Effects of Dehydroepiandrosterone Therapy on Pubic Hair Growth ...

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J Clin Endocrinol Metab, April 2009, 94(4):1182–1190 jcem.endojournals.org 1187 TABLE 2. Scores on the SCL-90-R at baseline and after 12 month treatment with DHEA or placebo Scale Baseline 12 months P value Reference Somatization 0.66 0.51 Placebo 0.41 0.37 0.81 0.63 0.40 0.52 DHEA 0.58 0.40 0.49 0.39 0.09 0.39 ns Obsessive-compulsive traits 0.77 0.54 Placebo 0.43 0.41 0.61 0.63 0.18 0.38 DHEA 0.81 0.56 0.46 0.39 0.35 0.41 0.049 Interpersonal sensitivity 0.80 0.62 Placebo 0.55 0.60 0.64 0.77 0.09 0.33 DHEA 1.06 0.66 0.53 0.48 0.53 0.49 0.030 Depression 0.77 0.59 Placebo 0.48 0.49 0.80 0.83 0.32 0.64 DHEA 0.78 0.54 0.45 0.58 0.33 0.41 0.049 Anxiety 0.67 0.57 Placebo 0.38 0.30 0.66 0.48 0.28 0.35 DHEA 0.50 0.45 0.29 0.24 0.21 0.36 0.016 Hostility 0.80 0.72 Placebo 0.29 0.36 0.41 0.57 0.12 0.38 DHEA 0.62 0.39 0.50 0.48 0.12 0.45 ns Phobic anxiety 0.25 0.33 Placebo 0.13 0.17 0.32 0.51 0.19 0.36 DHEA 0.40 0.49 0.17 0.32 0.23 0.12 0.011 Paranoid ideation 0.72 0.63 Placebo 0.26 0.33 0.61 0.75 0.35 0.45 DHEA 0.55 0.44 0.38 0.47 0.17 0.39 0.034 Psychotic tendencies 0.46 0.53 Placebo 0.20 0.28 0.46 0.47 0.26 0.31 DHEA 0.31 0.31 0.19 0.31 0.12 0.29 0.036 Global severity index 0.67 0.45 Placebo 0.38 0.35 0.65 0.57 0.27 0.35 DHEA 0.63 0.37 0.38 0.37 0.25 0.26 0.013 Reference data shown are from 139 randomly chosen German schoolgirls with an age between 16 and 17 yr (19). ns, Not significant. DHEAS and androstanediol glucuronide morning serum levels 2 h after drug intake; placebo had no effect (P 0.006) (Fig. 3A). Morning serum levels <strong>of</strong> androstenedione increased significantly in the DHEA group only but did not normalize (P 0.02). Testosterone serum levels increased only in two individuals and normalized in only one <strong>of</strong> the DHEA group (Fig. 3A). SHBG and IGF-I serum levels remained unchanged (data not shown). In urine, daily excretion rates for DHEA, ADIOL, and the sum <strong>of</strong> DHEA and its 16-hydroxylated downstream metabolites (DHEA and M) normalized in the DHEA group, but not in the placebo group (Fig. 3B). In addition, the overall androgen metabolite excretion (C19) was in the high-normal range in the DHEA group but stayed pathologically low in the placebo group (P 0.0001 for all comparisons). Adverse events The proportion <strong>of</strong> patients experiencing any adverse event was similar between the DHEA and placebo groups. Single adverse events reported in the DHEA group were a fracture <strong>of</strong> a finger, rhinitis, upper airway infection, and transient pain <strong>of</strong> the ankle joint. One girl in the DHEA group developed a mild moustache, but no other signs <strong>of</strong> hirsutism. Her Ferriman score was normal (n 2). Acne was not observed in any patient. In the placebo group, headache, nonorganic acral paresthesias (n 2), mood swings, and spraining <strong>of</strong> the ankle were reported. There was one severe adverse event in the DHEA group and two in the placebo group: one girl suffered from recurrent anxiety attacks that were reported after 4 month therapy. Similar psychological problems had occurred before the trial according to the parents. Nevertheless, because causality could not be excluded, medication was stopped. In the placebo group, one girl had a relapse <strong>of</strong> craniopharyngioma, and another exhibited the first manifestation <strong>of</strong> type 1 diabetes mellitus. In both cases, medication was stopped. Overall, the safety pr<strong>of</strong>ile <strong>of</strong> DHEA was very good. Discussion Oral administration <strong>of</strong> 25 mg DHEA daily for 1 yr in a group <strong>of</strong> female adolescents who suffered from central adrenal insufficiency caused a clear progress <strong>of</strong> pubic hair stage by I–III stages, whereas placebo had no effect. Psychological distress as measured by SCL-90 scores decreased when DHEA was substituted but increased in the placebo group. In addition, the CES-D score that measures the presence <strong>of</strong> depressive symptoms improved in the treatment group but decreased in the placebo group. These effects were associated with normalization <strong>of</strong> the morning serum levels <strong>of</strong> DHEA and androstanediol glucuronide 2 h after drug intake, as well as normalization <strong>of</strong> the 24-h urinary excretion rates <strong>of</strong> DHEA, DHEA and M, ADIOL, and C19-metabolites in the
