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Obstructive Sleep Apnea Due to Endogenous Testosterone Production in a Woman

1998; Elsevier BV; Volume: 73; Issue: 3 Linguagem: Inglês

10.4065/73.3.246

1942-5546

Donn Dexter, Erik J. Dovre,

Cardiac tumors and thrombi

Obstructive sleep apnea (OSA) is a common condition characterized by snoring, recurrent episodes of cessation of breathing (obstructive apneas), disrupted sleep, and excessive daytime somnolence. Associated serious complications are hypertension, increased risk of heart disease, stroke, and increased susceptibility to industrial and motor vehicle accidents. OSA is considerably more common in men than in women. In postmenopausal women, the incidence of OSA increases. These factors suggest that reproductive hormones have a role in the cause of OSA. Treatment with testosterone has been reported to cause OSA in men, and exogenous androgen administration has been reported to cause OSA in one woman. In a review of the English literature, we found no previous reports of OSA that was induced by endogenous testosterone in women. Herein we describe a nonobese 70-year-old woman with clinically significant OSA and a benign testosterone-producing ovarian tumor. After successful removal of the tumor, her OSA resolved, and her testosterone level normalized. This unique case supports the theory of male hormonal (testosterone) influence in the OSA syndrome. Obstructive sleep apnea (OSA) is a common condition characterized by snoring, recurrent episodes of cessation of breathing (obstructive apneas), disrupted sleep, and excessive daytime somnolence. Associated serious complications are hypertension, increased risk of heart disease, stroke, and increased susceptibility to industrial and motor vehicle accidents. OSA is considerably more common in men than in women. In postmenopausal women, the incidence of OSA increases. These factors suggest that reproductive hormones have a role in the cause of OSA. Treatment with testosterone has been reported to cause OSA in men, and exogenous androgen administration has been reported to cause OSA in one woman. In a review of the English literature, we found no previous reports of OSA that was induced by endogenous testosterone in women. Herein we describe a nonobese 70-year-old woman with clinically significant OSA and a benign testosterone-producing ovarian tumor. After successful removal of the tumor, her OSA resolved, and her testosterone level normalized. This unique case supports the theory of male hormonal (testosterone) influence in the OSA syndrome. A70-year-old woman was referred to our institution for evaluation of sleep attacks and excessive daytime somnolence. The patient also complained of loud snoring, increased nocturnal sleep time, nocturia twice nightly, and change in mood. She stated that her symptoms had been present for 2 to 3 years. Furthermore, she reported a substantially increased sex drive that she believed was inappropriate for her age. Consequently, she showered daily with cold water. Her past medical history was remarkable for "complete hysterectomy," chronic obstructive pulmonary disease, and chronic back pain. Medical records from the patient's operation performed in 1946 described a supracervical hysterectomy, with no mention of adnexal structures in the operative or pathology reports. Her medications included beclomethasone and albuterol inhalers and ibuprofen. She had a past history of tobacco (approximately 40 pack-years) and alcohol use but currently was abstinent. Her family history was unremarkable. Approximately 1 year before the current assessment, the patient had undergone formal polysomnography (PSG) elsewhere because of complaints of excessive somnolence. At that time, the sleep latency on the PSG was short at 1 minute, sleep efficiency was within normal limits at 92%, and all sleep stages were represented in essentially normal amounts. Pronounced snoring was noted but not graded. Sixty-two obstructive apneas and hypopneas were noted; the longest apnea was 54 seconds, and the lowest oxygen saturation was 72%. The respiratory disturbance index (average number of hypopneas and apneas per hour) was mildly increased at 8. An arousal index was not reported. The patient underwent a second night of PSG for nasal continuous positive airway pressure (CPAP) titration. At 6 cm of water pressure, disordered breathing was well