The Open Respiratory Medicine Journal




ISSN: 1874-3064 ― Volume 13, 2019
PERSPECTIVE ARTICLE

Is Obesity Hypoventilation Syndrome A Postmenopausal Disorder?



Ahmed S. BaHammam1, 2, *, Aljohara S. Almeneessier1, 2, 3
1 Department of Medicine, College of Medicine, The University Sleep Disorders Center, King Saud University, Riyadh, Saudi Arabia
2 Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia
3 Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Abstract

Previous studies have assessed the role of gender and menopause in Obstructive Sleep Apnea (OSA). It is well known that menopause is a major risk factor for OSA. However, analogous studies on obesity Hypoventilation Syndrome (OHS) are limited. Recent studies have suggested that OHS is more prevalent in postmenopausal women. Moreover, women with OHS seem to have excess comorbidities, including hypothyroidism, hypertension, pulmonary hypertension, and diabetes mellitus, compared to men. In the present perspective, we discuss recent data on the prevalence and comorbidities associated with OHS in women, as well as the use of noninvasive ventilation in women with OHS, and try to answer the question, “Is OHS a disorder of postmenopausal women?”

Keywords: hHpercapnia, Obstructive sleep apnea, Hypoxia, Progesterone, Sleep, OHS.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 51
Last Page: 54
Publisher Id: TORMJ-13-51
DOI: 10.2174/1874306401913010051

Article History:

Received Date: 24/07/2019
Revision Received Date: 21/09/2019
Acceptance Date: 15/10/2019
Electronic publication date: 15/11/2019
Collection year: 2019

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© 2019 BaHammam and Almeneessier

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia; Tel: +966114679179; Fax: +966114679495; E-mail: ashammam2@gmail.com





1. INTRODUCTION

Sleep-Disordered Breathing (SDB) is a constellation of disorders characterized by abnormal breathing during sleep. It includes Obstructive Sleep Apnea (OSA), Central Sleep Apnea (CSA), and Obesity Hypoventilation Syndrome (OHS). In general, SDB is under-recognized in women. Studies assessing gender differences in OSA patients have reported differences in its prevalence, clinical presentation, and polysomnographic features [1Ye L, Pien GW, Weaver TE. Gender differences in the clinical manifestation of obstructive sleep apnea. Sleep Med 2009; 10(10): 1075-84.
[http://dx.doi.org/10.1016/j.sleep.2009.02.006] [PMID: 19403333]
]. Previous studies have found an impact of gender and menopause on OSA. Specifically, it is well known that menopause is a major risk factor for OSA. OSA is approximately three times more prevalent in men than in women [2Lin CM, Davidson TM, Ancoli-Israel S. Gender differences in obstructive sleep apnea and treatment implications. Sleep Med Rev 2008; 12(6): 481-96.
[http://dx.doi.org/10.1016/j.smrv.2007.11.003] [PMID: 18951050]
]. However, analogous studies on obesity hypoventilation syndrome (OHS) are limited. Other than menopause, which is a well-established risk factor for OSA in women [3Young T. Menopause, hormone replacement therapy, and sleep-disordered breathing: Are we ready for the heat? Am J Respir Crit Care Med 2001; 163(3 Pt 1): 597-8.
[http://dx.doi.org/10.1164/ajrccm.163.3.ed09-01a] [PMID: 11254506]
], gender differences in the upper airway structure and function and ventilatory control during sleep, including increased sensitivity to carbon dioxide (CO2), in men compared to women, have been reported [4Weg JG, Calverly JR, Johnson C. Hypothyroidism and alveolar hypoventilation. Arch Intern Med 1965; 115: 302-6.
[http://dx.doi.org/10.1001/archinte.1965.03860150046008] [PMID: 14248360]
]. In this perspective, we discuss recent data on the prevalence and comorbidities associated with OHS in women, as well as the use of noninvasive ventilation in women with OHS, and try to answer the question “Is OHS a disorder of postmenopausal women?”

