalArt, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license, with BioRender.com, and with Microsoft PowerPoint 365 1 3 190 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 Although this hormonal therapy is especially effective when combined with radical therapeutic approaches such as radiotherapy, approximately 20% of the patients under this therapy will eventually develop resistance, progressing to a phenotype known as castration resistance prostate cancer (CRPC) [45–47], with limited therapeutic options. The main accepted risk factors contributing to PCa are older age, ethnic origin, and genetic predisposition [44, 48, 49]; however, hormonal changes and endocrine disruptors [36, 44, 50–54], as well as oxidative stress, diet and obesity [37, 55, 56], have also been associated with PCa risk and aggressiveness. This plethora of risk factors and molecular alterations associated with PCa development may be related to the high intra-tumoral complexity and heterogeneity observed in PCa [57]. Nonetheless, as previously mentioned, the identification of a growing number of central and peripheral prostate gland regulators supports the view that the control of prostate function is more complex than originally envisioned. In this scenario, and as will be described below, there is growing evidence indicating that most of the pituitary hormones, secretedbythedifferentpituitarycelltypes,candirectlyand indirectlyinfluencetheprostateglandhomeostasis. particularly from the pituitary gland, which also is a source of important direct or indirect regulators of the function of prostatic cells under both physiological and pathological conditions [19–21, 23, 24, 36–41]. 4 Understanding prostate changes and conditions The prostate gland is about the size and shape of a walnut but, prostate enlargement is a very common condition associatedwithagingwhichcanbeaccompaniedbydifferent prostate gland disorders [42]. In fact, prostate disorders are common, particularly in men aged over 50, and include inflammation(prostatitis),enlargedprostate[benignprostatic hyperplasia (BPH)], and prostate cancer (PCa). Despite prostatitis and BPH are non-tumoral pathologies, these conditions are associated with an increased risk to develop PCa [43], being this tumoral pathology the second most common cancer among male population worldwide [44]. In fact, PCa is highly dependent on androgen signaling, being androgen deprivation therapy the main pharmacological approach for treating PCa, inhibiting systemic androgen production. Fig. 3 Direct regulation of prostate gland cells by hormones produced at the testicles (testosterone), adipose tissue (estrogens) and the adrenal gland (Glucocorticoids). AR - Androgen Receptor; ER - Estrogen Receptor;GR-GlucocorticoidReceptors.Thisfigurewascreatedwith BioRender.com and with Microsoft PowerPoint 365 1 3 191 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 6 Oxytocin OXT is produced by the hypothalamus and released by the posterior pituitary gland [12]. Classically associated with uterus contraction and milk ejection, this hormone has also important actions on other organs through the activation of itsspecificreceptor(OXTR)[58]. In fact, it has been documented that OXT acts on several male reproductive system tissues [58]. At the prostate level, a considerable amount of OXT mRNA has been detected [59]. In line with this, some reports have indicated that OXT could be important in the ejaculation process helping the contraction and tone of the prostate gland [60, 61].Moreover,different OXTantagonists have recently been shown to reduce prostate contractility, which could be important for the premature ejaculation condition and to reduce involuntary contractions that may causedifficultiesinurinating[61–64] (Fig. 4). Notably, some studies have shown increased levels of OXT in plasma of PCa patients compared to controls without PCa [65], which might be involved in favoring the production of testosterone and its conversion to