CoChat
Sign Up
Cited by 25Hormonal and reproductive studiesAdrenal Hormones and DisordersEstrogen and related hormone effects

Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men

Open access
Chao, Jing, Rubinow, Katya B., Kratz, Mario, Amory, John K., Matsumoto, Alvin M., Page, Stephanie T.·2016·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2016-1482PMC PMC5052347
Open this paper in CoChat — free account

Abstract

CONTEXT: T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men. OBJECTIVE: This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blinded, placebo-controlled, randomized trial at an academic medical center of 56 healthy men, 19-55 years of age. INTERVENTIONS: Subjects received the GnRH antagonist acyline plus one of the following: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with letrozole (Normal T/Low E) daily for 4 weeks. Body composition and glucose tolerance were assessed at baseline and end of treatment. MAIN OUTCOME MEASURE: Insulin sensitivity was quantified by the Matsuda index. RESULTS: Predicted circulating sex steroid concentrations were achieved in all treatment groups. The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16). A significant time-by-group interaction was observed for fat mass (P = .003), with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016). A time-by-group interaction also was observed for lean mass (P = .03) and influenced by androgen exposure (P = .003). CONCLUSIONS: Short-term sex steroid withdrawal in healthy men causes adverse changes in body composition. These findings support the role of estradiol as a determinant of adiposity in men.

AI snapshot

Written from the paper’s full text.

TL;DR

In healthy men, 4 weeks of sex-steroid withdrawal via acyline caused rapid body-composition changes without weight change, with fat-mass increases attributable to estrogen withdrawal and lean-mass decreases to androgen withdrawal. The trial did not show a significant overall time-by-group effect on insulin sensitivity (Matsuda index P = .16), though sensitivity analyses suggested possible effects.

Key findings

  • Fat mass showed a significant time-by-group interaction (P = .003). The Castrate group increased fat mass by +1.1 ± 0.8 kg (P = .004); Low T/E and Normal T/Low E increased by +0.7 ± 0.8 kg and +0.5 ± 0.8 kg, respectively, but these did not reach significance after correction; Normal T/E changed by −0.4 ± 1.0 kg (not significant). Estradiol change predicted fat-mass change (β = −0.28 per 10 pg/mL; P = .016).
  • Lean mass also showed a significant time-by-group interaction (P = .03). Castrate decreased lean mass by −1.2 ± 1.0 kg (P = .003) and Low T/E by −1.4 ± 1.5 kg (P = .01); Normal T/E and Normal T/Low E were unchanged. Testosterone change was associated with lean-mass change (β = 0.14 per 1 ng/mL; P = .003).
  • The primary endpoint, insulin sensitivity by Matsuda index, had no significant time-by-group interaction (P = .16); HOMA-IR P = .14, IGI P = .66, and AUCglucose P = .865. With baseline values as covariate, Matsuda index showed a trend (P = .09) and HOMA-IR became significant (P = .04).
  • Between week 4 and week 10, the Castrate group had a further fat-mass increase (+1.9 ± 0.6 kg; P < .0001); all groups returned to baseline lean mass by week 10. Hormone suppression was achieved: Castrate total T fell from 4.9 ± 1.5 to 0.98 ± 1.5 ng/mL and estradiol from 25 (18–31) to 5 (3–9) pg/mL at week 2; Normal T/Low E estradiol was 2 (0–3) pg/mL.

Methods

  • Double-blinded, placebo-controlled randomized trial at an academic medical center. Fifty-six healthy men aged 19–55 were enrolled; 45 were included in final analyses (10 Castrate, 11 Low T/E, 11 Normal T/E, 13 Normal T/Low E).
  • All subjects received the GnRH antagonist acyline (300 mcg/kg sc at weeks 0 and 2) plus daily for 4 weeks: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with 5 mg letrozole (Normal T/Low E).
  • Primary outcome was Matsuda index; secondary outcomes included HOMA-IR, insulinogenic index, oral disposition index, glucose AUC during 75-g OGTT, and DXA fat/lean mass at baseline, week 4, and week 10. Main analysis was repeated-measures ANOVA, followed by post hoc linear regression and paired t tests with adjusted P ≤ .0125.

