Ovariectomy (OVX) causes a depletion of circulating estradiol (E2) and influences hypothalamic kisspeptin neurons, which govern gonadotropin-releasing hormone (GnRH) release and ultimately gonadotropin secretion. In this study, we examined the changes induced by OVX on the anterior pituitary gland in female rats. OVX significantly increased the mRNA expression of gonadotropin α, luteinizing hormone (LH) β, and follicle-stimulating hormone (FSH) β subunits within the pituitary gland compared with control (sham-operated) rats, and this was completely suppressed by E2 supplementation. High-dose dihydrotestosterone supplementation also prevented the OVX-induced increase in the expression of the three gonadotropin subunits. GnRH receptor mRNA expression within the pituitary was significantly increased in OVX rats, and this increase was completely inhibited by E2 supplementation. The mRNA expression of the receptors for adenylate cyclase-activating polypeptide and kisspeptin was unchanged by OVX. Although the mRNA levels of inhibin α, βA, and βB subunits within the pituitary gland were not modulated by OVX, follistatin gene expression within the pituitary gland was increased by OVX, and this increase was completely inhibited by E2 supplementation after OVX. In experiments using a pituitary gonadotroph cell model (LβT2 cells), follistatin itself did not modulate the mRNA expression of gonadotropin LHβ and FSHβ subunits, and the GnRH-induced increase in the expression of these genes was slightly inhibited in the presence of follistatin. Our current observations suggest that OVX induces several characteristic changes in the pituitary gland of rats.

Hyperandrogenism causes dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis in reproductive women. In this study, we examined the effects of dihydrotestosterone (DHT) on characteristic changes in rat anterior pituitary gland samples. DHT was administered to ovary-intact 6-week postnatal female rats for 7 days, after which the anterior pituitary glands were examined and compared with those in control rats. Estrous cyclicity was not drastically disrupted by DHT treatment. Common gonadotropin α subunit (Cga), luteinizing hormone β subunit (Lhb), and follicle-stimulating hormone (FSH) β subunit (Fshb) gene expression levels were not modulated by DHT treatment, while prolactin (Prl) gene expression was significantly repressed by DHT. Gonadotropin-releasing hormone (GnRH) receptor (Gnrh-r) gene expression was significantly inhibited by DHT, whereas pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (Pca1-r) gene expression was increased by DHT. Gene expression levels of the receptors encoded by thyrotropin-releasing hormone (Trh-r) and kisspeptin (Kiss1-r) genes were unchanged. Expression of inhibin α subunit (Inha) and activin βA subunits (Actba) within the pituitary was inhibited by DHT treatment, while activin B subunit (Actbb) and follistatin (Fst) gene expression was unchanged by DHT. In mouse pituitary gonadotroph LβT2 cells, DHT did not modulate the gene expression of Gnrh-r, but it inhibited the expression of Inha and Actba subunits within the LβT2 cells. In rat prolactin-producing GH3 cells, DHT did not modulate prolactin gene expression, but it increased Pac1-r gene expression. The present observations suggest that DHT directly or indirectly affects the anterior pituitary gland and induces characteristic changes in hormone-producing cells.

The (pro)renin receptor is a multifunctional protein with roles in angiotensin-II-dependent and -independent intracellular cell signaling and roles as an intracellular accessory protein for the vacuolar H+-ATPase, including hormone secretion. While (pro)renin receptor mRNA is widely expressed in various human tissues, localization of (pro)renin receptor protein expression has not yet been systemically determined. Therefore, this study localized (pro)renin receptor protein expression in human organs. Systemic immunohistochemical examination of (pro)renin receptor expression was performed in whole body organs of autopsy cases. (Pro)renin receptor immunostaining was observed in the cytoplasm of cells in almost all human organs. It was observed in thyroid follicular epithelial cells, hepatic cells, pancreatic duct epithelial cells, zona glomerulosa and zona reticularis of the cortex and medulla of the adrenal gland, proximal and distal tubules and collecting ducts of the kidney, cardiomyocytes, and skeletal muscle cells. In the brain, (pro)renin receptor staining was detected in neurons throughout all areas, especially in the medulla oblongata, paraventricular nucleus and supraoptic nucleus of the hypothalamus, cerebrum, granular layer of the hippocampus, Purkinje cell layer of the cerebellum, and the pituitary anterior and posterior lobes. In the anterior lobe of the pituitary gland, all types of anterior pituitary hormone-positive cells showed double staining with (pro)renin receptor. These data showed that (pro)renin receptor protein was expressed in almost all organs of the human body. Its expression pattern was not uniform, and cell-specific expression pattern was observed, supporting the notion that (pro)renin receptor plays numerous physiological roles in each human organ.