Eric Young

03/28/2017

Melehan, K.L., Hoyos, C.M., Yee, B.J., et al. Increased sexual desire with exogenous
testosterone administration in men with obstructive sleep apnea: a randomized placebo-
controlled study. Andrology. 2016; 55-61.

Introduction
Context 1. First trial done that looked at the effect of testosterone therapy on sexual
and neurocognitive function, as well as quality of life for men with
obstructive sleep apnea (OSA).
2. Studies have compared at least one factor with OSA, but not all three.
a. Apnea Positive Pressure Long-term Efficacy Study (APPLES)
performed in 2006 looked at OSA and neurocognitive performance.1
1) Results showed minor effects of OSA on neurocognitive
performance.
3. Important because obese men with OSA are at an increased risk for
sexual dysfunction, neurocognitive impairment, and reduced quality of
life.1-3

Background - OSA is characterized by partial or complete closure of the upper

airway during inspiration, and is commonly seen in obese males4,5.
- Some relationship exists between testosterone deficiency, sexual
dysfunction, obesity, and obstructive sleep apnea.
o Hypoxemia in men with OSA and increased fat lead to
androgen deficiency. 5,6
o Hypoxemia caused by OSA can cause neurocognitive
impairment.1
o CPAP therapy and weight loss have been shown to increase
blood testosterone levels in men with OSA and/or obesity.
o Caused by hypothalamo-pituitary-testicular dysregulation,
which can be irreversible if not treated early.5
o Untreated OSA can lead to hypertension, myocardial
infarction, cardiac failure, and death.1
- Use of testosterone therapy is controversial in patients with severe
sleep apnea- could cause exacerbation of sleep apnea.7

Registration/Fu 1. Registered with the Australia New Zealand Clinical Trials Network
nding (anzctr.org.au)
2. Registration number: ACTRN12606000404527
a. Number did not match study.

Sponsor: Royal Prince Alfred Hospital and the Woolcock Institute of

Medical Research, Sydney, Australia

Methods

Revised 01-20-2017
Trial Design Randomized, double-blind, placebo-controlled parallel group study.

Randomization Participants were randomly assigned to receive three IM injections of either

Method, & testosterone undecanoate 1000mg or a matching placebo.
Blinding

Participants & Inclusion criteria:

Setting - Men, age > 18
P - BMI > 30 kg/m2
- Mild OSA (apnea hypopnea index >10 events/hour)

Exclusion criteria:
- Severe OSA (minimum oxygen saturation <65% or RDI > 80)
- Use of drugs that alter androgen action
- C/I to testosterone therapy
- Desire for paternity within next 12 months
- Participating in sports that ban testosterone and require drug
monitoring
- Psychiatric disorders or drug abuse (unless well controlled)
- Fasting hematocrit >52%
- PSA >4 ng/mL
- Participation in another investigational drug trial in the last 30 days
- Concurrent treatment of sleep apnea with continuous positive airway
pressure or mandibular advancement devices
- Chronic medical conditions that are likely to interfere with or
influence study treatment or safety.

Interventions & 1. Control group: Placebo

Comparators 2. Experimental group: 1000mg testosterone undecanoate
I 3. Both groups were given three injections, one at baseline, one at
C week 6, and one at week 12.
4. All participants also underwent a weight loss program
a. 30 minutes brisk walking/day
b. 2500kJ (600kcal) daily deficit diet

Outcomes Objective: To determine the effects of testosterone treatment on sleep

O disordered breathing and cardio-metabolic health.

Primary outcome: Impact of testosterone administration on sexual function,

quality of life (including sleep quality), and neurocognitive performance.
1. LH, FSH, and total testosterone was measured using venous blood
samples.
2. Sexual function: Measured by questionnaires at week 6, 12, and 18
as well as a visual analog scale.
3. Quality of life: Assessed using Short Form 36 (SF-36);
a. Self-rated levels of sleepiness was assessed using Epworth

Page 2 of 6
 Sleepiness Scale
b. Momentary sleepiness was assessed using Karolinska and
Stanford Sleepiness Scales.
4. Neurocognitive performance: Measure at baseline, 6, 12, and 18
weeks.
a. Spatial cognition assessed using “Tower of London” test.
b. Executive memory assessed using “Stroop” test.
c. Reaction time was assessed using psychomotor vigilance task
(PVT)

Post-hoc analysis: Effects of baseline testosterone on testosterone treatment

at 8, 11, and 13 nmol/L.

Sample Size Total: n= 54

Testosterone group: n= 26
Placebo group: n= 28

Statistical - Used SAS statistical package (v. 9.2)

Methods - Significant differences: p < 0.05
o Calculated by Student’s t-test, Mann-Whitney U, or Fisher’s exact
test.
- Analyses were done using intention-to-treat population.
- Outcome variables were calculated from differences between baseline
and weeks 6, 12, and 18.
- Overall change was determined using mixed model analysis.
- Post-hoc analyses comparing treatment effect calculated for statistically
significant data.

Bias Summary 1.
a.
2.
a.
3.
a.
4.
a.
b.

Results
Participant Participant flow not provided.