Limitations

  • Stated: unexpectedly rapid body-composition changes prevented direct testing of whether sex steroids regulate insulin sensitivity independent of body composition. Baseline variance and unequal randomization may have obscured insulin-sensitivity effects; small sample size may have underpowered the study; OGTT is less sensitive than the hyperinsulinemic-euglycemic clamp; findings are limited to healthy men and may differ in men with insulin resistance or T2DM.
  • Stated: behavioral data on diet and activity were not collected, so behavioral changes could confound findings; prolonged hormonal effects of castration cannot be ruled out, though acyline effects are expected to reverse.
  • Evident: no group was selectively androgen-deficient, so attribution of effects to androgens versus estrogens relies on analytic modeling; the 4-week duration and multiple comparisons further limit inference.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/jc.2016-1482

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    A time-by-group interaction was observed for lean mass (P = .03).

    “A time-by-group interaction also was observed for lean mass (P = .03)”
    Quote in the paperNot a substantial claim
  • Findingnone given
    § Abstract

    Predicted circulating sex steroid concentrations were achieved in all treatment groups.

    “Predicted circulating sex steroid concentrations were achieved in all treatment groups.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Changes in fat mass were attributable predominantly to estrogen exposure in linear regression analysis (P = .016).

    “with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Significant differences in serum total T and estradiol concentrations among the four groups were achieved at week 2.

    “Significant differences in serum total T (P = .005 in overall RM-ANOVA) and estradiol (P < .0001) concentrations among the four groups were achieved at week 2 (Figure 2, A and B).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    A significant time-by-group interaction was observed for fat mass (P = .003).

    “A significant time-by-group interaction was observed for fat mass (P = .003)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 24

  • Classified as probably not a substantial claim.

    Findingown data
    § Results

    Acyline administration suppressed serum LH and FSH in all four groups.

    “As expected, acyline administration suppressed serum LH and follicular stimulating hormone (FSH) in all four groups (Supplemental Figure 1, A and B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Abstract

    The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16).

    “The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning
    § Results

    Serum free T concentrations showed similar magnitude of change relative to changes in total T levels.

    “Serum free T concentrations showed similar magnitude of change relative to changes in total T levels (Supplemental Figure 2)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the Castrate group, lean mass decreased significantly between baseline and week 4 (−1.2 ± 1.0 kg; P = .003) and the decrease was evident uniformly across subjects in this group.

    “In post-hoc analyses, decreases in lean mass between baseline and week 4 were significant in the Castrate group (−1.2 ± 1.0 kg; P = .003) and evident uniformly across subjects in this group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    The Normal T/E and Normal T/Low E groups maintained serum total T levels comparable to baseline and within the normal range at week 2.

    “The Normal T/E and Normal T/Low E groups maintained serum total T levels comparable to baseline values and within the normal range at week 2 (5.6 ± 3.9 and 5.2 ± 2.7 ng/mL, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the Low T/E and Normal T/Low E groups, fat mass increased by +0.7 ± 0.8 kg and +0.5 ± 0.8 kg, respectively, but these changes did not reach statistical significance after correction for multiple comparisons.

    “Smaller increments in fat mass were evident in the Low T/E and Normal T/Low E groups (+0.7 ± 0.8 kg and +0.5 ± 0.8 kg, respectively), although these changes did not reach statistical significance after correction for multiple comparisons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Serum sex steroid levels were similar at weeks 2 and 4 and recovered to baseline, normal levels in all experimental groups by week 10.

    “Serum sex steroid levels were similar at weeks 2 and 4 and recovered to baseline, normal levels in all experimental groups by week 10.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Significant time-by-group interactions were evident for fat mass (P = .001) and lean mass (P = .03) when baseline, week 4, and week 10 time points were analyzed together.

    “Significant time-by-group interactions were evident for fat mass (P = .001 in overall RM-ANOVA) and lean mass (P = .03 in overall RM-ANOVA) when baseline, week 4, and week 10 time points were analyzed together (Supplemental Figure 4, A and B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    An inverse relationship between circulating total T levels and insulin resistance has been observed in men.

    “An inverse relationship between circulating total T levels and insulin resistance has been observed in men (5, 6)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] 5. Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90(5):2636–2641. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [6] 6. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28(7):1636–1642. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Older men undergoing ADT for prostate cancer exhibit elevated risk of T2DM, CVD, and metabolic syndrome relative to controls matched for age and disease status.

    “Older men undergoing androgen deprivation therapy (ADT) for the treatment of prostate cancer exhibit elevated risk of T2DM, CVD, and metabolic syndrome relative to controls matched for age and disease status (8–10).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] 8. Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: Observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [9] 9. Derweesh IH, Diblasio CJ, Kincade MC, et al. Risk of new-onset diabetes mellitus and worsening glycaemic variables for established diabetes in men undergoing androgen-deprivation therapy for prostate cancer. BJU Int. 2007;100(5):1060–1065. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [10] 10. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006;24(24):3979–3983. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Endogenous T may contribute to the regulation of insulin sensitivity in men.

