Hypothalamic-pituitary-adrenal axis function and cytokine production in multiple sclerosis with or without interferon-beta treatment.

OBJECTIVES: Pro-inflammatory cytokines mediate brain damage in multiple sclerosis (MS); they can also influence the hypothalamic-pituitary-adrenal (HPA) axis function. We evaluated the possible abnormalities of HPA axis function in relapsing-remitting MS (RR-MS). MATERIAL AND METHODS: IFN-gamma, TNF-alpha and IL-6 production by ex-vivo lymphocytes from 10 normal volunteers and 10 RR-MS patients before and during IFN-beta therapy was assessed; pituitary-adrenal function was evaluated by means of CRH and ACTH stimulation tests. RESULTS: In untreated patients the production of IFN-gamma, TNF-alpha, IL-6 was increased, and was significantly decreased by IFN-beta. Neither basal, nor stimulated ACTH, cortisol, DHEA, DHEAs, 17-alpha-OH-progesterone levels differed between controls and RR-MS patients, both before and during treatment. Moreover, no correlation was found between endocrine and immune parameters. CONCLUSION: In MS the HPA axis function seems normal and not influenced by IFN-beta treatment. This result is discussed in relation to the increased production of pro-inflammatory cytokines found in this disease.

Failure of angiotensin II and insulin to stimulate transforming growth factor-beta1. Release from cultured bovine retinal pericytes.

BACKGROUND: Activation of the renin-angiotensin system (RAS) may induce cardiovascular and renal fibrosis in hypertension and diabetes. This fibrogenic effect is mainly mediated by Transforming Growth Factor-B1 (TGF-B1), a multifunctional citokyne released by endothelial, vascular smooth muscle and renal mesangial cells, that is able to increase extracellular matrix deposition. Retinal capillary pericytes have functions similar to those of mesangial cells, including ability to synthesize and release TGF-B1 and produce extracellular matrix. An intraocular RAS was described in the human eye and may produce effects similar to those observed in the heart and kidney, which could be mediated by TGF-B1. In particular, TGF-B1 might be involved in thickening of the capillary basement membrane in diabetic microangiopathy. We therefore aimed at evaluating the possible effects of Angiotensin-II on TGF-B1 secretion by cultured retinal pericytes (BRP). METHODS: BRP cultures were incubated with Angiotensin-II or insulin (known to play a permissive effect on TGF-B1 release from mesangial cells) or Angiotensin-II + insulin at final concentrations of 10-10, 10-8, 10-6, 10-4 mol/L. RESULTS: Baseline TGF-B1 concentrations in the supernatants of pericyte cultures were 6 139 +/- 1 919 pg/mL/106 cells; no changes of TGF-B1 concentrations resulted from adding increasing amounts of Ang II, insulin or both. CONCLUSIONS: Though confirming that cultured bovine retinal pericytes spontaneously release TGF-B1, Angiotensin-II did not produce any stimulatory effects of in our experimental system

Dehydroepiandrosterone sulfate levels in women. Relationships with age, body mass index and insulin levels.

Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1-89.6 yrs, median 42.2; BMI 15.7-57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7-67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

Alpha-melanocyte-stimulating hormone antagonizes the inhibitory effect of corticotropin-releasing hormone on luteinizing hormone secretion during the luteal phase in normal women.

CRH inhibits the secretion of gonadotropins by activating endogenous opioids, whereas alpha MSH, which displays various behavioral and neuroendocrine effects contrary to those of the opioids, stimulates their release. To evaluate the possible interaction of CRH and alpha MSH, eight women in the luteal phase underwent the following tests: 1) ovine CRH infused at 100 micrograms/h for 3 h, 2) alpha MSH (2.5 mg as an iv bolus 60 min after the start of saline infusion), 3) CRH plus alpha MSH (injected 60 min after the start of CRH infusion), and 4) placebo. LH, FSH, PRL, ACTH, and cortisol were determined every 15 min for 180 min. CRH significantly (P < 0.001) reduced serum LH. alpha MSH alone significantly (P < 0.001) increased LH to a peak within 15-30 min (baseline, 3.3 +/- 0.7 mIU/mL; maximum increase, 3.5 +/- 0.9 mIU/mL) and induced an even greater rise when injected during the CRH infusion (baseline, 2.8 +/- 03 mIU/mL; maximum increase 7.5 +/- 1.6 mIU/mL; P < 0.05 vs. alpha MSH alone). FSH was always unaffected. ACTH and cortisol increased (P < 0.001) during the CRH infusion and fell significantly (P < 0.001) during the placebo infusion. alpha MSH had no effect on these changes. PRL fell during the placebo infusion (P < 0.001). No changes were induced by CRH or alpha MSH. In conclusion, alpha MSH antagonizes CRH inhibition of LH secretion. This finding lends support to the view that differential posttranslational processing of POMC contributes to the regulation of LH secretion. Further investigation is needed to clarify the mechanism of the antagonism between alpha MSH and CRH.