The autoimmune underpinnings of many endocrine failure disorders lead to hypogonadism being associated with a variety of other endocrine disorders. Both Type I and Type II polyglandular autoimmune syndromes are associated with hypogonadism. Antisperm antibodies have been reported to be present in Type I polyglandular failure. POEMS syndrome consists of plasma cell dyscrasias with polyneuropathy, organomegaly, endocrinopathy (diabetes mellitus and primary gonadal failure), M protein in plasma, and skin changes (hyperpigmentation). The Kearns-Sayre syndrome is a rare syndrome characterized by myopathic abnormalities leading to ophthalmoplegia and progressive weakness associated with hypoparathyroidism, primary gonadal failure, diabetes mellitus, and hypopiruitarism. Patients with Down’s syndrome often develop hypogonadism. Adrenoleukodystrophy is a genetic paroxysmal disorder associated with progressive antral demyelinarion, primary adrenal insufficiency, and primary hypogonadism.

One in five patients with hyperthyroidism develop gynecomasria. This is associated with increased total and free estradiol levels. Ridgway et al. showed that the decreased plasma clearance rate of estradiol was due to increased binding of estradiol to sex hormone binding globulin. Hyperthyroidism had minimal effects on estradiol production rate. Serum estradiol levels decline after treatment of hyperthyroidism.

In hyperthyroidism, total testosterone and sex hormone binding globulin levels are increased, and free or bioavailable testosterone is decreased. Androstenedione and 17-hydroxyprogesterone levels are also elevated. The tesricular response to human chorionic gonadotropin has been found to be impaired. Prolactin levels are unchanged in hyperthyroidism.

Gonadotropin levels are increased in hyperthyroidism. There is no change in the pulsarility of luteinizing hormone and follicle-stimulating hormone secretion in hyperthyroidism. Patients with hyperthyroidism had an exaggerated response to gonadotropin-releasing hormone.

Zinc deficiency occurs in hyperthyroidism, and, as with other conditions previously mentioned, this has been demonstrated to be associated with a decline in testosterone production. The changes in the hormonal milieu in hyperthyroidism appear to be predominantly due to the increased sex hormone binding globulin levels associated with a mild defect in gonadal testosterone production.

Hypothyroid patients have abnormalities in spermatogenesis and Leydig cell function. Androgen secretion declines in hypothyroidism and the metabolic transformation of testosterone is shifted toward etiocholanolone rather than androsterone. The low testosterone levels in hypothyroidism are associated with low gonadotropin levels; thus, these patients have secondary hypogonadism. Sex hormone binding globulin levels are decreased in hypothyroid patients. Prolactin levels are elevated in some, but not all, patients with hypothyroidism. Thyroxin replacement reverts the hypothalamic-pituitary-gonadal axis to normal in patients with hypothyroidism.

Men with Addison’s disease have dehydroepiandrosterone (DHEA) levels that are one-tenth of those seen in normal men. They also have a decreased response of testosterone to human chorionic gonadotropin.

Persons with Cushing’s syndrome have decreased libido, impotence, oligospermia, and histological changes in the testes. Testosterone levels are reduced in males with Cushing’s syndrome. Steroids have an anrigonadorropic action on the Leydig cell membrane.

Testosterone decreases and luteinizing hormone increases when dexamethasone is administered acutely. It would appear, however, that the ability of steroids to inhibit luteinizing hormone at the pituitary level leading to secondary hypogonadism is the major reason for hypogonadism in patients with Cushing’s syndrome.

Diabetes Mellitus

Plasma total and free testosterone levels are reduced in men with diabetes mellitus, independent of age and body mass index. Furthermore, a stepwise decrease in mean testosterone levels per categorical increase in fasting plasma glucose is apparent in both diabetics and nondiaberics. In men with Type 1 diabetes mellitus, plasma testosterone is lowest when control is very poor, but there is no relationship between the severity of retinopathy or other complications and the level of plasma testosterone. Levels of sex hormone binding globulin have been reported to be either increased or decreased in diabetics. There is a mild impairment of the testosterone response to human chorionic gonadotropin in diabetics. Basal gonadotropin levels are normal in diabetics, but the luteinizing hormone and follicle-stimulating hormone response to gonadotropin-releasing hormone is impaired, particularly in the presence of hyperglycemia. Dihydrotestosterone, DHEA, and DHEA-sulfate, have all been found to be lower in patients with diabetes, whereas estradiol levels were found to be slightly increased in one study. Young men with diabetes exhibit prolactin secretion that has a normal pulse frequency, but a decline in maximal peak amplitude and peak area, whereas older persons with Type II diabetes were reported to have elevated prolactin levels.

Excessive visceral adiposity results in decreased plasma testosterone and insulin resistance and substantially increases the risk of diabetes mellitus. Administration of testosterone under these circumstances may decrease visceral fat and improve glucose tolerance. Type II diabetes mellitus is, however, associated with lowered plasma testosterone levels independent of obesity in both Melanesian and Caucasian men. In older diabetic men, there is a relationship between the presence of diabetic dyslipidemia and the decrease in plasma testosterone.

Total testosterone and sex hormone binding globulin have been associated with defects in nonoxidative glucose disposal and upper body adiposity in normoglycemic men. Insulin has been shown to stimulate testosterone production (and suppress sex hormone binding globulin production) in both normal and obese men. Administration of testosterone to centrally obese, hypogonadal, middle-aged men has improved insulin sensitivity.

Leptin is produced from fat cells, and while women have higher leptin levels than men when corrected for adipose cell mass, leptin levels are independently associated with testosterone level; testosterone replacement in hypogonadal males serves to reduce leptin levels.

Data from the Massachusetts Male Aging Study showed that after controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and sex hormone binding globulin.

In conclusion, persons with diabetes have low testosterone levels secondary to both gonadal and hypothalamic-pituitary defects. Testosterone replacement improves sexual performance in diabetes.

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