Gynecomastia.

Gynecomastia is a common finding in men and most often is idiopathic in origin or related to normal puberty. Medications are frequent causes of breast enlargement or tenderness, and hypogonadism of any cause, particularly primary hypogonadism, can lead to gynecomastia. Occasionally, the breast enlargement will reflect an underlying neoplasm that produces steroids or hCG. Underlying systemic disorders (liver disease, renal failure, thyrotoxicosis) can also result in gynecomastia. In most cases, the breast enlargement can be explained by an increased effective estrogen/androgen ratio acting at the breast itself. Therapy should be aimed at correcting any reversible causes, especially when related to medications, and treatment of any serious underlying disorders that are discovered, especially tumors. Medical treatment aimed at reducing the effective estrogen/androgen ratio, particularly with anti-estrogens, appears to be of some effectiveness. Careful surgical removal of excessive tissue can be very helpful, particularly in adolescence and young adulthood.

Adrenal insufficiency in a man with non-classical 21-hydroxylase deficiency: consequence or coincidence?

Deficiency of the adrenal enzyme 21-hydroxylase, which is required for cortisol synthesis, appears in two forms: a rare classical variant with severe enzyme deficiency, usually presenting in neonates with ambiguous genitalia (from androgen overproduction) or adrenal crisis (from glucocorticoid and mineralocorticoid underproduction), and a common (1% of the general population) non-classical variant with mild enzyme deficiency, usually presenting in young adults with findings of androgen excess but without clinical evidence of decreased steroid hormone production. We describe a 22-year-old man who had clinical and biochemical findings consistent with adrenal insufficiency, including a favorable response to hydrocortisone replacement, in whom elevated serum levels of the cortisol precursor 17-hydroxyprogesterone were diagnostic of non-classical 21-hydroxylase deficiency and in whom no other cause of adrenal insufficiency could be identified. These findings raise the possibility that non-classical 21-hydroxylase deficiency, an extremely frequent disorder which is generally thought to be without significant morbidity, might cause or contribute to adrenal insufficiency in adults.

Serum gastrin is not higher in subjects with colonic neoplasia.

Two previous studies have shown higher circulating gastrin levels in subjects with colonic neoplasia than in colonoscopy-negative controls. In this much larger study, sera were collected from fasting subjects undergoing colonoscopy. Colonoscopy with biopsy classified participants as having colonic adenomas (N = 139), colon carcinoma (N = 29), or controls without colonic neoplasia (N = 150). Frozen, stored sera were later analyzed for gastrin by radioimmunoassay. Serum gastrin values were no higher in subjects with colonic adenomas or carcinoma than in colonoscopy-negative controls. We conclude that elevated serum gastrin levels play little, if any, role in the initiation of colonic neoplasia.

Estrogen regulation of the nuclear 1,25-dihydroxyvitamin D3 receptor in rat liver and kidney.

We previously identified a receptor protein for 1,25-dihydroxyvitamin D3 in rat liver nuclei. The present studies were undertaken to investigate the ontogenesis of the hepatic nuclear vitamin D receptor (nVDR) and the estrogen regulation of this receptor in the liver, small intestine, and kidneys. The hepatic nVDR was significantly elevated in adult female rats compared to prepubertal female rats, while in male rats, this increase was not observed. Oophorectomized rats contained significantly less hepatic nVDR than did intact female rats. Administration of estradiol to castrated male or oophorectomized rats increased the hepatic nVDR. Further studies demonstrated that the increase in the hepatic nVDR was observed only after 2 weeks of estradiol treatment and was positively correlated with circulating estradiol concentrations. Castration of male rats did not alter the hepatic nVDR compared to intact male rats nor did testosterone administration to castrated male rats for 4 weeks change the hepatic nVDR concentration. Unlike the liver, intact female rats contained significantly less renal nVDR than did kidneys from intact male or castrated male rats. Estradiol administration to oophorectomized rats significantly decreased the renal nVDR. Renal nVDR concentrations correlated inversely with the serum concentration of estradiol. Castration of male rats had no effect on the renal nVDR. Intestinal nVDR concentrations were unaffected by castration of male rats or by treatment of castrated male rats with estrogen for up to 4 weeks. These results indicate that estradiol increases the nVDR in liver, decreases the nVDR in kidney and does not change the nVDR in the intestine. Physiological concentrations of testosterone do not regulate the nVDR in these tissues. Estradiol regulation of this receptor is organ specific and, therefore, conclusions about the regulation of the nVDR in one tissue cannot be extrapolated to other tissues.

Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis.

The antifungal drug ketoconazole, a cytochrome P450 inhibitor, has been shown to inhibit renal 1,25-dihydroxyvitamin D production in vitro and to lower serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with primary hyperparathyroidism. To assess the usefulness of this drug in the hypercalcemia of sarcoidosis, a condition thought to result from overproduction of 1,25-dihydroxyvitamin D by sarcoid-involved tissues, two men with sarcoidosis, hypercalcemia, and elevated serum levels of 1,25-dihydroxy-vitamin D were given ketoconazole, 600-800 mg per day, for four to six days. Serum 1,25-dihydroxyvitamin D levels were markedly reduced (by approximately 40%) in both patients during ketoconazole administration, but serum calcium was not affected. In both patients, renal function deteriorated during ketoconazole treatment. We conclude that ketoconazole administration can lower the elevated serum 1,25-dihydroxyvitamin D levels in sarcoidosis. However, deterioration of renal function during ketoconazole administration as well as failure of hypercalcemia to be affected during short-term ketoconazole treatment suggest that this drug might not be appropriate for acute treatment of hypercalcemic sarcoidosis.

Endocrine aspects of obesity.

As is obvious from the previous discussions, obesity is associated with a wide variety of changes in endocrine parameters (Table 1). Some of these changes, such as the reduction in SHBG without change in serum free testosterone levels, reflect merely laboratory abnormalities that may influence interpretation of diagnostic tests but have no important physiologic relevance. Other abnormalities have major clinical impact, such as hyperestrogenemia-endometrial carcinoma and hyperlipidemia-coronary artery disease. In some cases, endocrine changes in obesity are beneficial--that is, hyperestrogenemia leading to lower incidence of osteoporosis. In other cases, such as the profound suppression of growth hormone output in obesity, the physiologic relevance is unknown. Several endocrine changes in obesity, such as the impaired response of many hormones (growth hormone, prolactin, vasopressin, corticotropin) to insulin-induced hypoglycemia and elevated endorphin levels, suggest hypothalamic dysfunction. Furthermore, the failure of all of these abnormalities to be normalized after weight reduction raises the possibility of an underlying disorder leading to both endocrine dysfunction and obesity, rather than the endocrine dysfunction being simply a consequence of the obesity. Successful elucidation of the pathogenesis of obesity, which might then lead to much needed specific treatment modalities, may be advanced if we can solve some of these puzzles.

Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D and total serum calcium in hypercalcemic patients.

Administration of the antifungal drug ketoconazole reduces serum 1,25-dihydroxyvitamin D (1,25-D) levels in normal subjects. To determine whether a similar effect occurs in hypercalcemic patients, ketoconazole (200 mg every 8 h for 7 days) was given to nine patients with confirmed primary hyperparathyroidism, three patients with probable primary hyperparathyroidism who were awaiting surgery, and three patients with mild hypercalcemia of uncertain etiology who were being followed. Ketoconazole administration led to a significant reduction in mean serum 1,25-D levels in the hypercalcemic patients [basal, 64 +/- 7 (+/- SEM) pg/mL (154 +/- 17 pmol/L) vs. 36 +/- 5 pg/mL (86 +/- 12 pmol/L) after ketoconazole; P less than 0.001]. Serum total calcium fell slightly but significantly [basal, 11.05 +/- 0.17 mg/dL (2.76 +/- 0.04 mmol/L) vs. 10.77 +/- 0.16 (2.69 +/- 0.04 mmol/L) after ketoconazole; P less than 0.02], but the falls in total serum calcium and serum 1,25-D after ketoconazole treatment were not correlated with one another. Ketoconazole administration did not alter serum ionized calcium, 25-hydroxyvitamin D, phosphate, alkaline phosphatase, or PTH concentrations or urinary cAMP excretion. The responses to ketoconazole were similar in all three patient subgroups. We conclude that short term administration of ketoconazole to hypercalcemic patients causes a substantial fall in serum 1,25-D and a small fall in total serum calcium. These effects render ketoconazole a potentially useful agent for investigation of the importance of 1,25-D in patients with hypercalcemic disorders and for their treatment.

