Definition
Abstract obstructive sleep apnoea syndrome (OSAS) is a common disorder characterized by repetitive episodes of complete (apnoea) or partial (hypopnoea) obstruction of airflow during sleep. So, during an attack, the diaphragm and chest muscles have to work harder to open the obstructed airway and pull air into the lungs. Breathing usually resumes with a loud gasp, snort, or body jerk. The severity of OSAS is defined by the apnoea hypopnoea index (AHI) or number of obstructive episodes during sleep. People whose apnoea index is between 5–15 is considered as mild, 16–30 as moderate and those over 30 is considered as severe sleep apnoea syndrome. Obstructive sleep apnoea is one of the sleep disorders which affect the patients’ quality of life.
Symptoms
Obstructive sleep apnoea syndrome (OSAS) is associated with a variety of health-related consequences. The cardiovascular effects of obstructive sleep apnoea, for example, have been found to be very significant: systemic hypertension, stroke, cardiac arhythmias and atherosclerosis are often associated to OSA. Studies showed high co-morbidities of sleep apnoea/hypopnoea syndrome and chronic fatigue syndrome, neuropsychologic deficits includ¬ing decreased concentration, sleepiness, memory loss, irritability, moodiness and depression. However, more subtle but equally important, effects on the individual’s overall enjoyment and happiness with life have been investigated as well.
A significant impact on overall quality of life, has often been observed in large studies where OSAS was associated to sexual dysfunctions, including low testosterone (T) levels (normal, 280 to 1,250 ng/dL), loss of libido, erectile dysfunction (ED) and infertility.
(Defining association between sleep apnea syndrome and erectile dysfunction. 2006) http://www.ncbi.nlm.nih.gov/pubmed/16698364
Pathogenesis
It has been suggested that OSA can cause an increase in the level of prolactin (normal, less than 13 ng/mL) related with stress due to hypoxia and increase of prolactin (PRL) may also cause inhibition of Gonadotropin-Releasing Hormone and secondarily hypogonadism (also termed hypogonadotropic hypogonadism or secondary hypodonadism). The hypothalamus secretes GnRH and provides LH and FSH secretion from the anterior pituitary gland. FSH induces spermatogenesis at seminiferous tubules in the testes of men and LH stimulates the secretion of testosterone from interstitial Leydig cells. With the deficit at the hypothalamus and/or pituitary, FSH and LH are, thus, secreted at reduced levels, which also lead to decreased stimulation of Leydig cells. The resulting decrease T levels in serum is believed to be the cause of loss of libido and the erectile dysfunction. Men who have hyperprolactinemia have a high incidence of sexual dysfunction, and the erectile dysfunction appears more likely to resolve in patients with the most severe hyperprolactinemia once this glandular disorder is corrected.
Many studies (Quality of sexual life in men with obstructive sleep apnoea.2012 Mar 14) http://www.ncbi.nlm.nih.gov/pubmed/22419417 investigated the quality of sexual life of male obstructive sleep apnoea patients. Apnoea and non-apnoea participants were assessed with Golombok Rust Inventory of Sexual Satisfaction (GRISS) and Structured Clinical Interview for DSM-IV (SCID) before the sleep test. Folicule Stimulating Hormone (FSH), Luteinising Hormone (LH), prolactin and testosterone levels were evaluated. The apnoea group had a lower LH and testosterone levels than the non-apnoea group. Although there was a change in the hormonal levels of obstructive sleep apnoea patients, there were no differences in terms of sexual satisfaction in apnoea patients and non-apnoea group. Another research (Decreased pituitary-gonadal secretion in men with obstructive sleep apnea.2002 Jul8) http://www.ncbi.nlm.nih.gov/pubmed/12107256 reported a decreased libido in male patients with OSA. Serum LH and testosterone levels were determined every 20 min between 2200-0700 h with simultaneous sleep recordings in 10 men with sleep apnoea and in 5 normal men. LH and testosterone were significantly lower in OSA patients compared with controls. Four of 10 patients had hypogonadal morning (0700 h) serum testosterone levels. Analysis of covariance revealed that the 2 groups differed significantly in the amount of LH and testosterone secreted at night independent of age or degree of obesity. Findings suggest that OSA in men is associated with dysfunction of the pituitary-gonadal axis.
The relation between LH-testosterone profiles and the severity of OSA suggests that sleep fragmentation (1) in addition to hypoxia (2) and catecholamine secretion (3) may be responsible for hyperprolactinemia.