2. OBESITY HYPOVENTILATION SYNDROME IN WOMEN

OHS is the most severe form of SDB. The exact prevalence of OHS in the general population remains unknown; however, a conservative estimate in US adults ranges from 0.15% to 0.3% [5Littleton SW, Mokhlesi B. The pickwickian syndrome-obesity hypoventilation syndrome. Clin Chest Med 2009; 30(3): 467-478, vii-viii. [vii-viii.].
[http://dx.doi.org/10.1016/j.ccm.2009.05.004] [PMID: 19700045]
]. The prevalence of OHS among patients referred to sleep disorders clinics has been estimated in multiple studies to range from 8% to 20% [6Al Dabal L, Bahammam AS. Obesity hypoventilation syndrome. Ann Thorac Med 2009; 4(2): 41-9.
[http://dx.doi.org/10.4103/1817-1737.49411] [PMID: 19561923]
-8BaHammam AS. Prevalence, clinical characteristics, and predictors of obesity hypoventilation syndrome in a large sample of Saudi patients with obstructive sleep apnea. Saudi Med J 2015; 36(2): 181-9.
[http://dx.doi.org/10.15537/smj.2015.2.9991] [PMID: 25719582]
].

Unlike OSA, which is a disorder with a well-established predominance in men, OHS is not as commonly prevalent in men [9Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
]. In fact, OHS may be more prevalent in women than in men (15.6% and 4.5%, respectively), even after adjusting for Body Mass Index (BMI) differences. Women may also experience OHS-onset later than men (mean age 61.5 versus 49.1 years) [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. After the comparison of postmenopausal women to age-matched men with OHS, it was observed that the prevalence of OHS remained significantly higher (four times) in postmenopausal women, with no significant differences observed in age, Apnea-Hypopnea Index (AHI), or BMI [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
].

Gender differences and the impact of menopause on OHS mentioned previously have not been discussed in detail. However, in a recent review of the literature, Balachandran and his associates [11Balachandran JS, Masa JF, Mokhlesi B. Obesity hypoventilation syndrome epidemiology and diagnosis. Sleep Med Clin 2014; 9(3): 341-7.
[http://dx.doi.org/10.1016/j.jsmc.2014.05.007] [PMID: 25360072]
] carefully examined 11 studies from different countries, including a total of 4,150 patients with OSA, 714 of whom also had OHS. The authors concluded that in contrast to OSA, the male gender does not seem to present a significant risk for OHS [7Balachandran JS, Masa JF, Mokhlesi B. Obesity hypoventilation syndrome epidemiology and diagnosis. Sleep Med Clin 2014; 9(3): 341-7.
[http://dx.doi.org/10.1016/j.jsmc.2014.05.007] [PMID: 25360072]
]. However, the mean age of the subjects varied from 43 to 56 years in this study and the menopausal status of the female patients was not reported. The present perspective is the first review that seeks to bridge this gap by addressing the relationship between menopause and OHS.

It was previously reported that, among patients referred to sleep disorder centers for a possible diagnosis of SDB, the prevalence of OHS was 4.5% in men and 5.3% in premenopausal women [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. However, the prevalence of OHS in postmenopausal women was much higher- i.e. 21% [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. In fact, in King Saud University Sleep Disorders Center database of OHS patients, 89% of women with OHS were found to be postmenopausal [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. This new finding has not been previously discussed.

3. PROPOSED MECHANISMS UNDERLYING THE INCREASED PREVALENCE OF OHS AMONG POSTMENOPAUSAL WOMEN

The underlying cause of the potentially elevated prevalence of OHS among women is not known [9Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
, 10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. However, several potential mechanisms are proposed herein.

