Respiratory Abstracts 1

Sex steroid hormones and the neural control of breathing

         (Behan, Zabka et al. 2003) Download

We review evidence that sex steroid hormones including estrogen, progesterone and testosterone are involved in the central neural control of breathing. Sex hormones may exert their effects on respiratory motoneurons via neuromodulators, in particular, the serotonergic system. Recent studies have shown that levels of serotonin (5HT) in the hypoglossal and phrenic nuclei are greater in female than in male rats. Serotonin-dependent plasticity in hypoglossal and phrenic motor output also differs in male and female rats. Changing levels of gonadal hormones throughout the estrus cycle coincide with changing levels of 5HT in respiratory motor nuclei, and gonadectomy in male rats results in a decrease in 5HT-dependent plasticity in respiratory motor output. We speculate that sex steroid hormones are critically involved in adaptations in the neural control of breathing throughout life, and that decreasing levels of these hormones with increasing age may have a negative influence on the respiratory control system in response to challenge.

Sex steroidal hormones and respiratory control

         (Behan and Wenninger 2008) Download

There is a growing public awareness that sex hormones can have an impact on a variety of physiological processes. Yet, despite almost a century of research, we still do not have a clear picture as to the effects of sex hormones on the regulation of breathing. Considerable data has accumulated showing that estrogen, progesterone and testosterone can influence respiratory function in animals and humans. Several disorders of breathing such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS) show clear sex differences in their prevalence, lending weight to the importance of sex hormones in respiratory control. This review focuses on questions such as: how early do sex hormones influence breathing? Which is the most effective? Where do sex hormones exert their effects? What mechanisms are involved? Are there age-associated changes? A clearer understanding of how sex hormones influence the control of breathing could enable sex- and age-specific therapeutic interventions for diseases of the respiratory control system.


Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease

            (Casaburi, Bhasin et al. 2004) Download

Dysfunction of the muscles of ambulation contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). Men with COPD have high prevalence of low testosterone levels, which may contribute to muscle weakness. We determined effects of testosterone supplementation (100 mg of testosterone enanthate injected weekly) with or without resistance training (45 minutes three times weekly) on body composition and muscle function in 47 men with COPD (mean FEV(1) = 40% predicted) and low testosterone levels (mean = 320 ng/dl). Subjects were randomized to 10 weeks of placebo injections + no training, testosterone injections + no training, placebo injections + resistance training, or testosterone injections + resistance training. Testosterone injections yielded a mean increase of 271 ng/dl in the nadir serum testosterone concentration (to the middle of the normal range for young men). The lean body mass (by dual-energy X-ray absorptiometry) increase averaged 2.3 kg with testosterone alone and 3.3 kg with combined testosterone and resistance training (p < 0.001). Increase in one-repetition maximum leg press strength averaged 17.2% with testosterone alone, 17.4% with resistance training alone, and 26.8% with testosterone + resistance training (p < 0.001). Interventions were well tolerated with no abnormalities in safety measures. Further studies are required to determine long-term benefits of adding testosterone supplementation and resistance training to rehabilitative programs for carefully screened men with COPD and low testosterone levels.

