Ovarian inhibin subunit gene expression: regulation by gonadotropins and estradiol.
Inhibin and FSH maintain a dynamic inverse relationship throughout the rat estrous cycle. In particular, inhibin alpha- and beta A-subunit messenger RNAs (mRNAs) have been shown to be maximally expressed immediately after the midcycle gonadotropin surge, when both circulating estradiol (E2) and inhibin are also elevated. The current study was designed to investigate the regulation of inhibin subunit gene expression and secretion in vivo by recombinant human FSH (rhFSH) and estradiol. Initially, we determined if physiological levels of rhFSH regulated ovarian inhibin subunit gene expression and secretion. Hypophysectomized (HYPOX) adult female rats received hCG (10 IU, sc) and were then treated for 24 h with either rhFSH (0.5-20 IU every 6 h, i.v.) or saline. Hypophysectomy reduced inhibin subunit mRNAs as well as serum inhibin and estradiol. Although 0.5 IU rhFSH was ineffective in increasing inhibin subunit mRNAs, all doses between 2.5-20 IU increased inhibin subunit gene expression and inhibin secretion. Inhibin alpha-, beta A-, and beta B-subunit mRNAs were increased to a similar degree (3- to 5-fold) by all rhFSH doses of 5 IU or more. Similarly, serum E2 and inhibin were increased 2- and 3-fold, respectively, above HYPOX values after all doses of rhFSH of 5 IU or more. To investigate the role of a pure FSH signal in a physiological dose on inhibin subunit gene expression, HYPOX rats were given either rhFSH (5 IU, i.v., every 6 h for 24 or 48 h), hCG (10 IU, sc), or their combination. Neither gonadotropin when given alone altered inhibin subunit gene expression or serum E2 concentrations. Inhibin secretion rose in response to rhFSH alone, but not to hCG. The combination of hCG and rhFSH resulted in increased inhibin subunit mRNAs (3- to 5-fold) as well as circulating E2 and inhibin concentrations. We next studied the effects of E2 replacement in HYPOX rats at both physiological (serum approximately equal to 40 pg/ml) and higher doses (serum approximately equal to 800 pg/ml, to mimic intraovarian concentrations) in the presence or absence of exogenous gonadotropins (for 24 and 48 h). Although not as effective as gonadotropins, both E2 regimens increased inhibin alpha to a similar degree (2-fold), whereas beta-subunit mRNAs were unchanged at 24 h. Serum inhibin concentrations were increased only 48 h after high dose E2 treatments. As the actions of E2 and gonadotropins on alpha-subunit mRNA were not additive, E2 appears to mediate gonadotropin regulation of alpha-subunit gene expression.(ABSTRACT TRUNCATED AT 400 WORDS)
Aloi
J A
JA
Department of Internal Medicine, University of Virginia Medical Center, Charlottesville, Virginia 22908.
Dalkin
A C
AC
Schwartz
N B
NB
Yasin
M
M
Mann
B
B
Haisenleder
D J
DJ
Marshall
J C
JC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D004971:Estrus; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006062:Gonadotropins / Q000494:pharmacology*; D007265:Inhibins / Q000737:chemistry / Q000235:genetics*; D010053:Ovary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D006062:Gonadotropins; D011994:Recombinant Proteins; D004958:Estradiol; D007265:Inhibins; D005640:Follicle Stimulating Hormone