Mihaela Cosma

Antiandrogens for the Treatment of Hirsutism: A Systematic Review and Metaanalyses of Randomized Controlled Trials

CONTEXT The relative efficacy of antiandrogens for the treatment of hirsutism remains unclear. OBJECTIVE We performed a systematic review and metaanalyses of randomized controlled trials (RCTs) evaluating the effect of antiandrogens on hirsutism. DATA SOURCES We used librarian-designed search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006), review of reference lists, and contact with hirsutism experts to identify eligible RCTs. STUDY SELECTION Eligible studies were RCTs of at least 6 months of antiandrogen use in women with hirsutism. Reviewers, with acceptable chance-adjusted agreement (kappa = 0.72), independently assessed eligibility. DATA EXTRACTION Reviewers used structured forms to assess and collect methodological quality (allocation concealment, blinding, and loss to follow-up) and study data. DATA SYNTHESIS Of 348 candidate studies, 12 were eligible (18 comparisons). Their methodological quality was low. Random-effects metaanalyses showed that compared with placebo, antiandrogens reduce Ferriman-Gallwey scores by 3.9 [95% confidence interval (CI), 2.3-5.4; inconsistency (I(2)) = 0%]. When compared with metformin, spironolactone reduced hirsutism scores by 1.3 (CI, 0.03-2.6) and flutamide by 5.0 (CI, 3.0-7.0; I(2) = 0%). For these interventions, two to five women need to receive treatment for one to notice improvement. Spironolactone or finasteride in combination with contraceptives (1.7; CI, 0.1-3.3; I(2) = 0%) or flutamide with metformin (4.6; CI, 1.3-7.9; I(2) = 40%) appear superior to monotherapy with contraceptives and metformin, respectively. Only three RCTs reported patient self-assessments of hirsutism. CONCLUSIONS Weak evidence suggests antiandrogens are mildly effective agents for the treatment of hirsutism.

Insulin sensitizers for the treatment of hirsutism: A systematic review and metaanalyses of randomized controlled trials

CONTEXT Insulin sensitizers, including metformin and thiazolidinediones (TZDs), improve hyperinsulinemia and reproductive dysfunctions in some women with hyperandrogenism. The extent to which these agents improve hirsutism remains unclear. OBJECTIVE Our objective was to conduct a systematic review and metaanalyses of randomized controlled trials of metformin or TZDs for the treatment of hirsutism. DATA SOURCES We searched the following databases: MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006). Review of reference lists and contact with hirsutism experts further identified candidate trials. STUDY SELECTION Reviewers working independently and in duplicate, with acceptable chance-adjusted agreement (kappa = 0.72), determined trial eligibility. Eligible trials randomly assigned women with hirsutism to at least 6 months of insulin sensitizers or control and measured hirsutism outcomes. DATA EXTRACTION Reviewers working independently and in duplicate determined the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS Of 348 candidate studies, 16 trials (22 comparisons) were eligible. The methodological quality of these trials was low. Random-effects metaanalyses showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with placebo [pooled weighted mean difference (WMD) of -1.5; 95% confidence interval (CI), -2.8 to -0.2; inconsistency (I(2)) = 75%]. There was no significant difference between insulin sensitizers and oral contraceptives (WMD of -0.5; CI, -5.0, 3.9; I(2) = 79%). Metformin was inferior to both spironolactone (WMD of 1.3; CI, 0.03, 2.6) and flutamide (WMD of 5.0; CI, 3.0, 7.0; I(2) = 0%). CONCLUSIONS Imprecise and inconsistent evidence of low to very low quality suggests that insulin sensitizers provide limited or no important benefit for women with hirsutism.

A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials of DHEA Treatment Effects on Quality of Life in Women with Adrenal Insufficiency

CONTEXT Women with primary or secondary adrenal insufficiency report a decreased health-related quality of life (HRQOL) despite traditional adrenal replacement therapy. Dehydroepiandrosterone (DHEA) has been studied as an agent to improve HRQOL in these patients. OBJECTIVE We sought to conduct a systematic review and meta-analysis of randomized controlled trials of DHEA effects on HRQOL in women with adrenal insufficiency. DATA SOURCES We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, and PsycInfo) and reference lists of eligible studies through July 2008. STUDY SELECTION Eligible trials randomly assigned women with primary or secondary adrenal insufficiency to either DHEA or control and measured the effect of treatment on HRQOL. DATA EXTRACTION Reviewers working independently and in duplicate assessed the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS We found 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta-analysis showed a small improvement in HRQOL in women treated with DHEA compared with placebo [effect size of 0.21; 95% confidence interval, 0.08 to 0.33; inconsistency (I(2)) = 32%]. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant. CONCLUSIONS DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.

Estrogen Elevates the Peak Overnight Production Rate of Acylated Ghrelin

CONTEXT Acylated ghrelin is the putatively bioactive GH secretagogue. HYPOTHESIS Estradiol (E2) stimulates the synthesis rather than inhibits the metabolic clearance of acylated ghrelin. SETTING The study took place at an academic medical center. SUBJECTS Healthy postmenopausal women participated. INTERVENTIONS Interventions included prospectively randomized, double-blind separate-day iv infusions of saline or five graded doses of ghrelin in estrogen-deficient (n=12) and E2-supplemented (n=8) women. OUTCOMES Metabolic clearance rate (MCR), volume of distribution, half-life, and secretion rate of acylated ghrelin were assessed. RESULTS In pilot iv bolus ghrelin infusions, the median half-lives of acylated and total ghrelin were 21 and 36 min (P<0.01), MCRs 58 and 8.1 liters/kg.d (P<0.01), and volumes of distribution of 1.0 and 0.32 liters/kg (P<0.01), respectively. Transdermal E2 supplementation for 3 wk increased peak nighttime acylated ghrelin concentrations from 99+/-12 to 141+/-34 pg/ml (P=0.039). Exposure to E2 did not alter the linear relationships between 1) plasma acylated ghrelin concentration and ghrelin infusion rate (638+/-12 slope units), 2) MCR of acylated ghrelin and ghrelin infusion rate (10+/-2.5 slope units), and 3) MCR and plasma concentration of acylated ghrelin (0.017+/-0.004 slope units). These data predict peak nighttime production rates of acylated ghrelin of 3.8+/-0.9 (E2) and 1.9+/-0.2 (no E2) ng/kg.min (P=0.039). CONCLUSION Acylated ghrelin has a multifold larger distribution volume and MCR than total ghrelin. An estrogenic milieu augments synthesis and/or acylation of ghrelin peptide without altering its MCR.