Endocrinological disturbances in chronic obstructive pulmonary disease

            (Creutzberg and Casaburi 2003) Download

In this overview, the available literature on endocrinological disturbances in chronic obstructive pulmonary disease (COPD) is reviewed, with stress on growth hormone/insulin-like growth factor I (IGF-I), thyroid hormone and the anabolic steroids. In COPD, little is known about circulating growth hormone or IGF-I concentrations. Some authors find a decrease in growth hormone or IGF-I, others an increase. An increase of growth hormone might reflect a nonspecific response of the body to stress (for instance, hypoxaemia). Until now, only one controlled study on growth hormone supplementation has been published, which however did not reveal any functional benefits. Before growth hormone supplementation can be advised as part of the treatment in COPD, further controlled studies must be performed to investigate its functional efficacy. The prevalence of thyroid dysfunction in COPD and its role in pulmonary cachexia has not been extensively studied. So far, there is no evidence that thyroid function is consistently altered in COPD, except perhaps in a subgroup of patients with severe hypoxaemia. Further research is required to more extensively study the underlying mechanisms and consequences of disturbed thyroid function in this subgroup of COPD patients. A few studies have reported the results of anabolic steroid supplementation in chronic obstructive pulmonary disease. Although some studies have discerned that low circulating levels of testosterone are common in males with chronic obstructive pulmonary disease, little is known about the prevalence, the underlying causes or functional consequences of hypogonadism in these patients. The use of systemic glucocorticosteroids and an influence of the systemic inflammatory response have been suggested as contributing to low testosterone levels. It can be hypothesised that low anabolic hormones will reduce muscle mass and eventually result in a diminished muscle function. Further evidence is required before testosterone replacement can be recommended for males with chronic obstructive pulmonary disease.

Sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease

            (Fletcher and Martin 1982) Download

We studied 20 men (ages 46 to 69, mean 45 years) with chronic obstructive pulmonary disease (FEV1 of 0.55 to 2.1 L), to determine the relative importance of pulmonary impairment vs other occult physical or psychologic factors in the genesis of sexual dysfunction. Seven subjects had ceased sexual activity concomitant with worsening of their pulmonary symptoms; six because of erectile impotence and one due to dyspnea. Frequency of intercourse for the remaining 13 was 16 percent of prelung disease levels, and libido was decreased to 25 percent of premorbid levels. Nocturnal penile tumescence monitoring disclosed that six subjects had organogenic erectile impotence (OEI). None of the subjects showed signs of peripheral vascular disease as assessed by Doppler examination of peripheral pulses (including penile). The mean bulbocavernosus reflex latency (BCRL) for the OEI group (N = 5) was 40.2 msec, while that for the group with full nocturnal erections (N = 10) was 34.5 msec (P less than 0.005). Four subjects had occult diabetes mellitus evident on oral glucose tolerance tests, and one had evidence of an androgen deficit. The correlation coefficient for rank by sexual dysfunction vs pulmonary impairment and age was 0.66 (P less than 0.005) and 0.24 P greater than 0.05), respectively. Subjects with OEI tended to have the worst pulmonary function test results and the highest T-scores on the hypochondriasis, depression, and hysteria scales of the Minnesota Multiphasic Personality Inventory. Data suggest that sexual dysfunction worsens as lung disease worsens and that chronic obstructive pulmonary disease may be associated with male impotence in the absence of other commonly known causes.


Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease

            (Gow, Seth et al. 1987) Download

Serum pituitary and thyroid hormones, testosterone, and the response of pituitary hormones to thyrotrophin releasing hormone were measured in 20 inpatients (mean age 68, range 42-81 years) with severe chronic obstructive lung disease and in 15 control convalescent inpatients (mean age 73, range 57-83 years) who had normal respiratory function. No significant differences were found in total and free thyroid hormone concentrations and basal concentrations of thyrotrophin, growth hormone, and prolactin; and their increments after injection of thyrotrophin releasing hormone were similar in patients with chronic obstructive lung disease, and control patients. Three patients with chronic obstructive lung disease, however, had no thyrotrophin responses to thyrotrophin releasing hormone. In men, low testosterone concentrations were found both in patients with chronic obstructive lung disease and in controls. Luteinising hormone concentrations were higher in men with chronic obstructive lung disease (p less than 0.02), whereas concentrations of follicle stimulating hormone in the two groups were not significantly different. There was no significant correlation between arterial blood gas tensions and these hormone measurements. General effects of age and illness may be more important than direct effects of hypoxia in determining hypothalamic-pituitary function in elderly patients with chronic obstructive lung disease.

