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1. Introduction

Sleep-disordered breathing is a notable health concern. About one billion people aged 30-69 are estimated to suffer from sleep-disordered breathing worldwide (1). Another study revealed that the prevalence of sleep-disordered breathing was 24.0-83.8% in males and 9.0-76.6% in females (2). As sleep-wake disorders affect homeostasis and metabolic disturbances underlie the onset of sleep disorder, the impact of these clinical situations is notable. Differences in sleep duration and pattern between sexes are already known. Sex hormones including progesterone, androgens and estrogens are also related to respiratory disorders. In addition, men are more likely to have obstructive sleep apnea syndrome (OSAS), although women are more likely to develop it after menopause. According with a study, postmenopausal patients had a prevalence of sleep disturbed breathing that was 3-6 times higher than it was in premenopausal women (2). Women generally get better sleep than men (3). They have twice as many sleep spindles, deeper deep sleep and a slower age-related decrease in delta activity, a sign of deep sleep (4). Only 26% of women report excellent or very good quality sleep (5). Women aged 40-65 years are more likely to experience sleep problems (6). Between the ages of 20 and 70 years, 50% of females develop OSAS. A total of 20% of females exhibit moderate sleep apnea and 6% develop severe cases (7). Male rats undergoing intermittent and chronic hypoxia have altered testicular morphology and lose spermatogenic cells throughout the spermatogenic cycle (8).

Increasing evidence of clinically significant differences between the sexes and genders correlates with the rise in obesity and its associated comorbidities (1,3,9). Although most research shows the impact of sleep disorder on the cardiovascular system, the effect on sexual function and fertility have received less attention (10,11). Disturbed breathing during sleep leads to repeated hypoxemia, activation of the sympathetic nervous system and excessive daytime sleepiness. Of mechanisms that can underlie breathing-associated sleep-disorders, OSAS is the most common (12,13). OSAS is a heterogeneous disorder that includes anatomical compromise of upper airway patency, loss of tone of the pharyngeal dilator muscles and a reduced threshold for respiratory stimulus. Due to repeated interruptions of breathing during sleep, repeated episodes of hypoxemia and disturbances of normal sleep architecture appear such as decreased time in the deeper stages of sleep, poor sleep quality and microawakenings lasting up to several minutes (14). Consequently, sympathetic activation, cortical excitation, and circadian disturbance of hormonal secretions occur, generating cardiovascular disease and endocrine and reproductive disorder (15).

In patients with OSAS, a decrease in minute-ventilation during sleep, an increase in upper airway resistance and a decrease in the response of the respiratory centres to stimuli induced by hypoxia and hypercapnia are present (16,17). In response to respiratory changes during sleep, microtremors, erectile dysfunction or fertility disorders frequently emerge (18).

Large-scale epidemiological studies have estimated that ~4% of males and 2% of women suffer from OSAS (12,19). Additionally, it is estimated that 80-90% of OSAS cases remain undiagnosed (20).

Infertility is a notable issue for public health. According to the World Health Organization, infertility affects 48 million couples and 186 million individuals worldwide (21). To the best of our knowledge, the association between OSAS and infertility has rarely been studied (22,23). Infertility due to sleep-disordered breathing has been proposed to occur via direct mechanisms such as impaired spermatogenesis as well as indirect mechanisms, such as altered gonadal hormone secretion and decreased libido (22,23).

The present review aimed to describe the main mechanisms that alter the sex hormone homeostasis and fertility status in patients with OSAS and whether continuous positive airway pressure (CPAP) therapy can improve these.

2. OSAS pathogenesis

OSAS is characterized by repeated episodes of apnea and hypopnea with a frequency of at least five episodes/h, caused by partial or total obstruction of the pharynx. The pharynx is a duct that is kept open due to pharyngeal dilator muscle activity. Under normal conditions, when the tonus of the pharyngeal muscles decreases (as during sleep), there are no notable airflow changes. However, certain factors, including obesity and facial features (retrognathia, acromegaly, dental malocclusion, longer distance from the hyoid bone to the mandibular plane, relaxed pharyngeal soft tissue and large tongue base), may result in airflow disturbances due to increased upper airway resistance leading to severe apnea (24).

