In normal and obese young males [90--120% and > 160% of ideal body weight (IBW); IBW = 100%], plasma concentrations of testosterone, androstenedione, estrone, and estradiol were measured. Metabolic clearance and production rates of androstenedione and the conversion ratios of androstenedione to testosterone, estrone, and estradiol were determined using the constant infusion technique. In the obese subjects, IBW was inversely correlated (P < 0.001) with plasma concentrations of androstenedione (r = 0.81) and testosterone (r = 0.87), while the levels of estrone (r = 0.92) and estradiol (r = 0.95) increased with IBW (P < 0.001). Thus, when normal and obese subjects were compared as groups, plasma androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15 ng/ml (mean +/- SD) and plasma testosterone decreased from 5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml. The testosterone to androstenedione and the estradiol to estrone ratios were not different in obesity, but changes in IBW were positively correlated (P < 0.001) with differences in the estrone to androstenedione (r = 0.93) and estradiol to testosterone ratios (r = 0.93), indicating that fat tissue may aromatize androgens, whereas reduction of 17-oxo-steroid appears to be of minor importance. As the MCR of androstenedione increased with IBW (from 2156 to 2636 liters/day P < 0.05) while plasma levels decreased, the apparent production rate of androstenedione was not influenced by the degree of obesity. The conversion of androstenedione to estrone (r = 0.89) and of androstenedione to estradiol (r = 0.82) was enhanced in obese subjects (P < 0.001). We suggest that enhanced aromatization of androstenedione due to an increased adipose tissue mass may account for the high plasma estrogen levels observed in obese men.

In obese male subjects with 160 - 200% of ideal body weight (IBW = 100%) the decrease in total plasma testosterone is biologically ineffective since SHBG is concomitantly decreased from 30.0 +/- 3.6 to 20.0 +/- 3.4 nM/l. Conversely, in massively obese males with greater than 250% of IBW, the decrease in SHBG (to 10.6 +/- 1.8 nM/l) is too small to compensate for total testosterone decrease (from 6.04 +/- 0.57 to 1.72 +/- 0.32 ng/Ml). Therefore, free testosterone is markedly less in the massively obese patients (55 +/- 8 vs. 127 +/- 15 pg/ml in the controls). Despite this significant difference in free testosterone concentrations (p less than 0.01), plasma LH is even lower in the obese (6.8 +/- 0.8 mU/ml) than in the controls (10.0 +/- 1.0 mU/ml). This may be an effect of free estradiol, which rises from 0.48 to 1.52 pg/ml in the massively obese subjects. These alterations are clearly demonstrated by the imbalance of the estradiol/testosterone ratios, which increase 10-fold and 7-fold for the total and for the free sex hormones, respectively. We conclude that the decrease in SHBG, which prevents obese males from developing hypogonadism, is not sufficiently effective in the massively obese patients to compensate the marked decrease in testosterone. This, in connection with the observed increase of free estradiol, may cause hypogonadism and hyperestrogenism in these subjects.

Abstract. Calcium metabolism and plasma concentrations of vitamin D metabolites were investigated in 27 children on long-term anticonvulsant therapy. Serum calcium was in the low normal range, phosphorus was normal, parathyroid hormone concentrations and alkaline phosphatase were elevated. Plasma 25-hydroxyvitamin D (25-OH D) and 24,25-dihydroxyvitamin D (24,25-(OH)2D) were decreased, but 1,25-dihydroxyvitamin D (1,25-(OH)2D) was normal when compared with a synchronous control group. The serum concentrations of all anticonvulsant drugs given were measured. The decreases in 25-OH D and 24,25-(OH)2D did not depend on the blood level of a single drug, or any combination of drugs given, or on the duration of therapy. The 25-OH D levels were negatively correlated with the number of different drugs used, which may reflect the severity of the neurologic disorder, and therefore with non-specific factors such as exposure to sunlight, nutrition, or physical activity.Our data do not support the hypothesis that anticonvulsant drugs act on vitamin D metabolism. Key words: Calcium metabolism -Vitamin D metabolites - Anticonvulsant drugsAnticonvulsant drugs, particularly diphenylhydantoin (DPH) and phenobarbital (PB), are known to affect calcium metabolism and to cause rickets or osteomalacia [1,2]. In vitro, in the rat, Caspary [3] and Koch et al. [4] found that intestinal absorption of calcium was depressed by DPH but not by PB. The amounts of the vitamin D dependent calcium binding were found to be normal [3].Since PB induces hepatic microsomal enzymes, it has been suggested that due to increased 25-hydroxylase activity PB may increase the availability of25-OH D and its conversion to more polar but less active vitamin D metabolites, thus enhancing plasma clearance of vitamin D and leading to reduced serum and tissue levels of active vitamin D metabolites [5][6][7]. Conversely, in patients receiving anticonvulsant therapy plasma levels of 24,25-(OH)2D were decreased [8], and levels of 1,25-(OH)2D were reported to be normal [9]. It was concluded that in the presence of PB the intestine is less responsive to 1,25-(OH)2D, or that other factors than vitamin D metabolites may impair intestinal calcium transport. [10] found that in epileptic patients on anticonvulsant therapy absorption of calcium from the digestive tract was moderately depressed but that small doses of 1,25-(OH)2D as well as 25-OH D enhanced calcium absorption. They concluded that the sensitivity of the intestine to vitamin D was not impaired in these subjects. These results may indicate that in patients on anticonvulsant therapy the serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) abnormalities are not caused by a defect in 1,25-(OH)2D metabolism or action on the intestine. As vitamin D metabolism is particularly influenced by external factors such as seasonal changes and differences in exposure to sunlight, physical activity and nutritional status, control data may be derived only from carefully matched subjects. This was also cons...

