Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males.

Suppression of estrogen, via estrogen receptor or aromatase blockade, is being investigated in the treatment of different conditions. Exemestane (Aromasin) is a potent and selective irreversible aromatase inhibitor. To characterize its suppression of estrogen and its pharmacokinetic (PK) properties in males, healthy eugonadal subjects (14-26 yr of age) were recruited. In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period. Blood was withdrawn before and 24 h after the last dose of each treatment period. A PK study was performed (n = 10) using a 25-mg dose. Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P

Synergistic effects of testosterone and growth hormone on protein metabolism and body composition in prepubertal boys.

During human puberty there is a substantial increase in growth hormone (GH) and sex steroidal hormone concentrations, as well as in GH production rates and insulin-like growth factor-I (IGF-I) These studies were designed to investigate some of the interactions of testosterone (T) and GH in the metabolic changes of puberty. Ten boys with severe GH deficiency (GHD) were studied (mean age, 12.5 +/- 0.5 years) using stable isotope infusions, indirect calorimetry, and body composition analysis. After the baseline study, they received 2 doses of T enanthate (50 to 75 mg, intramuscular [IM]), and they were studied again 4 weeks later. The boys were then begun on daily subcutaneous (SC) GH (0.3 mg/kg/wk), while T therapy was continued for another 4 weeks and the studies repeated a third time. The treatment order was randomized. Protein oxidation rates decreased after T alone (-28%, P <.01), decreasing further after combined T/GH treatment (-36% v baseline, P <.01). The nonoxidative leucine disposal (NOLD), a measure of whole body protein synthesis, increased significantly after combined T/GH regardless of treatment order. The combination of T/GH also resulted in greater changes in body composition than T alone, with comparable decreases in %FM and corresponding increases in fat free mass (FFM). Measures of carbohydrate (CHO) metabolism, including glucose production and oxidation rates, were unaffected by either T or T/GH combination. Plasma IGF-I concentrations increased after T treatment and even more after T/GH combination, regardless of the treatment order. In conclusion GH and T are synergistic on whole body protein anabolism and body composition in males, even at a young age, but the positive effects of T on protein anabolism and body composition appear to need a basal amount of GH for those effects to be observed. GH and T both potentiate the development of the full body composition and metabolic changes of puberty.

Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study.

The present studies were designed to determine whether recombinant human growth hormone (rhGH) can counteract some of the catabolic effects of glucocorticosteroid therapy in children chronically treated with glucocorticosteroids. Whether rhGH can safely improve short-term linear growth was also investigated. The effect of rhGH on disease activity was also assessed. Ten children (6 boys, 4 girls) with inflammatory bowel disease (IBD) on oral prednisone for at least 4 months prior to these studies were recruited (mean +/- SE, 11.9 +/- 0.9 years). Leucine and glucose isotope studies, body composition, substrate oxidation and energy expenditure rates, and growth factors were measured at baseline (D1) and at 4 months after treatment with rhGH (0.05 mg/ kg. d subcutaneously [SC]) while continuing oral prednisone. Dual-emission x-ray absorptiometry (DEXA) and calcium kinetic analysis ((42)Ca/(46)Ca) were performed also. rhGH was continued for 6 months to assess linear growth in all 10 subjects, 7 of whom continued rhGH for 12 months. Body composition changed favorably with increased fat free mass (+3 kg, P =.001) and decreased percent fat mass (-3.5%, P =.001) after 4 months of treatment. Rates of whole body protein turnover, oxidation, and synthesis remained invariant, with no changes in substrate oxidation or resting energy expenditure rates. Linear growth velocity increased from 3.5 +/- 0.4 cm/yr when the patients were treated with prednisone only, to 7.7 +/- 0.9 after 6 months of combined prednisone/rhGH (P =.001). The growth velocity was sustained in the 7 patients treated with rhGH for 12 months. Plasma insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) concentrations also increased significantly while on rhGH treatment. No changes in calcium absorption were observed but there was a significant increase in kinetic rates of bone calcium accretion (P =.045) as well as in bone-specific alkaline phosphatase concentrations, a measure of bone formation (P =.03). Fasting and 2-hour postprandial glucose concentrations, fasting insulin levels, and HbA(1C) were invariant during combined rhGH/prednisone treatment. The Crohn's disease activity score was unchanged with rhGH therapy. In summary, rhGH treatment of corticosteroid-dependent patients with IBD was associated with positive changes in body composition, bone metabolism, and linear growth, without deterioration of carbohydrate tolerance or intermediate metabolism of substrates. We conclude that treatment with rhGH has beneficial effects in prednisone-dependent growing children. Larger studies will be needed to assess the long-term safety and efficacy of this approach.

An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys.

OBJECTIVE: To investigate whether 12 mo treatment with the aromatase inhibitor anastrozole can achieve sustained suppression of estrogen production and delay epiphyseal fusion in growth hormone deficient (GHD) adolescent males. STUDY DESIGN: 20 adolescents with GHD were recruited (mean age +/- SE: 14.7 +/- 0.5 yr). Ten continued on GH (control group), and 10 on GH and anastrozole (Rx group) for 12 mo. RESULTS: After 12 mo E2 concentrations declined 60% in the Rx group (from 1.8 +/- 0.5 to 0.7 +/- 0.3 pg/ml, p <0.05) whereas they increased in controls (from 1.2 +/- 0.7 to 1.8 +/- 0.7, p <0.05). Testosterone increased 117% in the Rx group (from 304 +/- 31 to 626 +/- 64 ng/dl), 47% in controls (from 274 +/- 89 to 398 +/- 51) (p = 0.03, ANOVA between groups). IGF-I increased 42% in controls (454 +/- 22 to 711 +/- 109 ng/ml, p <0.05), but remained invariant in the Rx group (446 +/- 29 to 540 +/- 80, p = NS). Bone markers, plasma lipids, insulin, glucose, and liver function tests were all unchanged between groups with no differences either in body composition or bone mineral density accrual. There were no differences in growth velocity, height SDS, bone age advancement, predicted adult height or testicular volumes between groups after 12 mo. CONCLUSIONS: Anastrozole treatment potently decreases estrogen concentrations in adolescent males with GHD while allowing normal virilization, without deleterious effects on body composition, plasma lipids, bone metabolism or the tempo of puberty. Twelve months of treatment, however, did not increase predicted adult height. Further studies are needed to ascertain whether more prolonged estrogen blockade is helpful in the treatment of growth retardation in puberty.

Anticipatory mourning in parents with a child who dies while hospitalized.

Even when prognosis is poor and death appears imminent, care of the dying child typically focuses on achieving cure. Parents are often ill-prepared to cope with the grief they experience as their child is dying. Anticipatory mourning allows time to begin grief work prior to the death of a loved one. An exploratory design was used to answer questions in focused semistructured interviews to determine the presence and the role of anticipatory mourning, and to describe the themes expressed by parents. Parents' descriptions of their experiences surrounding the death of their child reveal an environment and a health care team that are often ill-prepared to deal with the impending death of a child. Also described are instances that reflect a compassionate process that positively affects the experience while facilitating appropriate grief work. Offered are recommendations for health care professionals that may assist parents in coping with the death of their child.