LBOVI-A-3Identification of skin biomarkers following testosterone administration in postmenopausal women

Abstract

BACKGROUND/AIMS To pilot a pharmacodynamic (PD) model of short-term androgen administration that may be used to predict long-term effects of androgen administration in postmenopausal women. The study was specifically designed to identify biomarkers that evaluate early skin response to exogenous androgens. The clinical consequences of androgen administration include hirsutism and acne. Skin biopsies were performed to document morphological changes in the pilosebaceous unit (PSU) and gene expression changes (Taqman and microarray). Functional skin response was gauged by measuring sebum excretion rates (SER). METHODS A double-blind, randomized, placebo-controlled, parallel-group study was conducted in 36 healthy postmenopausal female subjects to identify early biomarkers of androgen administration. Subjects were randomized to receive either 2.5 mg of transdermal testosterone gel (TTG; AndroGel®), 300 μg of TTGtransdermal testosterone gel, or placebo gel, daily for 6 weeks in a 1:1:1 ratio. Skin biopsies were performed to document morphological changes in the pilosebaceous unit (PSU) and gene expression changes (Taqman and microarray). Five-mm skin punch biopsies were obtained from the back of subjects at baseline, after 6 weeks of treatment, and 4 weeks post treatment. Biopsies were analyzed for histological changes characterized by total sebaceous gland volume and sebocyte cell size. Skin biopsies were also analyzed for molecular skin changes using skin Taqman/microarray assays. Measurements of sebum excretion rates (SER) were obtained at baseline and after 6 weeks of treatment. RESULTS Six weeks of treatment with the 2.5-mg TTGdose of AndroGel® increased sebaceous gland volume on average by 42% (p=0.0410) and sebum excretion rateSER by 52% (p=0.0021) relative to placebo. Microarray and Taqman analyses on skin samples also demonstrated changes in the 2.5-mg TTG AndroGel® group. Histological and molecular findings were noted to be reversible 4 weeks after discontinuing therapy. Analysis of Total Sebaceous Gland Volume (106 μm3) at Week 6 (See Tables 1 and 2) Mean (SD) % Change from Baseline Treatment N Baseline Week 6 Mean (SD) LS Mean 95% CI Placebo 13 19.58 (32.51) 24.00 (32.27) 4.42 (33.53) 4.42 (−21.79, 30.63) 300 ug TTG 13 37.20 (39.16) 45.59 (47.20) 8.40 (51.97) 8.40 (−17.81, 34.61) 2.5 mg TTG 10 31.93 (36.34) 77.91 (71.76) 45.98 (53.01) 45.98 (16.10, 75.87) Analysis Results for SER at Week 6 Geometric Mean (CV) % Change from Baseline Treatment N Baseline Week 6 Geometric Mean (CV) Geometric LS Mean† 95% CI‡ Placebo 13 0.67 (0.52) 0.67 (0.51) −0.14 (0.29) −0.14 (18.22, −15.65) 300 ug TTG 12 0.81 (0.55) 0.89 (0.56) 10.80 (0.38) 10.80 (32.08, 7.05) 2.5 mg TTG 10 0.82 (0.43) 1.24 (0.42) 52.09 (0.22) 52.09 (84.37, 25.46) CONCLUSIONS TTG treatment is associated with marked increases in sebaceous gland volume and SER, consistent with side effects including hirsutism and acne. Biomarkers sufficiently robust to support using to test for androgen-mediated skin effects in postmenopausal women were identified. Clinical Pharmacology & Therapeutics (2005) 79, P84–P84; doi: 10.1016/j.clpt.2005.12.299