Following episodes of apnoea and hypopnoea, nocturnal hypoxemia is initially associated with impaired respiratory flow; when recovery capacity is exceeded on resumption of pulmonary ventilation, continuous hypoxia occurs due to carbon dioxide retention (25). In addition, at the end of apnea hypopnea episodes, due to increased respiratory effort, microtremors appear, which may produce a transition from sleep to wakefulness, with stage N1 increase and stage N3 and rapid eye movement (REM) decrease (26). Chronic nocturnal hypoxemia stimulates both hematopoiesis, causing polyglobulia and increased blood vascularity, and the gonadal glands, increasing hormone synthesis (27).

OSAS during infancy has been shown to influence normal growth and development by impairing the secretion of growth hormone (28). Data showing increased cortisol and adrenocorticotropic hormone levels associated with sleep-wake cycle disruption reflect the effort to maintain wakefulness (29,30). It is unclear whether apnea control via CPAP treatment normalizes testosterone levels. Testosterone therapy in patients with OSAS may generate notable adverse effects like increased cardiovascular morbidity, increase serum prostate-specific antigen levels, erythrocytosis. Thus, it should not be introduced without careful consideration (31). To the best of our knowledge, there is limited analysis of the impact of OSAS on female gonadal function (32-34).

The association between CPAP therapy and estrogen levels may depend on several factors (Fig. 1). Effective CPAP treatment can reduce hormonal problems related to OSAS, menstrual irregularities and PCOS risk, potentially increasing fertility and alleviating menopausal symptoms by enhancing sleep quality and managing weight problems (32).

Figure 1 Effects of CPAP therapy on estrogen levels. CPAP therapy can improve sleep quality and potentially contribute to weight loss, which may increase estrogen levels. Patients with untreated OSAS may experience menstrual irregularities due to sleep disturbances and hormonal imbalances. Effective CPAP treatment can alleviate these symptoms and normalize menstrual patterns. Patients with OSAS may have a higher risk of developing conditions such as PCOS, which can decrease the estrogen levels. CPAP therapy may manage OSAS and mitigate the risk of PCOS-related hormonal disruption. CPAP therapy can improve fertility by addressing sleep-associated issues that may affect hormone production and reproductive health. CPAP therapy can improve sleep quality and decrease the severity of the menopausal symptoms, such as hot flushes and night sweats. CPAP-, continuous positive airway pressure; PCOS-, polycystic ovary syndrome.

3. Hypothalamic-pituitary-gonadal axis

Gonadal function is controlled by gonadotropins secreted by the anterior pituitary, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In turn, the pituitary gonadotropins controlled by gonadotropin-releasing hormone (GnRH) released by the median eminence of the hypothalamus into fenestrated capillaries of portal circulation and carried to the anterior pituitary (35). The ovarian follicle granulosa cells are stimulated by FSH to release aromatase, which converts androgens produced by thecal cells into estradiol (E2). FSH stimulates ovarian follicles to grow and mature; in combination with intratesticular testosterone, it supports spermatogenesis. LH stimulates ovulation and corpus luteum development and controls the androgen synthesis by the Leydig cells. The loss of negative estrogen feedback to the hypothalamus and pituitary gland due to androgens leads to increased FSH and LH levels (36,37). Depending on the serum values of gonadotropin and sex steroids, it is possible to differentiate between gonadal or hypothalamic/pituitary reproductive deficiency. Gonadal dysfunction is characterized by elevated FSH levels and reduced sex steroid levels, indicating primary dysfunction of the ovaries or testes. Hypothalamic/pituitary dysfunction is marked by low FSH and LH levels with decreased or normal sex steroid levels, signaling a problem in the regulatory signals from the brain to the gonads (38).

