Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia.
ABSTRACT Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor.
To evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH).
Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI > 35 kg/m2, and serum total testosterone levels < 10 nmol/L. All patients started on 1 tablet of 2.5 mg/week, with subsequent dose escalation every month until a serum total testosterone of 20 nmol/L was reached. Endpoints: psychological function, body composition, exercise capacity, and glucose, lipid and bone metabolism.
39 patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1 ± 10.1 to 59.2 ± 6.1 pmol/L (P < 0.001), increased serum LH from 3.3 ± 0.3 to 8.8 ± 0.9 U/L (P < 0.0001), and raised serum total testosterone from 8.6 ± 0.7 to 21.5 ± 1.3 nmol/L (P < 0.0001). Significant effects on the predefined endpoints were not observed.
Despite a marked rise in serum testosterone, low dose aromatase inhibition had no somatic or psychological effects in men with OrHH.
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ABSTRACT: Introduction: Adulthood male hypogonadism (HG) is the most common form of HG. Although testosterone (T) replacement therapy (TRT) is the most common way of treating HG, other options are available depending on patient's needs and expectations. Areas covered: We analyze alternative options to TRT as a medical intervention in treating HG. Gonadotropin (Gn) therapy is the treatment of choice in men with secondary HG (sHG), who require fertility. Gonadotropin-releasing hormone therapy represents an alternative to Gn for inducing spermatogenesis in patients with sHG, however, its use is limited by the poor patient compliance and high cost. In obese HG men, lifestyle modifications and, in particular, weight loss should be the first step. Recent data suggest that antiestrogens represent a successful treatment for sHG. Other potential therapeutic options include the stimulation of hypothalamic activity (i.e., kisspeptin and neurokinin-B agonists). Conversely, the possibility of increasing Leydig cell steroid production, independently from Gn stimulation, seems unreliable. Expert opinion: Understanding the nature of male HG and patient's needs are mandatory before choosing among treatment options. For primary HG only TRT is advisable, whereas for the secondary form several alternative possibilities can be offered.Expert Opinion on Pharmacotherapy 12/2014; 16(3):1-19. DOI:10.1517/14656566.2015.993607 · 2.86 Impact Factor
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ABSTRACT: The influence of the aromatase enzyme in androgen-induced bone maintenance following skeletal-maturity remains somewhat unclear. Our purpose was to determine whether aromatase activity is essential to androgen-induced bone maintenance. 10 month old male Fisher 344 rats (n = 73) were randomly assigned to receive Sham surgery, orchiectomy (ORX), ORX + anastrozole (AN; aromatase inhibitor), ORX + testosterone-enanthate (TE, 7.0mg/week), ORX + TE + AN, ORX + trenbolone-enanthate (TREN; non-aromatizable, non-estrogenic testosterone analogue; 1.0mg/week), or ORX + TREN + AN. ORX animals exhibited histomorphometric indices of high-turnover osteopenia and reduced cancellous bone volume compared to Shams. Both TE and TREN administration suppressed cancellous bone turnover similarly and fully prevented ORX-induced cancellous bone loss. TE and TREN treated animals also exhibited greater femoral neck shear strength than ORX animals. AN co-administration slightly inhibited the suppression of bone resorption in TE-treated animals, but did not alter TE-induced suppression of bone formation or the osteogenic effects of this androgen. In TREN treated animals, AN co-administration produced no discernible effects on cancellous bone turnover or bone volume. ORX animals also exhibited reduced levator ani/bulbocavernosus (LABC) muscle mass and elevated visceral adiposity. In contrast, TE and TREN produced potent myotrophic effects in the LABC muscle and maintained fat-mass at the level of Shams. AN co-administration did not alter androgen-induced effects on muscle or fat. In conclusion, androgens are able to induce direct effects on musculoskeletal and adipose tissue, independent of aromatase activity. © 2014 American Society for Bone and Mineral ResearchJournal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; 29(11). DOI:10.1002/jbmr.2265 · 6.04 Impact Factor
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ABSTRACT: The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25–800 mg), 10 male volunteers received DMAU and two received placebo at two academic medical centres. DMAU was administered both fasting and after a high-fat meal (200–800 mg doses). Serial serum samples were collected over 24 h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800 mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200 mg DMAU and showed a dose-incremental increase up to 800 mg, with peak levels 4–8 h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12 h after DMAU administration with food at doses above 200 mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics.Andrology 05/2014; DOI:10.1111/j.2047-2927.2014.00216.x · 3.37 Impact Factor