dihydrotestosterone 5 Pituitary control of prostate gland under physiological and pathological conditions Asmentionedabove,thepituitaryglandfinelycontrolsthe physiologyofdifferenttissuesthroughthesecretionofmultiple hormones, specially OXT and AVP from the posterior pituitary gland, and GH, FSH, LH, PRL,ACTH, MSH-α andTSH,producedandsecretedfromdifferentcelltypesof the anterior pituitary gland. These hormones exert a direct actionactivatingtheirspecificreceptorsinthetargettissues ormayalsopresentindirecteffectsthroughthemodulation of other endocrine systems. This is the case of prostate gland whereindifferentpituitaryhormones(OXT,AVP,LH,FSH, PRL, GH, ACTH, MSH and TSH) can exert direct (Fig. 4) or indirect (Fig. 5) actions as summarized below. Fig. 4 Summary of the DIRECT actions of different pituitary hormones on prostate gland. ACTH - Adrenocorticotropic Hormone; AVP - Arginine Vasopressin; AVPR - Arginine Vasopressin Receptor; FSH - Follicle Stimulating Hormone; FSHR - Follicle Stimulating Hormone Receptor; GH - Growth Hormone; GHR - Growth Hormone Receptor; LH - Luteinizing Hormone; LHR - Luteinizing Hormone Receptor; MC2R - Melanocortin Receptor 2; MSH - Melanocyte Stimulating Hormone; OXT - Oxytocin; OXTR - Oxytocin Receptor; PRL - Prolactin; PRLR - Prolactin Receptor; TSH - Thyroid Stimulating Hormone; TSHR - Thyroid Stimulating Hormone Receptor. BPH -BenigneProstateHyperplasia;PCa-Prostatecancer.Thisfigurewas created with BioRender.com and with Microsoft PowerPoint 365. * Cell line dependent, **Cell line dependent, contradictory results 1 3 192 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 7 Arginine vasopressin AVP, also known as antidiuretic hormone, is mainly produced by the hypothalamus and stored in the posterior pituitary gland. The actions of this hormone are mediated by threespecificreceptors[i.e.AVPR1A,AVPR1BandAVPR2 [73]], which are expressed in several tissues. Besides the well-known effects of AVP on blood pressure and water reabsorption in the kidneys, it has also been shown to impact many other mechanisms, including the modulation ofpainperception,inflammationandcellproliferation,and also in metabolism and diabetes, [extensively reviewed in [73]]. However, with the exception of the contractile function [74] (Fig. 4), little is known about AVP actions on normal prostate function. The expression of considerable amounts of AVPR1A mRNA has been recently reported in different PCa cell lines [75]. Specifically, expression of AVPR1A has been detected in 22Rv1, CWR-R1, C4-2B, and LNCaP-abl, but not in PC-3, DU145, LNCaP, nor in normal prostate-derived cells RWPE-1. Moreover, the knocking-out of this receptor resulted in decreased proliferation in castration resistant prostate cancer cell lines 22Rv1, CWR-R1, C4-2B, and LNCaP-abl, while overexpression of AVPR1A in LNCaP (DHT) [60]. Thus, OXT could indirectly sensitize prostate glandcellstoandrogenssinceDHThashigheraffinityfor AR than testosterone [30], particularly in vitro this phenomenon was observed in LNCaP cells but not in PC-3 PCa cells [66]. Moreover, it has been shown that DHT and estrogens increased the OXT levels in primary BPH cell cultures promoting a positive feedback [67] (Fig. 5). Of note, immunohistochemistry studies in BPH tissues [68] and PCa samples [65] showed an increased expression of OXTR compared to normal prostate tissues. In this context, it has been suggested that OXT could have an important role in prostate gland growth and BPH development [69]. In fact, in vitro studies have shown that OXT treatment increased the proliferation rate of non-tumoral human prostate cell lines (RWPE and WPMY) [68, 70]. Accordingly, mice treated with OXT showed an enlargement of prostate gland when compared to non-treated control mice [70]. Controversially, anotherstudyreportednoeffectsofOXTonnormalhuman prostate epithelial cells [70]. Regarding tumoral behavior, treatment with OXT in vitro has been shown to increase the proliferation of LNCaP cells