Developmental programming: co-treatment with androgen antagonist fails to prevent the increase in estradiol in the female fetuses of gestational testosterone-treated sheep

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 548-560-Hyperandrogenic Disorders
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-553
Bachir Antoun Abi Salloum*1, Almudena Veiga-Lopez2, David Howard Abbott3, Puliyur S MohanKumar4, Sheba M J MohanKumar5 and Vasantha Padmanabhan6
1University of Michigan, Ann Arbor, MI, 2Univ of Michigan Med Schl, Ann Arbor, MI, 3Univ of WI-Natl Primate Rsch C, Madison, WI, 4Michigan State Univ, Okemos, MI, 5MICHIGAN STATE UNIV, East Lansing, MI, 6Univ of Michigan, Ann Arbor, MI
Exposure to excess testosterone (T) during fetal life induces reproductive defects at the neuroendocrine and ovarian levels including oligo-anovulation, LH hypersecretion, altered steroid feedback and ovarian follicular persistence. Defects in estradiol (E2) negative feedback appear to be mediated via androgenic actions while positive feedback from estrogenic action. In line with this, gestational T treatment increased T, as well as E2 in female fetal circulation during the window of treatment. Co-treatment with an androgen antagonist prenatally, reversed E2 negative feedback effects in adults, but surprisingly maintained preovulatory LH surges in 100% of females [1]. Because disruption of E2 positive feedback in T females is believed to be mediated via estrogenic programming, we tested the hypothesis that co-treatment with androgen antagonist would prevent the increase in circulating E2 in female fetuses. The study consisted of three groups of day 90 fetuses: controls (C group; n=9), prenatal T (100 mg of T propionate, twice weekly from days 30 to 90 of gestation, i.m.; T group; n=8), prenatal T plus anti-androgen, flutamide (15 mg/kg/day orally; TF group; n=6). Umbilical arterial cord blood samples were collected on fetal day 90 for steroid measures by liquid chromatography mass spectrometry. Statistical analysis was performed using the Kruskal-Wallis and post hoc test using Bonferroni correction for multiple comparisons, after adjusting for number of fetuses. Findings revealed that T levels were elevated in the T group (0.40±0.1 ng/ml) relative to the C group (0.02±0.0 ng/ml) (P<0.01), and not reversed in the TF group (0.38±0.1 ng/ml). E2 levels were also elevated (P<0.05) in the T group (30.0±9.0 pg/ml) compared to the C group (10.0±1.0 pg/ml), and not reversed in the TF group (40.0±10.0 pg/ml). Estrone levels were similar between T and C groups (T: 10.0±1.5 pg/ml vs. C: 10.0 ±0.9 pg/ml), but higher in TF group (20.0±3.1 pg/ml; P<0.05, TF vs. C or T). All other steroids (aldosterone, androstenedione, cortisol, 17α-OH-progesterone, 17α-OH-pregnenolone, dehydroepiandrosterone, pregnenolone, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone) were similar amongst groups. These findings indicate co-treatment with androgen antagonist does not reverse increased fetal exposure to E2 and suggest that the ablation of estrogenic programming effects may originate from androgen-influenced E2 receptor action or alternatively via metabolic changes.

Padmanabhan et al., 2012, Annual meeting of the Androgen Excess and PCOS Society June, 2012, Huston Texas, USA

Nothing to Disclose: BAA, AV, DHA, PSM, SMJM, VP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH PO1 HD44232 awarded to VP