• SleepApnoe

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Introduction:

Obstructive sleep apnea (OSA) is a disease where the soft tissues in the throat, including the tongue, collapse and are sucked against the back of the throat. This blocks the upper airway and air flow stops or decrease. When the oxygen level in the brain becomes low enough, the sleeper is partially awaken. The obstruction in the throat clears and the flow of air starts again, usually with a gasp. Most people are not aware this is occurring. Its main aspects are: systemic hypertension, cardiovascular disease and stroke.

Factors that have an effect on Obstructive Sleep Apnea are age, sex, genes, menopause, body weight (strongest risk factor) and, with less importance, alcohol intake and smoking. Based on research studies in Germany the daytime sleepiness is approximately 3-7 % for adult men and 2-5% for adult women.

Apnea is defined as the complete cessation of air flow of at least 10 seconds and is divided into two, obstructive and central.

Hypopnea is defined as the reduction in air flow that is followed by an arousal from sleep or a decrease in oxyhemoglobin saturation.

We will study in this essay the hormonal aspects of OSA and see how hormones can affect or be affected by OSA

Hormones of hypothalamic-pituitary-gonadal axis

Testosterone:

General information:

• Testosterone is a hormone which is produced in the gonads in both males and females (testis and ovaries). It is a sexual hormone which has a circadian production rhythm. We have to make the difference between total testosterone level which is the total amount of testosterone in the body and bioavailable testosterone which is the testosterone fraction available which will be used in the body processes.

Relation between Level of testosterone and Obstructive sleep apnea

• Different studies show that there is a relation between Obstructive Sleep Apnea (OSA) and low level of testosterone in males. It was demonstrated that males with lower testosterone levels has lower sleep efficiency with increased nocturnal awakening.Barrett-Connor and Al¹ . In patients without OSA syndrome, Robert E. Sandblom and al.² show that administration of testosterone lead to apparition and exacerbation of OSA clinical symptoms, but we have to notice that this study was done only on one patient. So it is obvious that alteration of testosterone level have a correlation with OSA.

Physiological aspects associated with low level of testosterone

• Low level of testosterone is linked to other physiological aspects in men with OSA which can decrease its level. Those are hypoxia, fragmented sleep, obesity and ageing. Obesity is a main factor of obstructive sleep apnea; it is often the cause of the respiratory problem during sleeping. However, some patients with sleep apnea are not obese so obviously other factors are to be examined.

Mechanism decreasing testosterone level

• The first mechanism which would ling low level of total and free testosterone and OSA is that testosterone is known to stimulate fat lipolysis and inhibit the lipase lipoprotein. So it regulates fat metabolism and limit fat increase. By acting against obesity testosterone prevents OSA. Moreover, in obese male, testosterone decrease while fat amount increase because of decreased globulin bound hormone synthesis and altered aromatase system in peripheral tissue which are needed for testosterone synthesis and transport. The second point is that testosterone has a circadian rhythm that is affected by the Hypoxia in patients with OSA. The production is disrupted by the perturbation of sleeping phases. Drimel Molina F. et Al.³ That can explain why OSA associated to sexual dysfunction.Kirbas G. et al.⁴

GROWTH HORMONE

GH levels and obstructive sleep apnea relations:

• Growth hormone is produced during the first 90 minutes of sleep. During sleep, respiration is affected so the secretion of GH hormone is reduced continuously. In obese patients with obstructive sleep apnea the level of GH hormone was found similar as to those patients with simple obesity and without any disorder of sleep. Furthermore, studies showed that this hormone is also affected by hypoxia, the decreased level of the hormone then results in disorders of sleep. Moreover insulin is an inhibitor of GH synthesis and secretion. It can stimulate the function of GH. As you can see below, OSA is often associated with insulin deficiency, so this is one of the reasons why patients with OSA have decreased level of GH. Fabio et al.⁵

GH levels and replacement therapy:

• Although GH level is decreased the replacement of the hormone during the “replacement therapy” might worsen or trigger obstructive sleep apnea. It may also shift from obstructive apnea to central apnea and hypopnea. In some cases the opposite might happen. The reason is that it is related with the central nervous system and the upper airways so if you confer GH to the organism it can affect sleep and breathing. Pekeret Y. al.⁶

Effect of decreased GH level:

• GH has an effect on lipolysis so it can reduce the amount of fat in the neck so the seriousness of sleep apnea will decrease.Mahssa Karimi et al.⁷ GH hormone is also affected by IGF-I hormone (insulin like growth factor). The levels of IGF-I hormone are reduced in patients with OSA so the decreased level causes an insufficiency in GH level. Moreover it inhibits the production of GH and also the secretion. GIANOTTI L. et al.⁸

PROGESTERONE AND ESTROGEN

• During pregnancy changes in sleep are related with increased level of female reproductive hormones (estrogen and progesterone). The high levels of these hormones influence ventilation. Progesterone will result in hyperventilation. It leads to reduction of carbon dioxide pressure in the arteries and respiratory alkalosis and increased tidal volume. It is a respiratory stimulant especially during pregnancy when the body weight is increased. Also during normal menstrual cycle there is a rapid peak during the mid-luteal phase which is related to sleep difficulties. Fotis Kapsimalis. Et al.⁹ Menopause increases the risks of OSA as well. Estrogen increase sleep awakenings especially during the luteal phase when the estrogen level is low. Also estrogen can regulate the temperature of the body because is a thermoregulatory hormone. High temperature affected from low estrogen level and can lead to increase of awakening. Eichling P-S. et al.¹⁰