controlled, and snoring was abolished. The respiratory disturbance index was improved at 1.3, and the minimal oxygen saturation improved to 88%. The patient was unable to comply with nasal CPAP therapy because of a skin rash caused by the plastic mask. She did not seek further evaluation or treatment until she came to our institution. On examination, the patient was 154.9 cm tall and weighed 63.5 kg. Her blood pressure was 128/78 mm Hg, and her pulse was 76 beats/min and regular. The nares and oropharynx were normal in configuration, no retrognatfha or neck mass was present, and no thyromegaly was palpable. Early male pattern baldness and increased facial hair were noted. Her skin was moderately oily without acne or rash. Her voice was deep and raspy. Nasal CPAP therapy was used empirically, and it effectively controlled the patient's snoring, apnea, excessive daytime somnolence, and mood changes. Unfortunately, her facial rash, which appeared to be acneiform, recurred, an outcome that made use of nasal CPAP somewhat difficult. Multiple attempts of treatment with use of different delivery systems were without benefit. Because of the patient's complaints of an increased sex drive and the signs of virilization noted on examination, a gynecologic evaluation was performed. The gynecologic examination revealed male pattern escutcheon and clitorimegaly; the clitoris was 1 cm in width and 2 cm in length. The vaginal wall was intact and well supported. The uterus was surgically absent, and no pelvic or abdominal masses were palpable. Computed tomography of the abdomen and pelvis revealed no pathologic masses. Findings on the rest of the gynecologic examination were unremarkable. Laboratory studies yielded an increased free testosterone value of 18.2 ng/dL (normal, 0.3 to 1.9), an increased total testosterone value of 650 ng/dL (normal, 20 to 80), and normal androstenedione, dehydroepiandrosterone sulfate, and cstradiol values. An ovarian source was thought to be the likely cause of the patient's abnormalities. She underwent an exploratory laparotomy, through a low vertical midline incision. Intraoperative findings included a yellow, translucent right ovarian cyst (1 cm) with no capsular disruption or excrescence. Left adnexal tissue was minimal, a finding that was unlikely to represent residual ovarian tissue. These structures were surgically extirpated, and a lipoid cell tumor of the right ovary (Fig. 1) and a benign fibrovascular stroma of the left adnexal tissue were revealed. Findings on upper abdominal exploration and palpation of the pelvic and periaortic lymph node-bearing regions were unremarkable. The patient tolerated the procedure well, and her convalescence was unremarkable. Three months postoperatively, the patient reported a decrease in her sex drive and noted loss of facial hair and the beginning of reversal of her male pattern baldness. She believed that her skin was less oily and that her voice seemed to be softer. She no longer had sleep apnea and had discontinued use of nasal CPAP; her snoring and daytime somnolence had not recurred. On physical examination, the patient's height was the same, and her weight (63.9 kg) was essentially unchanged. She continued to abstain from tobacco and alcohol use. Her blood pressure, pulse, and respiratory rate were all within normal limits. Her voice was not as deep. The oropharynx showed no abnormalities, the nares were patent bilaterally, and no discrete mass was detected on her neck. Her hair growth appeared to be improving slightly with some early hair growth where she had been previously balding. Her facial hair had decreased considerably. Results of her gynecologic examination were essentially unchanged. Laboratory studies revealed a dramatic decrease in the free testosterone level to 0.3 ng/dL and in the total testosterone level to 12 ng/dL (Table 1); her postmenopausal estradiol level was normal at 23 pg/mL.Table 1—Preoperative and Postoperative Findings in a Woman With Endogenous Testosterone ProductionFindingsFactorPreoperativePostoperativeFree testosterone (ng/dL)18.20.3Total testosterone (ng/dL)65012Respiratory disturbance index84Weight (kg)63.563.9Symptoms of androgen excessPresentDecreasedSymptoms of obstructive sleep apneaPresentNone Open table in a new tab Follow-up PSG was performed 5 months postoperatively to ensure absence of sleep apnea. The study was performed by using standard