and decreased the apoptosis rates in both LNCaP and PC-3 PCa cells [65, 71]. Moreover, OXT promoted PC-3 cell migration, but did not impact this parameter on DU145 PCa cells [72] (Fig. 4). Fig. 5 SummaryoftheINDIRECTactionsofdifferentpituitaryhormones on prostate gland. ACTH - Adrenocorticotropic Hormone; AR - Androgen Receptor; BPH - Benign prostatic hyperplasia; DHT - Dihydrotestosterone; FSH - Follicle Stimulating Hormone; GH -Growth Hormone; IGF1 - Insulin-Like Growth Factor 1; IGF1R - Insulin-Like Growth Factor 1 Receptor; LH - Luteinizing Hormone; OXT - Oxytocin; PRL - Prolactin; T - Testosterone; T3 - Triiodothyronine; T4 - Thyroxine; TRs - Thyroid Hormone Receptors; TSH - Thyroid Stimulating Hormone; BPH - Benigne Prostate Hyperplasia; PCa - Prostate cancer. ThisfigurewascreatedwithBioRender.comandwithMicrosoftPowerPoint 365. *cell line dependent 1 3 193 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 As recently reviewed, LH and FSH have been associated with PCa [81]. Specifically, FSH was shown to stimulate proliferation in BPH primary cell cultures [80], being FSHR overexpressed in PCa compared to BPH [81]. In addition, serum FSH levels were positively associated with extraprostatic tumor development [82]. In the same line, a study proposed that exogenous FSH administration could increase xenograft tumors of androgen-independent human PC-3 PCa cells [in castrated mice with endogenous FSH suppression (degarelix-treated, a GnRH antagonist) or in castrated mice], and in androgen-independent human prostate cancer cells DU-145 (in degarelix treated mice) [83]. On the other hand, high baseline LH plasma levels were associated with worse PCa prognosis [84]. Indeed, LH was capable to stimulate proliferation and maintain androgen receptor expression in LNCaP and 22RV1 cells [85]. Furthermore, treatment with LH stimulated androgen production in LNCaP cells [85], and higher circulating levels of LH inhumanswereassociatedwithincreasedProstateSpecific Antigen (PSA) levels and a worse prognosis [84] (Fig. 4). Therefore,despitethewell-knownindirecteffectofLH and FSH on prostate gland via androgens, limited but solid evidenceisavailablesupportingadirecteffectofthesetwo pituitary hormones on normal or tumoral prostate gland cells. 9 PRL PRL, secreted by lactotrope cells, is a well-known key player in lactation and mammary gland physiology in females. Additionally, PRL also participates in the normal development, growth and function of the prostate gland [86]. In fact, the discovery that human prostate expresses PRL-receptor (PRLR; a non-kinase single-pass transmembrane receptor) demonstrates that this organ might be a direct target of PRL [87]. Furthermore, PRL expression has also been demonstrated in the prostate itself, suggesting that this hormone might additionally act as a local growth factor via an autocrine or paracrine mechanism, distinct from its classical endocrine path [87]. Moreover, it has been demonstrated that PRL treatment directly stimulates cell proliferation in normal prostate explants organ cultures [87], and inhibits apoptosis of prostate epithelial cells in rats [88]. Interestingly,micewithoverexpressionofratPRL,specificallyon prostate gland (Pb-PRL mice), showed an enlargement of this gland, comparable to a BPH state [89, 90], supporting the autocrine importance of PRL in prostate (patho)physiology. Complementarily, the Pb-PRL transgenic mice with ubiquitous expression of PRL (Pb-PRL and Met-Δ1–9G129R-hPRL double transgenic mouse model) presented a reduction in STAT5 activation and cell proliferation when cells resulted in increased proliferation (in absence of androgen) and increased subcutaneous xenograft tumor growth in castrated mice. Furthermore, in vivo treatment with an AVPR1Aantagonist(Relcovaptan)resultedeffectiveinthe control of orthotopic and subcutaneous xenograft tumors growth after mice castration, suggesting that the stimulation of this receptor promotes tumor growth in castration resistant