    “Clinical data suggest that endogenous T may contribute to the regulation of insulin sensitivity in men.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] 5. Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90(5):2636–2641. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [6] 6. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28(7):1636–1642. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Materials and Methods

    The study was randomized.

    “Subjects were assigned by block randomization with a block size of four to one of the following drug regimens”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning
    § Materials and Methods

    The study enrollment goal was 60 to ensure 48 subjects completed all study visits, providing 80% power to detect a difference of at least 25% in the change in insulin sensitivity between any two groups, at an alpha error of 0.05.

    “The study enrollment goal was 60 to ensure 48 (n = 12 per group) subjects completed all study visits and related procedures, given that this would provide 80% power to detect a difference of at least 25% in the change in insulin sensitivity between any two groups, at an alpha error of 0.05.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Materials and Methods

    The study was double-blinded.

    “Both subjects and investigators were blinded to treatment group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    T deprivation in men leads to increased adiposity and reduced lean mass.

    “T deprivation in men leads to increased adiposity and reduced lean mass, both of which are reversed with exogenous T therapy (18, 19).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] 18. Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol. 2013;9(7):414–424. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [19] 19. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Results

    Final analyses included 45 subjects: 10 in the Castrate group, 11 each in the Low T/E and Normal T/E groups, and 13 in the Normal T/-E group.

    “Final analyses included 45 subjects: 10 in the Castrate group, 11 each in the Low T/E and Normal T/E groups, and 13 in the Normal T/-E group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The results of intervention trials of T replacement on insulin sensitivity are mixed.

    “the results of intervention trials are mixed (16, 17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] 16. Liu PY, Wishart SM, Celermajer DS, et al. Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin. Eur J Endocrinol. 2003;148(1):55–66. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [17] 17. Grossmann M, Hoermann R, Wittert G, Yeap BB. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: A systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol (Oxf). 2015;83(3):344–351. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Abstract

    The study was placebo-controlled.

    “This was a double-blinded, placebo-controlled, randomized trial”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given
    § Abstract

    The mechanisms whereby T may contribute to the regulation of insulin sensitivity in men remain poorly understood.

    “The mechanisms whereby T may contribute to the regulation of insulin sensitivity in men remain poorly understood.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Withdrawal of T replacement in men with idiopathic hypogonadotropic hypogonadism led to a significant decline in insulin sensitivity within 2 weeks in the absence of changes in body weight.

    “Interestingly, withdrawal of T replacement in men with idiopathic hypogonadotropic hypogonadism led to a significant decline in insulin sensitivity within 2 weeks in the absence of changes in body weight (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] 20. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92(11):4254–4259. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Physiologic T replacement has been shown to improve insulin sensitivity in some studies of hypogonadal men.

    “although physiologic T replacement has been shown to improve insulin sensitivity in some studies of hypogonadal men (14, 15)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] 14. Simon D, Charles MA, Lahlou N, et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: A 3-month randomized placebo-controlled trial. Diabetes Care. 2001;24(12):2149–51. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [15] 15. Jones TH. Effects of testosterone on Type 2 diabetes and components of the metabolic syndrome. J Diabetes. 2010;2(3):146–156. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Abstract

    Changes in body composition were due to both estrogen and androgen deprivation.

    “Changes in body composition were due to both estrogen and androgen deprivation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Acyline has no metabolic effects other than suppressing gonadal steroid production that would affect body composition or insulin sensitivity.
    • Rests on an assumption: Letrozole has no metabolic effects other than suppressing estradiol that would affect body composition.

  • May combine two claims.

    Premisecitation
    § Discussion

    Prior studies have demonstrated decreased lean mass and increased fat mass in healthy men following suppression of gonadal sex steroid production, but these studies employed longer treatment periods of 12-16 weeks.

    “Prior studies have demonstrated decreased lean mass and increased fat mass in healthy men following suppression of gonadal sex steroid production, but these studies employed longer treatment periods of 12–16 weeks (12, 19).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] 12. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91(4):1305–1308. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [19] 19. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Significant changes in fat mass were observed and attributable to estrogen withdrawal.

    “Significant changes in fat mass were observed and attributable to estrogen withdrawal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    These findings support important metabolic roles for both androgens and estrogens in men and demonstrate negative effects of even partial sex steroid deprivation over a short duration.

    “These findings nonetheless support important metabolic roles for both androgens and estrogens in men and demonstrate negative effects of even partial sex steroid deprivation over a short duration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning
    § Discussion

    Uncaptured differences in behavior across groups could have confounded findings.

