Paxil, Testosterone & Sexual Function; Sleep as a Regulator of Testosterone; Sleep Apnea and Abnormalities in Testosterone Physiology

Paxil, Testosterone and Sexual Function

Q: Is it true that selective serotonin reuptake inhibitors (SSRIs) like Paxil decrease Testosterone?

A: No. I do not know of any evidence that Paxil or for that matter antidepressants decrease serum testosterone levels. The antidepressants a a class do affect sexual function.

Epidemiological studies indicate that sexual dysfunction and erectile dysfunction in particular are common in the general population, but also frequent symptoms of both untreated and treated depression. The term 'sexual dysfunction' describes a disturbance in sexual desire and the psychophysiological changes that characterize the normal sexual response cycle, and cause marked personal distress and interpersonal difficulty.

The ideal antidepressant would control depression with no adverse effect on sexual function. Sexual side effects may compromise a person's lifestyle and result in a lack of compliance with the prescribed antidepressant to the detriment of the person's mental health. Sexual dysfunction (including altered desire, orgasmic dysfunction, erectile and ejaculatory problems) is a relatively common side effect of antidepressant medication. The impact of antidepressant-induced sexual dysfunction is substantial and negatively affects quality of life, self-esteem, mood, and relationships with sexual partners.

Most antidepressant drugs have adverse effects on sexual function, but accurate identification of the incidence of treatment-emergent dysfunction has proved troublesome. Erectile dysfunction and associated sexual dysfunction secondary to antidepressant therapy may occur in up to 90% of men with antidepressant-emergent sexual side effects; accurate assessment of prevalence rates depends on taking a detailed history regarding erectile dysfunction and other aspects of sexual function prior to treatment.

The currently available evidence is rather limited, with small numbers of trials assessing each strategy. However, while further randomized data is awaited, for men with antidepressant-induced erectile dysfunction, the addition of sildenafil appears to be an effective strategy.

Many approaches have been adopted for management of patients with sexual dysfunction associated with antidepressant treatment, including waiting for the problem to resolve, behavioral strategies to modify sexual technique, individual and couple psychotherapy, delaying the intake of antidepressants until after sexual activity, reduction in daily dosage, 'drug holidays', use of adjuvant treatments, and switching to a different antidepressant.

There may be some advantages for bupropion, moclobemide, nefazodone and reboxetine over other antidepressants. Mixed mediator, nonserotonergic antidepressants that block postsynaptic serotonin type 2 receptors (nefazodone, mirtazapine) or that primarily increase dopamine or norepinephrine levels (bupropion) were thought to be good choices for avoiding antidepressant-associated sexual dysfunction or for switching patients in whom antidepressant-associated sexual dysfunction emerged. Comparisons with serotonin reuptake inhibitors (SRIs) have revealed less desire and orgasm dysfunction with nonserotonergic bupropion, less orgasm dysfunction with nefazodone, and superior overall satisfaction with sexual functioning with bupropion or nefazodone.

Few proposed treatment options, apart from avoidance, have proved effective for antidepressant-associated sexual dysfunction, which can have negative consequences on depression management.

Sleep as a Regulator of Testosterone & Obstructive Sleep Apnea (OSA) and Abnormalities in Testosterone Physiology

Q: What is relationship between obstructive sleep apnea (OSA) and testosterone? How does sleep (or lack of sleep) affect testosterone levels?

A: OSA is a complex condition not readily explained by simple physiological mechanisms. The control of the HPTA is probably simpler than the underlying cause of OSA. Investigating the HPTA we are able to look at discrete variables, manipulate them, and than draw associations on cause and effect. Investigating OSA is on a completely different plane since OSA is not definable by a single variable itself. And some of the variables of OSA are not defined by discrete mathematical constructs. Certain conclusions can be drawn from investigations of OSA and comorbidities. Following I have attempted to answer your questions as best possible.