CORTISOL

• Cortisol release from adrenal cortex is facilitated by ACTH (adrenocorticotropic hormone) which the latter one is stimulated by CRH receptors. It is released by hypothalamic pituitary adrenal and it is a glucocorticoid product. Sleep disorders are related on a continuous release of cortisol[11]. Cortisol level is low during the night but with the onset of sleep the level starts to increase. Awakenings during sleep are associated with the increase of cortisol. However some studies showed that patients with obstructive sleep apnea who suffer from severe apnea may have different results from those patients who suffer from mild or moderate apnea.[12]

Other hormones

Leptin and Ghrelin hormones and OSA

General introduction

• Leptin is a hormone produced in adipocytes which play an important role in body composition, homeostasis and feeding behaviour in human being. Leptin levels are higher in obese patients. Changes in serum level or receptor-insensitivity lead to a progressive gain of weight. Ghrelin is a hormone recently discovered which influence appetite and metabolism. It stimulates hunger and food intake. Obesity is associated with decreased ghrelin level. Those two hormones are antagonists. Leptin is needed to reduce the weight, ghrelin induce weight increases.

Relation of those hormones with OSA

• Leptin levels in nonobese patients with OSAS where higher than nonobese control but leptin levels in obese patients with or without OSAS are the same. That means that obesity affect leptin level but OSA, not associated with obesity, also have an impact on those levels. Ghrelin levels are significantly higher in patients with OSA than in controls.

Continuous Positive Airway Pressure (CPAP) Treatment

• Continuous Positive Airway Pressure doesn’t have a great impact on leptin level. It decreases only marginally. That makes us believe that OSA only has a small impact on leptin level. In fact, even if leptin level is higher in nonobese patient with OSA than in those without OSA, this increased is still much lower than in obese patients with or without OSA. So the main determinant of leptin level is obesity, OSA contribute only to a small degree. In the case of increased ghrelin level in patients with OSAS, CPAP treatment quickly induces a decrease without any weight loss. With that treatment the ghrelin level get down to the level of obese patients without OSA. So ghrelin level has a strong link with OSA which is not only due to obesity associated with OSA. However, the mechanism which is responsible of the increase of ghrelin level in patients with OSA has not been studied yet. We can conclude that leptin levels are mainly regulated by obesity associated with OSA while Ghrelin levels shown direct consequences of OSA, independently of obesity. [13]

Effects of insulin on obstructive sleep apnea

General information:

• Insulin is a hormone produced by beta cells in the pancreas. Its role is to regulate carbohydrate and fat metabolism in the body. Insulin causes uptake glucose in liver, skeletal muscle and soft tissue cells. This glucose is stored in the tissues as glycogen and in adipocytes as triglycerides.

Relation between insulin and Obstructive Sleep apnea:

• In some studies performed to a variety of people it was shown that obstructive sleep apnea is independently associated with insulin resistance. In some other studies, it was shown that the obstructive sleep apnea syndrome is associated with conditions known to increase insulin resistance such as hypertension, obesity, and diabetes. There is a common point between sleep apnea, hypertension and cardiovascular disease, the insulin resistance syndromes, which can be hereditary or acquired defect .Sleep apnea has been recognized in cardiovascular morbidity and mortality so abnormalities in insulin resistance could play a role in obstructive sleep apnea syndrome or be an integral part in determining cardiovascular risk in patients with this syndrome. There are some specific factors which induce insulin resistance in Obstructive Sleep apnea patients, like obesity, sleep interaction.

How to treat Obstructive sleep apnea associated with insulin resistance:

• Together with an improvement of blood pressure and heart function due to Continuous Positive Airway Pressure therapy, the improvement in insulin sensitivity, clearly demonstrated in the different studies, show that it might be an important factor of OSA. The Continuous Positive Airway Pressure therapy contributes to a reduction of cardiovascular risk in patients with obstructive sleep apnea syndrome. [14]

Conclusion

• We can conclude that OSA is influenced by hormone like Testosterone and GH which, via fat lipolysis acting on obesity, factor which is strongly linked to OSA. Progesterone is a hormone which regulate directly the ventilation, so low level of it increase the risk of OSA. Leptin and Ghrelin, via their influence on the food intake and on weight, are associated with OSA via their impact on obesity.
• OSA is also the cause of hormonal deregulations. Every hormone which has a circadian rhythm of production will be affected such as testosterone, GH, Cortisol and insulin. Low Estrogen levels increase sleep awakening so it also influences production of circadian hormones.
• Insulin has also an indirect effect on OSA by acting on GH synthesis.

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• [10] Eichling P-S. et al. Menopause related sleep disorders. Journal of Clinical Sleep Medicine, Vol. 1, No. 3, 2005

• [11] Zuzana Lattova et al. The stress hormone system in various sleep disorders. Journal of Psychiatric Research 45:1223-1228. 2011

• [12] Lianne M. et al. Is obstructive sleep apnea associated with cortisol levels? A systematic review of the research evidence. Sleep Medicine Reviews 16:243-249. 2012

• [13] Kaparianos A. et Al.The metabolic aspects and hormonal derangements in Obstructive sleep apnoea syndrome and the role of CPAP therapy. European Review for Medical and Pharmacological Sciences. 10: 319-326. 2006

• [14] Kingam P.Strohl et Al. Diabetes and sleep apnea. Sleep 19(10):S225-s228. 1996.