Possible explanations for the higher prevalence of OHS among postmenopausal women include the role of female hormones in the course and development of OHS. Progesterone is a known respiratory stimulant that increases alveolar ventilation, lowers the arterial partial pressure of carbon dioxide (PaCO2), and augments the hypercapnic and hypoxic ventilatory responses [12Javaheri S, Guerra LF. Effects of domperidone and medroxyprogesterone acetate on ventilation in man. Respir Physiol 1990; 81(3): 359-70.
[http://dx.doi.org/10.1016/0034-5687(90)90116-G] [PMID: 2148014]
, 13Saaresranta T, Polo O. Hormones and breathing. Chest 2002; 122(6): 2165-82.
[http://dx.doi.org/10.1378/chest.122.6.2165] [PMID: 12475861]
]. Moreover, progesterone increases dilator muscle tone in the upper airway [14St John WM, Bartlett D Jr, Knuth KV, Knuth SL, Daubenspeck JA. Differential depression of hypoglossal nerve activity by alcohol. Protection by pretreatment with medroxyprogesterone acetate. Am Rev Respir Dis 1986; 133(1): 46-8.
[http://dx.doi.org/10.1164/arrd.1986.133.1.46] [PMID: 2935056]
]. Therefore, it is possible that the withdrawal of progesterone during menopause may, in part, contribute to the increased prevalence of hypoventilation in postmenopausal women via reduced respiratory drive and respiratory pathway relaxation. In a placebo-controlled, double-blind trial of postmenopausal women with OSA on Continuous Positive Airway Pressure (CPAP) therapy, women were randomized to Medroxyprogesterone Acetate (MPA) or a placebo for two weeks after discontinuing CPAP therapy [15Anttalainen U, Saaresranta T, Vahlberg T, Polo O. Short-term medroxyprogesterone acetate in postmenopausal women with sleep-disordered breathing: A placebo-controlled, randomized, double-blind, parallel-group study. Menopause 2014; 21(4): 361-8.
[PMID: 24253484]
]. Fourteen days after discontinuing the use of CPAP, nocturnal oxygen saturation remained higher and PaCO2 remained lower (P < 0.001) in the MPA treated group [15Anttalainen U, Saaresranta T, Vahlberg T, Polo O. Short-term medroxyprogesterone acetate in postmenopausal women with sleep-disordered breathing: A placebo-controlled, randomized, double-blind, parallel-group study. Menopause 2014; 21(4): 361-8.
[PMID: 24253484]
]. These results may support the role of progesterone in the development of hypercapnia. Despite these results, a randomized controlled trial is necessary to determine whether treatment with progesterone reverses hypercapnia associated with OHS in postmenopausal women.

Additional mechanisms have also been proposed to explain the gender difference in OHS. One such mechanism includes resistance to leptin, a powerful respiratory stimulant [16Atwood CW. Sleep-related hypoventilation: The evolving role of leptin. Chest 2005; 128(3): 1079-81.
[http://dx.doi.org/10.1378/chest.128.3.1079] [PMID: 16162684]
]. In general, obese individuals have higher leptin resistance than lean individuals, a condition that may affect the respiratory drive in obesity [17Pierce AM, Brown LK. Obesity hypoventilation syndrome: Current theories of pathogenesis. Curr Opin Pulm Med 2015; 21(6): 557-62.
[http://dx.doi.org/10.1097/MCP.0000000000000210] [PMID: 26390338]
]. Moreover, serum leptin levels are an independent predictor of hypercapnia [18Ladenson PW, Goldenheim PD, Ridgway EC. Prediction and reversal of blunted ventilatory responsiveness in patients with hypothyroidism. Am J Med 1988; 84(5): 877-83.
[http://dx.doi.org/10.1016/0002-9343(88)90066-6] [PMID: 3364447]
, 19Ambrosino N, Pacini F, Paggiaro PL, et al. Impaired ventilatory drive in short-term primary hypothyroidism and its reversal by L-triiodothyronine. J Endocrinol Invest 1985; 8(6): 533-6.
[http://dx.doi.org/10.1007/BF03348555] [PMID: 3833897]
]. Obese women have up to four times higher levels of leptin than obese men [20Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome, part 1: Clinical features. Sleep 2002; 25(4): 412-9.
[http://dx.doi.org/10.1093/sleep/25.4.409] [PMID: 12071542]
]. In theory, it is possible that obesity in women may lead to more resistance to the central effects of leptin compared to men and hence, a higher risk of hypoventilation and hypercapnia, which results in an increased prevalence of OHS. However, further research is needed to prove this hypothesis. A previous study that assessed the effects of postmenopausal hormone replacement therapy (pHT) on a large sample of healthy postmenopausal women demonstrated that leptin concentrations were significantly higher in obese postmenopausal women compared to their counterparts of normal weight, and that neither pHT nor serum estradiol concentrations had an effect on leptin concentrations, even after the adjustment for BMI [21Hadji P, Görke K, Hars O, Bauer T, Emons G, Schulz KD. The influence of Hormone Replacement Therapy (HRT) on serum leptin concentration in postmenopausal women. Maturitas 2000; 37(2): 105-11.
[http://dx.doi.org/10.1016/S0378-5122(00)00166-3] [PMID: 11137329]
]. Moreover, previous studies addressing the relationship between menopausal status and leptin concentration reported conflicting results. While most studies showed no differences in serum leptin concentration between pre- and postmenopausal women, others reported both decreased and increased leptin concentrations [22Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. Role of postmenopausal hormone replacement therapy on body fat gain and leptin levels. Gynecol Endocrinol 2005; 20(4): 227-35.
[http://dx.doi.org/10.1080/09513590400027372] [PMID: 16019366]
-24Gupta V, Mishra S, Mishra S, Kumar S, Gupta V. Association of Leptin: Adiponectin ratio and metabolic risk markers in postmenopausal women. Immunol Lett 2018; 196: 63-7.
[http://dx.doi.org/10.1016/j.imlet.2018.01.008] [PMID: 29410303]
].

