Novel and Emerging Strategies
Estrogen and progesterone. Interaction between sleep apnea and steroid hormones may partially explain the gender discrepancy in sleep apnea incidence. Female reproductive hormones appear to be protective against sleep apnea (Dursunoglu 2009; Tasali 2008). Postmenopausal women and women with polycystic ovary syndrome, two conditions marked by low estrogen and progesterone levels, are much more likely to have sleep apnea than healthy women in their reproductive years (Ehrmann 2012; Valipour 2012; Tamanna 2013). Also, women with sleep apnea have been found to have lower levels of estrogen and progesterone than women without sleep apnea (Netzer 2003).
Researchers have examined the role of estrogen and progesterone therapy in the treatment of sleep apnea in postmenopausal women. A large observational study found that postmenopausal women using hormone therapy were 50% less likely to have sleep apnea than women who did not use hormones (Shahar 2003). In one preliminary trial, after just one week of treatment with a combination of 1.25 mg of premarin (conjugated equine estrogens) and 20 mg of the progestin (synthetic progesterone-like compound) medroxyprogesterone acetate, a reduction in the number of apneic episodes was observed in nine surgically postmenopausal women (Pickett 1989). In another preliminary study, five postmenopausal women with sleep apnea experienced a 25% drop in apnea severity after taking 2 mg of micronized estradiol for 3–4 weeks, and a subsequent 50% reduction in severity from baseline when 10 mg of medroxyprogesterone acetate was added (Keefe 1999).
In another small preliminary trial, six postmenopausal women with mild-to-moderate sleep apnea used a transdermal estradiol patch providing 50 mg of estradiol per day for two weeks, and then added 200 mg per day of oral micronized progesterone for another two weeks. The women slept better and had fewer apneic and hypopneic episodes during treatment with estradiol, but the addition of progesterone produced no additional benefit (Manber 2003). In a preliminary trial involving five peri- or postmenopausal women with sleep apnea, a daily oral combination of 2 mg of estradiol plus 0.5 mg of the progestin trimegestone was associated with a mean 75% drop in sleep apnea severity (Wesstrom 2005).
Although the exact mechanism by which estrogen and progesterone might exert beneficial effects in sleep apnea is not entirely clear, studies sugest these hormones may play a role in maintaining muscular tone in the upper airway (Popovic 1998; Hou 2010; Liu 2009). Using bioidentical hormones, which are identical to the hormones produced naturally by the body, is the preferred method of hormone replacement.
More information about hormone replacement therapy for women is available in the Female Hormone Restoration protocol.
Testosterone. Sleep quality and testosterone levels are related, especially in older men, an effect largely explained by body fat content (adiposity). In men with obstructive sleep apnea, weight loss consistently restores testosterone levels, while the effect of CPAP on testosterone restoration is inconsistent (Barrett-Connor 2008; Wittert 2014; Zhang 2014; Bercea 2012; Knapp 2014). In addition, some researchers have noted that “Measuring testosterone level may be an additional helpful indicator in diagnosis of severity and in follow-up of [obstructive sleep apnea]” (Canguven 2010).
Testosterone therapy may have some positive impacts on cardiovascular and metabolic health in men with sleep apnea (Hoyos, Yee 2012), but some evidence shows a worsening of sleep apnea severity with testosterone therapy (Grech 2014; Andersen 2008; Hoyos, Killick 2012; Matsumoto 1985). However, one study found that the negative impact of testosterone therapy on sleep apnea resolved by week 18, suggesting a transient nature for this effect (Killick 2013). Nevertheless, current guidelines recommend against testosterone replacement therapy in men with untreated severe obstructive sleep apnea (Bhasin 2010). But some researchers have questioned this position, stating the evidence is weak and inconsistent (Hanafy 2007).
One possible approach is for men with low testosterone levels and untreated sleep apnea to receive treatment for their sleep apnea before initiating testosterone replacement therapy. These men should also lose weight if they are overweight. If low testosterone levels persist after successful sleep apnea treatment, then testosterone replacement therapy might be a reasonable consideration. Men who do initiate testosterone therapy after successful sleep apnea treatment should be closely monitored for reemergence of sleep apnea.
A more detailed discussion about testosterone replacement is included in the Male Hormone Restoration protocol.
Hypoglossal Nerve Stimulation
The hypoglossal nerve is one of the 12 cranial nerves (Gillig 2010). When stimulated, the hypoglossal nerve increases muscle tone in the tongue (Huang 2004; Gilliam 1995). Because increased tongue muscle tone may reduce airway obstruction, a hypoglossal nerve stimulating device has been developed for the treatment of sleep apnea. This device is surgically implanted on the chest wall and is connected to one or two chest leads, which measure breath cycles, and to a lead that delivers electrical stimulation to the hypoglossal nerve in the neck (Strollo 2014).