Pituitary-testicular reserve in men with low serum testosterone and normal serum luteinizing hormone.

Men with low serum testosterone levels who do not have elevated serum LH levels are generally thought to have hypothalamic-pituitary dysfunction. To evaluate this concept, seven men with a combination of low serum testosterone and normal serum LH underwent standard tests of hypothalamic-pituitary-testicular reserve. Pituitary reserve, tested with LHRH, showed exaggerated responses in two subjects, low-normal responses in one subject, and normal responses in the remaining four. Testing of hypothalamic-pituitary reserve with clomiphene showed normal gonadotropin responses in six subjects and blunted response in one (the same subject with the low LHRH response). Direct stimulation with hCG showed normal percentage increases in testosterone but low absolute levels, comparable to responses in patients with Klinefelter's syndrome. However, 17-OH-progresterone responses to hCG were lower in these subjects than in either controls or subjects with Klinefelter's syndrome. During follow-up, one subject developed frank primary testicular failure. It was concluded that men with low serum testosterone but normal serum LH are a heterogeneous group, and this pattern occasionally reflects early primary testicular failure rather than hypothalamic-pituitary dysfunction. Standard tests of pituitary-testicular reserve are generally not useful in defining abnormal hormonal output, although measurement of the 17-OH-progesterone response to hCG may improve their diagnostic utility.

Hematologic indexes in men attending an infertility clinic.

To assess whether oligospermia in infertile men might be associated with abnormalities of another rapidly dividing cell population, namely, blood cells, we studied retrospectively hematologic indexes in 72 unselected men initially attending an infertility clinic and 119 healthy controls. Red cell and platelet parameters were similar in the two groups. The infertility clinic patients had significantly reduced total leukocyte counts (5818 +/- 179 versus 6397 +/- 174 per mm3; p less than 0.05). This leukopenia reflected a reduction in lymphocyte count (1697 +/- 69 versus 2206 +/- 80 per mm3; p less than 0.0001) but not in neutrophil count (3331 +/- 144 versus 3678 +/- 139 per mm3; p = NS). Lymphopenia was not correlated with sperm density. A prospective study of 24 fertile controls and 12 infertile, oligospermic men revealed no differences between these groups in numbers of lymphocytes, T lymphocytes, T4 (helper) lymphocytes, or T8 (suppressor) lymphocytes. In conclusion, lymphopenia noted retrospectively in men attending an infertile clinic was unrelated to sperm density and was not confirmed in a prospective study. Combined with normal red cell and platelet parameters these findings suggest that hematologic indexes are probably normal in infertile men.

Amenorrhea in Olympic marathon runners.

Women who exercise heavily may develop secondary amenorrhea. Since the mechanism of so-called "runner's amenorrhea" has not been conclusively established, the authors examined the occurrence of amenorrhea in one of the most intensively exercising groups of female runners in the United States (average, 70 miles/week): those women participating in the marathon trials for the 1984 Olympics. Nineteen percent of these Olympic runners were amenorrheic. When compared with eumenorrheic marathon runners, these amenorrheic runners were significantly (P less than 0.05) younger (24.8 +/- 1.2 [standard error of the mean] versus 30.8 +/- 0.8 years), lighter (108.4 +/- 2.5 versus 114.6 +/- 1.7 lb), and leaner (11.2 +/- 0.5 versus 12.5 +/- 0.3% body fat). There were no differences between the two groups in weekly training mileage, proportion completing the marathon trial, finishing time, basal serum prolactin, or postmarathon serum prolactin. Although basal serum cortisol was slightly higher in the amenorrheic group (26.6 +/- 0.8 versus 22.3 +/- 0.7 micrograms/dl; P less than 0.05), postmarathon serum cortisol was similar in the two groups. This study supports the concept that training intensity above a certain threshold seems to have little effect on the development of runner's amenorrhea, and vigorously training national caliber marathon runners have a lower incidence of amenorrhea than previously predicted.

Sexual maturation in underfed weight-matched rats. A test of the "critical body weight" theory of pubertal timing in males.