Another potential but unlikely hypothesis for the gender differences in OHS is the differences in the ventilatory control in men and women. Studies assessing ventilatory responses to hypercapnia and hypoxia in men and women have reported conflicting results [25White DP, Douglas NJ, Pickett CK, Weil JV, Zwillich CW. Hypoxic ventilatory response during sleep in normal premenopausal women. Am Rev Respir Dis 1982; 126(3): 530-3.
[PMID: 7125340]
-27Regensteiner JG, Woodard WD, Hagerman DD, et al. Combined effects of female hormones and metabolic rate on ventilatory drives in women. J Appl Physiol (1985) 1989; 66(2): 808-13.]. One such study demonstrated that the hypercapnic ventilatory response in women decreased compared to men; however, after adjusting for the forced expiratory volume in one second (FEV1), the gender-difference was not oberved [28Sin DD, Jones RL, Man GC. Hypercapnic ventilatory response in patients with and without obstructive sleep apnea: do age, gender, obesity, and daytime PaCO(2) matter? Chest 2000; 117(2): 454-9.
[http://dx.doi.org/10.1378/chest.117.2.454] [PMID: 10669690]
]. Therefore, ventilatory control may not explain the differences in the prevalence of OHS between men and women. Nevertheless, future studies should examine the physiology of respiratory muscles in men and women with OHS.

Moreover, the prevalence of clinical and subclinical hypothyroidism is significantly higher in women than in men with OHS [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. Hypothyroidism suppresses the ventilatory response to hypercapnia [29Duranti R, Gheri RG, Gorini M, et al. Control of breathing in patients with severe hypothyroidism. Am J Med 1993; 95(1): 29-37.
[http://dx.doi.org/10.1016/0002-9343(93)90229-I] [PMID: 8328495]
] and hypoxia [30Zwillich CW, Pierson DJ, Hofeldt FD, Lufkin EG, Weil JV. Ventilatory control in myxedema and hypothyroidism. N Engl J Med 1975; 292(13): 662-5.
[http://dx.doi.org/10.1056/NEJM197503272921302] [PMID: 1113761]
]. Hypothyroidism may impair ventilatory responses, which could predispose patients to hypoventilation due to the increased resistive load of upper airway obstruction [31Rajagopal KR, Abbrecht PH, Derderian SS, et al. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984; 101(4): 491-4.
[http://dx.doi.org/10.7326/0003-4819-101-4-491] [PMID: 6476635]
]. Future research should thus, assess the effects of thyroid replacement therapies on hypoventilation in OHS patients.

4. OHS COMORBIDITIES IN WOMEN

Women with OHS have been reported to experience significantly more comorbidities than men, with a higher prevalence of hypertension, pulmonary hypertension, and diabetes, despite similar OSA severity and obesity levels [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
, 32Al Otair HA, Elshaer F, Elgishy A, et al. Left ventricular diastolic dysfunction in patients with obesity hypoventilation syndrome. J Thorac Dis 2018; 10(10): 5747-54.
[http://dx.doi.org/10.21037/jtd.2018.09.74] [PMID: 30505482]
, 33Almeneessier AS, Nashwan SZ, Al-Shamiri MQ, Pandi-Perumal SR, BaHammam AS. The prevalence of pulmonary hypertension in patients with obesity hypoventilation syndrome: A prospective observational study. J Thorac Dis 2017; 9(3): 779-88.
[http://dx.doi.org/10.21037/jtd.2017.03.21] [PMID: 28449486]
]. In a group of age-matched women and men with OHS, the prevalence of hypertension and diabetes was significantly higher in women [10BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
]. A recent study demonstrated that Pulmonary Hypertension (PHTN) was present in 71% of women and 62% of men with OHS [33Almeneessier AS, Nashwan SZ, Al-Shamiri MQ, Pandi-Perumal SR, BaHammam AS. The prevalence of pulmonary hypertension in patients with obesity hypoventilation syndrome: A prospective observational study. J Thorac Dis 2017; 9(3): 779-88.
[http://dx.doi.org/10.21037/jtd.2017.03.21] [PMID: 28449486]
]. Moreover, severe PHTN (systolic pulmonary artery pressure > 70 mmHg) was diagnosed in 28.6% of women and 14.3% of men with OHS [33Almeneessier AS, Nashwan SZ, Al-Shamiri MQ, Pandi-Perumal SR, BaHammam AS. The prevalence of pulmonary hypertension in patients with obesity hypoventilation syndrome: A prospective observational study. J Thorac Dis 2017; 9(3): 779-88.
[http://dx.doi.org/10.21037/jtd.2017.03.21] [PMID: 28449486]
].