(1) Prolactin is a polypeptide hormone that is secreted by the lactotroph cells of the anterior pituitary gland. Plasma prolactin concentration exhibits a sleep-dependent pattern, with highest levels during sleep and lowest levels during the waking period. Normal basal levels of serum prolactin are approximately 20-40 ng/ml in women, depending on the phase of their menstrual cycle, and 15ng/ml in men. Recent studies in the human suggest the hypothesis that endogenous sleep prolactin’s rhythm can be influenced by endogenous melatonin’s secretion (Influence of Melatonin on the Sleep-Independent Component of Prolactin Secretion) http://onlinelibrary.wiley.com/doi/10.1111/j.1600-079X.1990.tb00669.x/abstract .The syndrome of obstructive sleep apnoea could affect the sleep-entrained PRL rhythm. Treatment with nasal continuous positive airway pressure (CPAP) restores a normal sleep structure by successful abolition of the apnoeas and improves sleep quality. The effects of CPAP have been reported in other studies too (Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP) http://www.ncbi.nlm.nih.gov/pubmed/17537771 .Plasma melatonin levels were investigated in patients with obstructive sleep apnoea syndrome (OSAS). Melatonin levels were determined at 23:00 h (light period), at 02:00 h (dark period) and at 06:00 h (light period) in patients and control subjects. The control subjects showed a nocturnal melatonin peak value at 02:00 h. However, this nocturnal melatonin peak was absent in the OSAS patients. The highest melatonin value was found in OSAS patients on the night of diagnosis, at 06:00 h. It was found that the melatonin level in OSAS patients at 06:00 h was significantly lower in the night of titration with CPAP than in the diagnosis night. The abnormal melatonin secretion pattern and the absence of a nocturnal serum melatonin peak could be partially related to the difficulty that these patients have in achieving a normal sleep–wakefulness pattern.
(2) Hypoxia and the resultant hypoxemia are characteristic pattern of OSAS. One study (CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary) http://www.researchgate.net/publication/7661977 CRH receptor type 1 mediates continual hypoxia induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary reported that continual hypoxia-induced changes of prolactin mRNA expression in rat pituitary through the corticotropin-releasing hormone receptor 1 (CRHR1). Different situations of acute hypoxia (AH), continual hypoxia (CH), intermittent hypoxia (IH), stimulate prolactin release from the pituitary. This study investigates the involvement of the corticotropin-releasing hormone receptor 1 (CRHR1) in the hypoxia-induced PRL response. Hypoxia was induced by exposing the rats to high altitudes of 2 km (16.0% O2) or 5 km (10.8% O2). The data suggest that both CH and IH can stimulate rat PRL release in a time-course- and intensity-dependent manner. CRHR1 mediates PRL secretion and PRL mRNA expression in the pituitary under hypoxic exposure. Moreover corticotropin-releasing hormone (CRH) has-been implicated as a mediator of stress-induced effects on the reproductive axis (The CRH-R₁ receptor mediates luteinizing hormone, prolactin, corticosterone and progesterone secretion induced by restraint stress in estrogen-primed rats 2011 Nov). http://www.ncbi.nlm.nih.gov/pubmed/21959177
Another study (Activation of Type 1 CRH Receptor Isoforms Induces Serotonin Release from Human Carcinoid BON-1N Cells: An Enterochromaffin Cell Model) http://www.ncbi.nlm.nih.gov/pubmed/21123435 focused on the relationship between CRHR1 and serotonin (5HT). Both are expressed in human colonic enterochromaffin (EC) cell and their interaction was investigated in a human carcinoid cloned BON cell line (BON-1N).The expression of CRH1i was also confirmed in human brain cortex, pituitary gland, and ileum. Immunocytochemistry and immunoblot analysis confirmed that BON-1N cells were CRH1 and 5-HT positive. Findings define the expression of EC cell-specific CRH1 isoforms and activation of CRH1-dependent pathways leading to 5-HT release and synthesis (5-HT is a important promoter for PRL secretion); thus, providing functional evidence of a link exists between CRH and 5-HT systems, which have implications in stress-induced CRH1. At last, a recent study (8-Isoprostane, a Marker of Oxidative Stress, Is Increased in Exhaled Breath Condensate of Patients With Obstructive Sleep Apnea After Night and Is Reduced by Continuous Positive Airway Pressure Therapy) http://chestjournal.chestpubs.org/content/124/4/1386.full reported the important role of 8-isoprostane as marker of oxidative