The purpose of this investigation was to localize and characterize white blood cell populations in the human ovary through its physiological life cycle. Ovaries from 30 women of reproductive age and from three post-menopausal women were embedded in paraffin or frozen. Clinical information and pathology review were used to obtain accurate menstrual cycle information and to ensure the absence of ovarian disease. Tissue sections were stained for leukocyte phenotypes and the numbers of white blood cells in the ovary were semiquantitatively assessed by two separate examiners using a 0-3 plus (+) scoring system. Our results demonstrated that macrophages and T lymphocytes were the primary immune cells of the ovary, the concentrations of which were dependent on the location and stage of development of the structures containing leukocytes. Developing follicles contained few (+) macrophages located in the theca, while atretic follicles possessed moderate (+2) numbers in the granulosa and few (+) to moderate (+2) numbers in the theca. Newly formed corpora lutea contained few (+) macrophages, while regressing corpora lutea contained abundant (+3) numbers. Human leukocyte antigen (HLA)-DR positive cells were located predominantly at sites where macrophages were present. T lymphocytes were generally not present in the developing follicle but focal, small (+) numbers were observed in blood vessels of the theca. Atretic follicles contained few (+) T lymphocytes in the granulosa and few (+) to moderate (+2) numbers in the theca. Few (+) T lymphocytes were present in new corpora lutea, while moderate (+2) to abundant (+3) numbers were present in regressing corpora lutea. T lymphocytes at all sites were UCHL1 positive. The CD4 (T helper) to CD8 (T suppressor) ration in the corpus luteum was 1:1. B-lymphocytes and natural killer cells were generally absent in the pre-menopausal ovary. The post-menopausal ovary, in contrast, only contained few (+) macrophages, T lymphocytes and natural killer cells in the stroma. In conclusion, our results indicate that the human ovary is an immunologically dynamic tissue containing activated macrophages and T lymphocytes which provide an anatomical basis for immunoendocrine interactions within the ovary.

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Burger NZ, Kuzina OY, Osol G, Gokina NI. Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca 2ϩ . Am J Physiol Endocrinol Metab 296: E503-E512, 2009. First published January 6, 2009 doi:10.1152/ajpendo.90517.2008.-Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the regulation of vascular microcirculatory tone. This study explores the role of estrogen in controlling EDHF-mediated vasodilation of uterine resistance arteries of the rat and also analyzes the contribution of endothelial cell (EC) Ca 2ϩ signaling to this process. A parallel study was also performed with mesenteric arteries to provide comparison with a nonreproductive vasculature. Mature female rats underwent ovariectomy, with one half receiving 17␤-estradiol replacement (OVXϩE) and the other half serving as estrogen-deficient controls (OVX). Uterine or mesenteric resistance arteries were harvested, cannulated, and pressurized. Nitric oxide and prostacyclin production were inhibited with 200 M N G -nitro-L-arginine and 10 M indomethacin, respectively. ACh effectively dilated the arteries preconstricted with phenylephrine but failed to induce dilation of vessels preconstricted with high-K ϩ solution. ACh EC50 values were decreased by estrogen replacement by five-and twofold in uterine and mesenteric arteries, respectively. As evidenced by fura-2-based measurements of EC cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]i), estrogen replacement was associated with increased basal and ACh-stimulated EC [Ca 2ϩ ]i rise in uterine, but not mesenteric, vessels. These data demonstrate that EDHF contributes to endothelium-dependent vasodilation of uterine and mesenteric resistance arteries and that estrogen controls EDHFrelated mechanism(s) more efficiently in reproductive vs. nonreproductive vessels. Enhanced endothelial Ca 2ϩ signaling may be an important underlying mechanism in estrogenic modulation of EDHFmediated vasodilation in small resistance uterine arteries. endothelium-derived hyperpolarizing factor; acetylcholine; fura-2; high potassium THE VASCULAR ENDOTHELIUM plays an important role in the control of blood vessel tone through release of relaxing and contracting factors in response to mechanical or agonist-

Objective-To determine if insulin resistance associated with combination hormone replacement therapy (HRT) is mediated by changes in serum markers of inflammation or in serum adipocyte hormones.Study design-Forty-five postmenopausal women, aged 55 ± 7 years, were examined from a randomized, double-blind placebo-controlled trial evaluating the effect of HRT on insulin-stimulated glucose disposal and body composition. Volunteers were randomized to conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg vs. placebo for 1 year. At baseline and at 1 year, body composition was assessed by dual photon x-ray absorptiometry scans (DEXA); body fat distribution was measured by CT scans at the L4/L5 vertebral disc space; insulin sensitivity was measured by euglycemic hyperinsulinemic clamp; interleukin-6 (IL-6), leptin and adiponectin were measured by ELISA; and c-reactive protein (CRP) was measured by RIA.Results-HRT increased CRP by 121% compared to a 32% increase with placebo (p=0.03); HRT decreased glucose disposal by 17% compared to no change with placebo (p=0.04) as reported previously. HRT did not affect body composition, body fat distribution, IL-6, leptin, or adiponectin. The increase in CRP did not correlate with the decrease in glucose disposal in the HRT group (R=0.11, p=0.65).Conclusion-Treatment with HRT for one year increases CRP, but does not alter IL-6, adiponectin, or leptin. The change in CRP was not, however, related to the decrease in glucose disposal with HRT treatment.