Comparison of prophylactic oophorectomy specimens from carriers and noncarriers of a BRCA1 or BRCA2 gene mutation. United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group.
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BACKGROUND: The natural history of ovarian cancer is not well understood and, to date, there is conflicting evidence as to whether or not there is a demonstrable precursor lesion. Some women at high risk of developing ovarian cancer because of their family history elect to have a prophylactic oophorectomy. To determine whether or not a recognizable premalignant lesion could be defined in familial ovarian carcinogenesis, we reviewed ovarian tissue specimens from women whose ovaries were removed prophylactically before gene testing became available and who were tested subsequently for BRCA1 or BRCA2 gene mutations. METHODS: We analyzed ovarian tissue specimens from 37 women. The specimens were examined for the presence of the following four features: inclusion cysts, clefts and fissures, ovarian epithelial metaplasia, and the presence of papillae on the ovarian surface epithelium. The specimens were also examined closely for the presence of dysplasia and occult neoplasia. Furthermore, the occurrence of endometriosis and benign ovarian tumors was documented in these women. The protein truncation test, nonradioactive single-stranded conformation polymorphism analysis, and heteroduplex analysis, followed by DNA sequencing, were used to identify BRCA1 or BRCA2 mutations in either blood samples or ovarian tissue specimens. RESULTS: Eleven women had inherited a mutated BRCA1 or BRCA2 gene; 26 women had not. There was no difference between these groups for any of the features studied. CONCLUSIONS: Our data suggest that many of the histologic "abnormalities" described in "normal" ovaries are, in fact, variations of the normal and are not associated with the development of cancer. (+info)
Progesterone via its receptor antagonizes the pro-inflammatory activity of estrogen in the mouse uterus.
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Populations of macrophages and neutrophils in the uterus are under the control of the female sex steroids estrogen and progesterone (P4). Their influx is induced by estrogen, while P4 can both stimulate and inhibit leukocyte influx depending on the timing of P4 with respect to estrogen. Regulation of leukocytes has been implicated in changes in uterine immune responses during the estrous cycle, pregnancy, and implantation. This work demonstrates that P4 given concurrently with estrogen to ovariectomized mice for 4 days antagonizes the ability of estrogen to recruit macrophages and neutrophils into the mouse uterus. Using progesterone receptor knockout (PRKO) mice, we show that this effect is dependent on progesterone receptors (PR). In the absence of PR, neutrophils recruited by estrogen were found to be degranulated, partially explaining the edema that is observed with long-term treatment of PRKO mice with estrogen and P4. Populations of B lymphocyte cells were shown to be unchanged by estrogen and P4 treatment in both wild-type and PRKO mice. The neutrophil chemotactic chemokine MIP-2 was examined for down-regulation by P4 but was found to be unaffected by hormonal treatment. Together, these observations demonstrate that PR has a strong anti-inflammatory role in the mouse uterus when estrogen and P4 are present together. (+info)
Alteration in sexually dimorphic testosterone biotransformation profiles as a biomarker of chemically induced androgen disruption in mice.