Human sleep is under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness. This homeostatic process involves a putative neural sleep factor that increases during waking and decays exponentially during sleep. Slow wave sleep (SWS) is primarily controlled by the homeostatic process. Circadian rhythmicity is an oscillation with a near 24-hour period generated by a pacemaker located in the hypothalamic suprachiasmatic nucleus. Circadian rhythmicity plays an important role in sleep timing, sleep consolidation, and the distribution of REM sleep. The present data indicate that an alteration in sleep-wake homeostasis is an early biological marker of aging in adult men.

Decreased subjective sleep quality is one of the most common health complaints of older adults. The most consistent alterations associated with normal aging include increased wake time, minimal amount of deep SWS and declining rapid eye movement (REM) sleep. REM sleep appears to be relatively better preserved during aging. SWS decreases sharply from early adulthood to midlife, whereas wake time increases and REM sleep declines by about 30 and 10 min, respectively, per decade from midlife to late life. The age at which changes in amount and distribution of sleep stages appear is unclear because the majority of studies have been based on comparisons of young vs older adults.

Sleep is a major modulator of endocrine function, particularly of pituitary-dependent hormonal release. In healthy adult men, circulating levels of testosterone have a distinct pattern, with increasing levels during sleep toward a maximum around the time of awakening and a decrease during the day.

This pattern is often referred to as a circadian rhythm, despite the fact that disturbed sleep reduces or blunts the nocturnal rise of testosterone. Testosterone increases during day sleep in the same way as it does during night sleep in healthy young men. The reverse pattern is seen after waking: testosterone falls. Findings suggest that sleep is a more potent regulator of testosterone than circadian factors.

Changes in sleep efficiency and architecture have been associated with alteration in pituitary-gonadal function in healthy older men. In young adults, the sleep-related rise in testosterone has been linked with the first REM sleep episode and has been shown to be dependent on the integrity of the sleep process. Sleep fragmentation disrupts the diurnal testosterone rhythm, resulting in a considerable attenuation of the nocturnal rise.

Obstructive sleep apnea (OSA) is a common disorder affecting 4% of middle-aged men. Its prevalence increases with age, has a male preponderance with up to 25% of working age men having disturbed breathing during sleep, and up to 80% of cases of OSA remain undiagnosed.

The sequence of events in an episode of apnea consists of upper airway constriction, progressive hypoxemia secondary to asphyxia, autonomic and EEG arousal sufficient to prompt one to open and clear the airway to reverse the asphyxia, followed by successive relaxation of the airway, upper airway constriction, etc. Consequently, the repetitive episodes of upper airway obstruction in OSA are associated with hypoxia, hypercapnia, and sleep fragmentation.

About two-thirds of middle-aged men with OSA suffer from obesity, particularly central type, and one-third have hypertension. OSA is associated with increased cardiovascular and cerebrovascular, and neuropsychological morbidity. OSA in men is associated with dysfunction of the pituitary-gonadal axis.

Previous observations suggest that the abnormalities in testosterone physiology in OSA are distinct from those reported in aging and obesity. The reduced amounts of LH and testosterone and their significant association with RDI suggest that the pituitary-gonadal dysfunction is a consequence of OSA, rather than an independent primary disorder of the hypothalamic-pituitary-gonadal axis. Findings suggest that men with OSA have decreased nocturnal testosterone levels, possibly due to the combined effect of sleep fragmentation and hypoxia.

In one study sleep apnea patients maintained a normally oriented diurnal rhythm of testosterone; their nocturnal testosterone rise was significantly suppressed compared with that in control men of similar ages. Morning testosterone levels were in the hypogonadal range in 4 of the 10 patients (40%). The amounts of LH and testosterone secreted at night were significantly lower in OSA patients compared with controls independent of age and degree of obesity.

Androgen therapy may precipitate obstructive sleep apnea in men. A randomized, double-blind, placebo-controlled study examined effects of testosterone simultaneously on sleep, breathing, and function in older men who three injections of i.m. testosterone esters at weekly intervals (500 mg, 250 mg, and 250 mg) or matching oil-based placebo and then crossed over to the other treatment after 8 wk of washout. Polysomnography, anthropometry, and physical, mental, and metabolic function were assessed at baseline and after each treatment period.

