15 January 2015 Subscribe to our news feed

Testosterone thresholds and hypogonadal symptoms in young, middle-aged and elderly men

Testosterone thresholds and hypogonadal symptoms in young, middle-aged and elderly men

Hypogonadal symptoms are associated with different serum testosterone thresholds in middle-aged and elderly men. Ramasamy R, Wilken N, Scovell J, Kovac J, Lipshultz L. Urology 2014;84:1378–82.

Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. Scovell J, Ramasamy R, Wilken N, Kovac J, Lipshultz L. BJU Int 2014;doi:10.1111/bju.12970.

There are a number of symptoms associated with hypogonadism, categorised as sexual, psychological and physical symptoms. Two retrospective analyses of men who presented to the same outpatient men’s health clinic with a complaint of low testosterone (T) are summarised below. Both studies involved retrospective analysis of the charts of consecutive, T supplementation (TS) naïve men; aged 40–90 years (n=360),1 and those aged <40 years (n=352).2 All men had their T levels measured and completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire which assessed 10 hypogonadal symptoms.

Key Points

  • A retrospective analysis from a single US centre (between May 2013 and March 2014) involving TS naïve men presenting with symptoms of low T, aged 40–90 years (n=360; mean age 57.1±11.4 years; mean total T level 337.8±147.2 ng/dL) and <40 years (n=352; mean age 33.2±4.2 years; mean total T level 308±170 ng/dL)
  • In men aged 40–90 years, decreased libido, lack of energy, decrease in strength or endurance, falling asleep after dinner, and deterioration in the ability to play sports all exhibited significant differences (p<0.05) between men with serum T levels <300 ng/dL and >300 ng/dL

    • Compared with T levels >300 ng/dL, men with T levels <300 ng/dL had a higher prevalence of decreased libido (66% vs 52%; p=0.0107), lack of energy (50% vs 39%; p=0.0397), decreased strength/endurance (56% vs 39%; p=0.0021), falling asleep after dinner (42% vs 29%; p=0.0143), and deterioration in ability to play sports (41% vs 29%; p=0.0153) (Figure 1)
  • In men aged <40 years, the occurrence of feeling sad, lack of energy, decreased strength and endurance, deterioration in work performance, and a deterioration in the ability to play sports were significantly different (p<0.05) between men with serum T levels of <400 ng/dL and >400 ng/dL

    • Compared with T levels >400 ng/dL, men with T levels <400 ng/dL had higher occurrences of, feeling sad (31% vs 18%; p=0.0282), lack of energy (55% vs 32%; p=0.0006); decreased strength/endurance (46% vs 30%; p=0.0228), deterioration in work performance (24% vs 12%, p=0.0001), deterioration in ability to play sports (31% vs 15%; p=0.0076) (Figure 2)
  • In men aged 40–90 years there are unique T thresholds based on symptoms which are a better predictor of hypogonadism than a solitary predefined T level

    • 320 ng/dL for decreased ability to play sports, 340 ng/dL for decreased strength and endurance, 350 ng/dL for lack of energy, 360 ng/dL for increasingly falling asleep after dinner, 375 ng/dL for decreased libido
  • Men aged 40–90 years exhibited an inverse relationship between symptom expression and serum T levels
  • For men aged <40 years, hypogonadal symptoms appear to be associated with a total serum T level of <400 ng/dL
  • In men of all ages, lack of energy appears to be the most effective predictor of a total T level <400 ng/dL

    • On multivariate analysis in men aged <40 years, only lack of energy predicted T levels <400 ng/dL, odds ratio, 2.59 (95% confidence interval, 1.06–6.35; p=0.037)
  • Rather than a single predefined total serum T, different thresholds of T levels based on symptomatology are recommended

What is known

Historically a total serum T threshold of 300 ng/dL defined hypogonadism.3 Indeed, it has been shown that in most men T >300 ng/dL predicts a low likelihood of clinically significant hypogonadism.2 However, it should be noted that this threshold was based on a panel consensus.4 Symptoms can vary greatly between men with low T levels, such that a single serum threshold is not appropriate.5,6 Despite the suggested threshold, the T level below which symptoms are most apparent and would benefit TS is largely unknown and varies with age, the presence of comorbid conditions and affected target organs.2

Previously, it has been shown that there is a close association between low energy and testosterone levels.7-9 In a study of hypogonadal and eugonadal men, hypogonadal men reported greater fatigue (10.0 vs 7.0 on a question scale, p=0.03).9 In addition, in a placebo controlled study, hypogonadal men treated with T reported significantly less fatigue (p=0.03 vs placebo control).8 Furthermore, sexual symptoms, notably libido and erectile function, have been thought of as the best predictor of low T levels, as erectile dysfunction is common in hypogonadal men.10

