The relation between testosterone replacement therapy (TRT) and OSAS is more controversial. The aim of this review is to get more insight on this topic.

We conducted a literature review on PubMed, up to December 2022, using the words “OSAS and hypogonadism”, “OSAS and testosterone”, “obstructive sleep apnea syndrome and testosterone”, “sleep apnea and testosterone”.

We collected the following results: “OSAS and hypogonadism” (6 results), “OSAS and testosterone” (14 results), “obstructive sleep apnea syndrome and testosterone” (151 results), “sleep apnea and testosterone” (235 results). After excluding non-English results, case reports, other studies/reviews, studies without available manuscripts and studies regarding TRT and other conditions, we included the clinical studies that reported the severity of OSAS pre/post TRT or changes in sleep functions or quality. The process of results’ collection is shown in Figure 3. We obtained 7 results, that are reported in Table 1.

The first study was published in 1985 and evaluated 5 male patients in dialysis using polysomnography and found no change in sleep complaints or a decrease in the number of apnoeas and hypopneas during and off therapy (34). The second study, conducted by Liu et al. (35), evaluating 17 patients, found that testosterone treatment reduced total time slept (about 1 h), increased the duration of hypoxemia (about 5 min/night) and disrupted breathing during sleep, thus leading to the conclusion that short-term administration of high-dose testosterone might shorten sleep and worsen OSAS. On the other hand, Hoyos Cm et al. reported that testosterone therapy in 67 obese men with severe OSAS might mildly worsen sleep-disordered breathing in a time-limited manner, irrespective of initial testosterone concentrations. In fact, testosterone administration worsened ODI by 10.3 events/h and nocturnal hypoxaemia at 7 weeks, whilst testosterone therapy did not alter ODI or O₂ saturation at 18 weeks compared to placebo administration (36). The fourth study was conducted by Killick et al. (25) and reported no significant differences in ventilatory chemoreflexes between the testosterone and placebo group evaluated at 6 weeks and at 18 weeks. Melehan et al. (37) evaluated 33 obese men with mild-severe OSAS under TRT and 34 controls and found that in patients with baseline testosterone concentrations below 8 nmol/L TRT increased vitality and reduced reports of feeling down and nervousness, whilst subjective sleepiness did not differ between TRT and placebo group. In the sixth study (38) a higher risk of OSAS in TRT uses was noted (2-year risk 16.5% in the TRT group vs. 12.7% in the control group). Finally, Lundy SD et al. evaluated 474 hypogonadal men and reported that the development of polycythaemia in men on TRT was associated with an increased prevalence of OSAS (39).

Regarding the type of studies, just one is longitudinal (34), two are retrospective (38, 39), and few are randomised placebo-controlled clinical studies (25, 35–37). Mean testosterone concentrations at baseline are not always specified (34, 38) and, in some cases, it is even in the normal reference range (25, 36). Therefore, in some studies, testosterone therapy is not a real replacement therapy for hypogonadism, but rather a supplementation therapy. Type (38, 39) and length (34) of TRT are not uniform and not always clear. The number of patients is generally low, except for two studies (38, 39) that, on the other hand, have several limitations, such as the retrospective nature and the lack of information regarding the type of TRT. Furthermore, data on free testosterone are lacking. Finally, the primary aims of the studies are only sometimes directly related to the relation between OSAS and TRT, therefore creating further difficulties in the comprehension of this complex relation. In addition, there is a lack of long-term studies, which might prevent for example to possibly notice a positive effect of chronic low-dose TRT on OSAS symptoms, as suggested by some studies.

This review highlights that clinical data regarding TRT and OSAS are scarce and often lacking important clinical and/or biochemical data.

Although the data on TRT in patients with OSAS are limited and not uniform, as evidenced in this review, and there is a lack of convincing evidence that TRT causes and/or aggravates OSAS (25, 40–42), TRT is generally considered contraindicated in the presence of untreated or severe OSAS. The recent clinical practice guideline of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE), regarding adult and late-onset hypogonadism, suggests not considering a treated OSAS as an absolute contraindication for TRT, albeit considering the lack of data regarding the role of TRT in men with OSAS (13). Other guidelines, surprisingly, such as the Society for Endocrinology guidelines for TRT in male hypogonadism, do not even mention OSAS among contraindication of TRT (43) whilst the Endocrine Society Clinical Practice Guideline (40) recommends against starting TRT in patients with untreated severe OSAS and considers the presence of the induction or worsening of obstructive sleep apnoea as an uncommon adverse with a weak association with TRT. Furthermore, a recent systematic review, conducted by Twitchell et al. (44) and evaluating the controversies about TRT, reported a positive association between TRT and OSAS. In addition, the European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males does not consider the presence of OSAS as a contraindication for TRT but suggests evaluating the patient for hypoxia and sleep apnoea development during TRT (45). There are a variety of possible pathophysiological mechanisms by which TRT might exacerbate OSAS. TRT has been proposed to alter the central chemoreceptors (42, 46), therefore contributing to the development or worsening of OSAS via central mechanisms (26). A promising theory focuses on the role of androgens in neural response pathways to hypoxemia, but, according to the most recent data, the administration of testosterone has variable effects on ventilatory chemo-responsiveness and single unifying conclusion has not been reached yet. Notwithstanding, the evidence suggests that TRT might alter chemoreceptor stimulation thresholds or the ventilatory response to chemoreceptor stimulation by decreasing breathing stability (40).