Testosterone treatment reduced total time slept (1 h), increased the duration of hypoxemia (5 min/night), and disrupted breathing during sleep (total and non-rapid eye movement respiratory disturbance indices both increased by approximately seven events per hour). Short-term administration of high-dose testosterone shortens sleep and worsens sleep apnea in older men but did not alter physical, mental, or metabolic function. Thus the safety concerns of testosterone treatment in older men.

Testosterone may worsen breathing by a number of mechanisms because upper airway patency is determined by many structural and neuromuscular factors that control pharyngeal airway size and collapsibility. Although a direct anabolic effect on upper airway soft tissue growth could result in a physical reduction in upper airway dimension and this is thought to be how androgens induce OSA in women.

Testosterone may worsen breathing by neuromuscular mechanisms. Testosterone treatment increases upper airway collapsibility, ventilation, and hypoxic and hypercapnic ventilatory responses, leading to a reduced apneic threshold. Testosterone may directly alter sleep through central nervous system effects including altered serotingergic neurotransmission.

In order to understand the pathogenesis of OSA, it is important to identify the mechanism(s) that underlie the 'wakefulness stimulus' to the pharyngeal dilator muscles. Specifically, it is necessary to identify the neurochemical basis of the effects of sleep and wakefulness on both pharyngeal muscle tone and reflex responses, and especially the mechanisms that underlie the sleep-dependent loss of the neuromuscular compensation for the narrowed airspace. Identifying the neural substrate(s) for the wakefulness stimulus for pharyngeal motor neurons, and preventing loss of this stimulus in sleep, may theoretically lead to prevention of the critical reduction in pharyngeal dilator muscle activity that ultimately precipitates OSA.

The hypoglossal motor nucleus is the focus of the present review because the genioglossus (GG) muscle is an important pharyngeal dilator muscle, and loss of activity of this muscle during sleep, especially rapid eye movement (REM) sleep, contributes to the onset of airway narrowing and occlusion.

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter within the central nervous system that acts through multiple receptor subtypes. State-dependent modulation of serotonergic (5-hydroxytryptamine [5-HT]) inputs to hypoglossal motor neurons may be importantly involved in changing GG muscle activity as a function of sleep/awake states. These observations are consistent with the notion that increased neuronal activity in wakefulness may increase motor outflow to the GG muscle via increased 5-HT at the hypoglossal motor nucleus, whereas withdrawal of 5-HT in sleep may decrease GG muscle activity.

Based on this premise that a sleep-dependent decline in 5-HT at the hypoglossal motor nucleus may decrease GG muscle activity, there have been several attempts to manipulate brain 5-HT levels in order to increase GG muscle activity as a potential therapy for OSA.

Conversely, systemic administration of the 5-HT antagonist ritanserin, in order to simulate withdrawal of 5-HT in sleep, decreases pharyngeal dilator muscle activity, decreases airway size and increases sleep disordered breathing in bulldogs. Application of L-tryptophan, a precursor of 5-HT that leads to increased 5-HT production, also produces modest improvements in apnoea/hypopnoea index (AHI) in humans.

15 subjects with sleep apnea were treated with an average dose of 2500 mg L-tryptophan at bedtime. Comparison of pre- and post-drug polysomnograms showed significant improvement in obstructive sleep apnea but not with central sleep apnea. Most dramatic improvement is seen in subjects with obstructive sleep apnea in non-REM sleep only, but severity of apnea appears to be the most important factor determining improvement. L-tryptophan increased REM time and shortened REM latency but had no other significant effects on sleep architecture. Serotoninergic activity with a defect in feedback control of tryptophan-serotonin metabolism is postulated as a potential mechanism in the pathophysiology of obstructive sleep apnea.

Studies of gonadal steroids show they act as functional noncompetitive antagonists at the 5-HT3 receptor. Also, there are studies reflecting increased T levels with a decreased 5-HT.

Steroids with Michael Scally, M.D. #4