4. OSAS and gonads

There are strong interrelationships between sex hormones and the respiratory function (39) however it is not clear which hormone serves a crucial role. Androgens, progesterone and E2 act directly through receptors in the nervous system. Sleep-disordered breathing, such as OSAS, can alter the hormonal homeostasis. The mechanisms may be different between sexes, as there are differences in terms of prevalent hormones and breathing control due to differences in lung size, hormonal fluctuations and body composition (40).

Numerous studies have shown a negative association between changes in sleep duration or architecture and the gonadal axis (41,42). There is a complex association between testosterone secretion, OSAS severity and obesity. Obesity is the leading cause of OSAS and low testosterone levels have been associated with increased body mass index (BMI) (43). Conversely, low testosterone levels facilitate weight gain. Certain authors have attributed the severity of OSAS to decreased testosterone concentration (44,45). Although most studies have investigated male subjects, similar effects have been observed in other sexes, with patients being more affected after than before menopause (1,2).

A study found that testosterone levels decrease with the increase in OSAS severity and are lower compared with those in control subjects (45). In another study that included obese men with associated metabolic syndrome and OSAS, the control group comprising male patients with similar clinical characteristics but without OSAS revealed that oxygen desaturation index correlated negatively with total and free testosterone levels (44). Therefore, hypoxia exerts independent effects on the pituitary-gonadal axis. A study comparing patients with OSAS with severe oxygen desaturation and those with less severe desaturation found a significant correlation between peak testosterone levels and total desaturation time, suggesting that hypoxia affects the circadian rhythm of testosterone (46). Similar findings were demonstrated in a study that compared testosterone levels with oxygen saturation of arterial blood (44). Loss of sleep quality, as assessed by altered normal sleep stage architecture, is also associated with reduced serum testosterone (47) and LH-testosterone profile (48). Although with advanced age there is a notable risk of developing sleep disorders, Luboshitzky et al (48) demonstrated that hypogonadism in patients with OSAS is age-independent.

Subnormal morning LH levels have been observed in 16 men with OSAS in whom testosterone levels were normal (49). Decreased LH and testosterone levels and their notable association with the Respiratory Disturbance Index suggest that pituitary-gonadal dysfunction is a consequence of OSAS rather than a primary independent disorder of the hypothalamic-pituitary-gonadal axis (48).

Gonadal hormones receptors are present in various types of tissues, including the lungs. The gonadal hormones have been found in epithelial cells that line the airways and alveoli of the lungs and can influence airway responsiveness and mucociliary clearance (50-52). Estrogen has been shown to affect the production of mucus in the airways and contributes to symptoms in conditions such as asthma and chronic obstructive pulmonary disease (53).

Activation of gonadal hormone receptors on smooth muscle cells can affect airway tone and reactivity, potentially contributing to bronchoconstriction or airway hyperresponsiveness. Gonadal hormone receptors on endothelial cell influence vascular function, including vasodilation, which may affect blood flow and oxygen exchange in the lung. Some immune cells within lung tissue, such as macrophages and lymphocytes, also express these receptors and modulate immune response in the lungs and may affect inflammation and immune cell function in respiratory disease.

The literature has revealed potential sites of gonadal hormone receptors in the lungs (Table I) (50-58). Research on gonadal hormones receptors in the lungs and their specific functions is ongoing.

Table I Potential sites of gonadal hormone receptors in the lung.

Table I

Potential sites of gonadal hormone receptors in the lung.

Cell type	Gonadal hormone receptor	First author, year	(Refs.)
Epithelial	ERa, AR, PR	Tam et al, 2014; vom Steeg, 2020; Jain, 2012	(50-52)
Smooth muscle	ER, AR, PR	Bhallamudi, 2020; Kalidhindi, 2019; Matsui, 2000	(54-56)
Endothelial	ER	Bhallamudi, 2020	(54)
Immune	PR, ER, AR	vom Steeg, 2020; Azeez, 2021; Kovats, 2015	(51,57,58)

[i] ER, estrogen receptor; AR, androgen receptor; PR, progesterone receptor.