5. NON-INVASIVE VENTILATION IN WOMEN WITH OHS

Approximately 40% of OHS patients initially present with acute decompensation and hypercapnic respiratory failure [34BaHammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation syndrome. J Sleep Res 2016; 25(4): 445-53.
[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
, 35Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
]. This acute presentation is more common in women, indicating that OHS is under-recognized in women as compared to men till acute decompensation develops [35Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
]. Furthermore, in a study using the data from the national registry in Sweden to assess gender differences in patients undergoing long-term home Non-invasive Ventilation (NIV) treatment for OHS, the five-year survival rate was found to be 68.2% (95% CI, 63.6-72.3%) in men vs. 59.3% (95% CI, 54.2-64.0%) in women [35Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
]. This data collectively indicated increased disease severity in women. It is important to note, however, that after adjusting for age, these survival differences were not observed. [35Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med 2016; 110: 73-8.
[http://dx.doi.org/10.1016/j.rmed.2015.11.010] [PMID: 26680503]
] Another French study reported that women with OHS had better survival rates than men, though, as shown in the prior work discussed here; however, after adjusting for potential confounders, the gender differences in the survival rate disappeared [36Borel JC, Burel B, Tamisier R, et al. Comorbidities and mortality in hypercapnic obese under domiciliary noninvasive ventilation. PLoS One 2013; 8(1) e52006
[http://dx.doi.org/10.1371/journal.pone.0052006] [PMID: 23341888]
]. Therefore, at present, there is no clear evidence that gender drives differences in the survival rates among patients with OHS treated with long-term NIV.

CONCLUSION

Recent data from observational studies revealed that OHS is most prevalent among postmenopausal women and that women with OHS more often exhibit cardiometabolic comorbidities, such as hypertension, pulmonary hypertension, and diabetes. Increased knowledge and clinical awareness of the elevated prevalence of OHS among postmenopausal women may lead to earlier diagnosis and more timely and appropriate treatment. Further studies are needed to assess the prevalence of OHS in women and the effect of menopause on the pathophysiology of OHS and the increased risk and comorbidities of OHS.

DISCLOSURE

The authors report no conflicts of interest in this work.

AUTHORS’ CONTRIBUTION

The authors contributed equally to this manuscript.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This work was partially supported by the Strategic Technologies Program of the National Plan for Sciences and Technology and Innovation in the Kingdom of Saudi Arabia (MED511-02-08).

CONFLICT OF INTEREST

The authors declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

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[http://dx.doi.org/10.1016/j.sleep.2009.02.006] [PMID: 19403333]
[2] Lin CM, Davidson TM, Ancoli-Israel S. Gender differences in obstructive sleep apnea and treatment implications. Sleep Med Rev 2008; 12(6): 481-96.
[http://dx.doi.org/10.1016/j.smrv.2007.11.003] [PMID: 18951050]
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[http://dx.doi.org/10.1016/j.ccm.2009.05.004] [PMID: 19700045]
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[http://dx.doi.org/10.1111/jsr.12400] [PMID: 26990045]
[11] Balachandran JS, Masa JF, Mokhlesi B. Obesity hypoventilation syndrome epidemiology and diagnosis. Sleep Med Clin 2014; 9(3): 341-7.
[http://dx.doi.org/10.1016/j.jsmc.2014.05.007] [PMID: 25360072]
[12] Javaheri S, Guerra LF. Effects of domperidone and medroxyprogesterone acetate on ventilation in man. Respir Physiol 1990; 81(3): 359-70.
[http://dx.doi.org/10.1016/0034-5687(90)90116-G] [PMID: 2148014]
[13] Saaresranta T, Polo O. Hormones and breathing. Chest 2002; 122(6): 2165-82.
[http://dx.doi.org/10.1378/chest.122.6.2165] [PMID: 12475861]
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