A low-dose adrenocorticotropin test reveals impaired adrenal function in cancer patients receiving megestrol acetate therapy.

Megestrol acetate (MA) has glucocorticoid activity and can induce significant secondary adrenal suppression. We designed this study to determine the extent of adrenal insufficiency in cancer patients receiving MA by utilising a sensitive low-dose adrenocorticotropin (ACTH) stimulation test. Adrenal function was assessed by a low-dose (0.625 microg) ACTH (1-24) stimulation test in 30 patients receiving MA for metastatic cancer. 10 of the patients who failed this test underwent a standard (250 microg) test on another day. Adrenal function was also evaluated in 15 of the patients by measuring the excretion of free cortisol in 24-h urine samples. Peak serum cortisol levels following stimulation with low-dose (0.625 microg) ACTH (1-24) were <18 microg/dl in 16 of 30 (53%) patients, of whom 9 had a basal serum cortisol level of <5 microg/dl. Five of 16 poor responders to the low-dose test showed normal stimulation with the standard (250 microg) ACTH (1-24) test. Thus, adrenal insufficiency would fail to be detected by the standard high dose test in these patients. Patients who failed the low-dose ACTH (1-24) test had lower 24-h urinary free cortisol excretion (8.7+/-10.3 microg/24 h) than normal responders (35+/-12.7 microg/24 h). Impaired adrenal function is common in cancer patients receiving MA. The low-dose ACTH (1-24) test is apparently capable of revealing adrenal insufficiency undetected by the standard high-dose ACTH test. Patients receiving MA might have inadequate adrenal function during episodes of infection or after withdrawal of MA therapy and this may require prompt corticosteroid treatment.

Selective modulation by vitamin D of renal response to parathyroid hormone: a study in calcitriol-resistant rickets.

Calcitriol-resistant rickets (CRR) is an autosomal recessive disease caused by mutated nonfunctioning vitamin D receptors. Because of their lack of biological activity of vitamin D, CRR patients were studied to investigate whether vitamin D modulates the effects of PTH on renal tubules. Five patients with CRR and three controls were studied. After normalization of serum calcium, phosphorus, and PTH levels by oral and i.v. administration of calcium, exogenous PTH-(1-34) was infused, and timed fractions of urine were collected for measurements of cAMP, sodium, potassium, phosphorus, calcium, and bicarbonate. Serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] was measured before and after PTH-(1-34) infusion. Urinary cAMP and fractional excretion of potassium, phosphorus, and bicarbonate were similar in CRR patients and controls, as was the rise in the serum 1,25-(OH)2D3 concentration after PTH-(1-34) infusion. However, urinary excretion of calcium and sodium decreased after PTH-(1-34) infusion in controls, but not in CRR patients. These results suggest a selective modulation by vitamin D of the renal response to PTH; 1,25-(OH)2D3 facilitates PTH-induced calcium and sodium reabsorption, but does not influence PTH-induced cAMP excretion; phosphorus, potassium, and bicarbonate tubular transport, or 1 alpha-hydroxylation of 25-hydroxyvitamin D3.

Sex-specific response of bone cells to gonadal steroids: modulation in perinatally androgenized females and in testicular feminized male rats.

We have found previously that rat diaphyseal bone in vivo, as well as rat embryo calvaria cells in culture, show a sex-specific response to gonadal steroids in stimulation of creatine kinase (CK)-specific activity, and the rate of [3H]thymidine incorporation into DNA; male-derived cells responded only to testosterone or to dihydrotestosterone (DHT), whereas female-derived cells were stimulated exclusively by estradiol (E2). In this study, we tested whether developmental hormone manipulation could alter this sex specificity. We showed that diaphyseal bone of prenatally or neonatally androgenized female rats responds to a single injection of either E2 (5 micrograms/rat) or DHT (50 micrograms/rat) at 3-4 weeks postandrogenization. This response of androgenized female diaphyseal bone to androgen gradually declines; 3 months posttreatment, diaphyseal bone no longer responds to DHT and reverts to its original sex specificity. Rat embryo calvaria cell cultures prepared from female fetuses androgenized in utero showed the same lack of hormonal specificity, that is, the cells responded to both E2 (30 nM) or DHT (300 nM). Cells derived from the male siblings of the prenatally androgenized rats were not affected and responded only to DHT. In contrast to experiments in utero, in vitro administration of testosterone (1 microM) or E2 (1 microM) to calvaria cells from female embryos failed to cause the cells to respond to DHT. Androgen receptor-deficient (Tfm) male rats, which have approximately 10% of the normal response to androgens, also showed a response to both testosterone and E2 in comparison to their normal male siblings, whose bones responded only to androgens.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6-GnRH).