Aromatase and 5α-Reductase Inhibition during an Exogenous Testosterone Clamp Unveils Selective Sex Steroid Modulation of Somatostatin and Growth Hormone Secretagogue Actions in Healthy Older Men

BACKGROUND How endogenous testosterone (Te), 5alpha-dihydrotestosterone (DHT), and estradiol (E(2)) regulate pulsatile GH secretion is not understood. HYPOTHESIS Conversion of Te to androgenic (Te-->DHT) or estrogenic (Te-->E(2)) products directs GH secretion. SUBJECTS AND LOCATION: Healthy older men (N = 42, ages 50-79 yr) participated at an academic medical center. METHODS We inhibited 5alpha-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and L-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion. ENDPOINTS Deconvolution-estimated basal and pulsatile GH secretion was assessed. RESULTS Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E(2) concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E(2) by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P < 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P < 0.001); 2) Te and E(2) jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E(2), P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression. CONCLUSION The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E(2) along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

Estrogen Supplementation Selectively Enhances Hypothalamo-Pituitary Sensitivity to Ghrelin in Postmenopausal Women

CONTEXT Sex-steroid hormones amplify pulsatile GH secretion by unknown mechanisms. Ghrelin is the most potent natural GH secretagogue discovered to date. A plausible unifying postulate is that estradiol (E(2)) enhances hypothalamo-pituitary sensitivity to ghrelin (a physiological effect). The hypothesis is relevant to understanding the basis of hyposomatotropism in aging and other relatively hypogonadal states. OBJECTIVE Our objective was to test the hypothesis that E(2) supplementation potentiates ghrelins stimulation of pulsatile GH secretion. SETTING The study was conducted at an academic medical center. SUBJECTS Healthy postmenopausal women (n = 20) were included in the study. INTERVENTIONS Separate-day iv infusions of saline vs. five graded doses of ghrelin were performed in volunteers prospectively randomly assigned to receive (n = 8) or not receive (n = 12) transdermal E(2) for 21 d were performed. MEASURES GH secretion was estimated by deconvolution analysis and abdominal visceral fat mass determined by computerized axial tomography were calculated. RESULTS E(2) supplementation augmented ghrelins stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P = 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P = 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P = 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R = -0.346; P < 0.005). CONCLUSIONS Transdermal E(2) supplementation potentiates GH secretion stimulated by physiological but not pharmacological concentrations of acylated ghrelin, and concomitantly regularizes patterns of bioactive ghrelin secretion in postmenopausal women. Accordingly, the estrogen milieu appears to control sensitivity of the hypothalamopituitary unit to acylated ghrelin.

Estradiol supplementation in postmenopausal women attenuates suppression of pulsatile growth hormone secretion by recombinant human insulin-like growth factor type I.

BACKGROUND Why pulsatile GH secretion declines in estrogen-deficient postmenopausal individuals remains unknown. One possibility is that estrogen not only enhances stimulation by secretagogues but also attenuates negative feedback by systemic IGF-I. SITE: The study took place at an academic medical center. SUBJECTS Subjects were healthy postmenopausal women (n=25). METHODS The study included randomized assignment to estradiol (n=13) or placebo (n=12) administration for 16 d and randomly ordered administration of 0, 1.0, 1.5, and 2.0 mg/m2 recombinant human IGF-I sc on separate days fasting. ANALYSIS Deconvolution analysis of pulsatile and basal GH secretion and approximate entropy (pattern-regularity) analysis were done to quantify feedback effects of IGF-I. OUTCOMES Recombinant human IGF-I injections increased mean and peak serum IGF-I concentrations dose dependently (P<0.001) and suppressed mean GH concentrations (P<0.001), pulsatile GH secretion (P=0.001), and approximate entropy (P<0.001). Decreased GH secretion was due to reduced secretory-burst mass (P=0.005) and frequency (P<0.001) but not basal GH release (P=0.52). Estradiol supplementation lowered endogenous, but did not alter infused, IGF-I concentrations while elevating mean GH concentrations (P=0.012) and stimulating pulsatile (P=0.008) and basal (P<0.001) GH secretion. Estrogen attenuated IGF-Is inhibition of pulsatile GH secretion (P=0.042) but was unable to restore physiological GH pulse frequency or normalize approximate entropy. CONCLUSION Short-term estrogen replacement in postmenopausal women selectively mutes IGF-I-mediated feedback on pulsatile GH secretion. Disinhibition of negative feedback thus confers a novel mechanism by which estrogen may obviate hyposomatotropism.

Testosterone supplementation in older men restrains insulin-like growth factor's dose-dependent feedback inhibition of pulsatile growth hormone secretion.

BACKGROUND Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia. HYPOTHESIS Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I. SUBJECTS Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study. METHODS We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2). ANALYSIS Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted. RESULTS Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-Is inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity. CONCLUSION The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.