oxytocin and Hypogonadism

Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.

Topics: Adenoma; Adrenocorticotropic Hormone; Autoimmune Hypophysitis; Brain Injuries, Traumatic; Dwarfism, Pituitary; Empty Sella Syndrome; Endocrine System Diseases; Genetic Diseases, Inborn; Humans; Hypoglycemia; Hypogonadism; Hypophysitis; Hypopituitarism; Hypothyroidism; Immune Checkpoint Inhibitors; Oxytocin; Pituitary Apoplexy; Pituitary Neoplasms; Subarachnoid Hemorrhage

Hypogonadotropic hypogonadism (HH) is a form of hypogonadism which also known as secondary or central hypogonadism. Congenital HH can occur due to defect in gonadotropin releasing hormone (GnRH) neurons, upstream regulators of GnRH neurons or pituitary gonadotropic cells. Testosterone or gonadotropins therapy are widely used to treat HH patients, however both have undesirable effects and GnRH treatment for HH patients is time and cost consuming. Direct delivery of therapeutics to the brain via the nasal route is located in the center of attention during the last decade and trial application of intranasal oxytocin as a method of enhancing social interactions are reported. It has been delineated that oxytocin stimulates GnRH release from the rat hypothalamic explants and intranasal applied oxytocin up-regulates GnRH expression in the male rat hypothalamus. Therefore application of intranasal oxytocin might be a new strategy to cure HH patients.

Topics: Administration, Intranasal; Animals; Central Nervous System; Gonadotropin-Releasing Hormone; Gonadotropins; Hypogonadism; Hypothalamus; Male; Models, Theoretical; Neurons; Oxytocin; Rats; Testosterone; Up-Regulation

Epididymis is a sex steroid (androgen + estrogen)-sensitive duct provided with spontaneous motility, allowing sperm transport. We previously reported that the oxytocin (OT) receptor (OTR) mediates an estrogen-dependent increase in epididymal contractility. Because endothelin (ET)-1 also regulates epididymal motility, we tested its sex steroid dependence in a rabbit model. We demonstrated that estrogens up-regulate responsiveness to ET-1, which is reduced by blocking aromatase activity (letrozole, 2.5 mg/kg) or by triptorelin (2.9 mg/kg)-induced hypogonadism, whereas it is fully restored by estradiol valerate (3.3 mg/kg weekly) but not by testosterone enanthate (30 mg/kg weekly). However, changing sex steroid milieu did not affect either ET-1, its receptor gene, or protein expression. Two structurally distinct OTR-antagonists [(d(CH2)5(1), Tyr(Me)(2), Orn(8))-OT and atosiban] almost completely abolished ET-1 contractility, without competing for [125I]ET-1 binding, suggesting that OT/OTR partially mediates ET-1 action. Immunohistochemical studies in human and rabbit epididymis demonstrated that both OT and its synthesis-associated protein, neurophysin I, are expressed in the epithelial cells facing the muscular layer, suggesting local OT production. Quantitative RT-PCR demonstrated a high abundance of OT transcripts in human epididymis. OT transcript was also originally detected and partially sequenced in rabbit epididymis. To verify whether ET-1 regulates OT release, we used rabbit epididymal epithelial cell cultures. These cells expressed a high density of [125I]ET-1 binding sites and responded to ET-1 with a dose-dependent OT release. Hence, we propose that an ET-1-induced OT/OTR system activation underlies the estrogen-dependent hyperresponsiveness to ET-1. These local sources might promote the spontaneous motility necessary for sperm transport.

Topics: Animals; Endothelin-1; Epididymis; Estradiol; Hypogonadism; Letrozole; Male; Muscle Contraction; Nitriles; Oxytocin; Rabbits; Rats; Triazoles; Triptorelin Pamoate

