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What is the relationship between low testosterone levels and elevated estradiol levels in obese men? What is the impact of elevated estradiol?
Response by Adrian S. Dobs, MD, Posted 11/04/08

Obesity in men is associated with depressed levels of free and total testosterone and elevated levels of estradiol.1,2 In a vicious cycle, increasing abdominal obesity worsens hypogonadism, and without a compensatory gonadotropin response, hypogonadism worsens obesity. Worsening obesity is accompanied by increased aromatase activity in adipose tissue, rapidly converting testosterone to estradiol.

Low testosterone adversely affects overall health in many ways. Libido and sexual function are diminished,3,4 resulting in less sexual activity. Psychological effects of hypogonadism include depressed mood, decreased energy, and impaired cognition.3,4 Physical consequences are decreased bone density and higher risk of metabolic syndrome.2-8

The potential impact of high estradiol on men’s health includes an increased risk of cardiovascular disease, including stroke9 and lower-extremity peripheral arterial disease (PAD).10 Abbott et al found that men in the highest quintile of estradiol concentrations face a significantly greater risk of stroke even after adjustment for age and other cardiovascular risk factors (relative risk, 2.2; 95% confidence interval, 1.5-3.4; P<.001).9 The Swedish arm of the international Osteoporotic Fractures in Men (MrOS) study found that free testosterone independently positively correlates and free estradiol independently negatively correlates with lower-extremity PAD, as defined by ankle-brachial index.10 Compared with the general population, lower-extremity PAD is 3.72 times more common for men with both lowest-quartile levels of testosterone and highest-quartile levels of estradiol. Elevated estradiol levels have also been associated with risk for impaired cognition and dementia (ie, Alzheimer disease).11 Cognitive function declines over time with age but deterioriates significantly more rapidly in men when levels of estradiol are in the highest quartiles.

The Endocrine Society Clinical Practice Guideline recommends testosterone therapy for symptomatic men who have low testosterone levels with the goal of inducing and maintaining secondary sex characteristics and improving sexual function, sense of well-being, muscle mass and strength, and bone mineral density.3,4 Treatment should aim to restore testosterone levels to the mid-normal range. The Food and Drug Administration has approved both short-acting and long-acting testosterone formulations: implant pellets, transdermal patches, buccal tablets, topical gels, and short-acting injectables—testosterone propionate, testosterone enanthate, and testosterone cypionate—that are administered every 7 to 14 days.3,4,12

Testosterone undecanoate (TU) 750 mg, delivered by intramuscular injection every 10 weeks, is in clinical development as a long-acting therapy for the treatment of primary or secondary hypogonadism. In 130 men with an average body mass index of 32.0, testosterone was restored to normal physiologic levels (average concentration 300-1000 ng/dL) and maintained in 94% of patients for the entire 10-week dosing period.13,14 Estradiol was maintained at mid-normal range and dihydrotestosterone levels remained in the low-normal range during the dosing interval.

Efficacy of TU appears comparable to other formulations, with significant improvements in all International Index of Erectile Function domains of sexual desire and function (eg, erectile function), psychosexual function,15 mood states (eg, tension, depression, anger), energy, and cognition, even for patients who were clinically depressed.16 Although not clinically established, it may be concluded that maintaining normal levels of testosterone and other sex hormones, such as estradiol, may contribute to the observed benefits of testosterone therapy.

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References

  1. Cohen PG. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt—a major factor in the genesis of morbid obesity. Med Hypotheses. 1999;52(1):49-51.
  2. Shabsigh R, Arver S, Channer KS, et al. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome [review]. Int J Clin Pract. 2008;62(5):791-798.
  3. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):439-456.
  4. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
  5. Kuchuk NO, van Schoort NM, Pluijm SMF, Smit JH, de Ronde W, Lips P. The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clin Endocrinol (Oxf). 2007;67(2):295-303.
  6. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91(3):843-850.
  7. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036-1041.
  8. 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.
  9. Abbott RD, Launer LJ, Rodriguez BL, et al. Serum estradiol and risk of stroke in elderly men. Neurology. 2007;68(8):563-568.
  10. Tivesten Å, Mellström D, Jutberger H, et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men: the MrOS Study in Sweden. J Am Coll Cardiol. 2007;50(11):1070-1076.
  11. Geerlings MI, Strozyk D, Masaki K, et al. Endogenous sex hormones, cognitive decline, and future dementia in old men. Ann Neurol. 2006;60(3):346-355.
  12. Testosterone. MESO-Rx Web site. http://www.mesomorphosis.com/steroid-profiles/testosterone.htm. Accessed August 6, 2008.
  13. Morgentaler A, Dobs AS, Kaufman JM, et al. Safety, efficacy, and pharmacokinetics of testosterone undecanoate long-acting injection in the treatment of hypogonadism: results of a phase 3 clinical trial. Poster presented at: Annual Meeting of the American Urological Association; May 17-22, 2008; Orlando, FL.
  14. Swerdloff RS, Wang C, Dobs AS, et al. Pharmacokinetics of a long-acting testosterone injection, testosterone undecanoate, on serum total testosterone and other sex hormones in the treatment of hypogonadism at steady state: results from a phase 3 clinical trial. Poster presented at: Annual Meeting of the American Urological Association; May 17-22, 2008; Orlando, FL.
  15. Morgentaler A, Miner M, Steidle C, et al. Improved male sexual function with a novel, long-acting testosterone undecanoate intramuscular injection. Abstract presented at: Annual Meeting of the Northeastern Section of the American Urological Association; September 18, 2008; Santa Anna Pueblo, NM. Abstract 88.
  16. Miner M, Hellstrom W, Steidle C, Goldfischer E, Shabsigh R. Improved depression-related outcomes in men treated with a novel long-acting testosterone undecanoate intramuscular injection. Abstract presented at: Annual Meeting of the Northeastern Section of the American Urological Association; September 18, 2008; Santa Anna Pueblo, NM. Abstract 65.

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