A popular current theory proposes that the timing of puberty is related to attainment of a critical level of body weight or body fatness. These critical body weight and critical body fat theories have been studied almost exclusively in females. To explore these theories in males, we tested a corollary of these hypotheses: are male rats of the same weight all at the same level of sexual maturation irrespective of prior growth rate? Male rats growing in body weight at five different rates due to various degrees of underfeeding (beginning at weaning) were sacrificed at body weight milestones of 123 and 279 grams. At the first weight milestone, significant (P less than 0.01) inverse correlations were observed among these weight-matched rats between the preceding rate of body weight growth and prostate weight, seminal vesicle weight, testis weight, serum testosterone, and daily sperm production rate, indicating that the underfed animals were more sexually mature. Testis histology also showed that spermatogenic development increased progressively as the prior rate of body weight growth was reduced. These parameters of sexual maturation tended to correlate inversely with body fatness (i.e., leaner animals were more sexually mature) and directly with body length (i.e., longer animals were more sexually mature). By the second body weight milestone, however, the degree of prior underfeeding exerted little effect on those indices of sexual development. We conclude that the degree of sexual maturation in weight-matched animals with varying previous patterns of body weight growth correlates inversely with body fatness and the rate of body weight growth but correlates directly with body length.(ABSTRACT TRUNCATED AT 250 WORDS)

Exaggerated gonadotropin response to luteinizing hormone-releasing hormone in amenorrheic runners.

Most studies of exercise-induced amenorrhea have compared amenorrheic athletes (usually runners) with sedentary control subjects. Such comparisons will identify hormonal changes that develop as a result of exercise training but cannot determine which of these changes play a role in causing amenorrhea. To obviate this problem, we assessed reproductive hormone status in a group of five amenorrheic runners and compared them to a group of six eumenorrheic runners matched for body fatness, training intensity, and exercise performance. Compared to the eumenorrheic runners, the amenorrheic runners had lower serum estradiol concentrations, similar basal serum luteinizing hormone and follicle-stimulating hormone concentrations, and exaggerated responses of serum gonadotropins after administration of luteinizing hormone-releasing hormone (100 micrograms intravenous bolus). Serum prolactin levels, both basally and after thyrotropin-releasing hormone administration (500 micrograms intravenous bolus) or treadmill exercise, was similar in the two groups, as were serum thyroid function tests (including thyrotropin response to thyrotropin-releasing hormone). Changes in serum cortisol levels after short-term treadmill exercise were similar in both groups, and serum testosterone levels increased after exercise only in the eumenorrheic group. In neither group did such exercise change serum luteinizing hormone, follicle-stimulating hormone, or thyrotropin levels. We concluded that exercise-induced amenorrhea is not solely related to the development of increased prolactin output after exercise training. The exaggerated gonadotropin response to luteinizing hormone-releasing hormone seen in amenorrheic runners in comparison with matched eumenorrheic runners is consistent with a hypothalamic etiology for the menstrual dysfunction, analogous to that previously described in "stress-induced" or "psychogenic" amenorrhea.

Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve.

The antifungal drug ketoconazole is known to inhibit testosterone biosynthesis and decrease serum testosterone concentrations. To assess whether the ketoconazole-induced reduction in serum testosterone might stimulate LH and FSH output in a manner suitable as a test of pituitary gonadotropin reserve, we gave normal men ketoconazole every 8 h for 1 week in dosages of 300-1200 mg/day. Ketoconazole administration caused a dose-dependent reduction in serum testosterone which correlated inversely with serum ketoconazole (r = -0.82; P less than 0.001). This fall in serum testosterone stimulated increases in serum LH and FSH which were maximal at a ketoconazole dose of 900 mg/day [LH increase, 127 +/- 27% (+/- SEM); FSH increase, 63 +/- 15%]. Ketoconazole tended to blunt the LH and FSH responses to LHRH. Ketoconazole increased serum 17-hydroxyprogesterone, reflecting blockade of 17,20-desmolase by the drug, while having inconsistent effects on serum estradiol. I conclude that ketoconazole administration for 1 week to normal men stimulates LH and FSH output in a fashion that makes it potentially suitable, after additional verification in subjects with normal and abnormal pituitary-testicular function, as a test of pituitary gonadotropin reserve.