stress in patients with OSAS, situation that may compromise oxidative balance. Study’s aim was to investigate whether oxidative stress is determined by nocturnal apnoeas and could be reduced by CPAP therapy, and whether there is a relation between local and systemic oxidative stress in these patients. A positive correlation was found between morning exhaled 8-isoprostane levels and the apnoea-hypopnoea index and 8-isoprostane levels and neck circumference. Findings suggest that systemic and local oxidative stress are increased in OSA patients, and that they are higher after nocturnal apnoea and reduced by CPAP therapy (Infertility and obstructive sleep apnoea: the effect of continuous positive airway pressure therapy on serum prolactin levels. 2010) http://www.springerlink.com/content/0174k11h06201268
(The isoprostanes are a family of eicosanoids of non-enzymatic origin produced by the random oxidation of tissue phospholipids by oxygen radicals. Isoprostanes appear as artifacts in tissue and plasma samples which have undergone oxidative degradation during prolonged or improper storage. They also appear in the plasma and urine under normal conditions and are elevated by oxidative stress. The 8-isoprostane (8-epi PGF2α), has been shown to have biological activity. It is a potent pulmonary and renal vasoconstrictor and has been implicated as a causative mediator of hepatorenal syndrome and pulmonary oxygen toxicity. The 8-Isoprostane has been proposed as a marker of antioxidant deficiency and oxidative stress and elevated levels have been found in heavy smokers. Plasma from healthy volunteers contains modest amounts of 8-isoprostane (40-100 pg/ml) that increase with the age of the test subject).
(3) Different models (Effects of Intermittent Hypoxia on Blood Gases Plasma Catecholamine and Blood Pressure) http://www.ncbi.nlm.nih.gov/pubmed/19536495 of intermittent hypoxia (IH) of moderately high intensity (30 episodes/h) have been used to evaluate arterial blood gases and plasma catecholamines as main effectors in determining arterial blood pressure. Male rats were exposed to IH with a regime of 80s, 20% O2 // 40s, 10%O2, 8 h/day, 8 or 15 days. Plasma epinephrine (E) and norepinephrine levels showed a tendency to increase, being significant the increase of norepinephrine (NE) levels in the group exposed to intermittent hypoxia during 15 days. The conclusion that IH causes an increase in sympathetic activity and a concomitant increase in NE levels which in turn would generate an increase in vascular tone and arterial blood pressure.
Main Points
• Patients with apnoea sleep syndrome (OSAS) present high prolactin serum levels
• The excess of prolactin induces hyperprolatictinemia and it is due to many factors such as oxidative stress, catecholamine secretion, hypoxemia (secondarily to hypoxia) and sleep fragmentation
• Hyperprolactinemia induces hypogonadism, interfering with secretion of gonadotropin-releasing hormone, resulting in decreased testosterone levels and sexual dysfunctions.
Therapy
Treatment with nasal continuous positive airway pressure (CPAP) has been reported to be valuable (Pituitary-gonadal function in men with obstructive sleep apnea. The effect of continuous positive airways pressure treatment. 2003 Dec) http://www.ncbi.nlm.nih.gov/pubmed/15073577 .Measurement of the nocturnal serum LH and T levels were done before and after nine months of CPAP treatment in five men with OSA. Patients were evaluated during nocturnal sleep at base line and during CPAP treatment. Serum LH and testosterone levels were determined at 20 minutes interval between 1900h and 0700h with concomitant determination of sleep quality, respiration and oxygen saturation: conclusions were that testosterone and LH increased using CPAP.
Other mechanisms to overcome hyperprolactinemia consist in the use of dopamine. Dopamine from higher brain centers stimulates release of prolactin inhibitory factor (PIF). This forms the basis of medical treatment for hyperprolactinemia: dopamine agonists, such as bromocriptine, exert their antiprolactinemic effects by inhibiting the secretion of prolactin by the pituitary cells, which normally secrete prolactin. In hyperprolactinemia induced by exogenous medications, once the suspect medication is stopped, the prolactin and serum T levels and the erectile function (if the impotence is caused by elevated prolactin levels) usually return to normal.
There is now evidence to suggest that treating OSAS may be an effective treatment for ED. It is the opinion of most different studies’ author that patients with erectile dysfunction would benefit from a sleep evaluation.