Progesterone

Progesterone may help prevent premenopausal apnea (59). The bronchodilator effect of progesterone is caused by changes in smooth muscle tone of the airways (60). Progesterones, such as E2, prevent endothelial dysfunction and have a strong vasodilatory effect on the pulmonary circulation (61,62). Progesterone correlates with peak expiratory flow rate in humans during the luteal phase of the menstrual cycle (63). In classic interstitial pneumonia, progesterone receptors are expressed in the fibrotic regions (64). In the lung, progesterone results in upregulated IL-10, IL-1β, IL-5, IL-6, IL-22, tumor necrosis factor (TNF)-α, IL-4, steroid receptor coactivator/cyclin-dependent kinase inhibitor 1A, Erk, IL-9 and IL-13 as well downregulated or inhibited NF-κB, TGF-β1, connective tissue growth factor, transgelin, plasminogen activator inhibitor-1 and IFN-γ (65,66).

Progesterone is associated with hyperventilation during pregnancy. Animal studies have shown that lack of progesterone receptor correlates with loss of responsiveness to hypoxia, suggesting a beneficial role of progesterone on the airways (67,68,69).

Mouse responses to hypoxia and hypercapnia are suppressed after receiving small interfering RNA (siRNA) against membrane progesterone receptor-β but not receptor-αin the dorsal brainstem. Furthermore, the number of apnea episodes increases. The same study also revealed that membrane progesterone receptor β in the dorsal brainstem establishes sex-specific chemoreflex responses and reduces apnea frequency in adult mice, with females showing a higher ventilatory response to hypoxia and hypercapnia than males. Effects are eradicated by membrane progesterone receptor-β siRNA but not α (70).

Sleep duration can influence human reproduction by affecting hormonal regulation, menstrual regularity, fertility, stress levels and sexual function, all of which serve a role in reproductive health (32).

Some studies contend that the effect of progesterone on breathing is mediated by cells in the hypothalamus that contain progesterone receptors, either by modulating release of neuromodulators such as serotonin or by binding to and altering the function of γ-aminobutyric acid receptors (40,71,72).

Testosterone

Testosterone serves a protective role in the lung because it relaxes the bronchial lumen and decreases histamine response and airway inflammation (73-75). Furthermore, testosterone causes up-[IL-2, IFN-γ, haemoglobin subunit (Hbb)-β1, Hbb-γ and Hbb-θ1] and downregulation (IL-33, thymic stromal lymphopoietin, IL-4, IL-5, IL-13, angiopoietin-like 4 and cytochrome P450, family 1, subfamily A, polypeptide 1) of cytokines and inflammatory mediators in the lung (76-79).

A study suggested that the influence of testosterone on respiratory function is mediated by the action of estrogens (80). However, testosterone secretion is dependent on sleep cycle; its serum concentration increases during REM sleep. In addition, sleep of short duration (3 h) but with normal architecture is sufficient for normal levels of testosterone secretion (81). However, changes in serum testosterone levels have been demonstrated in sleep disorders in both animal models and human studies (82,83). A study of male rats found that sleep deprivation is followed by a reduction in serum testosterone levels and sperm quality compared with controls (82). Testosterone and prolactin levels are significantly lower in sleep-deficient individuals (83).

Although shorter sleep duration does not appear to alter testosterone levels, studies have shown that sleep duration of 5 h/night is associated with a 10-15% decrease in blood testosterone, decreased libido and vigour scores (assessed by measuring vitality, energy and general physical and mental well-being) (84,85).

In healthy young men, in the first part of sleep, dominated by periods of REM sleep, there is an increase in testosterone secretion (86). Sleep disturbance leads to decreased daily testosterone secretion (87). Following testosterone therapy, ventilatory sensitivity to carbon dioxide during sleep and wakefulness is enhanced in female patients (88).