protocol and scoring as outlined by Rechtschaffen and Kales.1Rechtschaffen A Kales A A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. BIS/BRI, UCLA, Los Angeles1968Google Scholar During this study, the patient had a sleep efficiency of 87%, and all stages of sleep were represented in essentially normal amounts. Snoring was noted to be mild, and few apneas (3) and hypopneas (31) were observed; the respiratory disturbance index was 4. At the most recent follow-up (about 6 months postoperatively), the patient continued to do well and had no signs of apnea, snoring, or daytime somnolence. Her sex drive had diminished to a level that she believed was normal. Obstructive sleep apnea (OSA) is a common medical condition characterized by repetitive episodes of upper airway obstruction that manifest clinically with snoring, apneas, restless sleep, daytime somnolence, and hypertension.2Diagnostic Classification Steering Committee International Classification of Sleep Disorders: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester (MN)1990Google Scholar, 3Guimetnlnault C Clinical features and evaluation of obstructive sleep apnea.in: Kryger MH Roth T Dement WC Principles and Practice of Sleep Medicine. Saunders, Philadelphia1989: 552-558Google Scholar It is more common in men than in women4Block AJ Boysen PG Wynne JW Hunt LA Sleep apnea, hypopnea and oxygen desaturation in normal subjects: a strong male predominance.N Engi J Med. 1979; 300: 513-517Crossref PubMed Scopus (472) Google Scholar and is more common in postmenopausal women than in premenopausat women.5Block AJ Wynne JW Boysen PG Sleep disordered breathing and nocturnal oxygen desaturation in postmenopausal women.Am J Med. 1980; 69: 75-79Abstract Full Text PDF PubMed Scopus (127) Google Scholar These findings have led to the hypothesis that reproductive hormones have a role in the cause of OSA. In one study, a treatment trial of medroxyprogesterone in postmenopausal women with OSA provided no clear benefit for disordered breathing.6Block AJ Wynne JW Boysen PG Lindsey S Martin C Cantor B Menopause, medroxyprogesterone and breathing during sleep.Am J Med. 1981; 70: 506-510Abstract Full Text PDF PubMed Scopus (109) Google Scholar Progesterone has been used to treat OSA in male patients, and success has been limited.7Sutton Jr, FD Zwillich CW Creagh CE Plerson DJ Weil JV Progester-one for outpatient treatment of Pickwickian syndrome.Ann Intern Med. 1975; 83: 476-479Crossref PubMed Scopus (155) Google Scholar, 8Orr WC Imes NK Martin RJ Progesterone therapy in obese patients with sleep apnea.Arch Intern Med. 1979; 139: 109-111Crossref PubMed Scopus (86) Google Scholar, 9Strohl KP Hensley MJ Saunders NA Scharf SM Brown R Ingram Jr, RH Progesterone administration and progressive sleep apneas.JAMA. 1981; 245: 1230-1232Crossref PubMed Scopus (106) Google Scholar, 10Robinson RW Zwillich CW The effect of drugs on breathing during sleep.Clin Chest Med. 1985 Dec; 6: 603-614PubMed Google Scholar These trials support the theory that testosterone is an important hormonal influence in OSA. Testosterone has been reported to be causally related to OSA in male patients.11Sandblom RE Matsumoto AM Schoene RB Lee KA Giblin EC Bremner WJ et al.Obstructive sleep apnea syndrome induced by testosterone administration.N Engi J Med. 1983; 308: 508-510Crossref PubMed Scopus (152) Google Scholar, 12Cistulli PA Grunsteln RR Sullivan CE Effect of testosterone administration on upper airway collapsibilily during sleep.Am J Respir Crit Care Med. 1994; 149: 530-532Crossref PubMed Scopus (108) Google Scholar, 13Schneider BK Picket CK Zwillich CW Well JV McDermott MT Santen RJ et al.Influence of testosterone on breathing during sleep.J Appl Physiol. 1986; 61: 618-623PubMed Google Scholar, 14Wittels EH Obesity and hormonal factors in sleep and sleep apnea.Med Clin North Am. 1985 Nov; 69: 1265-1280PubMed Google Scholar, 15Matsumoto AM Sandblom RE Schoene RB Lee KA Glblln EC Plerson DJ et al.Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep.Clin Endocrinol. 