Oxytocin (OT) is released by the posterior pituitary during male orgasm and is supposed to participate in the ejaculatory process. We now report evidence demonstrating the presence of an OT receptor gene (real-time RT-PCR and Northern blot) and protein (immunohistochemistry, Western blot, and binding studies) expression in the rabbit and human corpus cavernosum (CC) and its possible involvement in postorgasmic penile detumescence. OT receptor is expressed in the penis at a concentration similar to that present in other portions of the male genital tract and mediates CC contractility. OT-induced CC contractility is clearly regulated by the changing sex steroid milieu. In fact, we found that in a rabbit model of hypogonadotropic hypogonadism (induced by a single administration of the long-acting GnRH agonist triptorelin pamoate, 2.9 mg/kg), OT responsiveness was strongly reduced and was completely restored by estradiol valerate (3.3 mg/kg weekly), but not by testosterone enanthate (30 mg/kg weekly). As we found that CC expresses both subtypes of estrogen receptors and P450 aromatase, we hypothesized a physiological role for endogenous estrogens in regulating OT responsiveness. We therefore treated adult rabbits with an aromatase inhibitor (letrozole, 2.5 mg/kg) or an antiestrogen (tamoxifen, 0.25 mg/kg) for 3 wk. Both treatments significantly reduced CC responsiveness to OT stimulation. In conclusion, these findings indicate that OT might participate in inducing postorgasmic penile flaccidity and suggest a new role for estrogens in the male: regulation of CC responsiveness to OT.

Topics: Animals; Aromatase Inhibitors; Enzyme Inhibitors; Estradiol; Estrogen Antagonists; Estrogens; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; In Vitro Techniques; Letrozole; Male; Muscle Contraction; Muscle, Smooth; Nitriles; Osmolar Concentration; Oxytocin; Penis; Rabbits; Receptors, Oxytocin; Tamoxifen; Triazoles; Triptorelin Pamoate

Previous binding and contractility studies indicate that oxytocin (OT) receptors are present in rabbit epididymis. To investigate the effect of changing endocrine milieu on OT responsiveness, we induced hypogonadism (hypo) in rabbits with a single administration of a long-acting GnRH analog, triptorelin, and we replaced hypogonadal rabbits with different sex steroids. After 2 months from triptorelin administration, testosterone (T) plasma levels were decreased and OT responsiveness abolished. Administration of T to hypo rabbits restored T plasma levels but not OT sensitivity. Because Western blot analysis indicated that both estrogen receptors and aromatase are expressed in the epididymis, we treated hypo rabbits with estradiol valerate (E2v). E2v not only completely restored OT responsiveness but also even amplified it. Accordingly, Northern and Western blot analysis indicated that both OT receptor gene and protein were strongly induced by E2v but not by T. Surprisingly, also the class I estrogen receptor antagonist, tamoxifen restored OT sensitivity in hypo rabbits. To verify whether endogenous estradiol is involved in the regulation of OT receptor responsiveness, we treated intact rabbits with an aromatase inhibitor, letrozole. Blocking aromatase activity almost completely abolished OT sensitivity. These findings suggest a new function of estrogens in the male: regulation of OT responsiveness in epididymis.

Topics: Androgens; Animals; Aromatase Inhibitors; Blotting, Northern; Blotting, Western; Enzyme Inhibitors; Epididymis; Estradiol; Estrogen Antagonists; Estrogens; Gene Expression Regulation; Hypogonadism; Letrozole; Male; Nitriles; Oxytocin; Rabbits; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tamoxifen; Testosterone; Triazoles; Triptorelin Pamoate

Immunoreactive oxytocin is present in the testis and it has been shown that this hormone increases the contractility of seminiferous tubules. We have investigated the relationship between testicular oxytocin, tubular movements and the effects of LH and testosterone using, as a model, the hypogonadal (hpg/hpg) mouse, which is deficient in hypothalamic LH-releasing hormone (LHRH). Whilst both testicular oxytocin and seminiferous tubule movements, resembling those seen in the rat, can be found in normal adult mice, neither can be found in hypogonadal mice. After 2 weeks of treatment with LH (200 ng to 100 micrograms daily) low levels of testicular oxytocin and tubular movements were observed. Treatment with large doses of testosterone for 2-12 weeks led to higher concentrations of testicular oxytocin and tubular movements resembling those seen in the normal adult mouse. The results support the evidence that testicular oxytocin modulates seminiferous tubule movements. We suggest that testosterone may play a part in the accumulation of oxytocin in the testis.

Topics: Animals; Hypogonadism; Luteinizing Hormone; Male; Mice; Mice, Mutant Strains; Movement; Oxytocin; Seminiferous Tubules; Testis; Testosterone