Estrogen

The effect of estrogen on lung disease is not fully known. In the lung, estrogens induce cytokine and inflammatory mediator up-(IL-1β, IL-6, type I-IFN, TNF-α, NF-κB and toll-like receptor 8) and downregulation (TGF-β1 and IL-10) (58,89,90). The increased activity of thioredoxin, activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and p38 mitogen-activated protein (p38 MAP) kinases, inhibition of vagal C-fibers and decrease expression of hypoxia-inducible factor (HIF)-1 have been linked to the positive effects of estrogen and phytoestrogens on obstructive sleep apnea and associated co-morbidities by decreasing OSAS severity, improving sleep quality, and mitigating hormonal and cardiovascular factors (91). The activation of p38 MAP kinase by estrogen may suppress HIF-1 to decrease lung inflammation, which may inhibit activation of vagal C-fibers to decrease bronchoconstriction to avoid obstruction when sleeping. In addition, estrogen-mediated thioredoxin and Nrf-2 upregulation enhances antioxidant defense and decreases inflammation (91). Another study reveals that the estrogen-related receptor-α/slow myosin heavy chain transcriptional regulatory cascade is a key factor in E2-mediated muscle protection, suggesting a potential novel therapeutic target for the treatment of postmenopausal OSAS (92).

OSAS is significantly more prevalent during and after the menopause. Decreased E2 may be associated with increased risk of OSAS in hormonally depressed patients during the peri- and postmenopause, in addition to greater BMI and age, supporting the hypothesis that decreased E2 associated with menopause affects upper airway patency (93). Patients are more likely to develop OSAS during pregnancy, polycystic ovary syndrome, during late menopause and post-menopause (94). There is an inverse link between E2 and OSAS based on reports that postmenopausal patients receiving hormone replacement therapy (HRT; estrogen or estrogen + progesterone) have a lower prevalence of OSAS than those without (32,91,92). Consequently, estrogen may provide protection during OSAS pathogenesis, but it is unclear if estrogen causes OSAS (93).

A previous study suggested that patients with an apnea-hypopnea index ≥25 require CPAP because they do not respond to HRT. HRT may be a good option for patients with less severe OSAS (94,95).

5. Fertility and OSAS

HIF-dependent and -independent pathways are two distinct mechanisms that can explain hypoxic effects on endocrine cells (96). Variations in protein phosphorylation and global transcription/translation efficiency are the key regulators of the HIF-independent process. Long-term control of the HIF-dependent pathway is triggered when HIF changes the expression of target genes.

As an effect of hypoxia, protein phosphorylation may change HIF activity (Fig. 2). Thus, protein phosphorylation serves an important role in mediating the activity of HIFs by regulating their stability, nuclear translocation and interaction with coactivators. This allows cells to adapt to hypoxic conditions by adjusting expression of specific genes involved in oxygen homeostasis and cell survival (e.g. erythropoietin, vascular endothelial growth factor, glucose transporter 1) (97,98).

Figure 2 HIF pathway in chronic hypoxia. HIFs are heterodimeric proteins composed of α (HIF-1α, HIF-2α or HIF-3α) and β subunits. Under normoxic conditions, HIF-α subunits are rapidly degraded by the proteasome. However, under hypoxic conditions, PHDs that target HIF-α for degradation become less active due to decreased oxygen availability. This leads to the stabilization of HIF-α subunits. Once stabilized, HIF-α subunits translocate into the cell nucleus, where they form a complex with HIF-1β. This complex is required to form either transcription factor HIF-1 or HIF-2. Phosphorylation of HIF-α subunits enhances their interaction with coactivator proteins, such as p300/CBP and CITED2. These coactivators recruit RNA polymerase and other transcriptional machinery to the target genes, promoting gene expression. Phosphorylation regulates the stability of HIF-α subunits. Phosphorylation of HIF-α subunits occurs as a result of signaling pathways activated by growth factors, cytokines or other stimuli. Phosphorylation modulates HIF activity in response to cellular signals. DNA sequences influence HREs by containing specific binding sites that allow HIF proteins to attach to them, regulating the expression of target genes under hypoxic conditions. HIF, hypoxia-inducible factor; PHD, prolyl hydroxylases; p300-a transcriptional coactivator; CBP CREB-binding protein; CITED2p300, CBP-interacting transactivator with Glu/Asp-rich C-terminal domain 2; HRE, hypoxia response element.

