Testosterone treatment and sleep disorders

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Testosterone therapy and obstructive sleep apnea: is there a real connection?
Hanafy HM. J Sex Med 2007;4(5):1241-1246.

Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnea: a randomized placebo-controlled trial.
Hoyos CM, Killick R, Yee BJ, Grunstein RR, Liu PY.Clin Endocrinol 2012;77(4):599-607.

Millions of men have received testosterone therapy over the past several decades, but only a few studies have addressed the possible link between testosterone treatment and obstructive sleep apnea (OSA). Despite the small number of patients studied, publications have generally cautioned clinicians about the possible cause or aggravation of OSA by testosterone therapy. A review of the literature by Hanafy in 2007 evaluated the scientific data behind these cautionary statements and found a lack of consistent findings from case studies and different patient groups and that the link between testosterone and OSA was weak. Further well designed studies in this area were recommended from this review.

To address this gap a recent randomized, placebo-controlled study evaluated the effect of testosterone therapy in obese men with severe OSA. Eligible subjects (recruited from sleep clinics in Sydney, Australia) were enrolled into an 18-week weight loss program and randomized to receive three intramuscular injections of either testosterone undecanoate 1,000 mg or placebo. Sleep and breathing parameters were measured (by nocturnal polysomnography) at 0, 7 and 18 weeks.

Compared with placebo treatment, testosterone mildly worsened the oxygen desaturation index (ODI, p=0.03) and nocturnal hypoxemia (sleep time with oxygen saturation <90%, SpO2T90%, p=0.01) at 7 weeks but not at 18 weeks. The time-dependent effects of testosterone treatment on ODI and SpO2T90% were not influenced by baseline testosterone concentrations.
Key Points


In 2007 a review of the scientific literature by Hanafy indicated that the link between testosterone therapy and OSA was weak. This was mainly due to methodological issues in many studies often involving low patient numbers
The largest study in terms of numbers of subjects that examined the effect of supraphysiologic doses of testosterone on OSA included 16 healthy men ≥60 years, randomized to receive three intramuscular injections of high doses of testosterone esters at weekly intervals (500, 250 and 250 mg), or matching placebo, then crossed over to the other treatment after an 8-week washout1


Testosterone treatment reduced the total time slept, increased duration of hypoxia and disrupted breathing during sleep, but with no changes in the upper airway dimensions, Epworth Sleepiness Scale or insulin resistance
Hanafy argued that hypogonadal patients with OSA should not be denied testosterone because of inconclusive results based on methodological issues and small numbers of men in the studies. There is a need for well-designed multicenter studies, using physiologic doses of testosterone, of large groups of middle-aged and older patients (including documented hypogonadal patients)
To address this evidence gap, a double-blind, placebo controlled, parallel-group study was designed to examine the effects of testosterone on sleep and breathing in 67 obese men with severe OSA
Eligible adult obese men with OSA (defined as aged ≥18 years, body mass index [BMI] >30 kg/m2 and apnea hypopnea index [AHI] >10 events/h by in-laboratory polysomnography) recruited from sleep clinics at the Royal Prince Alfred Hospital and the Woolcock Institute of Medical Research, Sydney, Australia were enrolled into an 18-week weight loss program and randomized to receive three intramuscular injections (at 0, 6 and 12 weeks) of either Reandron™ (testosterone undecanoate 1,000 mg in 4 mL castor oil vehicle, n=33) or 4 mL oil vehicle placebo (n=34)


The weight loss program included a dietician-prescribed 2500 kJ (600 kcal) daily deficit diet plus increased physical activity (30 minutes daily walking)
Sleep and breathing were assessed by attended overnight, in-laboratory polysomnography at 0, 7 and 18 weeks. Sleep staging, respiratory events and arousals were all scored by study personnel blinded to treatment allocation
Blood samples were taken at 0, 6, 7, 12 and 18 weeks and stored at
-80°C for subsequent batched analysis of LH, FSH, total- and free-testosterone concentrations
Testosterone therapy in obese men with OSA mildly worsened sleep disordered breathing in a time-dependent manner


