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Volume 15 No. 10
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On Not Knowing What We Don’t Know to Knowing What We Don’t Know: Obstructive Sleep Apnea in the Transgender Community

David C. Earl, MD, PharmD1; Lee K. Brown, MD2,3
1Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, New Mexico; 2University of New Mexico Health System Sleep Disorders Centers, Albuquerque, New Mexico; 3Sleep Medicine Section, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico

ABSTRACT

Earl DC, Brown LK. On not knowing what we don’t know to knowing what we don’t know: obstructive sleep apnea in the transgender community. J Clin Sleep Med. 2019;15(10):1393–1395.


…we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns — the ones we don't know we don't know.

—Secretary of Defense Donald H. Rumsfeld, February 12, 2002

Examples of not knowing what we don’t know abound throughout the history of medical practice. The entity of obstructive sleep apnea (OSA) was virtually unknown until the 1960s, and physicians encountering patients exhibiting OSA symptoms did not know what questions needed answers. Today, an estimated 425 million adults have moderate to severe OSA worldwide,1 and we know of many questions to ask. As a profession, we have not previously asked questions about OSA associated with gender reassignment therapy because, up until recently, we did not know there were such questions. Going forward, there are many questions needing answers since individuals undergoing gender reassignment are presenting to our sleep disorders centers in greater numbers. Robust data from Sweden, where a 1972 statute protocolled surgical and legal sex reassignment2 tell us that pharmaceutical treatment for female-to-male (FtM) transitioning tripled from the decades between 1972–2000 compared to the decade 2001–2010, and for male-to-female (MtF) transitioning increased four-fold (Table 1). Undoubtedly, a parallel trend is occurring in the U.S. and elsewhere, and practicing sleep medicine physicians require answers, particularly with respect to OSA in these individuals.

Incidence of female to male and male to female applications for gender reassignment in Sweden by decade, in individuals > 17 years of age.

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Table 1

Incidence of female to male and male to female applications for gender reassignment in Sweden by decade, in individuals > 17 years of age.

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In this issue of the Journal of Clinical Sleep Medicine, Robertson and colleagues present us with a small case series that hints at the issues we now face.3 They report 3 patients who have had changes in OSA status after hormone therapy for gender affirmation. In Case 1, a 47-year-old MtF transgender patient with an initial history of moderate, then later severe, OSA demonstrated complete resolution of symptoms and normalization of AHI 5 months after the start of transdermal estrogen and oral spironolactone. The authors maintain that spironolactone and/or the modest reduction in BMI were not responsible for these findings. Cases 2 and 3 reflect on the potential effects of androgens during an FtM transition. In each case the AHI prior to treatment was normal, but was indicative of moderately severe OSA in one and mild to moderately severe OSA in the other on testosterone.

Estrogen therapy in women and androgen therapy in both men and women are commonly employed for various other indications, and there are data concerning OSA in most. However, Robertson et al are breaking new ground, since the entire literature on sleep and gender reassignment appears to be: (1) sleep quality is unchanged4; (2) scores on the Pittsburgh Sleep Quality Index worsen5; (3) polysomnography (PSG) in MtF reveal changes in sleep architecture6; and (4) one clinical practice guideline recommends monitoring for OSA in FtM individuals on hormone therapy.7 Virtually all other reviews covering both FtM and MtF management, including one focusing on the elderly, do not mention OSA.811

We are left only to cite the literature on breathing during sleep when androgens and estrogens are used outside of the context of gender reassignment; some indications are relevant and some are not, depending on whether the population studied is more or less similar to those seeking gender reassignment. To our mind, this rules out the literature on polycystic ovary syndrome, although we can be persuaded otherwise. Given that caveat, we know that the general population of men and women differ with respect to upper airway dimensions and function: males exhibit a longer upper airway compared to females, and upper airway length is significantly related to OSA.12,13 Dilator muscle activation under resistive loading appears to be similar in both genders.14 Upper airway anatomic and functional changes also occur on a continuum with progressive age in both genders,15 and we note that the Swedish data most recently include a significant proportion of older individuals (30% of FtM applications ranged from > 30 years of age up to age 60; 60% of MtF applications ranged from >30 years of age up to 75 years).2 It can be assumed that gender reassignment hormonal therapy is superimposed on these known anatomic and functional upper airway substrates and data from other clinical uses for hormonal therapy can potentially be relevant to OSA.