Neuroendocrine alterations in obese patients with sleep apnea syndrome

            (Lanfranco, Motta et al. 2010) Download

Obstructive sleep apnea syndrome (OSAS) is a serious, prevalent condition that has significant morbidity and mortality when untreated. It is strongly associated with obesity and is characterized by changes in the serum levels or secretory patterns of several hormones. Obese patients with OSAS show a reduction of both spontaneous and stimulated growth hormone (GH) secretion coupled to reduced insulin-like growth factor-I (IGF-I) concentrations and impaired peripheral sensitivity to GH. Hypoxemia and chronic sleep fragmentation could affect the sleep-entrained prolactin (PRL) rhythm. A disrupted Hypothalamus-Pituitary-Adrenal (HPA) axis activity has been described in OSAS. Some derangement in Thyroid-Stimulating Hormone (TSH) secretion has been demonstrated by some authors, whereas a normal thyroid activity has been described by others. Changes of gonadal axis are common in patients with OSAS, who frequently show a hypogonadotropic hypogonadism. Altogether, hormonal abnormalities may be considered as adaptive changes which indicate how a local upper airway dysfunction induces systemic consequences. The understanding of the complex interactions between hormones and OSAS may allow a multi-disciplinary approach to obese patients with this disturbance and lead to an effective management that improves quality of life and prevents associated morbidity or death.

Decreased pituitary-gonadal secretion in men with obstructive sleep apnea

            (Luboshitzky, Aviv et al. 2002) Download

Decreased libido is frequently reported in male patients with obstructive sleep apnea (OSA). The decline in morning serum testosterone levels previously reported in these patients was within the normal adult male range and does not explain the frequent association of OSA and sexual dysfunction. We determined serum LH and testosterone levels every 20 min between 2200-0700 h with simultaneous sleep recordings in 10 men with sleep apnea and in 5 normal men free of any breathing disorder in sleep. The mean levels and area under the curve of LH and testosterone were significantly lower in OSA patients compared with controls [LH, 24.9 +/- 10.2 IU/liter.h vs. 43.4 +/- 9.5 (P < 0.005); testosterone, 67.2 +/- 11.5 nmol/liter.h vs. 113.3 +/- 26.8 (P < 0.003)]. Four of 10 patients had hypogonadal morning (0700 h) serum testosterone levels. Analysis of covariance (ANCOVA) revealed that the 2 groups differed significantly in the amount of LH and testosterone secreted at night independent of age or degree of obesity. After partialing out body mass index, there was a significant negative correlation between the amounts of LH and testosterone secreted at night and the respiratory distress index, but not with degree of hypoxia. Our 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 and, to a lesser extent, hypoxia in addition to the degree of obesity and aging may be responsible for the central suppression of testosterone in these patients.

Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea

            (Meston, Davies et al. 2003) Download

OBJECTIVE: Obstructive sleep apnoea (OSA) is a relatively common condition producing disabling somnolence and profound physiological responses to hypoxaemic episodes during sleep, including significant oscillations in blood pressure. This study aimed to provide controlled data on the interaction between OSA and endocrine axes to establish whether overrepresentation of pathology such as hypertension and hypogonadism in OSA subjects might have an endocrine basis. DESIGN, SETTING AND SUBJECTS: Parallel randomized sham placebo controlled 1-month trial of nasal continuous positive airway pressure (nCPAP) in 101 male subjects with OSA presenting to a respiratory sleep clinic. METHODS: Analysis of gonadotrophins, testosterone, sex hormone binding protein (SHBG), prolactin, cortisol, thyroid stimulating hormone (TSH), free thyroxine (free T4), insulin-like growth factor-1 (IGF-1), renin and aldosterone were performed at baseline and after 1 month's active or placebo nCPAP intervention. Quality of life questionnaire scoring was also recorded over the same time period. RESULTS: Testosterone and SHBG showed significant negative correlations with baseline OSA severity. Active treatment of OSA produced SHBG elevation and TSH reduction (P< or =0.03). Both groups showed an increase in aldosterone (P<0.001) and IGF-1 (P< or =0.03), associated with a large improvement in subjective quality of life scoring. CONCLUSIONS: These findings demonstrate significant changes in endocrine axes not previously reported in a placebo-controlled trial. OSA is a recognized reversible cause of testosterone reduction; SHBG suppression correlating to baseline OSA severity supports a diagnosis of secondary hypogonadism. Significant rises in aldosterone and IGF-1 on treatment coincide with increased physical activity and an improved quality of life score.