What this study adds

Despite a T level of ≤300 ng/dL being recommended for treating hypogonadism,3 and previous findings suggesting low likelihood of hypogonadism in men with T levels >300 ng/dL, the studies reported here found a number of patients presenting symptoms with T levels between 300–400 ng/dL.1,2 Indeed, it was suggested that in men aged 40–90 years there are multiple symptom-specific thresholds, and in men aged <40 years physical and psychological symptoms were most closely associated with a T level of <400 ng/dL.2

Contrary to previous studies,10-12 in men aged 40–90 years there were no symptoms from the ADAM questionnaire that were significantly predictive of T levels <300 ng/dL. Furthermore, in men aged <40 years only a lack of energy was predictive of T levels <400 ng/dL.

In contrast with previous findings, none of the sexual symptoms predicted a low T level. Men aged 40–90 years only displayed a significant difference in the prevalence of reduced libido, however in the univariate and multivariate analyses, for both men aged <40 years and 40–90 years, there were no sexual symptoms predictive of low T. In men aged 40–90 years, erectile dysfunction was the most often reported symptom, but contrary to results from the European Aging Male study10 it did not predict a T level <300 ng/dL.

One of the main differences noted between young and middle-aged and elderly men, was the prevalence and clustering of different symptoms between the age groups, especially noted in the sexual specific category, suggesting that specific age and population-based questions should be taken into consideration before initiating TS.

Rather than a single pre-specified testosterone level, a range of 320–375 ng/dL based on different symptoms is more appropriate in men aged 40–90 years.1 Furthermore, in men aged <40 years a total serum T level of 400 ng/dL was identified as there were no symptoms that predicted T levels <300 ng/dL.2

These findings confirm that serum testosterone is the laboratory measure most important for confirming a clinical suspicion of hypogonadism.13 Furthermore, although reference ranges (for partitioning testosterone levels into low or normal) are essential for the diagnosis of androgen deficiency,14 it is clear that symptoms accumulate gradually with decreasing testosterone levels.15

Figures

Figure 1. Prevalence of hypogonadal symptoms in men with T levels <300 ng/dL and >300 ng/dL in men aged 40–90 years (p<0.05 for all symptoms)
Figure 1. Prevalence of hypogonadal symptoms in men with T levels <300 ng/dL and
Figure 2. Prevalence of hypogonadal symptoms in men with T levels <400 ng/dL and >400 ng/dL in men aged <40 years (p<0.05 for all symptoms)
Figure 2. Prevalence of hypogonadal symptoms in men with T levels <400 ng/dL and >400 ng/dL in men aged <40 years (p<0.05 for all symptoms)

References

1. Ramasamy R, Wilken N, Scovell JM, et al. Hypogonadal Symptoms Are Associated With Different Serum Testosterone Thresholds in Middle-aged and Elderly Men. Urology 2014;84(6):1378-1382.
2. Scovell JM, Ramasamy R, Wilken N, et al. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400ng/dL. BJU international 2014
3. Rosen RC, Araujo AB, Connor MK, et al. The NERI Hypogonadism Screener: psychometric validation in male patients and controls. Clinical Endocrinology 2011;74(2):248-256.
4. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism 2006;91(6):1995-2010.
5. Lackner JE, Rucklinger E, Schatzl G, et al. Are there symptom-specific testosterone thresholds in aging men? BJU International 2011;108(8):1310-1315.
6. Morgentaler A, Khera M, Maggi M, et al. Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions. The Journal of Sexual Medicine 2014;11(7):1636-1645.
7. Bercea RM, Mihaescu T, Cojocaru C, et al. Fatigue and serum testosterone in obstructive sleep apnea patients. The Clinical Respiratory Journal 2014
8. Del Fabbro E, Garcia JM, Dev R, et al. Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Supportive Care in Cancer 2013;21(9):2599-2607.
9. Lasaite L, Ceponis J, Preiksa RT, et al. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia 2014;46(10):1107-1112.
10. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. The New England Journal of Medicine 2010;363(2):123-135.
11. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. The Journal of Clinical Endocrinology and Metabolism 2005;90(2):678-688.
12. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. The New England Journal of Medicine 2013;369(11):1011-1022.
13. Nieschlag E, H.M. B, editors. Andrology, Male Reproductive Health and Dysfunction. Second ed. Berlin, Heidelberg, New York.: Springer-Verlag; 2000.
14. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. The Journal of Clinical Endocrinology and Metabolism 2011;96(8):2430-2439.
15. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. The Journal of Clinical Endocrinology and Metabolism 2006;91(11):4335-4343.

Last updated: 2018
G.MKT.GM.MH.01.2018.0500