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Department of Obstetrics and Gynecology, CSMC Burns and Allen Research Institute (R.J.Z., S.R.W., D.A.M.), and University of California School of Medicine (R.J.Z., D.A.M.), Los Angeles, California 90048
Address all correspondence and requests for reprints to: Dr. Rob Zachow, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Davis Building, Room 2056, 8700 Beverly Boulevard, Los Angeles, California 90048-0750.
During ovarian follicle growth, precise regulation of the onset of
androgen production by ovarian theca-interstitial cells (TIC) is
necessary for maintaining follicle viability. Thus, temporary
suppression of TIC androgen production in preantral follicles is the
key to promoting follicle development. Evidence indicates that this
process is coordinated via intraovarian growth factors. Hepatocyte
growth factor (HGF) can induce granulosa cell (GC) proliferation and
suppress follicular atresia, indicating a role for HGF in promoting
follicle growth and viability. To determine whether HGF could
reversibly suppress androgen production, this study investigated the
effect of HGF on TIC differentiation and steroid production.
Twenty-six-day-old rats were used in all studies. HGF messenger RNA
(mRNA) expression in TIC and GC was determined by reverse
transcription-PCR. Agarose gel electrophoresis of the PCR products
yielded a single band corresponding to the 290-bp HGF product for both
TIC and GC. HGF expression in cultured TIC and GC was not blocked by
gonadotropins or HGF. To investigate the effects of HGF on TIC
steroidogenesis, TIC were isolated from the ovaries of
hypophysectomized rats. TIC (3.0 x 104 cells/well)
were cultured with LH (0–3 ng/ml) and/or HGF (0–100 ng/ml) for
48 h, and androsterone levels were measured by RIA. HGF did not
alter androsterone levels in the absence of LH; however, HGF reversibly
impaired LH-dependent androsterone production by as much as 57%
(IC50 = 1.5 ± 0.01 ng/ml). LH (0.3 ng/ml) stimulated
progesterone (P4) synthesis by TIC (1201 ± 190 pg/ml)
compared to that by control cells (210 ± 30 pg/ml). HGF
stimulated basal P4 production, and LH-dependent
P4 synthesis was augmented 2.6-fold by HGF
(ED50 = 0.3 ± 0.01 ng/ml). The DNA content and cell
viability in TIC cultures were not affected by HGF. The effect of HGF
on steroidogenic enzyme gene expression in TIC was also investigated
via PCR. HGF did not alter the level of basal or LH-induced P450
side-chain cleavage and 3ß-hydroxysteroid dehydrogenase mRNAs;
however, LH-dependent P45017
hydroxylase/C17,20 lyase mRNA content was reduced 4.5-fold
in the presence of HGF. Thus, HGF is expressed in both TIC and GC
obtained from the immature rat ovary, suggesting its presence in
growing follicles. In TIC, HGF stimulated P4 synthesis, but
impaired androgen production, concurrent with a down-regulatory effect
on P45017 hydroxylase/C17,20 lyase gene
expression. Collectively, these results indicate that HGF reversibly
impairs LH-stimulated androgen production in TIC. Such effects may help
promote folliculogenesis.
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