Testosterone restores respiratory long term facilitation in old male rats by an aromatase-dependent mechanism

            (Nelson, Bird et al. 2011) Download

Steroidal sex hormones play an important role in the neural control of breathing. Previous studies in our laboratory have shown that gonadectomy in young male rats (3 months) eliminates a form of respiratory plasticity induced by intermittent hypoxia, known as long term facilitation (LTF). Testosterone replenishment restores LTF in gonadectomized male rats, and this is dependent on the conversion of testosterone to oestradiol by aromatase. By middle age (12 months), male rats no longer exhibit LTF of hypoglossal motor output; phrenic LTF is significantly reduced, and this persists into old age. We tested the hypothesis that LTF can be restored in old male rats by administration of testosterone. Intact Fischer 344 rats (>20 months) were implanted with Silastic tubing containing testosterone (T), T plus an aromatase inhibitor (T+ADT), or 5alpha-dihydrotestosterone (DHT), a form of testosterone not converted to oestradiol. One week post-surgery, LTF of hypoglossal and phrenic motor output was measured. By comparison with control rats, hypoglossal LTF was increased in testosterone-treated rats, with levels approaching that of normal young rats. LTF was not restored in T+ADT or DHT-treated rats. Aromatase levels in hypoglossal and phrenic nuclei did not change with age. As serum testosterone levels did not decline with age, local bioavailability of testosterone in old rats may be a limiting factor in the expression of this form of respiratory plasticity. Our findings suggest that testosterone supplementation could potentially be used to enhance upper airway control in the elderly.


Testosterone Supplementation during Respiratory Rehabilitation

            (Puhan and Schunemann 2005) Download

Hormones and breathing

            (Saaresranta and Polo 2002) Download

A number of hormones, including hypothalamic neuropeptides acting as neurotransmitters and neuromodulators in the CNS, are involved in the physiologic regulation of breathing and participate in adjustment of breathing in disease. In addition to central effects, some hormones also control breathing at peripheral chemoreceptors or have local effects on the lungs and airways. Estrogen and progesterone seem to protect from sleep-disordered breathing, whereas testosterone may predispose to it. Progesterone and thyroxine have long been known to stimulate respiration. More recently, several hormones such as corticotropin-releasing hormone and leptin have been suggested to act as respiratory stimulants. Somatostatin, dopamine, and neuropeptide Y have a depressing effect on breathing. Animal models and experimental human studies suggest that also many other hormones may be involved in respiratory control.

Influence of testosterone on breathing during sleep

            (Schneider, Pickett et al. 1986) Download

Apneas and hypopneas during sleep occur more frequently in men than women. Disordered breathing is also reported to increase in hypogonadal men following testosterone administration. This suggests a hormonal influence on sleeping respiratory pattern. We therefore studied respiratory rhythm during sleep in 11 hypogonadal males both on and off testosterone-replacement therapy. In four subjects the anatomy (computerized tomography) and airflow resistance of the upper airway were also determined on both occasions. Sleep stage distribution and duration were unchanged following androgen administration. However, both apneas and hypopneas increased significantly during testosterone replacement so that the total number of disordered breathing events (apneas + hypopneas) per hour of sleep rose from 6.4 +/- 2.1 to 15.4 +/- 7.0 (P less than 0.05). This was a highly variable event with some subjects demonstrating large increases in apneas and hypopneas when androgen was replaced, whereas others had little change in respiration during sleep. Upper airway dimensions, on the other hand, were unaffected by testosterone. These results suggest that testosterone contributes to sleep-disordered breathing through mechanisms independent of anatomic changes in the upper airway.