Testosterone treatment significantly increased the ODI and SpO2T90% compared with placebo at week 7 (mean ODI: 10.3 events/h, 95% confidence interval [CI] 0.8–9.8 events/h, p=0.03; mean SpO2T90%: 6.1%, 95% CI 1.5–10.6%, p=0.01), but not at week 18 (ODI: 4.5, -5.4–14.4 events/h, p=0.36; SpO2T90%: 2.9%, -1.9–7.7%, p=0.23) (Figure 1)
Testosterone treatment did not significantly alter sleep style or any other sleep or breathing variable compared with placebo (all p>0.05)
Apnea and hypopnea durations did not significantly differ between the two groups (both p>0.05) and subjective sleepiness improved in both groups (each p<0.01 from baseline), but equivalently between groups (p>0.05)
There was no correlation of blood testosterone concentrations with either ODI or SpO2T90% (all p>0.19)
No individual was discontinued because of development of severe sleepiness or any other sleep-related problem
Testosterone may alter ventilatory control, thereby exacerbating sleep disordered breathing2
The concurrent weight loss program resulted in significant reductions in BMI and waist circumference from baseline (p<0.001) across both groups
Caution remains for testosterone use in otherwise untreated men with OSA. Larger, more intensive, longer-term studies are recommended, particularly in men with the lowest blood testosterone concentrations in whom the overall risk-benefits of testosterone therapy may be more favourable

What is known
OSA is a common disorder affecting up to 25% of middle-aged adult men3, many of whom are obese4,5. Biochemical androgen deficiency is also often observed in obese men and in men with OSA6,7 and the severity of this deficiency increases with greater hypoxemia in men with OSA8 and increasing adiposity in obese men9. Therefore, obese men with OSA are likely to be at greatest risk for androgen deficiency.

Blood testosterone levels in men with OSA or obesity can be increased by continuous positive airway pressure therapy (CPAP)8 and weight loss,10 ,11 respectively. Testosterone treatment to address androgen deficiency in obese men with OSA is attractive, but (despite the lack of systematic studies) concerns have been raised regarding the respiratory safety of testosterone therapy12. However, men who developed or worsened their sleep apnea received higher doses of testosterone and had other identifiable risk factors for sleep apnea13.
What this study adds
Results from the Hoyos study, in conjunction with earlier findings, suggest that near-conventional dose testosterone therapy mildly worsens sleep hypoxemia acutely, as shown by the two available measures of ODI and SPO2T90%. This effect may not be seen in the longer term1.

In this study, the first to purposefully treat men with severe OSA with testosterone, mild respiratory changes were observed for at least 7 weeks (and potentially up to 18 weeks). Larger and longer-term studies will be required to document the long-term morbidity and survival arising from these changes as well as the degree of inter-individual variability in testosterone response. Until such studies are conducted, patients requiring testosterone therapy should continue to be cautiously monitored and assessed on an individual basis. Nevertheless, lifestyle modification to achieve weight loss remains first-line therapy for all obese men with OSA.

Hoyos et al. chose to examine baseline total and free testosterone thresholds (validated for late onset hypogonadism9). They found no evidence, from post-hoc analysis and confirmed by correlational analyses, that the effect of testosterone therapy on sleep disordered breathing was influenced by baseline testosterone concentrations. However, they suggest larger, more intensive and longer-term studies be planned, particularly in men with the lowest blood testosterone concentrations in whom the overall risk-benefits of testosterone therapy may be more favorable.

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References
1. Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 2003;88(8):3605-3613.
2. Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol 2008;105(5):1389-1405.
3. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328(17):1230-1235.
4. Grunstein RR, Stenlof K, Hedner J, et al. Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS) Study. Int J Obes Relat Metab Disord 1995;19(6):410-418.
5. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol 2005;99(4):1592-1599.
6. Barrett-Connor E, Dam TT, Stone K, et al. The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. J Clin Endocrinol Metab 2008;93(7):2602-2609.
7. Liu PY, Caterson ID, Grunstein RR, et al. Androgens, obesity, and sleep-disordered breathing in men. Endocrinol Metab Clin North Am 2007;36(2):349-363.
8. Grunstein RR, Handelsman DJ, Lawrence SJ, et al. Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab 1989;68(2):352-358.
9. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123-135.
10. Hammoud A, Gibson M, Hunt SC, et al. Effect of Roux-en-Y gastric bypass surgery on the sex steroids and quality of life in obese men. J Clin Endocrinol Metab 2009;94(4):1329-1332.
11. Strain GW, Zumoff B, Miller LK, et al. Effect of massive weight loss on hypothalamic-pituitary-gonadal function in obese men. J Clin Endocrinol Metab 1988;66(5):1019-1023.
12. 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.
13. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350(5):482-492.

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Awesome write up....