One of the most debated parameters that seems to worsen after TRT is the morphological change in the upper airway. In particular, testosterone seems to impact the contraction of the airway dilator muscles and the following airway collapsibility. However, a consensus has not been found yet (26). A further connection between TRT and OSAS resides in the risk of polycythaemia. In fact, OSAS is a risk factor for secondary polycythaemia and TRT exacerbates polycythaemia in some patients (39, 40, 44). Furthermore, TRT may also induce higher metabolic rates, resulting in greater oxygen consumption leading to hypoxia (26). Finally, another possible explanation regarding the worsening of OSAS during TRT deals with a possible role of testosterone on the alteration of ventilatory response to hypoxia and hypercapnia, the alteration of serotonergic pathway and the reduction in time slept (26, 35).

Although the possible risks of TRT in subjects with OSAS are far to be clearly elucidated, it is important to note the benefit of restoring normal testosterone concentrations in men with hypogonadism. TRT is suggested in hypogonadal men for its clinical benefits regarding, among others, cardiometabolic risk, sexual function, bone metabolism and body composition (43, 47). Moreover, a recent clinical study (48) reported an improvement in sleep disturbance [defined as three or more points in question 4 of the ageing male symptoms (AMS) questionnaire] after 1 year of TRT in male affected by MH without OSAS. Therefore, while caution in TRT prescription should be maintained in patients with OSAS (38), a balanced and personalised counselling between risks and benefits should be discussed with the patients, taking also in consideration the possible co-morbidities and concomitant therapies. To this regard, it seems reasonable to delay TRT in hypogonadal men affected by untreated OSAS or severe OSAS. This review highlights also that modulation of type and dosage of TRT in the different patients is advisable. For example, it seems that short-term high-dose TRT could worsen OSAS, but these adverse effects could disappear with time (13, 42) and eventually determinate a clinical improvement of OSAS’ symptoms after 1 year of TRT (48). Therefore, a low dose TRT in the form of transdermal gel, which is more malleable if the clinical condition worsens, seems preferable. Finally, we suggest considering the assessment by polysomnography in patients who develop signs and symptoms of OSAS during TRT, with possible reduction or discontinuation of TRT if necessary.

Further considerations are necessary in this context. The severity of OSAS seems related to bone mineral density (BMD), as a recent prospective case–control study, enrolling 93 individuals (59 with OSAS and 34 as controls), reported lower BMD and vitamin D in patients with OSAS than controls, with a negative correlation between AHI and BMD (49). The risk of fracture and osteoporosis appears to be increased in patients with OSAS, probably due to different mechanisms, such as hypoxia, OSAS-related respiratory acidosis, leptin, OSAS-related comorbidities and, of course, hypogonadism (49). The assessment of bone status may become, in future, a parameter to evaluate when considering TRT in patients affected by OSAS, since the well-known positive effects of TRT in improving the bone status in hypogonadal patients (13, 50). On the other hand, the therapy of OSAS may improve the gonadal status and sexual functions. In fact, OSAS-related sleep fragmentation might disrupt the testosterone rhythm, with noteworthy attenuation of the nocturnal increase in testosterone (26). Studies showed a linear association between weight loss and increased serum testosterone concentrations in obese men (26). Few studies showed that the treatment of OSAS—both by surgery (51) and cPAP (52)—improve the gonadal function and testosterone concentrations. Nevertheless, other studies reported opposite results (26, 32, 46). In particular, a recent systematic review and meta-analysis (53) found that the cPAP use was not associated with a significant change in total testosterone concentrations, suggesting against the hypothesis of a direct interaction between OSAS and testosterone, albeit the conclusion that cPAP has no effect on testosterone concentrations is highly premature due to the low-quality available studies (54).

In addition, OSAS has been associated with altered HPG function and sexual dysfunction, manifested primarily as erectile dysfunction and decreased libido (22). Sexual functions of patients with OSAS and MH are thought to improve upon TRT, albeit this result should be confirmed in larger studies (37, 55). On the other hand, the therapy of OSAS might improve the OSAS-related erectile and sexual dysfunctions (26, 46). Finally, there are new concerns regarding testosterone hormone therapy in transgender males (assigned females at birth). In particular, Robertson et al. (56) reported two cases of transgender males in whom OSAS developed following initiation of testosterone therapy, with documented absence of OSAS before the sex affirming therapy.

In this review, we described the relation between OSAS and MH, which are two under-recognized and inter-connected medical disorders, with particular attention to TRT and OSAS. The analysis of the literature highlights the general lack of well-done studies and therefore the evidence is of low quality. We cannot confirm or reject the guidelines that suggest avoiding TRT in the presence of untreated or severe OSAS, as this appears a reasonable clinical practice. Indeed, some evidence suggests that short-time high-dose TRT might indeed worsen OSAS, whereas chronic low-dose TRT might improve OSAS. Notwithstanding, the therapy of OSAS might benefit the gonadal status and sexual functions. In the light of the few and sometimes inconclusive studies in this field, and therefore of the limited evidence and large grey areas, we wish for further studies and more active collaboration between endocrinologists and otolaryngologists.