Several studies have looked at the effect of hypoglossal nerve stimulation in people with sleep apnea who were unsuccessful in using CPAP. In general, these have been uncontrolled trials lasting for 6 to 12 months in people with moderate-to-severe apnea. Use of these nerve-stimulating devices was associated with high degrees of safety and compliance, reductions of greater than 50% in apneic and hypopneic episodes, decreases in symptoms of sleep apnea, and improvements in quality of life measures (Eastwood 2011; Van de Heyning 2012; Strollo 2014; Mwenge 2013; Kezirian 2014). Although early data indicate a promise of benefit, hypoglossal nerve stimulators are still being studied and are approved only for investigational use in the United States as of early 2015 (Oliven 2011; Freedman 2014).
In sleep apnea, sleep is fragmented, which causes chronic overstimulation of the sympathetic nervous system; in other words, a prolonged stress response (Adeseun 2010; Canales 2008). One way the body responds to stress is by raising blood pressure to ensure sufficient blood flow to tissues like the heart, muscles, and brain. This occurs in large part by means of sympathetic nerve signaling via the renal nerves; this signal triggers vasoconstriction and sodium and fluid retention, resulting in increased blood pressure (Dusek 2009; Kannan 2014). Thus, it follows that one of the most prevalent and serious conditions correlated with sleep apnea is resistant hypertension, which is high blood pressure that persists despite aggressive drug treatment (Pedrosa 2011; Parati 2014; AHA 2014). Renal denervation, a technique in which renal sympathetic nerve fibers are selectively removed, is a new strategy being explored for the treatment of resistant hypertension as well as sleep apnea (Kannan 2014; Ukena 2013).
Renal denervation has been found, in preclinical and clinical models, to not only lower blood pressure but also improve severity of obstructive sleep apnea (Bohm 2013; Zhao 2013; Witkowski 2011). One study compared the effects of renal denervation to CPAP treatment in patients with moderate-to-severe obstructive sleep apnea as well as high blood pressure. Both treatments had a positive impact on sleep apnea and hypertension (Zhao 2013). A rigorous analysis of research into renal denervation for obstructive sleep apnea was published in 2014. This analysis examined data from five separate studies, involving a total of 49 people, all of whom were followed for six months after renal denervation. In these patients, renal denervation was associated with a significant decrease in severity of obstructive sleep apnea (Shantha 2014).
By reducing elevated sympathetic tone, thus interrupting the stress response, renal denervation may reduce severity of obstructive sleep apnea, and have broad benefits for cardiovascular health, glucose control, and weight management (Thomopoulos 2013). In fact, one study in 10 subjects with sleep apnea and treatment-resistant hypertension reported improved glucose control as well as reduced blood pressure and sleep apnea severity six months after renal denervation (Witkowski 2011).
However, as of early 2014 the only randomized controlled trial conducted on renal denervation for resistant hypertension found no benefit from the procedure, with only poor quality, unblinded studies showing a positive effect—though analysis of the data continues. Renal denervation may be associated with renal artery stenosis, which can actually raise blood pressure (Mahfoud 2013; Kwon 2014; Boyles 2014; Mandrola 2014).
Nasal Expiratory Positive Airway Pressure and Oral Negative Pressure Therapy
Because many people find CPAP difficult to use, other devices working on the same principle—using air pressure to keep airways open—have been developed.
Nasal expiratory positive airway pressure. This treatment creates positive pressure only in the expiratory phase of the breath cycle, rather than continuously. The pressure is generated by adhesive nasal patches that function as one-way valves that close during exhalation, providing air resistance pressure. These nasal patches may be more tolerable to some people than a CPAP facemask. Expiratory positive airway pressure reduces frequency and duration of apneas in people with obstructive sleep apnea, but works best in mild cases, and compares poorly to CPAP in severe obstructive sleep apnea. Expiratory positive airway pressure is contraindicated for people with nasal obstruction, obstructive lung disease, blood gas abnormalities, or severe obstructive sleep apnea (Freedman 2014; De Dios 2012).
Oral negative pressure therapy. In this therapy, negative pressure is provided through an oral suction device that draws the soft palate forward, maintaining airway patency. In a preliminary trial, oral negative pressure therapy significantly reduced obstructive sleep apnea severity, improved sleep quality, and decreased symptoms in a subgroup of participants. People who had positive effects from this treatment generally did so from the first night of use, and people with severe, moderate, and mild sleep apnea had equal chances of benefiting (Colrain 2013).