PCa [75] (Fig. 4). On the other side, the AVPR2 receptor is also expressed in PCa cells. Indeed, agonists of this receptor have been shown to reduce proliferation, doubling time and migration ofPC-3cells,indicatingapotentialantitumoraleffectofthe activation of this receptor [76]. Another study supported the same results showing that desmopressin treatment, a synthetic analog of AVP that binds to AVPR2, blocked proliferation in PC-3 and LNCaP cells, but only impacted the migration and invasion capacity of PC-3 cells, and prevented tumor growth in PC-3 xenografts [77] (Fig. 4). Therefore,AVPseemstofavordifferenttumoralbehaviors depending on the activated receptor. Overall, these data could suggest an oncogenic role for the activation of AVPR1A,whereasananti-tumoraleffectisobservedwhen AVPR2 is activated, and the expression ratio of these receptors may help to predict the evolutions of PCa. Contrary, a recent study presented contradictory results since showed that desmopressin could increase LNCaP, C4-2B and 22Rv1 cell proliferation, and the inhibition of AVPR2 (with Tolvaptan) and AVPR1A (with Relcovaptan), alone or combined, were able to reduce C4-2B xenograft tumors in mice [78] (Fig. 4). 8 LH/FSH It is widely accepted that the endocrine control of male reproductive system (i.e. testicles, prostate, etc.) is primarily regulated by the neuroendocrine activity of the hypothalamic-pituitary axis [17].Specifically,LHandFSHare secreted in a pulsatile fashion and mediate their actions at the level of the testicles (i.e. production and secretion of testosterone) via specific transmembrane receptors [LHR (predominantly expressed in the interstitial Leydig cells) and FSHR (predominantly expressed in the Sertoli cells within the seminiferous cords/tubules), respectively]. Moreover, although testosterone produced from the testicles, in response to LH signaling, is one of the major regulators of prostate function [79] (Fig. 5), it has also been described that LHR and FSHR are also expressed at the prostate gland level [80], suggesting that both pituitary hormones might also act directly on the prostate gland, acting locally as hormones and growth factors. 1 3 194 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 apoptosis, regulated the expression of cancer-related genes in PTEN-P2, PTEN-CaP2, PTEN-P8, and PTEN-CaP8 cells [106], and increased LNCaP cells migration and invasion capacity [107] (Fig. 4). In addition, GH was not only shown to be essential for prostate gland homeostasis, regulating its development [39, 40], but also for the local expression of IGF1 and its receptor (IGF1R) [94, 104, 108]. In this line, GH/IGF1 axis acts as an important regulatory system in prostate disorders and PCa development [37, 109–111]. In this sense, systemic and locally produced IGF1 can play an important role in prostate glandfunctionregulatingcellproliferation,differentiation and also apoptosis [37, 41, 106, 112], acting as a paracrine and/or autocrine factor. In fact, prostate gland and different PCa cell lines express both GHR and IGF1R [37]. In fact, IGF1 treatment was able to increase the proliferation in PC-3 and LNCaP cells and the migration rate in PC-3 cells [37] (Fig. 5). Interestingly enough, acromegaly in male patients, a disease characterized by hypersecretion of GH by the pituitary gland and as consequence increased plasma IGF1 levels, was associated with a 33% increased risk of the diagnosis of PCa [113]togetherwiththeincidenceofdifferent prostate conditions [reviewed in [103]]. Of note, human GH also has the capacity to activate PRLR [114], which signals through STAT5, suggesting that both GH and PRL could have a common participation in PCa development [88]. Interestingly, it was found that GH treatment stimulated AR synthesis at the prostate level, indicating that GH might act on this gland by potentiating the effectsofandrogens[94] (Fig. 5). On the other way around, androgens have been also shown to modulate GH synthesis and secretion in somatotroph cells [115], suggesting the existence of regulatory loop between the gonads and the somatotroph cells. 