The association between hypoxia caused by lung disease, such as chronic obstructive pulmonary disease, and decreased serum testosterone in men has been described (99,100). It has also been shown that erectile dysfunction is frequently present in these patients (99). Other factors that may contribute to infertility include increased oxidative stress, insulin resistance, systemic inflammation and aberrant secretion of reproductive hormones (100).

Sexual dysfunction has been reported in people with from sleep disorders and is a pathology of interest (101).

Oxidative stress is considered the link between OSAS and infertility. Increased oxidative stress may be an etiological factor for decreased sperm fertility and studies on mice and human male subjects have revealed that intermittent hypoxia correlates with increased testicular oxidative stress and decreased sperm motility (102,103). Chronic inflammation is associated with impairments in spermatogenesis, sperm quality and, consequently, fertility (104). In chronic inflammation, IL-6, TNF and C-reactive protein are the primary markers increased in patients with OSAS but are decreased by CPAP (105).

The risk of infertility is significantly increased with duration of OSAS. In addition, patients with untreated OSAS have an increased risk of infertility (22).

6. CPAP therapy

CPAP therapy has not been unequivocally shown to normalize the pituitary-gonadal axis in male patients (36,37,48). Studies published so far show controversial effects, as is the case with testosterone therapy (31,88). Although studies have shown that CPAP therapy contributes to increased testosterone levels, meta-analyses have not confirmed significant changes in this hormone after initiation of therapy (106-109). Conflicting results may be generated by suboptimal studies or therapeutic methodologies, such as insufficient duration of CPAP therapy (Table II).

Table II Effect of continuous positive airway pressure therapy on plasma testosterone in patients with obstructive sleep apnea syndrome.

Table II

Effect of continuous positive airway pressure therapy on plasma testosterone in patients with obstructive sleep apnea syndrome.

First author, year	Number of patients	Duration of study, months	Timing of measurement	Testosterone levels	(Refs.)
Meston et al, 2003	101	1	Mid-morning	Decreased	(109)
Zhang et al, 2016	207	3	Morning	No change	(107)
Celec et al, 2014	67	6	Morning	No change	(33)

The independent effect of OSAS on blood testosterone concentration has been demonstrated in certain studies (44,110-114) but not in all cross-sectional studies (33,47).

Following 3 months of CPAP treatment, serum testosterone concentration is normalized (115,116). CPAP therapy (long- or short-term) does not affect hormonal status in female patients (117). Compared with female patients, higher long-term CPAP is required for male patients with minimally symptomatic OSAS (118).

Serum levels of FSH, LH, progesterone and testosterone are significantly lower in 153 patients with OSAS patients than in controls (8). CPAP therapy has no effect on prolactin, E2 and progesterone levels and increases serum levels of FSH, LH and testosterone (119). The hypothalamic-pituitary-gonadal axis is primarily influenced by nocturnal hypoxemia and sleep disturbances in OSAS, which lowers blood levels of sex hormones. The decrease in testosterone is likely caused by a decrease in Leydig cell population, according to a study on brown Norway rats (120). Long-term exposure to hypoxia can lead to low sperm count and infertility as testosterone is a key paracrine factor for spermatogenesis (121).

Weight loss may be a key factor in reversing gonadal dysfunction; massive weight loss (20% weight loss) normalizes testosterone levels (34,48,122).

7. Discussion

According to studies, sleep-disordered breathing is underdiagnosed and may underlie several multisystem disorders (6,12,13,19). Hypoxia, frequent nighttime awakening and stress influence hormonal secretion, which affects physical and cognitive development, obesity and infertility, which pose public health problems (92,100,102,103).

Studies have reported associations between sexual dysfunction, hormonal disorder and severity of apnea-hypopnea index (123,124). These studies have shown lower levels of progesterone and estrogen in patients with OSAS associated with development of sexual disorder. OSAS can have a negative impact on sexual function, either through direct effects or by causing hormonal imbalances (95,125).

