Modulation of bone morphogenetic protein activity by melatonin in ovarian steroidogenesis

Abstract

Background: Melatonin regulates circadian and seasonal rhythms and the activities of hormones and cytokines that are expressed in various tissues, including the ovary, in which melatonin receptors are expressed. In the ovary, follicular growth occurs as a result of complex interactions between pituitary gonadotropins and autocrine and paracrine factors, including bone morphogenetic proteins (BMPs) that are expressed in the ovary.

Methods: The effects of melatonin and BMPs on steroidogenesis were examined by using the primary cultures of rat granulosa cells.

Main findings results: It was shown that melatonin has antagonistic effects on BMP-6 actions in the granulosa cells, suggesting that melatonin is likely to contribute to balancing the biological activity of endogenous BMPs that maintain progesterone production and luteinization in the growing follicles. Similar interactions between melatonin and BMP-smad signaling also were shown in the mechanism of controlling ovarian steroidogenesis by other ligands.

Conclusion: A new role of melatonin in the regulation of endocrine homeostasis in relation to BMP activity is introduced in this review.

Keywords: bone morphogenetic protein; follicle‐stimulating hormone; granulosa cells; melatonin; smad; steroidogenesis.

Figure 1

Interaction of melatonin and bone morphogenetic proteins (BMPs) in ovarian steroidogenesis. The BMPs commonly inhibit follicle‐stimulating hormone (FSH) actions by suppressing the cascade of follicle‐stimulating hormone receptor (FSHR) to adenylate cyclase (AC) activity, resulting in the suppression of progesterone production and the luteinization of granulosa cells. The inhibitory effect of the BMPs on FSH‐induced progesterone production is impaired by melatonin action. The FSH‐induced steroidogenesis in the granulosa cells is regulated by the balanced interaction of the BMP signaling and melatonin activity. cAMP, cyclic adenosine monophosphate; MTR, melatonin receptor

Figure 2

Regulation of bone morphogenetic proteins (BMPs)–smad signaling in ovarian granulosa cells. The mechanism by which melatonin suppresses BMP activity in the granulosa cells was found to be in the reduction of inhibitory smad6/7 expression in the granulosa cells. Androgen (T), growth hormone (GH), and insulin‐like growth factor (IGF)‐I were found to be the key molecules that can induce smad6/7 expression. On the contrary, prolactin (PRL), somatostatin (SST), and incretins were found to be suppressors of the expression of inhibitory smad6/7 in the granulosa cells. The modulatory effects on BMP activity in the granulosa cells via smad6/7 functions are likely to be critical for controlling steroidogenesis via endogenous BMP signaling. AC, adenylate cyclase; AR, androgen receptor; BMPR‐I and ‐II, BMP type‐1 and ‐2 receptors; cAMP, cyclic adenosine monophosphate; FSH, follicle‐stimulating hormone; FSHR, follicle‐stimulating hormone receptor; GHR, growth hormone receptor; GIPR, GIP receptor; HSD, 3β‐hydroxysteroid dehydrogenase; IGF‐IR, IGF‐I receptor; MT1, melatonin type‐1 receptor; P, progesterone; P450scc, P450 steroid side‐chain cleavage enzyme; PRLR, PRL receptor; SSA, single strand annealing; SSTR, SST receptor; StAR, steroidogenic acute regulatory protein

Figure 3

Functional interaction of melatonin and bone morphogenetic proteins (BMPs) in the hypothalamic–pituitary–adrenal (HPA) axis. In addition to its regulatory effect on ovarian steroidogenesis, melatonin is involved in the regulation of the HPA axis, including the suppression of adrenocorticotropin (ACTH) production, in cooperation with BMP‐4 action, in the pituitary corticotrope cells, a reduction of adrenal cortisol production, activation of aldosterone production that is induced by ACTH and activin in the adrenocortical cells, and the suppression of catecholamine production by cooperating with BMP‐4 in the adrenomedullary cells. CRH, corticotropin‐releasing hormone