Numerous systemic diseases alter gonadal function in males, either by inhibiting testosterone synthesis in the testes or by altering the release of luteinizing hormone and follicle-stimulating hormone from the pituitary. Severe systemic illness results in the marked inhibition of luteinizing hormone and follicle-stimulating hormone release, thereby causing subsequent hypotestosteronemia. Luteinizing-hormone pulsatility is likewise decreased during critical illness. Administration of dopamine during the period of critical illness further decreases gonadorropin secretion. Table summarizes the changes in the hypothalamic-piruitary-testicular axis that occur in a variety of chronic diseases. Unfortunately, these are limited studies that examine the effect of testosterone replacement in disease states, making it nearly impossible to conclude whether or not the testosterone decrease observed in disease processes is protective or harmful.
This post will review literature involving several of the most common systemic disease states that alter gonadal function, detailing the specific hormonal changes observed in each condition and what is known about their resultant effects on male sexual function.
Patients with chronic renal failure commonly have a poor libido, decreased potency, and diminished testic-ular size. Testicular biopsy of renal failure patients shows diminished Leydig cells and a thickened basement membrane with maturation arrest of the germinal epithelium. The majority of patients with end-stage renal failure have severe oligospermia or azoospermia.
Numerous studies have found low testosterone levels in patients with chronic renal failure, which may be explained by increased metabolic break down of testosterone. Although there is preservation of the testosterone circadian rhythm as well as the response to human chorionic gonadorropin in renal failure patients, there is no uniformity in the reports on sex hormone-binding globulin (sex hormone binding globulin).
Renal failure produces almost a universal increase in gonadorropin levels, including bioactive and immunoactive luteinizing hormone, and follicle-stimulating hormone levels, and gonadotropin response to gonadotropin-releasing hormone is exaggerated in most cases. Levels of estradiol and inhibin are similarly increased. Erythropoietin increased testosterone and sex hormone binding globulin but did not lower prolactin levels.
In some renal failure patients, low zinc levels may also be associated with the low testosterone levels. In one study, zinc replacement was shown to increase testosterone in patients on dialysis. Renal transplantation improves gonadal function in some, but not all patients. Some of the continued deterioration appears to be due to immunosuppressive therapy. Uncontrolled trials have suggested that anabolic steroids improve anemia, malnutrition, and sexual dysfunction in uremic patients. This was confirmed in a control study utilizing nandrolone.
Testicular atrophy, decreased libido, and gynecomastia are common manifestations in patients with cirrhosis of the liver. In addition, there is a reduction in prostate size and decreased incidence of benign prostatic hypertrophy.
In some studies, both the production rates and the plasma levels of total and free testosterone are reduced in patients with cirrhosis, whereas, in others, total plasma testosterone levels are not significantly different from that measured in controls. Discrepancies in studies may relate to differences in the severity of liver disease, since testosterone decreases in proportion to the severity of the liver disease or the cause of the cirrhosis.
Particularly in the case of alcohol-induced cirrhosis, plasma sex hormone binding globulin concentrations are typically increased, at least partly as a consequence of increased plasma estrone and estradiol / and, therefore, bioavailable testosterone is usually decreased. This increase in sex hormone binding globulin could explain why total testosterone levels are not always decreased in patients with cirrhosis compared to controls.
In cirrhosis due to idiopathic hemochromatosis, sex hormone binding globulin concentrations and the peripheral conversion of androgens to estrogens are similar to the levels of healthy men. The peripheral conversion of androgens to estrogens (i.e., androstenedione to estrone and testosterone to estradiol) is increased in alcohol-induced cirrhosis. The function of the hypothalamus and pituitary is essentially normal in alcohol-induced cirrhosis.
Basal luteinizing hormone and follicle-stimulating hormone levels are often slightly elevated, and the primary abnormality appears to be the function of the testes. The gonadorropin response to gonadotropin-releasing hormone is mostly normal, but hyper-responsiveness is seen in some patients and can be suppressed in end-stage disease.
In male patients with viral cirrhosis, significant alterations in plasma estradiol and testosterone levels either do not occur or mimic those changes seen as the result of alcohol-induced cirrhosis. Patients with nonalcoholic liver disease have low total and free testosterone levels and increased levels of sex hormone binding globulin. Gonadal function improved, but was not normalized, one year after liver transplantation, and the gonadotropin response to gonadotropin-releasing hormone suggested the presence of a hypothalamic defect.
Plasma prolactin levels have been found to be normal or increased in males with cirrhosis. Although there is a normal prolactin response to thyrotropin-releasing hormone in most patients, an exaggerated response occurs in some. The prolactin circadian rhythm becomes lost in cirrhosis. Elevated prolactin levels correlate with elevated “free” tryptophan levels. The increased prolactin levels present in some cirrhotics appear to be due to the elevated estrogen levels and delayed prolactin clearance by the liver.
The mechanism of the gonadal hormonal changes would appear to be due to increased estrogen production, secondary to increased peripheral conversion of androgens. The elevated estrogens lead to an increase in sex hormone binding globulin with a resultant decrease in free testosterone. The increased prolactin levels may be secondary to the increase in estrogen levels. Tesricular damage may also occur, particularly in cases when the cirrhosis is secondary to known testicular toxins such as alcohol.
Testosterone supplementation in men with alcoholic cirrhosis is of minimal benefit. It should be noted, however, that in men with hypogonadism due to hemochromatosis, the administration of testosterone treatment produces an almost immediate recovery in well-being, libido, and potency, with no adverse effects on liver function.