Page 3 of 6
Flow: o Screening procedure not provided.
o No interim analysis

Baseline Data Refer to Table 1 in Appendix (pg. 14)

o Mean age in control group: 49 + 1.6; 48 + 1.6 in experimental group.
o BMI in control group: 36.6 kg/m 2 + 4.9; 34.9 + 4.3 in experimental
group.

No significant differences between the groups at baseline.

o Type 2 diabetes significant (p= 0.02) but only present in control
group.

Cohorts Total number of patients randomized: n= 67 (54 completed study; 2

Analysed participants withdrew early)
a. Modified Intent to Treat

Patients who withdrew completed an exit visit and questionnaire; data was
included in final results.

Outcomes Primary outcome: See Table 2 in Appendix (p. 15)

Control Contro Testo Testoster Mean P

group l group stero one group differenc value
baseline overall ne overall between
change grou change groups
(95% p (95% CI) (95% CI)
CI) baseli
ne
LH 3.47 + 1.54 0.17 3.46 + -2.75 -2.92 <0.0001
(U/L) (-.043, 2.31 (-2.15, -3.35) (-3.76, -2.07)
0.76)
FSH 4.42 + 0.13 4.41 + -3.25 -3.38 <0.0001
(U/L) 2.67 (-0.60, 3.94 (-2.52, -3.99) (-4.42, -2.35)
0.86)
Testost 11.96 + 0.94 12.24 + 6.43 5.49 <0.0001
erone 3.90 (-0.49, 5.60 (4.95, 7.91) (3.43, 7.55)
(mmol/ 2.37)
L)
Free 0.28 + 0.004 0.29 + 0.11 0.11 <0.0001
testoste 0.07 (-0,03, 0.12 (0.07, 0.15) (0.06, 0.16)
rone 0.04)

Page 4 of 6
 (mmol/
L)
Sexual 0.69 + 0.27 0.02 0.63 + -0.14 0.16 0.004
desire (-0.054, 0.27 (-0.22, 0.06) (0.05, 0.27)
(0-1) 0.096)

All other data were clinically and statistically not significant.

- No differences in sexual function other than sexual desire.
- No differences in sleepiness or other neurocognitive functions
- No differences in weight loss.

Post-hoc analyses:
- Showed improvements in the following areas when baseline testosterone
was less than 8 mmol/L:
o Improvements in feeling down (p= 0.0021)
o Vitality (p= 0.004)
o Nervousness (p= 0.04)
- No significant differences when testosterone levels were above 8
mmol/L

Adverse Effects No adverse effects reported.

Discussion
Author's 1. Did not have enough patients in study to account for effects of
Explicit testosterone on patients with concurrent diseases (i.e. diabetes
Limitations mellitus)
2. Needed better characterization of specific subject characteristics to
predict responses to testosterone therapy.
3. Length of study not long enough to see improvements in some areas
(i.e. erectile function); maximal response typically seen in 1 year.

Author’s Testosterone therapy improved sexual desire in obese men with OSA
Generalizability regardless of their baseline testosterone levels.

Reviewer’s Strengths:
Interpretation 1. Study compared clinical findings with other trials, and were
consistent with results, increasing validity of trial results.
2. Study took a multi-faceted approach to trial- included
neurocognitive performance, hormone analysis, etc.

Page 5 of 6
 Weaknesses:
1. No mention of patient’s adherence to weight loss program; could
have interfered with results of study.
2. Number of patients enrolled in study was small- limits applicability
of study.
3. No explanation of why patients withdrew from study
4. No reports of adverse effects

Conclusion: Although effects on testosterone improved the sexual desire for

patients with sleep apnea, the study did not find enough statistical and
clinical differences to conclusively say that testosterone improved overall
sexual function in this patient population.

Citations of 1. Quan SF, Chan CS, Dement WC, et al. The association between
Previous obstructive sleep apnea and neurocognitive performance- the Apnea
Literature Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011;
Reviewed 34:303-314B.
2. Young, T, Peppard PE, Gottlieb D. Epidemiology of obstructive sleep
apnea- A population health perspective. Am J Respir Crit Care Med.
2002; 165: 1217-1239.
3. Budweiser S, Enderlein S, Jorres RA, HItzl AP, et al. Sleep apnea is an
independent correlate of erectile and sexual dysfunction. J Sex Med.
2009; 6:3147-3157.
4. Dopp JM, Phillips BG. Chapter 55. Sleep Disorders. In: DiPiro JT,
Talbert RL, Yee GC, Matzke GR, Wells BG, Posey
L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York,
NY: McGraw-Hill;
2014. http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/con
tent.aspx?bookid=689&sectionid=45310506.
5. Hoyos CM, Killick R, Yee BJ, Grunstein RR, et al. Effects of
testosterone therapy on sleep and breathing in obese men with severe
obstructive sleep apnoea; a randomized placebo-controlled trial. Clin
Endocrinol (Oxf). 2012a; 77:599-607.
6. Liu, PY, Caterson ID, Grunstein, RR., et al. Androgens, obesity, and
sleep-disordered breathing in men. Endocrinology and Metabolism
Clinics of North America. 2007; 36:349-363.
7. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone
replacement therapy: a review. Therapeutics and Clinical Risk
Management. 2009;5:427-448.

Page 6 of 6