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Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic β cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic-pituitary-gonadal axis or the pancreas-bone-gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

It has long been known that sex steroid hormones regulate bone mass accrual. This observation raises the testable hypothesis that bone may in turn regulate the synthesis and secretion of sex steroid hormones in one or both genders. This hypothesis is comprised within a more general hypothesis that bone mass, energy metabolism, and reproduction are regulated coordinately. The identification of osteocalcin as an osteoblast-specific secreted molecule allows us to address this question in molecular terms. This review details how the regulation of male fertility by osteocalcin was unraveled, and how osteocalcin signaling in Leydig cells of the testis occurs. It also discusses the implication of this novel mode of regulation of testosterone synthesis observed in males but not in females.

In many species of oviparous reptiles, the first steps of gonadal sex differentiation depend on the incubation temperature of the eggs. Feminization of gonads by exogenous oestrogens at a male-producing temperature and masculinization of gonads by antioestrogens and aromatase inhibitors at a female-producing temperature have irrefutably demonstrated the involvement of oestrogens in ovarian differentiation. Nevertheless, several studies performed on the entire gonad/adrenal/mesonephros complex failed to find differences between male- and female-producing temperatures in oestrogen content, aromatase activity and aromatase gene expression during the thermosensitive period for sex determination. Thus, the key role of aromatase and oestrogens in the first steps of ovarian differentiation has been questioned, and extragonadal organs or tissues, such as adrenal, mesonephros, brain or yolk, were considered as possible targets of temperature and sources of the oestrogens acting on gonadal sex differentiation. In disagreement with this view, experiments and assays carried out on the gonads alone, i.e. separated from the adrenal/mesonephros, provide evidence that the gonads themselves respond to temperature shifts by modifying their sexual differentiation and are the site of aromatase activity and oestrogen synthesis during the thermosensitive period. Oestrogens act locally on both the cortical and the medullary part of the gonad to direct ovarian differentiation. We have concluded that there is no objective reason to search for the implication of other organs in the phenomenon of temperature-dependent sex determination in reptiles. From the comparison with data obtained in other vertebrates, we propose two main directions for future research: to examine how transcription of the aromatase gene is regulated and to identify molecular and cellular targets of oestrogens in gonads during sex differentiation, in species with strict genotypic sex determination and species with temperature-dependent sex determination.

In a previous study pituitary-testicular function was shown to be maintained in a New World primate after the administration of an LHRH agonist implant. In the present study the mechanism of action of the same LHRH agonist (buserelin) on pituitary-gonadal function in the marmoset was investigated and a comparison made between the effects of treatment in three intact males, six adult cyclic females with regular ovulatory cycles, and six long-term ovariectomized animals. These were injected s.c. with an LHRH agonist implant (1.5 mg buserelin in a rod 0.5 cm long). In both the males and intact females, basal plasma LH concentrations were maintained within the normal range throughout the expected duration of agonist action (at least 3 months). Despite this, an absence of response to an LHRH challenge indicated that pituitary desensitization had occurred. In the intact females, ovulation was inhibited in five of six animals, plasma progesterone concentrations initially being maintained but subsequently remaining suppressed until 136 +/- 18 (S.E.M.) days after treatment. Responsiveness to administered LHRH returned prior to onset of return to ovarian cycles. In contrast, in ovariectomized marmosets, plasma LH was markedly suppressed to concentrations which were at or below the limit of detection of the assay and were therefore less than those observed in the buserelin-implanted intact animals. These results show that apparently normal pituitary-gonadal function in this species disguises an underlying pituitary desensitization to LHRH. This allows continuation of testosterone secretion in the male, but in the female ovulation is prevented, presumably as a result of failure of the desensitized pituitary to produce an LH surge.(ABSTRACT TRUNCATED AT 250 WORDS)

The concentration of LH in the plasma of guinea-pigs from day 50 of gestation to day 45 of postnatal life was assayed by radioimmunoassay utilizing a cross-reaction with anti-ovine LH antiserum. The effect of gonadectomy in infancy and in the adult upon the plasma concentration of LH was also studied. The LH concentration in the plasma of male or female foetuses was high immediately prenatally and fell at birth. High levels of LH were again detected in male, with a lesser increase in female, guinea-pigs over the first 10 days postnatally. Maternal plasma concentrations of LH remained consistently low. Removal of the gonads on days 0, 5, 10, 15, 25 or 35 of postnatal life, followed by blood collection at autopsy 10 days later, caused a significant rise in plasma LH content at all ages. The rise in plasma LH after gonadectomy in adults was less marked in male than in female guinea-pigs.

The concentration of FSH in the plasma of guinea-pigs from day 50 of gestation to day 45 of postnatal life was assayed by a radioimmunological procedure utilizing a cross-reaction with the NIAMDD S6 antiserum to rat FSH. At 68 days of gestation the mean plasma FSH concentration of female foetuses was greater than that of the males, although the concentrations in the two sexes were similar on day 50 of gestation. Maternal levels remained consistently low throughout gestation. Postnatally there were no marked changes in plasma FSH levels through to maturity, although a transient rise in the male occurred over the first 3 days after birth. Gonadectomy on days 0, 5, 10, 15, 25 or 35 of postnatal life, or when adult, resulted in a significant increase in plasma levels of FSH within 10 days. The rise in plasma FSH concentration was greater in males than in females at all ages, although, a larger increase was observed in females spayed at 5 or 10 days of age than at other times.

Previous studies have shown that an increase in prolactin secretion coincides with the beginning of the photorefractory phase in starlings (Sturnus vulgaris). To determine how closely this increase is associated with the onset of refractoriness, we kept starlings on photoperiods which would induce refractoriness at different rates. Four groups of males and females were transferred from 8h light:16h darkness (8L:16D) to either 18L:6D, 13L:11D, 11L:13D or 8L:16D. Weekly blood samples were assayed for LH, FSH and prolactin and the males were frequently laparotomized to determine testis volume. In males, both 18L and 13L induced marked increases in plasma gonadotrophin levels and rapid gonadal maturation. A photoperiod of 18L induced an earlier onset of refractoriness (2-4 weeks) than 13L (6 weeks). In both cases prolactin levels began to increase immediately before the onset of refractoriness. Males on 11L showed a slight increase in gonadotrophin levels and slow gonadal maturation. There was no increase in prolactin levels and these birds did not become refractory. Hormonal data from the females were similar to those from males. These results confirm that increased prolactin secretion is associated, in some way, with the onset of photorefractoriness in this species, although whether it is a cause or consequence of photorefractoriness, or simply of gonadal regression, remains unclear.