Administration of GnRH agonist analogs to women may result in a hypoestrogenic state and bone mass reduction. In the present study we examined bone mineral density (BMD) and parameters of mineral metabolism in elderly men with benign prostatic hyperplasia before and during a hypoandrogenic state induced by the long-acting GnRH agonist D-Trp6-LHRH (decapeptyl). Our results showed that decapeptyl treatment caused a significant decrease in serum testosterone concentrations in all patients and resulted in a significant decrease in individual vertebral BMD in 10 of 17 patients. A significant decrease in BMD was observed in 5 patients after 6 months of treatment. Another 5 patients showed a decreased BMD only after 12 months. The mean serum concentrations of osteocalcin, phosphorus, and alkaline phosphatase activity increased after 6-12 months of treatment with decapeptyl. Serum calcium, vitamin D metabolites, and PTH concentrations remained unchanged during treatment. Urinary calcium excretion was slightly, but not significantly, increased after 6 months of treatment. These results demonstrate that long-acting GnRH agonist treatment may cause high turnover accelerated bone loss in some men during the first year of GnRH agonist treatment, as has been previously shown in women.

Prolonged treatment with finasteride (a 5 alpha-reductase inhibitor) does not affect bone density and metabolism.

OBJECTIVE: Since it is not clear whether testosterone or dihydrotestosterone is the active hormone in bone metabolism, we wished to assess the effect of finasteride, a 5 alpha-reductase inhibitor, or vertebral bone mineral density and parameters of bone and mineral metabolism. DESIGN: Patients were treated in a randomized, double-blind controlled study with either placebo, 1 or 5 mg/day finasteride. PATIENTS: Twenty-three men with benign prostatic hyperplasia (BPH) were included in this study; eight received placebo, seven were allocated to treatment with 1 mg/day, and eight to 5 mg/day finasteride for 12 months. MEASUREMENTS: Vertebral bone mineral density was measured at the lumbar spine by dual energy X-ray bone densitometry. Serum calcium, phosphorus, parathyroid hormone, osteocalcin and vitamin D metabolites were measured regularly. Urinary calcium and creatinine excretion were monitored as well. RESULTS: Finasteride caused a significant decrease in serum dihydrotestosterone after 6 and 12 months, but no effect on serum testosterone. Vertebral bone mineral density remained unaltered. None of the other parameters monitored were affected except for a small unexplained increase in 1.25-dihydroxyvitamin D in the group receiving 5 mg finasteride/day. CONCLUSIONS: Testosterone is probably the active hormone in bone metabolism. However, oestradiol, the product of testosterone aromatization (which remains unaltered under finasteride) may yet be another possible responsible steroid in the maintenance of bone density. We can also not rule out that the small amount of dihydrotestosterone remaining under finasteride administration is sufficient for maintaining normal bone metabolism.

Vitamin D deficiency in elderly patients in a general hospital.

Serum 25-hydroxyvitamin D (25-OHD) levels were measured in 338 elderly patients admitted to the Geriatric Medicine Departments of a general hospital in Israel in the course of one year. The mean (+/- SD) serum 25-OHD levels were significantly lower (P less than .01) in the elderly patients (13.5 +/- 8.9 ng/mL) than in healthy young controls (24.7 +/- 6.1 ng/mL). One hundred ten patients (35.5%) were either vitamin D deficient (25-OHD less than 5 ng/mL) or had borderline serum levels of 25-OHD (5-9 ng/mL). The mean (+/- SD) serum 25-OHD concentration of patients who were completely mobile before hospitalization was 15.5 +/- 8.8 ng/mL (n = 239). In patients mainly immobilized but able to leave the house occasionally, it was 10.2 +/- 6.3 ng/mL (n = 84) and of bed-ridden patients, it was 5.2 +/- 3.2 ng/mL (n = 15). No correlation was found between serum 25-OHD levels and the patients' age or serum calcium, phosphorus, alkaline phosphatase, and albumin values. Thus, in order to detect vitamin D deficiency in the elderly, it is necessary to measure serum 25-OHD concentration. The results demonstrate that vitamin D deficiency is common among elderly patients even in sunny climates and indicate the need for development of effective programs of prevention and treatment.

Single oral high-dose vitamin D3 prophylaxis in the elderly.

A poor vitamin D status is common in the elderly during the winter months. Because it is possible that hypovitaminosis D may be a cause of senile osteopenia, a simple method of prophylaxis would be useful. The single, oral, high-dose method was tested in two old-age homes, and the efficacy of vitamin D3 was compared with that of 25-hydroxyvitamin D3 (25-OHD3). The trials showed that 25-OHD3 caused a higher peak value in the serum 25-OHD levels in the second week than did vitamin D3. However, follow-up after four to five months showed that in those patients who received a single, oral dose of 25-OHD3, the serum 25-OHD levels had returned to the baseline low values, whereas in those patients who had had oral vitamin D3, the serum 25-OHD levels still remained significantly raised compared with the baseline values and were within normal limits. It is concluded that the single, oral, high-dose method using vitamin D3 is a safe and simple method of prophylaxis and could be used easily in large populations of elderly persons.