Hypothalamic-pituitary dysfunction in respiratory hypoxia

            (Semple, Beastall et al. 1981) Download

Eight hypoxic male patients with stable chronic obstructive airways disease were submitted for combined anterior pituitary function testing. All subjects showed normal growth hormone and essentially normal cortisol responses to adequate hypoglycaemia, two subjects showed delayed responses of thyroid stimulating hormone to administered thyrotrophin releasing hormone and all had basal prolactin levels within normal limits. Basal levels of luteinising hormone were significantly lower than in the group of age-matched controls (p less than 0.02) but there was a normal increment after the injection of gonadotrophin releasing hormone. Basal levels of follicle stimulating hormone were significantly lower than in the controls (p less than 0.01), and there was also a reduced response from the pituitary after injection of gonadotrophin releasing hormone (p less than 0.01). Resting levels of the thyroid hormones thyroxine and tri-iodothyronine were normal while the expected subnormal testosterone level was observed (p less than 0.05). These results show that hypoxia can produce abnormalities of hypothalamic-pituitary function and that these are primarily located in the hypothalamic-pituitary-testicular axis.

Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease

            (Semple, Hume et al. 1988) Download

Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial

            (Svartberg, Aasebo et al. 2004) Download

The aim of this study was to assess the effect of a low-dose testosterone on body composition and pulmonary function, as well as on quality of life, sexuality, and psychological symptoms in patients with chronic obstructive pulmonary disease (COPD). Twenty-nine men with moderate to severe COPD were allocated to receive either 250 mg of testosterone or placebo intra-muscularly, every fourth week, during the 26 weeks study period. Fat-free mass increased in the treatment group (P<0.05), and a significant difference between the treatment and the control group was seen after 26 weeks (P<0.05). Fat mass decreased in the treatment group (P<0.05), and there was a significant difference between the treatment and the control group after 12 weeks (P<0.01). A significantly better erectile function was reported in the treatment group at the final visit (P<0.05), and the overall sexual quality of life was significantly better in the treatment group after 12 weeks (P<0.05). No improvement in pulmonary function was found. In conclusion, administration of a low-dose testosterone to men with COPD for 26 weeks was associated with improvement of body composition, better erectile function and sexual quality of life. Furthermore, there were no clinical or biochemical side effects.

Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats

            (Zabka, Mitchell et al. 2006) Download

Sex hormones modulate plasticity in the central nervous system, including respiratory long-term facilitation (LTF), a form of serotonin-dependent respiratory plasticity induced by intermittent hypoxia. Since gonadectomy (GDX) attenuates LTF in male rats, we tested the hypotheses that: (1) testosterone replenishment restores LTF in gonadectomized male rats, and (2) that the conversion of testosterone to oestradiol (under the influence of aromatase) is required for these effects. Intact and sham operated male F344 rats were compared to gonadectomized rats implanted with Silastic tubing containing testosterone (T), T plus an aromatase inhibitor (ADT), or 5alpha-dihydrotestosterone (DHT), a form of testosterone not converted to oestradiol. Seven days postsurgery, LTF was studied in anaesthetized, neuromuscularly blocked and ventilated rats while monitoring integrated phrenic and hypoglossal (XII) motor output. LTF was elicited by three 5 min hypoxic episodes (P(a,O(2)) = 35 - 45 mmHg). Although significant phrenic and XII LTF were observed in all rat groups, GDX reduced both phrenic and XII LTF, an effect reversed by T. In contrast, LTF was not restored in T + ADT or DHT-treated gonadectomized rats. We conclude that the conversion of testosterone to oestradiol modulates phrenic and XII LTF in male F344 rats.

