Maintaining physiological testosterone levels by adding dehydroepiandrosterone to combined oral contraceptives: I. Endocrine effects.

OBJECTIVE: To determine whether adding dehydroepiandrosterone to combined oral contraceptives (COCs) maintains physiological levels of free testosterone. STUDY DESIGN: A randomized, double-blind, placebo-controlled, two-way crossover study conducted in 81 healthy women (age range: 20-35 years; Body mass index (BMI) range: 18-35 kg/m2) using oral contraceptives. Androgens, sex hormone-binding globulin (SHBG), estradiol (E2) and estrone (E1) were measured, and free testosterone and the free testosterone index were calculated. Subjects discontinued oral contraceptive use for at least one menstrual cycle before being randomized to receive five cycles of ethinyl estradiol (EE) combined with either levonorgestrel (EE/LNG group) or drospirenone (EE/DRSP group) together with either dehydroepiandrosterone (DHEA) (50 mg/day orally) or placebo. Subsequently, all subjects crossed over to the other treatment arm for an additional five cycles. RESULTS: Both COCs decreased the levels of all androgens measured. Significant decreases (p<.05) were found with EE/LNG and EE/DRSP for total testosterone (54.5% and 11.3%, respectively) and for free testosterone (66.8% and 75.6%, respectively). Adding DHEA to the COCs significantly increased all androgens compared to placebo. Moreover, including DHEA restored free testosterone levels to baseline values in both COC groups and total testosterone levels to baseline in the EE/LNG group and above baseline in the EE/DRSP group. SHBG concentrations were significantly higher with EE/DRSP compared to EE/LNG (p<.0001). The addition of DHEA did not affect the levels of SHBG. CONCLUSIONS: Taking COCs reduces total and free testosterone levels and increases SHBG concentrations. By coadministration with DHEA, physiological levels of total and free testosterone are restored while using EE/LNG. With EE/DRSP, only the free testosterone level is normalized by DHEA coadministration. IMPLICATIONS: A daily oral dose of 50-mg DHEA maintains physiological free and total testosterone levels in women who are using an EE/LNG-containing COC.

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I. Endocrine effects.

OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA). STUDY DESIGN: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34 kg/m²), a COC containing 30mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50 mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Δ4-androstenedione (AD), 3α-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). RESULTS: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period -- 1.3±1.2 nmol/L vs. 0.0±0.4 nmol/L; p<.0001) -- and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E2. CONCLUSIONS: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50 mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. IMPLICATIONS: When using a COC that increases SHBG considerably, a daily dose of 50 mg DHEA is insufficient to normalize free T levels completely.

Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women.

BACKGROUND: Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease. However, research relating serum levels of sex hormones to cardiovascular disease is sparse, and the results are inconclusive. METHODS: We measured sex hormones in longitudinally collected samples of 180 postmenopausal women, 91 randomized to 17beta-estradiol and 89 to placebo, in the Estrogen in the Prevention of Atherosclerosis Trial. Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness (CIMT), which was also assessed longitudinally over 2 yr. RESULTS: In all women, changes in serum estrone (P = 0.02), total estradiol (P = 0.01), free estradiol (P = 0.02), and SHBG (P = 0.005) were significantly inversely associated with CIMT progression, controlling for age and body mass index. All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol (all P < 0.0001), whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol (P < 0.003). Despite an increase in serum-free estradiol with estradiol therapy, women with unchanged SHBG and free testosterone levels had an average (se) progression in CIMT of 8.53 (4.72) microm/yr, whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [-5.45 (2.77) microm/yr; trend P = 0.03]. CONCLUSION: Estrogen and SHBG are associated with reduced subclinical atherosclerosis progression in healthy postmenopausal women. These associations are partially mediated by their beneficial effects on lipids. Among women taking estradiol, the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone.