Obstructive Sleep Apnea Is Associated to Low Testosterone Stages

Abstract

Keywords: obesity, metabolic syndrome, sleep apnea, testosterone, male

Introduction

Obesity is a advanced metabolic dysfunction with a markedly elevated prevalence in each the developed and underdeveloped international locations. Over the last four a protracted time, the proportion of overweight of us has doubled amongst females and quadrupled amongst males (1, 2).

Extra physique weight is a genuinely valuable possibility factor for mortality and morbidity, especially in overweight males with physique mass index (BMI) over 35 kg/m² (1, 3). The probability of developing male infertility increases with obesity severity. Alterations in intercourse steroid hormones make a contribution to infertility in overweight males (4). Obesity in males is connected with low testosterone and low measured or calculated free and bioavailable testosterone (1). Men with a BMI of 35–40 kg/m² can have as much as 50% less free and total testosterone when put next to age-matched chums with a protracted-established BMI (5). Low testosterone ranges in overweight males are regarded as a final result of decreased intercourse hormone binding globulin (SHBG) synthesis, elevated androgens aromatization to estradiol, and central gonadal axis suppression. Advanced metabolic disorders, elevated legitimate-inflammatory adipocytokines, impaired insulin signaling within the central worried blueprint, dysregulated leptin signaling, and elevated estrogen could well result in hypothalamic suppression through outcomes on kisspeptin neurons in overweight males (6, 7).

Moreover, metabolic syndrome, as an unfavorable health final result of obesity, is connected with decrease testosterone ranges neutral of age and BMI (8, 9). Disrupted sleep impacts cardio-metabolic and reproductive health. The biggest scientific cause within the inspire of disrupted sleep is obstructive sleep apnea syndrome (OSAS) (10). OSAS is emerging as a brand unusual dwelling of pastime for andrological disorders (4). It is characterized by repetitive episodes of upper airway obstruction that occur sooner or later of sleep and is connected with a total (apnea) or incomplete (hypopnea) cessation of airflow. This is gradually accompanied by loud loud night breathing and discount in blood oxygen saturation, followed by arousal, fragmented sleep, and daylight hours sleepiness (11, 12). The biggest epidemiological possibility factor for sleep apnea is obesity, earlier age, and male gender (13). The prevalence of OSAS in overweight participants is over 30%, and 50-98% in morbidly overweight sufferers (14). There could be rising evidence to toughen an neutral association of OSAS with cardiovascular, neuropsychiatric, pulmonary, and renal disorders as well to with metabolic and endocrine co-morbidities. There could be convincing evidence that OSAS is furthermore an neutral possibility factor for metabolic syndrome (15). It is clinically noticeable that overweight males with sleep apnea have decrease than anticipated concentrations of total testosterone (TT) and free testosterone (FT) (3, 9, 10). On the replace hand, the neutral assemble of OSAS on blood testosterone concentrations has been shown in some (9, 16–20) however now not in all snide-sectional be taught (21, 22).

Pondering the inconclusive information, the aim of this look was once to pick the affect of obstructive sleep apnea on TT and FT ranges in severely overweight males.

Materials and Suggestions

Topics

This was once an observational, snide-sectional look. We have gotten evaluated 165 severely overweight males (BMI ≥ 35kg/m²), historical 20 to 60, admitted to the Division for Obesity, Metabolic and Reproductive Issues on the Medical institution for Endocrinology, Diabetes and Metabolic Ailments University, Clinical Centre of Serbia between 2006 and 2016.

Detailed deepest history, the biochemical and endocrinological analysis was once performed in repeat to detect and exclude sufferers with: hypercortisolism (0) and/or hypothyroidism (5), history of alcohol consumption (≥ 2 devices per day) or substance abuse (2), hormonal therapy (3), hypogonadism ensuing from the pituitary (3) or testicular ailments (3), craniofacial abnormalities (2), liver or kidney ailments (2), neuromuscular ailments (4), power obstructive pulmonary disease (4), bronchial asthma (3), manifest cardiologic ailments (13), malignancies (2), psychiatric ailments (3) and lacking information (12). In total, sixty-one sufferers were excluded from the look as equipped within the STROBE flowchart (
Determine 1
).

STROBE flowchart of the demonstrate look.

This look was once designed in agreement with the Declaration of Helsinki and was once current by the native Ethical Committee. The sufferers gave their educated consent.

Outcomes

The long-established characteristics of the look topics are summarized in
Table 1
. The indicate age was once 41.8 ± 11.9 years, the indicate BMI was once 45.7 ± 7.4 kg/m², and the indicate weight was once 144.9 ± 24.2 kg. 77.9% of sufferers had MetS, 48.1% had low concentrations of the TT, and 29.8% had low concentrations of FT. The prevalence of sleep apnea was once 96.2%, out of which 15.4% had gentle, 16.3% reasonable, and 64.5% had severe obstructive sleep apnea.

Sufferers were divided into groups basically basically basically based on AHI ranges in repeat to illustrate values of scientific parameters in a truly easy-to-perceive sort. Taking into account that the neighborhood and not utilizing a OSAS was once too miniature (easiest 4 sufferers), we categorized sufferers into 3 AHI groups: AHI < 15 (20 sufferers), AHI 15 - 29.9 (17 sufferers), and AHI ≥ 30 (67 sufferers) as offered in
Table 1
. Our outcomes confirmed a certain valuable incompatibility between AHI groups in TT and FT ranges (p<0.001). There was once furthermore a valuable incompatibility between AHI groups in terms of age, BMI, waist and neck circumference, blood stress ranges, hypertension prevalence, triglyceride, excessive-density lipoprotein and FPG ranges, metabolic syndrome prevalence, and siMS fetch (
Table 1
). There was once no valuable incompatibility in TT (12.8 ± 5.3 vs. 13.1 ± 5.5 nmol/l; p = 0.734) or FT level (346.1 ± 124.9 vs. 331.6 ± 154.1 pmol/l; p = 0.605), AHI (46.4 ± 29.7 vs. 44.7 ± 27.4; p = 0.762) and ODI (44.5 ± 31.8 vs. 42.7 ± 29.9; p = 0.767) between smokers and non-smokers.

There was once a valuable damaging correlation between TT and AHI (r = -0.409, p < 0.001) and ODI (r = -0.458, p < 0.001) ranges. There was once furthermore a valuable damaging correlation between FT and AHI (r = -0.389, p < 0.001) and ODI (r = -0.438, p <0.001) ranges (
Determine 2
). Each TT and FT ranges were in a valuable damaging correlation with BMI (r = -0.269, p = 0.006 and r = -0.311, p = 0.001, respectively), weight (r = -0.203, p = 0.039 and r = -0.227, p = 0.02, respectively), hip circumference (r = -0. 234, p = 0.017 and r = -0.243, p = 0.013, respectively), some metabolic parameters similar to waist circumference (r = -0.374, p < 0.001 and r = -0.398, p < 0.001, respectively) DBP (r = -0.264, p = 0.007 and r = -0.294, p = 0.002, respectively), FPG (r = -0.274, p = 0.005 and r = -0.296, p = 0.002, respectively), and furthermore with MetS prevalence r = -0.193, p = 0.049 and r = -0.195, p = 0.048, respectively) and siMS fetch ranges (r = -0.321, p = 0.001 and r = -0.283, p = 0.004, respectively) (
Table 2
). FT ranges were in a valuable damaging correlation with age (r = -0.346, p<0.001) (
Table 2
).

Correlations between total testosterone and free testosterone with apnea-hypopnea index and oxygen desaturation index.

Moreover, there was once a valuable obvious correlation between AHI and ODI ranges with age (r = 0.320, p = 0.001 and r = 0.339, p < 0.001, respectively), BMI (r = 0.382, p < 0.001 and r = 0.391, p < 0.001, respectively), weight (r = 0.300, p = 0.002 and r = 0.298, p = 0.002, respectively) waist (r = 0.413, p < 0.001 and r = 0.429, p < 0.001, respectively), hip (r = 0.230, p = 0.019 and r = 0.246, p = 0.012) and neck circumference (r = 0.490, p < 0.001 and r = 0.469, p < 0.001, respectively), SBP (r = 0.280, p = 0.004 and r = 0.324, p = 0.001, respectively), DBP (r = 0.314, p = 0.001 and r = 0.322, p = 0.001, respectively), FPG (r = 0.275, p = 0.005 and r = 0.250, p = 0.001, respectively), and siMS fetch ranges (r = 0.283, p = 0.004 and r = 0.312, p< 0.001, respectively) (
Table 2
).

In multiple regression prognosis, after adjustment for age, BMI, siMS fetch and MetS parts, each AHI and ODI were in valuable correlation with TT and FT (p < 0.05) (
Table 3
). The outcomes of multiple linear regression prognosis failed to trade in subgroup of sufferers with BMI ≥ 40kg/m² (80 sufferers in total) (
Table 4
). The calculated variance inflation components confirmed no multicollinearity in regression models.

In repeat to evaluate if TT and FT could well most certainly be historical as discriminative variables for the overview of sleep apnea severity (the utilization of 15 and 30 level slash-off for AHI) we’ve performed receiver-working characteristic (ROC) curves prognosis. AUC for AHI ≥ 15 for TT was once AUC_TT = 0.714 (95% CI 0.587 – 0.841; p = 0.003) with slash off = 14.5 (Sn = 0.726; Sp = 0.650), and for FT AUC_FT = 0.719 (95% CI 0.588 – 0.851; p = 0.002) with slash off = 412 (Sn = 0.821; Sp = 0.600) (
Determine 3A
).

AUC for AHI ≥ 30 for TT was once AUC_TT = 0.748 (95% CI 0.648 – 0.849; p < 0.001) with slash off = 14.3 (Sn = 0.806; Sp = 0.649) and for FT AUC_FT = 0.728 (95% CI 0.620 – 0.836; p < 0.001) with slash off = 396 (Sn = 0.866; Sp = 0.568) (
Determine 3B
).

Discussion

Obesity is regarded as to be the vital cause within the inspire of hypogonadism in males. Hypogonadism is a scientific entity characterized by low serum TT focus and/or FT focus and connected signs and signs of testosterone deficiency (30). Obesity-connected hypogonadism is purposeful, and it’ll also most certainly be reverted by great weight loss finished with non-surgical or surgical interventions (31). Hypoandrogenemia is a term relating to the discovering of subnormal testosterone concentrations in males without considering scientific signs or signs of decreased serum testosterone ranges. The prevalence of hypoandrogenemia is 4% to 5% within the long-established male population and as worthy as 20% to 40% in overweight males (30). In our look, 48.1% of severely overweight males had TT level < 348.3 ng/dl, and 29.8% had FT level < 70.0 pg/ml. Our outcomes are per the old information that the presence of low TT and FT in males is closely connected to the elevated BMI with the excellent hypoandrogenemia in more severe obesity (30).

Age is the most famed predictor of most ailments in humans. Chronological getting older per se and age-connected changes in total health and life-style are connected with pure declines in serum testosterone (32), offered in our look as a harmful relationship between FT and age. Stomach adiposity is indubitably one of 5 scientific possibility components historical as diagnostic criteria for metabolic syndrome. Even even supposing obesity and metabolic syndrome veritably coexist, here’s now not constantly the case.

A large percentage of overweight participants lift out now not have metabolic syndrome, and, conversely, metabolic syndrome could well most certainly be demonstrate in non-overweight participants (33). In our look, 77.9% of severely overweight males had metabolic syndrome. The metabolic syndrome in overweight males is connected with a extra decline in testosterone level, with a harmful inverse relationship between TT and/or FT ranges and metabolic syndrome (8, 34, 35), furthermore noticed in our look.

The most striking result to emerge from our information is that OSAS, measured by each AHI and ODI, is an neutral determinant of serum testosterone focus in severely overweight males after adjustment for BMI, age, or siMS fetch. Moreover, the ROC prognosis confirmed that every TT and FT ranges will seemingly be historical as discriminative variables for the overview of sleep apnea severity.

Sufferers with OSAS have decreased quality and quantity of sleep ensuing from sleep fragmentation, intermittent nocturnal hypoxia, decreased deep and snappily think slide (REM) sleep, decreased sleep duration, and sleep efficiency, all of which result in pituitary-gonadal dysfunction and low testosterone ranges in male sufferers (5, 36).

The association of respiratory hypoxia and low serum testosterone in males was once noticed as early as 40 years ago when it was once shown that in sufferers with power obstructive pulmonary disease, erectile dysfunction and low serum testosterone concentrations correlated with the diploma of arterial hypoxia (37, 38). About a years later, the the same outcomes were acquired in sufferers with pulmonary fibrosis (39), pulmonary coronary heart (40), and Pickwick syndrome (41). Kouchiyama et al., within the look performed on 24 sufferers, confirmed that bigger nocturnal oxygen desaturation in males resulted in the disruption of the circadian rhythm of testosterone secretion (42).

Within the animal models, be taught specializing within the outcomes of continuous or intermittent hypoxia on intercourse hormones were inconclusive because – reckoning on the look – they confirmed an expand (43), decrease (44, 45), and unchanged testosterone concentrations (46).

Partial or total upper airway obstruction in OSAS sufferers is the cause within the inspire of now not easiest nocturnal oxygen desaturation however furthermore sleep fragmentation. A large replace of be taught have been implemented by Luboshitzky and colleagues to review whether reproductive hormones are correlated with sleep patterns in males with OSAS. They confirmed that the sufferers with fragmented sleep had a blunted nocturnal upward push of testosterone easiest if they did now not demonstrate REM sleep (47). The the same group urged that OSAS in male sufferers is connected with decreased androgen secretion due to altered pituitary-gonadal purpose (48). This is caused by obesity and getting older, with hypoxia and sleep fragmentation being extra contributing components in reducing pulsatile testosterone secretion in these sufferers (49).

Clinical evidence is contradictory, with some (9, 16–20), however now not all (21, 22), be taught reporting that OSAS is a part favoring hypoandrogenemia neutral of obesity. This could well be ensuing from excessive heterogeneity of look assemble, sufferers’ characteristics similar to age and BMI, exclusion or inclusion criteria, miniature or absent covariates within the guidelines analyses, and the time point of information sequence (9, 16–22).

Hammoud et al. revealed a look similar to ours. This look included 89 severely overweight males with a BMI ≥ 35 kg/m² to demand the assemble of sleep apnea on the reproductive hormones and sexual purpose in overweight males. They confirmed that elevated severity of sleep apnea is connected with decrease TT and FT ranges neutral of age and BMI, which is per the outcomes of our look (18). Their look, now not like our look, failed to specialize within the metabolic syndrome as a contributing factor to hypoandrogenemia in overweight males.

Concerning this latter side, there could be easiest one look revealed by Gambineri et al. that analyzed the severity of OSAS, testosterone ranges, and a couple of of the parameters of MetS (waist circumference, FPG, HDL, Tg) in severely overweight males. They urged that OSAS could well make a contribution to causing metabolic abnormalities in males and that this relationship could well most certainly be in share connected to the decreased testosterone concentrations (9). Taking this into consideration, we included metabolic syndrome as a seemingly confounding factor for hypoandrogenemia in our overweight males.

Gambineri and colleagues documented that in males with obesity and OSAS, the severity of hypoxia measured by ODI could well most certainly be an additional factor in reducing testosterone ranges, no matter BMI and abdominal fatness (9). Our look reveals that AHI and ODI, as pivotal markers of OSAS severity are in valuable correlation with TT and FT neutral of age, BMI, siMS fetch and MetS parts in severely overweight males.

The outcomes of OSAS therapy on testosterone ranges are arguable. Continuous obvious airway stress (CPAP) is the most easy non-surgical therapy for OSAS. Moreover, the efficacy of CPAP on hypoandrogenemia in OSAS male topics are quiet controversial. Reasonably analysis have demonstrated that CPAP elevates testosterone ranges (49, 50). On the replace hand, the huge majority of different be taught, collectively with two meta-analyses, have reached a different conclusion (51, 52). As identified by indubitably one of many most contemporary systematic opinions, a miniature replace of included be taught in their meta-prognosis reported an ample CPAP exercise (4 h per night on as a minimal 70% of nights), and thus the outcomes could well replicate, as a minimal in share, suboptimal CPAP therapy. Moreover, Santamaria et al. completely performed a seemingly look of uvulopalatopharyngoplasty therapy outcomes on testosterone ranges in male topics with reasonable and severe OSAS. Interestingly, they confirmed development in testosterone ranges three months after the surgical plot, with correlated development in sleep-disordered respiration without valuable changes in BMI (53). On the replace hand, CPAP as the mainstay of therapy for OSAS is now not going to medication obesity, as a cornerstone of OSAS and metabolic syndrome, as well to hypoandrogenemia in overweight males. As a minimal, valuable weight loss clearly improved OSAS, metabolic syndrome, and hypogonadism connected with obesity (1–5, 54).

Some limitations of this investigation needs to be acknowledged. The assemble of our look failed to provide for monitoring the signs of sexual dysfunction and hypogonadism within the topics. Thus, we are able to focus on intercourse hormones easiest from the attitude of hypoadrogenism and now not in terms of hypogonadism. Every other limitation of our look is that in location of the utilization of ‘fleshy’ polysomnography, we historical a seven-channel portable sleep recorder. Given the indisputable fact that there was once no electroencephalography monitoring, we provide out now not have information about the relationships between sleep phases and intercourse hormone ranges. Moreover, we are able to also now not assess if the bodily exercise or traditional alcohol consumption influenced the outcomes of our look, as we failed to have this information on the market.

Conclusion

Our information demonstrate that obstructive sleep apnea syndrome is in valuable correlation with TT and FT ranges in severely overweight males. Extra be taught is wanted to clarify the advanced link between sleep apnea and testosterone ranges in overweight males for the aim of acceptable management of these sufferers.

Recordsdata Availability Assertion

The raw information supporting the conclusions of this article will seemingly be made on the market by the authors, without undue reservation.

Ethics Assertion

The be taught inspiring human participants were reviewed and current by The Faculty of Medication, University of Belgrade, Ethics Committee. The sufferers/participants equipped their written educated consent to employ half in this look.

Creator Contributions

MT-G, MV, and SV: conceived and designed the look, quiet and contributed to the guidelines, and analyzed and interpreted information. MT-G: wrote the manuscript. MV and SV: revised the article. MI, LM, ZA, MS, and AĐ: quiet and contributed to the guidelines and revised the article. AK: analyzed and interpreted information, and revised the article. IS: analyzed and interpreted information, made tables, and revised the article. All authors contributed to the article and current the submitted version.

Warfare of Hobby

The authors affirm that the be taught was once performed within the absence of any industrial or monetary relationships that will seemingly be construed as a seemingly conflict of pastime.

Publisher’s Stutter

All claims expressed in this article are completely those of the authors and lift out now not basically checklist those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that could well most certainly be evaluated in this article, or affirm that could well most certainly be made by its manufacturer, is now not guaranteed or urged by the publisher.

Abbreviations

BMI, physique mass index; SHBG, intercourse hormone-binding globulin; OSAS, obstructive sleep apnea syndrome; Tg, triglyceride; HDL, excessive-density lipoprotein; LH, luteinizing hormone; FSH, follicle-stimulating hormone; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MetS, metabolic syndrome; siMS, continuous metabolic syndrome fetch.

References