Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]
[This is a series of abstracts apparently done on the same male subjects. The first abstract is important at least insofar it describes a study finally on the possible role of E2 in libido!!! There are other animal studies consistent with the abstract. I am hopeful there will be a follow-up with a full-text article. And, further studies on the role of E2 in libido and erection function. I have posted far too many times that E2 manipulation for libido and erection function is without support. However, the anecdotal evidence is there and studies will hopefully clarify the issue.]
[P3-206] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Sexual Desire in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-206
BZ Leder, H Lee, EW Yu, S-AM Burnett-Bowie, JC Pallais, ML Webb, KE Wulczyn, AB Servais, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.
Testosterone (T) is thought to be the primary hormonal regulator of libido/sexual desire (SD) in men.
Methods: To determine if SD is also regulated by estrogen (E), we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. SD was assessed using both the International Index of Erectile Function (SD-M1) and a previously-validated question asking subjects to compare their sex drive now with baseline levels (-2=much less, -1=somewhat less, 0=the same, +1=somewhat more, +2=much more) (SD-M2).
Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. Specifically, if T has an independent effect on SD, subjects in the T/E- cohort who receive no or little testosterone replacement should experience decreased SD compared to those receiving higher doses (as E levels will be the same). Conversely, if E has an independent effect on SD, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 (because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort).
Results: Mean serum T levels in G1-5 were 43, 173, 346, 477, and 882 ng/dL in the T/E+ cohort and 34, 199, 329, 475, and 857 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). SD declined more in men receiving placebo T than in the other T dose groups in both the T/E+ (P<0.005 vs G2, 3, 4 and 5 by SD-M1 and SD-M2) and the T/E- (P<0.02 vs G4 and G5 by SD-M1 and P<0.01 vs G3, 4, and 5 by SD-M2) cohorts. Aromatase inhibition further reduced SD in men receiving T gel (G2-5, P<0.0001 by both SD-M1 and SD-M2) but had no effect on SD in men receiving placebo T gel (G1, P=0.72 by SD-M1 and P=0.53 by SD-M2).
Conclusions: As expected, lowering T levels reduces SD in men. Surprisingly, S[exual]D[esire] is further reduced in men treated with an aromatase inhibitor to reduce E production. These results suggest that non-aromatizable androgens may be less effective than aromatizable androgens for hypogonadal men with low sexual desire.
[P3-204] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Body Composition in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-204
JS Finkelstein, S-AM Burnett-Bowie, BZ Leder, JC Pallais, EW Yu, BJ Thomas, ML Webb, KE Wulczyn, JM Youngner, H Lee. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.
Testosterone (T) therapy increases lean mass and decreases fat mass in men.
Methods: To determine if these effects are due to T itself or to its conversion to estrogen (E), we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. Total body fat and lean mass were assessed by DXA and subcutaneous (SC) fat and thigh muscle areas were measured by CT at wk 0 and 16.
Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. If T has an independent effect on body composition, differences vs the placebo T group should most likely occur as the T dose increases within the T/E- cohort because E levels should be similarly low in all groups while T levels become progressively more discordant. Conversely, if E has an independent effect on body composition, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort.
Results: Mean serum T levels in G1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort and 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). Changes in fat measures were similar across groups within the T/E- cohort. In men who received placebo T (G1), aromatase blockade had no effect on total body fat (P=0.36) or SC fat area (P=0.66). However, in men receiving T gel (G2-5), total body fat (P<0.001) and SC fat area (P<0.001) increased more in the T/E- than the T/E+ cohort. Lean mass and thigh muscle area decreased significantly in G1 vs G2-5 in the T/E- cohort (P<0.01 for all comparisons). Aromatase blockade had no effect on changes in lean mass (P=0.17 for G1, P=0.39 for G2-5) or thigh muscle area (P=0.65 for G1, P=0.36 for G2-5).
Conclusions: These results suggest that T alone regulates lean mass and muscle size while E, but not T, regulates fat mass in men. Treatment of hypogonadal men with non-aromatizable androgens may have undesirable effects on fat accumulation.
[P3-205] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Lipid Profiles in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-205
S-AM Burnett-Bowie, AF Moore (deceased), BZ Leder, HS Lee, EW Yu, LF Borges, BF Jones, AH Linker, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.
Studies examining the effects of androgens and estrogens on lipids in men have produced inconsistent results.
Methods: To assess the effects of androgens and estrogens on lipids in men, we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous testosterone (T) and estradiol (E). Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. Fasting total cholesterol, HDL, LDL, and triglycerides were measured every 4 weeks.
Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. If T has an independent effect on lipids, differences vs the placebo T group should most likely occur as the T dose increases within the T/E- cohort because E levels should be low in all groups while T levels become more discordant. Conversely, if E has an independent effect on lipids, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort.
