The Journal of clinical endocrinology and metabolism
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J. Clin. Endocrinol. Metab. · Jun 2001
Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women.
Endotoxin stimulates the release of the inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha, which are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Recent studies in the rodent and in the primate have shown that the HPA responses to endotoxin and IL-1 were enhanced by gonadectomy and attenuated by estradiol (E2) replacement. In addition, there is some evidence, in the rodent, that estrogen modulates inflammatory cytokine responses to endotoxin. ⋯ Mean cytokine levels with and without E2 replacement peaked at 341 +/- 94 pg/mL vs. 936 +/- 620 pg/mL for IL-6, 82 +/- 14 ng/mL vs. 133 +/- 24 ng/mL for IL-1 receptor antagonist, and 77 +/- 46 pg/mL vs. 214 +/- 87 pg/mL for TNF-alpha, respectively. We conclude that inflammatory cytokine and HPA responses to a low dose of endotoxin are attenuated in postmenopausal women receiving E2 replacement. These data show, for the first time in the human, that a physiological dose of estrogen can restrain cytokine and neuroendocrine responses to an inflammatory challenge.
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J. Clin. Endocrinol. Metab. · Jun 2001
Randomized Controlled Trial Clinical TrialAromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men.
The present clinical study examines the neuroregulatory hypothesis that feedback restraint of LH and FSH secretion by testosterone requires in vivo aromatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective and potent aromatase inhibitor, anastrazole (5 mg orally twice daily). Blood was sampled every 10 min for 27 h on the last day of intervention to quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH release. ⋯ A 3-fold administration of anastrazole, KTCZ, and testosterone completely opposed exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished testosterone-dependent inhibition of 3-h GnRH-stimulated LH and FSH release. In summary, assuming the specificity of anastrazole's inhibition of aromatase activity, we conclude that circulating testosterone in healthy men curtails endogenously driven as well as exogenous GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
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J. Clin. Endocrinol. Metab. · Jun 2001
Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly.
The effects of a 12- to 24-month treatment with depot long-acting octreotide (OCT-LAR) on hormone profile, tumor mass, and clinical symptoms were reported in 36 patients with active acromegaly [GH, 34.2 +/- 5.6 microg/L; insulin-like growth factor I (IGF-I), 784.5 +/- 40.4 microg/L]. Fifteen patients were de novo whereas 21 had previously undergone unsuccessful surgery. Serum GH (P < 0.0001) and IGF-I levels (P < 0.0001) significantly decreased as early as after the first injection of OCT-LAR and progressively declined during the 12-24 months of treatment both in de novo and in operated patients. ⋯ OCT-LAR treatment was well tolerated by most patients. In conclusion, long-term treatment with OCT-LAR was effective in controlling GH and IGF-I hypersecretion in most patients with acromegaly, when applied either as primary therapy or as adjunctive therapy after surgery. Tumor shrinkage was observed in de novo patients during OCT-LAR treatment, suggesting that it can be successfully applied as primary therapy in patients bearing invasive tumors, who are less likely to be cured after surgery.
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J. Clin. Endocrinol. Metab. · Mar 2001
What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women?
Although obesity is often associated with insulin resistance and a cluster of metabolic disturbances, the existence of a subgroup of healthy but obese individuals has been postulated. It is unclear why some obese individuals fail to show traditional risk factors associated with the insulin resistance syndrome despite having a very high accumulation of body fat. To address this issue, we identified and studied a subgroup of metabolically normal but obese (MNO) postmenopausal women to gain insight into potential physiological factors that may protect them against the development of obesity-related comorbidities. ⋯ Stepwise regression analysis showed that visceral adipose tissue and the age-related onset of obesity explained 22% and 13%, respectively, of the variance observed in insulin sensitivity (total r(2) = 0.35; P: < 0.05 in both cases). Our results support the existence of a subgroup of obese but metabolically normal postmenopausal women who display high levels of insulin sensitivity despite having a high accumulation of body fat. This metabolically normal profile is associated with a lower accumulation of visceral adipose tissue and an earlier age-related onset of obesity.