    “Thus, uncaptured differences in behavior across groups also could have confounded findings, and future studies will control for altered patterns of diet and/or activity consequent to treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Differences in fat mass among the treatment groups persisted throughout the recovery period, particularly in the Castrate group, suggesting that the detrimental metabolic effects of severe sex steroid deprivation may not be immediately reversible.

    “Notably, differences in fat mass among the treatment groups persisted throughout the recovery period, particularly evident in the Castrate group, suggesting that the detrimental metabolic effects of severe sex steroid deprivation may not be immediately reversible.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Discussion

    Behavioral data were not collected in the study.

    “Although subjects were instructed to maintain their usual diet and activity level, behavioral data were not collected in our study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    ADT worsens glycemic control in men with diabetes and reduces insulin sensitivity in nondiabetic men.

    “ADT worsens glycemic control in men with diabetes and reduces insulin sensitivity in nondiabetic men (9, 12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. Derweesh IH, Diblasio CJ, Kincade MC, et al. Risk of new-onset diabetes mellitus and worsening glycaemic variables for established diabetes in men undergoing androgen-deprivation therapy for prostate cancer. BJU Int. 2007;100(5):1060–1065. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [12] 12. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91(4):1305–1308. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    T exposure may influence motivation, mood, and physical activity in men.

    “T exposure may influence motivation, mood, and physical activity in men (30); thus, resultant findings could reflect behavioral changes resulting from sex steroid manipulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] 30. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–2559. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    The effects of acyline have been shown to be reversed within 14-16 days of injection with normalization of serum T levels by 21 days postinjection.

    “the effects of acyline have been shown to be reversed within 14–16 days of injection with normalization of serum T levels by 21 days postinjection (29)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] 29. Herbst KL, Coviello AD, Page S, Amory JK, Anawalt BD, Bremner WJ. A single dose of the potent gonadotropin-releasing hormone antagonist acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men. J Clin Endocrinol Metab. 2004;89(12):5959–5965. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Previous studies have found increased insulin resistance after androgen withdrawal in men, including studies of men undergoing ADT for treatment of prostate cancer.

    “Previous studies have found increased insulin resistance after androgen withdrawal in men, including studies of men undergoing ADT for treatment of prostate cancer (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] 12. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91(4):1305–1308. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Estradiol plays an important role in the regulation of adiposity in men, whereas androgen exposure was not a significant determinant of changes in fat mass.

    “Similar to the recent study by Finkelstein et al (19), our results also suggest that estradiol plays an important role in the regulation of adiposity in men, whereas androgen exposure was not a significant determinant of changes in fat mass.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 19. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    The authors previously showed that acute T deprivation led to significant increases in HOMA-IR in a small cohort of young, healthy, eugonadal men.

    “We previously have shown that acute T deprivation led to significant increases in HOMA-IR in a small cohort of young, healthy, eugonadal men (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] 21. Rubinow KB, Snyder CN, Amory JK, Hoofnagle AN, Page ST. Acute testosterone deprivation reduces insulin sensitivity in men. Clin Endocrinol (Oxf). 2012;76(2):281–288. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    These data add to a growing body of evidence demonstrating the metabolic harm of sex-steroid deprivation in men, even of short duration, and suggest contributory roles of both androgen and estrogen deficiency.

    “Thus, these data add to a growing body of evidence demonstrating the metabolic harm of sex-steroid deprivation in men, even of short duration, and suggest contributory roles of both androgen and estrogen deficiency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    In men with idiopathic hypogonadotropic hypogonadism, acute androgen withdrawal of only 2 weeks yielded increases in fasting insulin levels and greater insulin resistance.

    “Similarly, in men with idiopathic hypogonadotropic hypogonadism, acute androgen withdrawal of only 2 weeks yielded increases in fasting insulin levels and greater insulin resistance (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] 20. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92(11):4254–4259. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § Discussion

    Treatment effects on insulin sensitivity may have been missed as a result of the small sample size; thus, the study may have been inadequately powered.

    “Treatment effects on insulin sensitivity also may have been missed as a result of our small sample size; thus, our study may have been inadequately powered.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given
    § Discussion

    Insulin sensitivity was assessed through oral glucose tolerance testing, a less-sensitive method than the gold standard of the hyperinsulinemic-euglycemic clamp.

    “Finally, insulin sensitivity was assessed through oral glucose tolerance testing, a less-sensitive method than the gold standard of the hyperinsulinemic-euglycemic clamp.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Discussion

    The study design benefitted from use of a GnRH antagonist to achieve short-term sex steroid suppression, thus avoiding the transient flare in sex steroids that may be seen with the use of GnRH agonists.