Results: Mean serum T levels in G1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort and 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). Changes in LDL were similar in G1 vs G2-5 in both cohorts. Aromatase blockade had no effect on changes in LDL (P=0.48 for G1, P=0.37 for G2-5). In both cohorts, HDL levels increased more in men who received placebo T (G1) than in men who received T (G2-5) (P<0.03 vs G3, 4, and 5 of T/E+ and P<0.005 vs each group of T/E-). Aromatase blockade had no effect on the rise in HDL in men receiving placebo T gel (G1, P=0.69). However, in men receiving T gel (G2-5), HDL increased less (P<0.01) in the T/E- than the T/E+ cohort.
Conclusions: Across a wide range of levels, androgens and estrogens have no effect on LDL levels in men. In contrast, T withdrawal increases HDL levels in men and aromatase blockade attenuates these increases. These results suggest that using non-aromatizable androgens to treat hypogonadal men may have undesirable effects on HDL levels in adult men.
[OR35-4] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Prostate-Specific Antigen in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR35-4
JC Pallais, H Lee, EW Yu, S-AM Burnett-Bowie, BZ Leder, CW Hahn, NE Perros, CV Barry, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.
Using a GnRH agonist and different doses of testosterone (T) add-back, we had previously shown that lowering T levels below baseline reduced PSA levels whereas increasing T levels above baseline did not alter PSA levels in young men.
Methods: To determine if these effects are due to T itself or to its conversion to estrogen (E), we recruited 2 cohorts of healthy men age 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block T to E conversion. A third control cohort (n=35) received only placebo medications. Serum PSA levels were measured at baseline and every 4 wks for 16 wks. Within the T/E- cohort, changes in PSA between T dose groups were evaluated to assess independent T effects. PSA changes between same T dose groups were compared across the T/E+ and T/E- cohorts to assess independent E effects.
Results: Mean serum T levels in Groups 1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort, 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts), and 584 ng/dL in the control cohort (P=NS vs men receiving 5g of T in the T/E+ and T/E- cohorts). Within both the T/E+ and T/E- cohorts, there was a strong dose response relationship between T doses and change in PSA. The percent changes in PSA in Groups 1-5 of the T/E+ and T/E- cohorts were -59%, -38%, -28%, -18%, and -1% and -52%, -42%, -24%, -15%, and -6%, respectively. Compared with the percent change in PSA in the control cohort (2%), PSA values decreased in men in both cohorts treated with less than 5g of T, but did not change in those receiving more than 5g of T. Aromatase inhibition had no effect on PSA changes at any T dose when compared across the T/E+ and T/E- cohorts.
Conclusions: Androgens regulate PSA levels in a dose-dependent manner in healthy young men. Prostate responsiveness is more sensitive to androgen deficiency rather than excess, at least in the short term. E does not appear to be involved in the hormonal regulation of PSA at T levels ranging from pre-pubertal to the upper end of the reference range.
[P1-473] Letrozole Normalizes Serum Testosterone but Has No Clinical Effects in Men with Obesity-Related Hypogonadotropic Hypogonadism http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-473
S Loves, J de Jong, A van Sorge, D Telting, A Hermus, H de Boer. Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Radboud University Medical Centre, Nijmegen, Netherlands.
Introduction: Hypogonadotropic hypogonadism is frequently observed in morbidly obese men, due to aromatase-dependent conversion of androgens to estrogens in adipocytes. The clinical impact of this sex hormone imbalance is not known.
Aim: To evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypogonadism.
Methods: Double-blind, placebo-controlled, 6-month trial in severely obese men (BMI > 35 kg/m2) with obesity-related hypogonadism (serum total testosterone < 10 nmol/l). Predefined drug regimen (letrozole or placebo): Starting dose 1 tablet/week, subsequent dose escalation every month up to a maximum of 7 tablets/week or until a serum total testosterone of 20 nmol/L. The dose was reduced if serum estradiol decreased below 40 pmol/L.
Results: 42 patients were included and 39 completed the study according to protocol: 18 on Letrozole and 21 receiving placebo. Mean age 44.6 ± 1.1 years (mean ± SE), BMI 41.1 ± 0.8 kg/m². At baseline, both groups were well matched for all study parameters. Placebo treatment did not affect serum hormone levels, whereas Letrozole decreased serum estradiol from 119.1 ± 10.1 to 59.2 ± 6.1 pmol/L (P = 0.0001, normal range (NR) 40 - 160 pmol/L), increased serum LH from 3.3 ± 0.3 to 8.8 ± 0.9 U/L (P < 0.0001, NR: 2.0 – 9.0 U/L) and free testosterone from 244 ± 19 to 691 ± 39 pmol/L (P < 0.0001, NR: 225 - 625 pmol/L). Both groups demonstrated a comparable decrease in body weight of about 5 kg, and a decrease in abdominal circumference of about 4 cm. Changes in fat free mass, fat mass and bone density also did not differ between groups. Glucose metabolism, lipid profiles, physical exercise capacity and psychological characteristics did not change during treatment.
Conclusion: Despite a marked rise in serum free testosterone, low dose aromatase inhibition had no somatic or psychological effects in men with obesity-related hypogonadotropic hypogonadism. We hypothesize that, with respect to non-sexual somatic and psychological parameters, males primarily thrive on oestrogens, not testosterone.