1188 Binder et al. DHEA Replacement in Young Females J Clin Endocrinol Metab, April 2009, 94(4):1182–1190 FIG. 3. Chronological changes <strong>of</strong> the androgen levels in serum (A) and the daily androgen amount excreted in the urine (B) from baseline to 12 month therapy. The boxes indicate the 50% confidence interval, whiskers the 100% confidence interval, and lines inside the boxes the median. The grayshadowed areas represent the 90% confidence interval <strong>of</strong> a healthy age-related female reference population (22–25). DHEA group, whereas these parameters remained pathologically low in the placebo group. DHEA therapy was safe and well tolerated. Adolescence is the time <strong>of</strong> the only DHEA peak during the human life span. The normal mean serum DHEAS level at this age is at 2000 ng/ml. Therefore, DHEA deficiency is most severe when adolescent individuals are affected by adrenal insufficiency: our patients had serum DHEAS levels less than 200 ng/ml. The therapeutic substitution <strong>of</strong> a severe deficiency for a hormone should cause positive effects if the hormone is <strong>of</strong> any relevant physiological value for the human being. DHEA is the major source <strong>of</strong> androgens in females. Most <strong>of</strong> the girls treated had no pubarche or an immature stage <strong>of</strong> pubic hair development because <strong>of</strong> a lack <strong>of</strong> androgens at baseline. They experienced a clear progress <strong>of</strong> sexual hair growth during the trial. Interestingly, these clinical changes happened in the absence <strong>of</strong> a measurable normalization <strong>of</strong> testosterone in the morning serum, whereas the overall androgen metabolite excretion in the urine (C19 metabolites) reached a normal level. In addition, morning serum levels <strong>of</strong> androstanediol glucuronide normalized in the DHEA group, which has been proposed as a marker <strong>of</strong> peripheral androgen production and action (28). These observations suggest that normalization <strong>of</strong> morning serum DHEAS and androstenedione was sufficient to increase locally produced testosterone and dihydrotestosterone to an extent that enabled sexual hair growth. The same discrepancy between normal amounts <strong>of</strong> androgen metabolites and low-active androgens has been observed in DHEA trials with DHEA-deficient women or healthy postmenopausal women in the past (10, 29). Beside sexual hair growth in puberty, we could confirm that DHEA and androgens have beneficial effects on the psychological well-being. The exact biochemical path that is used by DHEA to cause such effects is still obscure, and a separation from effects caused by metabolites <strong>of</strong> DHEA is difficult. Such effects are <strong>of</strong> most importance in young patients having a chronic disease. This is the first controlled trial analyzing replacement <strong>of</strong> DHEA in pediatric patients. Craen et al. (16) reported on the individual treatment results in six girls who had hypopituitarism and low DHEAS serum levels using 15 mg DHEAS /m 2 body surface. Central adrenal insufficiency was present in some, but not in all, <strong>of</strong> these patients according to the abstract published (16). Duration <strong>of</strong> treatment was between 6 and 28 months. In this preliminary report, they observed an increase <strong>of</strong> serum DHEAS and a progress <strong>of</strong> pubic hair development to PH2 or more in all patients. Wit et al. (8) reported their experience with the individual treatment <strong>of</strong> four girls with central or peripheral adrenal insufficiency (age range 15–17.3 yr) using DHEAS at a dose <strong>of</strong> 25–50 mg orally. Treatment duration was between 2 and 4 yr. They reported a positive effect on pubic hair development and normalization <strong>of</strong> DHEAS serum levels. Adverse effects <strong>of</strong> DHEAS were not reported in these two studies.
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