Testicular atrophy was first recognized in patients with hemochromatosis in the 1930s. A later study of 1000 patients with hemochromatosis revealed an incidence of testicular atrophy approaching 17%. Most studies have suggested that patients with hemochromatosis have low luteinizing hormone levels and an impaired response to gonadotropin-releasing hormone. Long-term treatment with human chorionic gonadotropin serves to elevate testosterone levels. These findings are compatible with the finding that iron deposits are prominent in the pituitary but scanty in the testes. Venesection has produced partial reversal of the hypogonadotropic hypogonadism seen in hemochromatosis, but only in persons less than 40 years of age. Patients with hypogonadism from hemochromatosis have symptomatic improvement when treated with testosterone.
In conclusion, hemochromatosis produces a secondary hypogonadism. Liver disease plays little-to-no role in the pathogenesis of the hypogonadism.
Patients with beta-thalassemia receive frequent blood transfusions that often lead to secondary hemosiderosis. This condition may be responsible for delayed puberty, hypogonadism, and short stature. Thalassemic patients have a poor responsiveness of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. Some children with delayed puberty, however, have been shown to respond to pulsatile gonadotropin-releasing hormone administration, suggesting an actual problem of impaired hypothalamic gonadotropin-releasing hormone release. Testosterone therapy given at the time of puberty typically produces a growth spurt, with an increase in nocturnal growth hormone levels and insulin-like growth factor-I and insulin growth-like factor binding protein 3 (IGFBP-3).
Sickle Cell Anemia
Sickle cell anemia is similarly associated with delayed puberty. In a large series of sickle cell patients, one-third were found to be hypogonadal, exhibiting testicular atrophy. In this study, the patients also had low levels of androstenedione and dihydrotestoster-one. luteinizing hormone and follicle-stimulating hormone levels were elevated basally and there was an exaggerated response to gonadotropin-releasing hormone with a diminished testosterone response. Other researchers have reported a similar hormonal profile suggestive of primary hypogonadism in sickle cell disease. The low serum testosterone levels in sickle cell disease are associated with low erythrocyte zinc levels. As in the case of renal failure mentioned previously, Prasad et al. found that zinc replacement in persons with sickle cell disease increased testosterone levels.
Other studies have suggested that testosterone deficiency in sickle cell disease is due to pituitary infarction secondary to intravascular thrombosis. Modebe and Ezeh reported normal follicle-stimulating hormone, luteinizing hormone, and prolactin levels in patients with sickle cell disease and low testosterone levels. Landefeld et al. reported the case of a 19-year-old male with sickle cell disease, who demonstrated an increase in testosterone, luteinizing hormone, and follicle-stimulating hormone levels when treated with oral clomiphene. One major complication of testosterone therapy in hypogonadal males with sickle cell disease is the possibility of priapism.
Overall, it would appear that most cases of hypogonadism in patients with sickle cell disease are due to testicular failure. Some patients, however, clearly develop a secondary hypogonadism. The role of zinc deficiency in patients with hypogonadism due to sickle cell disease deserves further investigation.
Obstructive Sleep Apnea
Sleep apnea results in decreased plasma testosterone and sex hormone binding globulin levels in proportion to the severity of the sleep apnea. Gonadotropin levels are normal. Men with obstructive sleep apnea have lower plasma testosterone levels than those men who only snore, even when matched for body mass index. Furthermore, successful treatment of sleep apnea results in an improvement in both plasma testosterone levels and sexual function. Conversely, testosterone administration has been demonstrated to depress venrilatory drive and increase sleep apnea in adult men by affecting the neuromuscular control of upper airway patency during sleep. This would appear to be an effect of exogenously administered testosterone, since one week of androgen blockade using flutamide had no clinically significant effect on sleep, sleep-disordered breathing, or chemosensi-tivity in patients with moderate-to-severe sleep apnea. Snyder et al. demonstrated no deleterious effects of testosterone in patients with sleep apnea when the testosterone was administered by patch resulting in physiologic levels of testosterone.
Chronic Obstructive Pulmonary Disease
In 1979, Semple et al. reported that persons with chronic obstructive pulmonary disease (COPD) had very low testosterone levels. The decrease in circulating testosterone levels was related to the severity of hypoxia, and was associated with a marked decline in sexual activity in men with COPD. Oral glucocorricoid treatment produces a marked decrease in testosterone due to a direct effect on the hypothalamic-pituitary axis. Similar effects on testosterone are not seen with inhaled corticoste-roids. The low testosterone levels are reversed by oxygen therapy. Overall, the cause of the low testosterone levels appears to involve both tesricular and hypothalamic-pituitary defects.
In 1986, Gordon et al. reported that males with rheumatoid arthritis had low testosterone and a free testosterone index associated with an increase in luteinizing hormone and follicle-stimulating hormone compared to age-matched controls. Subsequently, others have confirmed the low testosterone levels in patients with rheumatoid arthritis. These patients have low testosterone response to human chorionic gonadotropin when compared to normal subjects. Testosterone levels decrease during rheumatoid arthritis flares and increase slowly after the flare settles. Luteinizing hormone and follicle-stimulating hormone levels are elevated in patients with rheumatoid arthritis who are not taking glucocorricoids. Salivary testosterone, androstenedione, and DHEA-sulfate are also decreased in patients with rheumatoid arthritis. Serum pro-lacrin levels are also elevated in these patients.
A pilot study suggested that testosterone replacement may increase the CD8+ testosterone cells and decrease immunoglobulin M rheumatoid factor levels. This was associated with an improvement in clinical correlates of rheumatoid arthritis. A randomized clinical trial of testosterone for nine months failed to show a positive effect of testosterone on disease activity in males with rheumatoid arthritis.