Skeletal demineralization occurs in thyrotoxicosis. Fecal calcium excretion may be enhanced, and calcium balance tends to be negative. We investigated intestinal calcium transport in 12 hyperthyroid patients. Absorption was measured by segmental perfusion in the proximal jejunum at calcium concentrations commensurate with those in the fasting and postprandial states. At low luminal concentrations, under conditions where calcium is transported predominantly by active processes, the calcium absorption rate was reduced though not abolished in hyperthyroid patients (16 +/- 4 (SE) mumol/h . 30 cm segment) as compared to normal subjects (71 +/- 8 mumol/h; P less than 0.001). When perfusate calcium was raised to 5 mmol/liter there was little increment of the net absorption rate in the hyperthyroid group (45 +/- 11 mumol/h), whereas that in the normal subjects rose to 183 +/- 17 mumol/h. Likewise, the unidirectional calcium flux out of the lumen was low in hyperthyroidism (43 +/- 7 mumol/h), suggesting that low net absorption rates were not due to transmucosal calcium loss. D-Xylose permeation was similar in all study groups. Treatment of the thyroid disease led to a marked increase in calcium absorption rates from 33 +/- 10 to 124 +/- 20 mumol/h (at 2 mmol/liter P less than 0.001; n = 5) into the range of values in normal subjects (124 +/- 9 mumol/h). Circulating levels of 1,25-dihydroxyvitamin D were low in hyperthyroid patients (38 +/- 11 pg/ml) and increased during treatment to 63 +/- 11 pg/ml (P less than 0.025; n = 9), whereas 25-hydroxyvitamin D was normal and remained unchanged. We conclude that intestinal calcium transport, particularly its active component, is reversibly decreased in hyperthyroidism. The association with low plasma levels of the active vitamin D metabolite suggests that the decrease in calcium absorption may be related to calcium-regulating mechanisms as a consequence of the net calcium efflux from bone in this disease.

Digoxin has been reported to induce feminizing effects in man. It does not compete for estradiol cytosol receptors in human breast carcinoma cells, however, and has no uterotrophic effect. We therefore investigated whether feminization might be due to digoxin action on plasma concentrations of sex steroids. Six healthy men (31.5 +/- 4 yr old) received therapeutic doses of digoxin for 43 days. We measured plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estrone, estradiol, progesterone, 17-hydroxyprogesterone, cortisol, and aldosterone. During 35 days on digoxin levels of these steroids remained in the normal range and there was no change from before-drug values. Digoxin was in the therapeutic range of 1.9 +/- 3 nmol/l throughout. After stimulation by adrenocorticotropic hormone or human choriongonadotropin, the rise in plasma steroids was in the same range as when digoxin was given, as well as 16 wk after it had been discontinued. A normal rise in luteinizing hormone after luteinizing hormone-releasing hormone showed that the hypothalamogonadal feedback was not altered by digoxin. Free testosterone, estradiol, and cortisol concentrations under basal conditions and after stimulation were also the same before and after drug. It is concluded that the estrogen-like activity of digoxin cannot be explained by altered steroid availability from plasma. Feminizing effects attributed to digoxin may be caused by other conditions known to influence sex steroid hormones that are common in patients with heart disease. Our data suggest that digoxin may be the preferred digitalis therapy to avoid feminizing effects.