Effect of testosterone on the apneic threshold in women during NREM sleep

            (Zhou, Rowley et al. 2003) Download

The hypocapnic apneic threshold (AT) is lower in women relative to men. To test the hypothesis that the gender difference in AT was due to testosterone, we determined the AT during non-rapid eye movement sleep in eight healthy, nonsnoring, premenopausal women before and after 10-12 days of transdermal testosterone. Hypocapnia was induced via nasal mechanical ventilation (MV) for 3 min with tidal volumes ranging from 175 to 215% above eupneic tidal volume and respiratory frequency matched to eupneic frequency. Cessation of MV resulted in hypocapnic central apnea or hypopnea depending on the magnitude of hypocapnia. Nadir minute ventilation as a percentage of control (%Ve) was plotted against the change in end-tidal CO(2) (Pet(CO(2))); %Ve was given a value of zero during central apnea. The AT was defined as the Pet(CO(2)) at which the apnea closest to the last hypopnea occurred; hypocapnic ventilatory response (HPVR) was defined as the slope of the linear regression Ve vs. Pet(CO(2)). Both the AT (39.5 +/- 2.9 vs. 42.1 +/- 3.0 Torr; P = 0.002) and HPVR (0.20 +/- 0.05 vs. 0.33 +/- 0.11%Ve/Torr; P = 0.016) increased with testosterone administration. We conclude that testosterone administration increases AT in premenopausal women, suggesting that the increased breathing instability during sleep in men is related to the presence of testosterone.


References

Behan, M. and J. M. Wenninger (2008). "Sex steroidal hormones and respiratory control." Respir Physiol Neurobiol 164(1-2): 213-21.

Behan, M., A. G. Zabka, et al. (2003). "Sex steroid hormones and the neural control of breathing." Respir Physiol Neurobiol 136(2-3): 249-63.

Casaburi, R., S. Bhasin, et al. (2004). "Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease." Am J Respir Crit Care Med 170(8): 870-8.

Creutzberg, E. C. and R. Casaburi (2003). "Endocrinological disturbances in chronic obstructive pulmonary disease." Eur Respir J Suppl 46: 76s-80s.

Fletcher, E. C. and R. J. Martin (1982). "Sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease." Chest 81(4): 413-21.

Gow, S. M., J. Seth, et al. (1987). "Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease." Thorax 42(7): 520-5.

Kunz, F., C. Pechlaner, et al. (2005). "The smoker's paradox and the real risk of smoking." Eur J Epidemiol 20(2): 161-7.

Lanfranco, F., G. Motta, et al. (2010). "Neuroendocrine alterations in obese patients with sleep apnea syndrome." Int J Endocrinol 2010: 474518.

Luboshitzky, R., A. Aviv, et al. (2002). "Decreased pituitary-gonadal secretion in men with obstructive sleep apnea." J Clin Endocrinol Metab 87(7): 3394-8.

Meston, N., R. J. Davies, et al. (2003). "Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea." J Intern Med 254(5): 447-54.

Nelson, N. R., I. M. Bird, et al. (2011). "Testosterone restores respiratory long term facilitation in old male rats by an aromatase-dependent mechanism." J Physiol 589(Pt 2): 409-21.

Puhan, M. A. and H. J. Schunemann (2005). "Testosterone Supplementation during Respiratory Rehabilitation." Am J Respir Crit Care Med 172(3): 399; author reply 399-400.

Saaresranta, T. and O. Polo (2002). "Hormones and breathing." Chest 122(6): 2165-82.

Schneider, B. K., C. K. Pickett, et al. (1986). "Influence of testosterone on breathing during sleep." J Appl Physiol 61(2): 618-23.

Semple, P. D., G. H. Beastall, et al. (1981). "Hypothalamic-pituitary dysfunction in respiratory hypoxia." Thorax 36(8): 605-9.

Semple, P. D., R. Hume, et al. (1988). "Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease." Thorax 43(11): 945-6.

Svartberg, J., U. Aasebo, et al. (2004). "Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial." Respir Med 98(9): 906-13.

Zabka, A. G., G. S. Mitchell, et al. (2006). "Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats." J Physiol 576(Pt 3): 903-12.

Zhou, X. S., J. A. Rowley, et al. (2003). "Effect of testosterone on the apneic threshold in women during NREM sleep." J Appl Physiol 94(1): 101-7.