1985; 22: 713-721Crossref PubMed Scopus (190) Google Scholar, 16Robinson RW Zwillich CW The effects or drugs on breathing during sleep.in: Kryger MH Roth T Dement WC Principles and Practice of Sleep Medicine. Saunders, Philadelphia1989: 501-512Google Scholar In most of these reports, the patients were treated with exogenous testosterone. The effect of weight gain in male patients treated with testosterone is controversial.17Camargo CA Obstructive sleep apnea and testosterone [letter].N Engl J Med. 1983; 309: 314-315Crossref PubMed Scopus (10) Google Scholar In one report, testosterone administration did not cause OSA.18Mlllman RP Kimmel PL Shore ET Wasserstein AG Sleep apnea in hemodialysis patients: the lack of testosterone effect on its pathogenesis.Nephron. 1985; 40: 407-410Crossref PubMed Scopus (82) Google Scholar Most of the information, however, seems to support that testosterone has a role in the pathogenesis of OSA in men. To our knowledge, only one previous report in the English literature has described testosterone associated with OSA in a woman.19Johnson MW Anch AM Remmers JË Induction of the obstructive sleep apnea syndrome in a woman by exogenous androgen administration.Am Rev Respir Dis. 1984; 129: 1023-1025PubMed Google Scholar A 54-year-old nonobese woman had development of OSA after she received androgen therapy for anemia associated with chronic renal failure. The OSA resolved after use of the androgen therapy was discontinued but recurred when a second trial was instituted. No weight gain was noted; thus, this report is a compelling case for the influence of testosterone in OSA. Another report (abstract)20Mohamed G Lopata M Kukreja S Schraufnagel D Androgen levels in women with sleep apnea syndrome [abstract].Am Rev Respir Dis. 1983; 127: 237PubMed Google Scholar suggests that women with sleep apnea have higher serum androgen levels than do female patients without sleep apnea. Based on these reports, OSA in women may be influenced by their levels of male sex hormones. The mechanism of OSA due to testosterone has been reported to be secondary to increased collapsibility of the airway.11Sandblom RE Matsumoto AM Schoene RB Lee KA Giblin EC Bremner WJ et al.Obstructive sleep apnea syndrome induced by testosterone administration.N Engi J Med. 1983; 308: 508-510Crossref PubMed Scopus (152) Google Scholar In a patient with the pickwickian syndrome, hypo ventilation and a blunted central response to carbon dioxide seemed to be caused by testosterone.21Strumpf IJ Reynolds SF Vash P Tashkin DP A possible relationship between testosterone, central control of ventilation and the Pickwickian syndrome [abstract].Am Rev Respir Dis. 1978; 117: 183Google Scholar Another report, however, suggested no pronounced adverse effect of testosterone in the control of ventilation in a series of male subjects with hypogonadism.22White DP Schneider BK Santen RJ McDermott M Plekett CK Zwillich CW et al.Influence of testosterone on ventilation and chemo-sensitivity in male subjects.J Appl Physiol. 1985; 59: 1452-1457PubMed Google Scholar Although the exact mechanism of OSA remains controversial, testosterone-induced sleep apnea is an obvious occurrence. Most hormonally functional ovarian tumors are stromal tumors, which constitute approximately 5% of all ovarian neoplasms. Lipoid cell tumors are a rare subset of andro-genic stromal tumors; approximately 100 cases have been reported in the literature.23Hayes MC Scully RE Ovarian steroid cell tumors (not otherwise specified): a climcopathologtcal analysis of 63 cases.Am J Surg Pathol. 1987; 11: 835-845Crossref PubMed Scopus (209) Google Scholar Typical clinical characteristics have not been clearly delineated in the literature. Suggested malignant features include size of more than 8 cm, contiguous organ spread, and high mitotic activity microscopically. Clinical features usually involve virilization, often commensurate with the increases in testosterone. Symptoms are often indolent and typically resolve dramatically after surgical extirpation. Our patient had concomitant clinical resolution of OSA and excessive libido and decreased free and total testosterone levels postoperatively. Temporal balding and voice deepening do not typically improve substantially, as in our patient. In our patient, the substantially increased testosterone level caused by a benign stromal tumor was associated with OSA. No weight gain or other confounding variables were identified. Although the severity of her OSA on preoperative PSG was not dramatic, her unequivocal response to CPAP therapy strongly supports the clinical diagnosis of OSA. Our patient's symptoms resolved after her tumor was removed. This unique case further supports the theory of male hormonal influence in the OSA syndrome.