Unequivocal evidence from the prospective Wisconsin cohort ties menopause to an increase in the incidence of OSA in women, steadily rising through premenopause and on to postmenopause.16 This occurred with or without estrogen therapy, reinforcing the findings of a randomized controlled crossover trial performed years previously.17 A recent review by Zhang and colleagues summarized human and animal studies associating estrogen deficiency with OSA, and suggested a variety of mechanisms.18 However, the reverse seems not to be true. Adding back estrogen in humans appears not to consistently reverse the effect and the reason remains unexplained.16 It is more likely that, in Case 1, some other factor was responsible such as the known night-to-night variability of AHI determined by PSG.19 Fluid status, with a consequent variability in the degree of rostral fluid shift during sleep, may be one factor.20 Other possibilities include variability of time in REM, body position, or interactions between body position when in REM and nonREM sleep.

The findings in Cases 2 and 3 are also subject to alternative explanations. It is highly unlikely that women exposed to gender reassignment therapy with androgens develop an anatomically male upper airway.12,13 Moreover, clarity is lacking that androgen therapy affects OSA even in men. Robertson and colleagues themselves cite a review by Grech et al from 2014 suggesting that testosterone replacement therapy for males appears to only transiently worsen OSA.21 A more recent retrospective cohort study of OSA in 3,422 male U.S. military members and their dependents prescribed testosterone replacement for low testosterone levels revealed a 2-year OSA incidence of 16.5% (95% confidence interval 15.1–18.1) in the treatment group versus 12.7% (11.4–14.1) in the control group, a statistically significant but arguably not a clinically important finding.22 Robertson et al mention 2 case reports of women with findings associating androgens and OSA.23,24 In one woman treated with androgens, the appearance of OSA is compelling.23 The scant data in the second report, of a woman with a testosterone producing tumor of the ovary, is less convincing.24 A third case report, not mentioned, presents a more thorough picture but involves a 13-year-old child with Marfan syndrome who had mild snoring before testosterone treatment to arrest excessive progression of his height.25 Severe snoring, weight gain, hypersomnolence, and witnessed sleep apneas developed on treatment; PSG confirmed OSA. Interestingly, polysomnography and measurement of critical closing pressure (Pcrit) were performed at peak and trough testosterone levels and 3 months after discontinuation of testosterone. AHI was highest at peak and one-third lower at trough testosterone levels; it was normal at 3 months. Measured Pcrit mirrored the changes in AHI in the expected direction, suggesting an effect on upper airway collapsibility. Although the findings are credible, this patient would not represent a typical candidate for FtM treatment. Androgens used to treat hypoactive sexual desire in postmenopausal women have yielded no evidence of OSA complicating this treatment when randomized controlled trials were reviewed.26 There also exist 2 randomized controlled short-term studies of exogenous testosterone in men.27,28 Neither demonstrated any clinically significant difference in AHI when testosterone vs. placebo was administered acutely to patients with OSA27 or to normal elderly men.28 As Hanafy observed in a review some years ago, the link between androgen administration and OSA is weak, and it appears to remain so.29 Consequently, the findings reported in Cases 2 and 3 may be further examples of night-to-night variability of AHI for reasons detailed above.

Robertson and colleagues correctly point to the paucity of literature on this increasingly important subject, and call for further research. Until then, we now know of many questions needing answers. For the time being, sleep professionals encountering FtM patients should screen for OSA during encounters, and consider the possibility that MtF patients with known OSA may undergo remission and no longer need treatment.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Dr. Earl reports no conflicts of interest. Dr. Brown has participated in advisory panels for Philips Respironics, and was an insurance claims reviewer for Considine and Associates, Inc. He is an associate editor and section editor (Emerging Technology) of the JCSM. He co-edits the Sleep and Respiratory Neurobiology section of Current Opinion in Pulmonary Medicine, wrote on CPAP treatment for obstructive sleep apnea in UpToDate and on obstructive sleep apnea in Clinical Decision Support: Pulmonary Medicine and Sleep Disorders. He co-edited an issue of Sleep Medicine Clinics on positive airway pressure therapy. He serves on the Polysomnography Practice Advisory Committee of the New Mexico Medical Board and chairs the New Mexico Respiratory Care Advisory Board.

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