Biphasic regulation of activin A secretion by gonadotropins in cultured human ovarian granulosa-luteal cells leads to decreasing activin:inhibin ratios during continuing gonadotropin stimulation

Abstract

Pituitary gonadotropins mediate part of their effects on ovarian function via local hormones and growth factors produced by granulosa cells. Activins and inhibins are among these factors, and they have often opposite effects on various components of the reproductive system. The purpose of this study was to investigate the regulation of ovarian activin A secretion using cultured human ovarian granulosa-luteal cells as a model. The granulosa-luteal cells, obtained from women taking part in an in vitro fertilization program, were cultured and treated with FSH, LH, 8-bromo cAMP (8-BrcAMP, a protein kinase A activator) and 12-O-tetradecanoyl phorbol-13-acetate (TPA, a protein kinase C activator). Conditioned cell culture media were analyzed for activin A, inhibin A and progesterone concentrations with specific enzyme immunoassays. FSH and LH (1-100 IU/l) increased activin A secretion with 24 h of treatment (to 132% and 253% of control respectively; P<0·05 for both), but their effects were inhibitory in 48-h treatments (26% and 16% decreases respectively; P<0·05 for both). In the same experiments, FSH and LH increased inhibin A and progesterone secretion after both 24 and 48 h of treatment. 8-BrcAMP (0·1-100 µM) increased activin A in 24-and 48-h experiments (to 206% and 148% of control respectively; P<0·01 for both). Inhibin A and progesterone secretion were stimulated by 8-BrcAMP time-and dose-dependently. TPA increased activin A secretion dose-dependently (0·1-100 ng/ml) in both 24-and 48-h experiments. At 100 ng/ml concentration, it increased activin A up to 61-fold and inhibin A up to 16-fold of control in 24-h experiments. We conclude that gonadotropins regulate immunoreactive activin A secretion biphasically in cultured human granulosa-luteal cells: initial stimulation is followed by inhibition. In contrast, gonadotropins increase inhibin A and progesterone secretion continuously. Consequently, continuing gonadotropin stimulation leads to a decreasing activin:inhibin ratio, which may have a significant role in the local fine-tuning of ovarian steroidogenesis.

Expression of Activin/Inhibin Receptor and Binding Protein Genes and Regulation of Activin/Inhibin Peptide Secretion in Human Adrenocortical Cells

“…TPA, an activator of PKC, increased activin A and inhibin A production, and activin A treatment increased inhibin B production in NCI-H295R cells. Similar regulation is seen in human ovarian granulosa cells (26,28). The molecular basis for the effects of cAMP and TPA is well explained by the cAMP response element in the ␣-and ␤A-subunit genes and the activating protein-1 response element, also known as 12-O-tetradecanoyl phorbol-13-acetate response element, in the activin/inhibin ␤A gene (29,30).…”

Characterization of Functionally Typical and Atypical Types of Polycystic Ovary Syndrome

“…Several granulosa cell factors are potential mediators of the normal paracrine inhibitory effect of FSH on thecal testosterone production (8,22,(43)(44)(45). Estradiol seems unlikely to play this role because estradiol and androgenic responses to FSH did not correlate.…”

Placental production and maternal serum and urine levels of inhibin A and activin A are modified by antihypertensive therapy in hypertensive disorders of pregnancy

“…An almost universal effect of α 2 ‐adrenoreceptor stimulation is the inhibition of adenyl cyclase which leads to decreased production of cAMP 40,41 . cAMP has been shown to increase the production of inhibin A and activin A in cultured human ovarian granulosa‐luteal cells 42 . It has also been shown in the same tissue that cAMP induces mRNA for both the α and β A subunits of inhibin A and activin A 43 .…”

“…40,41 cAMP has been shown to increase the production of inhibin A and activin A in cultured human ovarian granulosa-luteal cells. 42 It has also been shown in the same tissue that cAMP induces mRNA for both the α and β A subunits of inhibin A and activin A. 43 In fact, α subunit mRNA is induced via this cAMP-dependent pathway in a remarkably similar way in a variety of tissues in different species, including human.…”