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Assessment of the impact of environmental chemicals on androgen homeostasis in rodent models is confounded by high intraindividual and interindividual variability in circulating testosterone levels. Our goal was to evaluate changes in testosterone biotransformation processes as a measure of androgen homeostasis and as a biomarker of exposure to androgen-disrupting chemicals. Sex-specific differences in hepatic testosterone biotransformation enzyme activities were identified in CD-1 mice. Gonadectomy followed by replacement of individual steroid hormones identified specific sex differences in biotransformation profiles that were due to the inductive or suppressive effects of testosterone. Notably, significant androgen-dependent differences in testosterone 6[alpha]- and 15[alpha]-hydroxylase activities were demonstrated, and the ratio of 6[alpha]- and 15[alpha]-hydroxylase activities proved to be an excellent indicator of the androgen status within the animal. The male or "masculinized" testosterone 6[alpha]/15[alpha]-hydroxylase ratio was significantly less than the female or "feminized" ratio. Male mice were exposed to both an antiandrogen, vinclozolin, and to a compound that modulates serum androgen levels, indole-3-carbinol, to test the utility of this ratio as a biomarker of androgen disruption. Treatment with the antiandrogen vinclozolin significantly increased the 6[alpha]/15[alpha]-hydroxylase ratio. Indole-3-carbinol treatment resulted in a dose-dependent, but highly variable, decrease in serum testosterone levels. The 6[alpha]/15[alpha]-hydroxylase ratio increased as serum testosterone levels decreased in these animals. However, the increase in the ratio was much less variable and more sensitive than serum testosterone levels. These investigations demonstrate that the 6[alpha]/15[alpha]-hydroxylase ratio is a powerful measure of androgen modulation and a sensitive indicator of exposure to androgen-disrupting chemicals in CD-1 mice. (+info)
Granule cells in aging rats are sexually dimorphic in their response to estradiol.
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Normal aging comprises cognitive decline, including deterioration of memory. It has been suggested that this decline in memory is sexually dimorphic because of the cessation in gonadal steroid secretion that occurs during reproductive aging in female, but not male, mammals. We wondered whether neurons in brain regions associated with learning and memory underwent morphological changes that were dimorphic as well and whether cessation of the secretion of gonadal steroids influenced these morphological changes. To explore these questions, we deprived and restored estrogens to young and old gonadectomized females and males and studied the morphology of dentate granule cells by intracellular dye filling in a lightly fixed slice preparation. We found the following: (1) Aged female dentate granule cells deprived of gonadal steroids long-term have a paucity of dendritic spines compared with young females deprived short-term; however, aged male dentate granule cells deprived of gonadal steroids long-term have no decrease in dendritic spines compared with young males deprived short-term. (2) Aged female dentate granule cells with long-term estrogen replacement at either high or low levels still had a decline in spine density. (3) Aged female dentate granule cells with short-term estradiol replacement had spine density increased to levels normally observed in young adults, whereas aged males with short-term estradiol replacement had decreased spine density. These data suggest that the response of rat dentate granule cells to aging and estradiol is sexually dimorphic and that, in females, the responsiveness of granule cells depends on the temporal pattern of estradiol replacement. (+info)
Progesterone stimulates pancreatic cell proliferation in vivo.
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Treatment of cyclic and pregnant rats with progesterone stimulates cell proliferation within the islets of Langerhans. It was investigated whether this effect of progesterone depends on sex and/or the presence of the gonads or the presence of oestradiol. For this purpose, Silastic tubes containing progesterone were inserted s.c. in intact and gonadectomized male and female rats, and in gonadectomized female rats treated with oestradiol. After 6 days of progesterone treatment, rats were infused for 24 h with 5-bromo-2'-deoxyuridine (BrdU) and dividing cells were identified in pancreatic sections by immunostaining for BrdU. Progesterone treatment increased islet-cell proliferation in intact male and female rats (P < 0.05), but not in gonadectomized male and female rats or in gonadectomized female rats supplemented with oestradiol. Furthermore, in intact male and female rats, progesterone treatment also stimulated cell proliferation in extra-islet pancreatic tissue (P < 0.05). Identification of the proliferating cells, by double-immunocytochemistry, revealed that progesterone treatment stimulated proliferation of both alpha and beta cells within the pancreatic islets. In extra-islet pancreatic tissue, progesterone treatment stimulated proliferation in both duct (cytokeratin 20-immunoreactive) and non-duct cells. Progesterone treatment did not increase the number of single glucagon or insulin-containing cells outside the pancreatic islets, nor that of cytokeratin 20/insulin double-positive cells, suggesting that progesterone treatment did not stimulate differentiation of duct cells into endocrine cells. Progesterone treatment did not affect insulin responses to an i.v. glucose load (0.5 g/kg body weight). It is concluded that progesterone stimulates pancreatic cell proliferation indirectly; gonadal factor(s), not identical to oestradiol, is (are) probably involved. (+info)
Clinical outcome after unilateral oophorectomy in patients with polycystic ovary syndrome.