Although most studies (43-46) have reported an association between sleep disorders and plasma testosterone levels, estrogens and progesterone impact on upper airway stability and respiratory control during the menstrual cycle. These hormones have been characterized as protective and are hypothesized to results in lower rates of OSAS in female patients. Levels of progesterone, E2 and 17-OH progesterone are lower in female patients with OSAS (123). In addition, previous polysomnographic investigations have shown that, regardless of body weight, OSAS is more common and severe in postmenopausal compared with premenopausal patients (2,124).

Breathing disorders during sleep affect secretion of gonadal hormones through various mechanisms (32-34). Sleep apnea often leads to disrupted sleep patterns characterized by repeated awakening due to breathing interruptions (14,41,42). These awakenings affect the normal circadian rhythm of gonadal hormone secretion (123). Prolactin secretion typically follows a diurnal pattern, with higher levels during the night and lower levels during the day. Sleep disruption can alter this pattern, leading to irregular prolactin secretion (123). These interruptions affect the normal circadian rhythm of hormone secretion, including progesterone (9). Progesterone levels typically vary throughout the menstrual cycle and are influenced by sleep quality and duration. Sleep apnea can be a source of chronic stress for the body, as it continually activates the stress response system, including the release of stress hormones such as cortisol (29,30). Elevated stress hormones can decrease the secretion of gonadal hormones. Prolonged stress leads to changes in the balance of gonadal hormones (32). Sleep apnea is characterized by episodes of hypoxia during breathing interruptions. Hypoxia can affect the function of the hypothalamus and pituitary gland, which are involved in regulating gonadal hormone secretion and changes in ovarian function (36,37). Thus, hypoxia can lead to dysregulation of hormone secretion pathways, potentially altering hormones levels. Sleep apnea is often associated with obesity and metabolic changes, such as insulin resistance (100). These factors contribute to alterations in gonadal hormone regulation. Sleep apnea leads to increased activity of the sympathetic nervous system (12). This heightened sympathetic activity influences hormone secretion, including prolactin. The exact mechanisms by which sympathetic activation affects prolactin are complex and not fully understood (12).

CPAP therapy is currently the gold standard of treatment for patients with sleep apnoea syndrome (13). Although this therapy allows effective control of breathing during sleep, a notable number of patients stop using it or use it inconsistently 12 months after initiation (118). Studies on the effect of CPAP therapy suggest that conflicting results may also be due to suboptimal studies or therapeutic methodologies, such as insufficient duration of CPAP therapy (36,37,107,118). On the other hand, although respiratory events are resolved by CPAP treatment, obesity may be an important risk factor for hypogonadism (38,48).

To the best of our knowledge, there is relatively limited data on the link between hypoxia induced by sleep-disordered breathing and gonadal hormonal imbalance (99,100,121). Moreover, data are often inconsistent, potentially due to the presence of factors such as obesity, stress and the long time required for the onset of sleep-disordered breathing disease. Social factors including obesity, socio-economic disparities, lifestyle choices, environmental conditions, urban noise pollution and sleep schedules influenced by workplace demands may also contribute to sleep-disordered breathing.

CPAP therapy does not have a clear positive impact on restoring gonadal hormonal balance (107). Long-term therapy may be more likely to normalize gonadal function, but, to the best of our knowledge, long-term studies have not been performed.

Although there is an association between sleep-disordered breathing and gonadal dysfunction via direct effects of hypoxia and hypothalamic-pituitary-gonadal axis dysfunction, CPAP therapy does not normalize this dysfunction (36,37). Patients suffering from sleep-disordered breathing diseases might experience a prolonged period before their serum gonadal hormone levels return to normal due to these dysfunctions (32). Hormonal dysfunctions secondary to sleep apnea syndrome affect quality of life and hormonal homeostasis.

Acknowledgements

The authors would like to thank Professor Florin Pinzariu (George Enescu National University of Arts, Iasi, Romania) for constructing figures.

Funding

Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

CC and EC conceptualized the study. CC, EC, LP, CP and SDR designed the methodology and wrote the manuscript. CC, EC, LP, CP and SDR performed the literature review. SDR constructed tables. LP and CP edited the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References