11 ACTH and MSH ACTH and MSH, secreted by corticotrope cells, are essential for the adrenal gland function and skin darkness, respectively [reviewed in [12, 13]]. Although ACTH and MSH exertdifferentroles,bothhormonesaregeneratedfromthe same mRNA transcript (proopiomelanocortin), suffering post-translational processing generating ACTH, α-MSH, β-MSHandγ-MSH(beingα-MSHthemostrelevantamong MSH products). These hormones exert their function activatingthemelanocortinreceptors(MCRs1-5)withdifferent affinities.Specifically,ACTHbindstoMC1RandMC2R, whereas MSH binds to MC-1R, -3R, -4R and −5R [13]. Despite the well-known roles of these hormones, there are limited and/or inconclusive studies addressing the role of ACTH and MSH on prostate gland function. Indeed, to the compared with the prostate glands from Pb-PRL mice [90]. In fact, a potential prooncogenic role PRL in 22Rv1 and VCaP PCa cells has been suggested in vitro [91], indicating a putative connection between prostate tumorigenesis and excessive local PRL production. In this sense, it has been shownthattheantiapoptoticandproliferativeeffectsofPRL in PCa cells might be either direct (STAT5-mediated) [91, 92] (Fig. 4) or indirect [93] (Fig. 5), implying PRL-induced expression of receptors for growth factors such as IGF1R or AR [94]. However, these effects seem to be cell-line dependent since PRL induced apoptosis in LNCaP cells but hadnoeffectsonPC3cells[95].Nevertheless,theeffects of PRL at the prostate gland level may be rather autocrine than paracrine since neither the PRL levels in plasma are not increased in PCa nor the PRLR is overexpressed in PCa samples compared to non-tumoral samples [86]. Despite theabsenceofdifferencesofPRL(inplasma)orPRLR(in tissue) between PCa patients and healthy subjects, it was recently reported that metastatic CRPC patients with low PRL plasma levels had a better response to abiraterone treatment when compared to patients with high PRL plasma levels, suggesting a predictive value of PRL plasma levels of the response to abiraterone treatment [96]. Curiously, it has been proposed that prostate gland could be involved in the regulation of serum levels of different pituitaryhormones.Specifically,subcutaneousadministration of prostate extracts was able to restore PRL and FSH plasma levels of castrated and prostatectomized rats [97], which further suggests the presence of a direct regulatory feedbackloopbetweentheprostateanddifferentpituitary cell types. 10 GH GH, secreted by the somatotropic cells in a pulsatile pattern, is a fundamental regulator of a plethora of relevant physiological functions such as growth, metabolism, wholebody endocrine homeostasis, reproduction, etc [98–100]. Moreover, GH and IGF1 [mainly secreted by the liver in response to GH [101]] system have been also shown to exert an important regulatory role in the development and homeostasis of prostate gland under normal and pathophysiological conditions [39, 40, 102, 103] (Figs. 4 and 5). Particularly, it has been demonstrated that prostate glands and human PCa cell lines (LNCaP, PC-3, MAT-Lu, MATLyLu, and Pif-1) express GH receptor (GHR) [37, 104]. Moreover, the transcription factor STAT5, activated by GH, has been shown to be upregulated in PCa promoting growth and metastatic behavior in vitro and in vivo [reviewed in [105]]. Another study reported that GH could promote proliferation, while pegvisomant (a GH antagonist) reduced 1 3 195 Reviews in Endocrine and Metabolic Disorders (2025) 26:187–203 and hypothyroid status and the risk of prostate cancer. PLoS ONE.2012;7(10):e47730.h t t p s : / / d o i . o r g / 1 0 . 1 3 7 1 / j o u r n a l . p o n e . 0  0 4 7 7 3 0. 124.Krashin E, Piekiełko-Witkowska A, Ellis M,Ashur-Fabian O. ThyroidhormonesandCancer:aComprehensiveReviewofPreclinical and Clinical studies. 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