    “Our study design benefitted from use of a GnRH antagonist to achieve short-term sex steroid suppression, thus avoiding the transient flare in sex steroids that may be seen with the use of GnRH agonists.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data
    § Discussion

    The randomization strategy did not result in equal distribution of variance across treatment groups, which may have compromised the ability to capture small changes in insulin sensitivity.

    “Our randomization strategy did not result in equal distribution of variance across treatment groups, which may have compromised our ability to capture small changes in insulin sensitivity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Discussion

    These discrepant results may be attributable, in part, to differences across the populations studied including age, developmental exposure to sex steroids, and perhaps baseline BMI.

    “These discrepant results may be attributable, in part, to differences across the populations studied including age, developmental exposure to sex steroids, and perhaps baseline BMI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    Rabiee et al did not observe any changes in body composition, which may in part be attributable to lesser suppression of serum estradiol levels relative to that achieved in the current study.

    “However, Rabiee et al did not observe any changes in body composition, which may in part be attributable to lesser suppression of serum estradiol levels relative to that achieved in our current study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data
    § Discussion

    The present findings are limited to healthy men, and the metabolic effects of short-term sex steroid deprivation could differ among men with extant insulin resistance, T2DM, or other baseline metabolic dysregulation.

    “Importantly, the present findings are limited to healthy men, and the metabolic effects of short-term sex steroid deprivation could differ among men with extant insulin resistance, T2DM, or other baseline metabolic dysregulation.”
    Quote in the paperNot a substantial claim
43 of 43

  • The paper relies on this without support.

    Acyline has no metabolic effects other than suppressing gonadal steroid production that would affect body composition or insulin sensitivity.

    “All subjects received 300 mcg/kg of the GnRH antagonist acyline subcutaneously, at weeks 0 and 2, to suppress endogenous gonadal steroid production.”

  • The paper relies on this without support.

    Letrozole has no metabolic effects other than suppressing estradiol that would affect body composition.

    “administration of the aromatase inhibitor letrozole resulted in significant suppression of serum estradiol concentrations in Normal T/Low E group subjects (2 [0–3] pg/mL) at week 2.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Oestradiol may be important for sexual function, prevention of abdominal adiposity, and insulin sensitivity.

    “In addition to bone health, 119 oestradiol may be important for of sexual function, prevention of abdominal adiposity 68 and insulin sensitivity.69,120”

    From Hypogonadism and male obesity: Focus on unresolved questions (2018) · cites this paper as [69]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. [1]1. U.S. Centers for Disease Control and Prevention National Diabetes Statistics Report, 2014. 2014. Atlanta, GA: U.S. Dept. of Health and Human Services, Centers for Disease Control and Prevention. [Google Scholar]
  2. [32]32. Samocha-Bonet D, Dixit VD, Kahn CR, et al. Metabolically healthy and unhealthy obese—The 2013 Stock Conference report. Obes Rev. 2014;15(9):697–708. [DOI] [PMC free article] [PubMed] [Google Scholar] Articles from The Journal of Clinical Endocrinology and Metabolism are provided here courtesy of The Endocrine Society

Cited by

Sorted by citations

Related

Authors
Chao, J., Rubinow, K. B., Kratz, M., Amory, J. K., Matsumoto, A. M., & Page, S. T.
Affiliations
University of Washington (US)
Corresponding author
Page, Stephanie T.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2016-10
Volume
101
Issue
10
Pages
3724-3731
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2016-1482
PMC
PMC5052347
OpenAlex
W2504837934
Semantic Scholar
0766f77d8239cfb7d390844ec8650265aa90f129
Cited by
25
References
31
Citations by year
2023: 4 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 1
FWCI
4.35
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • AbbVie
  • University of Washington
  • National Institutes of Health (5r01ag037603-02)
  • National Institute on Aging (R01-AG-037603)
  • National Heart, Lung, and Blood Institute (T32HL007028)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007247)
  • NIH Clinical Center
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD042454, K12HD053984)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
testosterone withdrawal, estradiol, insulin sensitivity, adiposity, body composition, fat mass, lean body mass, letrozole, GnRH antagonist, acyline, Matsuda index, glucose tolerance, healthy men
MeSH terms
Letrozole, Adult, Androgens, Blood Glucose, Double-Blind Method, Estradiol, Hormone Antagonists, Humans, Insulin Resistance, Gonadotropin-Releasing Hormone, Male, Middle Aged, Nitriles, Testosterone, Triazoles, Aromatase Inhibitors, Adiposity, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review