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The objective of this study is to report retrospectively on the clinical outcome of unilateral oophorectomy in 14 women with polycystic ovary syndrome who had undergone this treatment 14-18 years ago in our hospital for clomiphene citrate-resistant anovulation and long standing infertility or for severe hirsutism. The main outcome measures were menstrual cycle, pregnancy, hirsutism, testosterone concentrations, and premature ovarian failure. Unilateral oophorectomy restored regular menstrual cycles in 12 of the 14 patients. Thirteen years later, nine out of 12 patients still had regular menstrual cycles. Ten patients wished to become pregnant. Seven of them conceived spontaneously. Eleven patients complained of severe hirsutism. After unilateral oophorectomy, hirsutism regressed subjectively in six. Testosterone blood concentrations decreased significantly within the first year after unilateral oophorectomy in 11 patients. None of the women entered menopause within 14-18 years after surgery. Our results indicate that unilateral oophorectomy restores ovulatory function for many years in the majority of patients and does not result in premature ovarian failure. However, unilateral oophorectomy should not be recommended as a standard treatment for clomiphene citrate-resistant patients with polycystic ovary syndrome. (+info)
Leptin concentrations in normal women following bilateral ovariectomy.
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To study the relationships between gonadal steroids and leptin, 20 women with normal cycles were investigated during the postoperative period following a laparotomy. Fourteen women underwent bilateral ovariectomy plus total hysterectomy either in the mid- to late follicular phase (n = 7, group 1) or in the early to midluteal phase (n = 7, group 2). The remaining six of the 20 women underwent cholocystectomy in the early to midfollicular phase of the cycle and were used as controls (group 3). In all three groups, serum leptin values decreased rapidly up to post-operative day 4. Then, leptin values increased significantly only in group 3 (P < 0.05). Leptin values before and after the operation showed significant positive correlations with body mass index (BMI), oestradiol and progesterone. However, with multiple regression analysis, BMI was the only parameter significantly correlated with leptin in group 3 (days 0 and 4-7), whereas in groups 1 and 2 progesterone and BMI showed independent significant correlations with leptin (days 0 and 8, r = 0.601 and r = 0.602 respectively). These results demonstrate for the first time a significant reduction in leptin concentrations in normal women following bilateral ovariectomy. Although BMI seems to be the predominant factor, it is also suggested that oestradiol and progesterone may participate in the control of leptin production during the human menstrual cycle. (+info)
Endometrial steroid receptors during decidualization in rhesus monkey (Macaca mulatta); their modulation by anti-oestrogen CDRI-85/287.
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With a view to elucidating the hormonal control of decidualization in rhesus monkey, we studied the effects of CDRI-85/287, a potent anti-oestrogen, on endometrial steroid receptors in vivo and in vitro. Compound 85/287 was administered (i.m.) on days 8, 9 and 10 of steroid treatment cycle at a dose of 15 mg/monkey. Deciduoma was induced on day 16. Histological examination of endometrial tissue on days 24 and 30 of the cycle showed an apparent inhibition in uterine epithelial and subepithelial decidual cell plaque formation and a decrease in leukocytic infiltration into the stroma in anti-oestrogen-treated animals. As observed on day 24, a significant decrease in progesterone receptors (PR) (nuclear + cytosolic) was observed in the 85/287-treated group, whereas oestrogen receptor (ER) content remained unaltered. On day 30 total ER as well as total PR content was markedly reduced in treated animals. In-vitro results clearly demonstrated a competitive antagonism of 85/287 at the ER level only. The results are discussed in relation to the histological changes and modulation of steroid receptors, thereby suggesting the decidualization inhibitory activity of anti-oestrogen molecule 85/287 in primate species. (+info)