Test Cyp and Insomnia: Sleep Apnea vs Better Sleep

Does testosterone cypionate improve sleep?

The injection studies do not establish improved sleep: one small study found an increase in REM sleep, while another found shorter sleep and worse breathing [1][4]. A randomized trial of testosterone in older men, the Testosterone Trials, gave 790 men aged 65 or older with serum testosterone below 275 ng/dL testosterone gel or placebo gel for one year [5]. It found no significant benefit in vitality as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, although men on testosterone reported slightly better mood and less severe depressive symptoms, and sexual function improved [5]. That trial used gel rather than injections.

Sleep-stage and breathing data on injections come from two small studies. In the 1985 study of five hypogonadal men, the share of sleep time spent in REM rose from 14% to 22% while they were on treatment (P<0.01) [1]. The 2003 study of 17 healthy older men found shorter sleep and worse breathing on high-dose testosterone injections [4].

What the injection studies found

The 1985 study used testosterone enanthate and the 2003 study used unspecified testosterone esters, so neither shows directly how cypionate affects sleep. The 1985 study used testosterone enanthate in men with androgen deficiency. Five men had sleep studies off treatment and again after six weeks of testosterone enanthate 200 mg intramuscularly every two weeks [1]. Hypoxic ventilatory drive fell from 158 to 88 (P<0.05), while the response to carbon dioxide did not change significantly. Obstructive sleep apnea developed in one man and markedly worsened in another; both also had marked drops in oxygen saturation with heart rhythm changes during sleep and large rises in hematocrit. The other three men had no significant apnea on or off testosterone. Apneic episodes tended to occur during non-REM sleep [1].

A 2003 randomized, double-blind, placebo-controlled crossover study tested a much larger exposure: 17 healthy men over 60 received three weekly injections of testosterone esters at 500 mg, 250 mg and 250 mg, or placebo, with an eight-week washout between periods [4]. Testosterone shortened total sleep time by about one hour, lengthened the time spent hypoxemic by about five minutes a night, and raised the total and non-REM respiratory disturbance indices by about seven events per hour each (P<0.05). Upper airway dimensions did not change on acoustic reflectometry, and sleepiness scores, mood, quality of life and insulin resistance were unchanged [4].

Does the dose change the sleep effect?

The two studies differ in almost every way, so they cannot be added together into a dose rule. The 1985 study used a replacement-type regimen in men who were androgen deficient and found apnea in two of five. The 2003 study used supraphysiologic weekly dosing in healthy older men and found roughly seven more breathing events per hour across the group. Neither compared doses head to head.

What the labels say

The Depo-Testosterone label says testosterone can increase blood pressure, which can increase cardiovascular risk over time, and that blood pressure should be monitored periodically, especially in men with hypertension; testosterone products are not recommended for use in patients with uncontrolled hypertension [3]. The label lists polycythemia among reported adverse reactions [3].

The same label describes insomnia as part of the withdrawal syndrome that can follow supratherapeutic doses of testosterone, alongside depressed mood, fatigue, craving, restlessness, irritability, anorexia and decreased libido [3]. It gives a dose of 50 to 400 mg every two to four weeks and a half-life of about eight days after intramuscular injection [3].

Both sleep-apnea cases in the 1985 study also had large hematocrit rises, so hematocrit is worth knowing about. A review of testosterone-induced erythrocytosis found the risk well established, with short-acting injectable formulations having the highest associated incidence [6]. A network meta-analysis of 29 placebo-controlled trials in 3,393 men found intramuscular enanthate or cypionate raised mean hematocrit versus placebo by 4.0% (95% CI 2.9 to 5.1), versus 3.0% for gel and 1.4% for patch; intramuscular enanthate/cypionate rose significantly more than patch, and the other comparisons were not significantly different [7]. A retrospective review of 178 hypogonadal men found erythrocytosis (hematocrit above 50%) in 66.7% of those on injectable testosterone versus 12.8% on gels, but the injection group was younger and started with a higher baseline hematocrit, and the study was not randomized [8].

Sleep apnea before starting testosterone

The Endocrine Society guideline recommends against starting testosterone therapy in men with untreated severe obstructive sleep apnea, and also in men with elevated hematocrit, uncontrolled heart failure, or a heart attack or stroke within the previous six months [2]. The same guideline recommends monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year of treatment [2].

For diagnosis, the American Academy of Sleep Medicine calls polysomnography the standard test and recommends against using questionnaires or prediction algorithms to diagnose obstructive sleep apnea without polysomnography or home sleep apnea testing [9].

The other direction: sleep and your own testosterone

Sleep and testosterone are related in both directions: sleep duration predicted morning testosterone in one study, while reviews describe testosterone changes during sleep and lower androgen levels after sleep curtailment [10][11]. In 12 healthy men aged 64 to 74, polysomnography-measured sleep time independently predicted morning total testosterone (Beta 0.792, P=0.017) and free testosterone (Beta 0.741, P=0.029) [10]. A review of the sleep and androgen literature notes that testosterone rises during sleep and peaks around REM onset, that poorer sleep efficiency and fewer REM episodes in older men are associated with lower circulating testosterone, and that sleep curtailment lowers androgen levels [11]. In a study of seven middle-aged and six young men with overnight sampling every 15 minutes, the nocturnal testosterone rise came earlier in the young men, and the normal timing link between that rise and the first REM episode was not seen in middle-aged men, although sleep quality was similar in both groups [12].

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