Soy isoflavone effects on the adrenal glands of orchidectomized adult male rats: a comprehensive histological and hormonal study.

Genistein (G) and related soy phytoestrogens have been studied for potential usefulness in different chronic diseases, and may ameliorate signs of aging. They have a profound influence on the hypothalamo-pituitary-adrenal (HPA) axis. The present study utilized the rat model of mild andropause to thoroughly evaluate the effects of G and soy extract on the adrenal gland and related blood hormones. Adult male rats were orchidectomized (Orx) or sham operated (SO). Orx rats received daily subcutaneous injections for 3 weeks of solvent, or G (Orx+G, 30 mg/kg), or commercial soy extract (Orx+Soy, 30 mg/kg). Adrenal glands and blood were harvested at the end of the treatment for hormone analyses, histology and design-based stereology. Compared to SO rats Orx evoked significant (P<0.05) changes including: the replicating cell number in the 3 adrenocortical zones; vascularity and cortical volume and blood levels of adrenocorticotropic hormone (ACTH), aldosterone and dehydroepiandrosterone (DHEA). When comparing Orx vs. Orx+G groups the following significant (P<0.05) changes were observed: a further increase in number of replicating cells in zonas glomerulosa and reticularis, vasculature network presence, cortical and zona reticularis volumes, ACTH and corticosterone concentrations, and lower DHEA levels. Comparing Orx vs. Orx+Soy resulted in elevated (P<0.05) ACTH and corticosterone levels. Structural integrity of the adrenal gland was unchanged vs. SO rats. Overall, G and soy extract treatments resulted in proliferative activity and/or vasculature support in the adrenal cortex. The data and current literature support the impression of a beneficial effect of soy components on the homeostatic response to stress.

Mechanism of action of levonorgestrel emergency contraception.

There has been much debate regarding levonorgestrel emergency contraception's (LNG-EC's) method of action since 1999 when the Food and Drug Administration first approved its use. Proponents of LNG-EC have argued that they have moral certitude that LNG-EC works via a non-abortifacient mechanism of action, and claim that all the major scientific and medical data consistently support this hypothesis. However, newer medical data serve to undermine the consistency of the non-abortifacient hypothesis and instead support the hypothesis that preovulatory administration of LNG-EC has significant potential to work via abortion. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room protocols. In the future, technology such as the use of early pregnancy factor may have the potential to quantify how frequently preovulatory LNG-EC works via abortion. Lay Summary: How Plan B (levonorgestrel emergency contraception) works has been vigorously debated ever since the Food and Drug Administration approved it in 1999. Many doctors and researchers claim that it has either no-or at most-an extremely small chance of working via abortion. However, the latest scientific and medical evidence now demonstrates that levonorgestrel emergency contraception theoretically works via abortion quite often. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room rape protocols.

Age-dependent modulation of central ghrelin effects on food intake and lipid metabolism in rats.

Ghrelin is an endogenous peptide potentially useful in therapy of anorexia and other age-related metabolic disturbances. We evaluated the influence of age on the orexigenic and lipid metabolism-altering effects of ghrelin. Peripubertal, young, adult and middle-aged rats (1, 2, 7 and 12 months old, respectively) were treated with 5 daily intracerebroventricular injections of ghrelin (0.15 nmol) or saline (control). The food intake was measured daily before treatment, while white adipose tissue and serum/plasma samples for detection of lipid metabolites/hormones were collected at the end of the experiment. The values of cumulative food intake and body weight gain declined, while the white adipose tissue deposits and blood concentrations of triglycerides, cholesterol and free fatty acids all increased with age. Ghrelin significantly increased all parameters, but the stimulatory effects on body weight gain and food intake were more pronounced in peripubertal/young rats, while the increase in white adipose mass, triglyceride and low-density lipoprotein cholesterol levels was more noticeable in adult/middle-aged animals. The decrease in sensitivity to ghrelin-mediated stimulation of food intake in older animals could not be explained by alterations in ghrelin's ability to reduce anorexigenic hormones insulin and leptin. However, the higher responsiveness of aged rats to ghrelin-mediated increase in lipid metabolites was accompanied by an increase in adrenocorticotropic hormone and corticosterone levels. These results indicate that aging, while reducing sensitivity to ghrelin-mediated increase in body weight gain and food intake, might enhance the responsiveness to the stimulatory effects of ghrelin on lipid metabolites and hypothalamic-pituitary-adrenal axis activity.

Central effects of ghrelin on the adrenal cortex: a morphological and hormonal study.

Ghrelin, a growth hormone secretagogue that exerts an important role in appetite and weight regulation, participates in the activation of the hypothalamo-pituitary-adrenal (HPA) axis. Male Wistar rats (5/group) received daily for 5 days, via an ICV (intracerebroventricular) cannula, 5 microl phosphate buffered saline with or without 1 microg of rat ghrelin. Two hours after the last injection, blood and adrenal glands were collected from decapitated rats for blood hormone analyses and histologic and morphometric processing. Ghrelin treatment resulted in increased (p<0.05) body weight (13%), absolute whole adrenal gland weight (18%) and whole adrenal gland volume (20%). The absolute volumes of the entire adrenal cortex, ZG, ZF, and ZR also increased (p<0.05) after ghrelin by 20%, 21%, 21% and 11%, respectively. Ghrelin-treated rats had elevated (p<0.05) blood concentrations of ACTH, aldosterone and corticosterone (68%, 32% and 67%, respectively). The data clearly provide both morphological and hormonal status that ghrelin acts centrally to exert a global stimulatory effect on the adrenal cortex. Clarifying of the ghrelin precise role in the multiple networks affecting the stress hormone release, besides its well known energy and metabolic unbalance effects, remains a very important research goal.

Hydrogen peroxide induces lysosomal protease alterations in PC12 cells.

Alterations in lysosomal proteases have been implicated in many neurodegenerative diseases. The current study demonstrates a concentration-dependent decrease in PC12 cell viability and transient changes in cystatin C (CYSC), cathepsin B (CATB), cathepsin D (CATD) and caspase-3 following exposure to H2O2. Furthermore, activation of CATD occurred following exposure to H2O2 and cysteine protease suppression, while inhibition of CATD with pepstatin A significantly improved cell viability. Additionally, significant PARP cleavage, suggestive of caspase-3-like activity, was observed following H2O2 exposure, while inhibition of caspase-3 significantly increased cell viability compared to H2O2 administration alone. Collectively, our data suggest that H2O2 induced cell death is regulated at least in part by caspase-3 and CATD. Furthermore, cysteine protease suppression increases CATD expression and activity. These studies provide insight for alternate pathways and potential therapeutic targets of cell death associated with oxidative stress and lysosomal protease alterations.

6-Hydroxydopamine induces cystatin C-mediated cysteine protease suppression and cathepsin D activation.

Alteration in the lysosomal system (LS) may represent a central mechanism in neurodegeneration. 6-Hydroxydopamine (6-OHDA) induces oxidative stress and cell death in catecholaminergic cells. The LS and caspases participate in apoptosis, although the mechanism(s) that is involved is not completely understood. Here, we show that Pheochromocytoma (PC12) cells exposed to 6-OHDA results in lysosomal dysregulation, caspase activation and cell death. Cells exposed to 6-OHDA increased expression and release of cystatin C (CC) and suppressed cathepsin B (CB). CB activity significantly declined 24h following exposure to 6-OHDA, however neutralization of CC restored CB activity. Cathepsin D (CD) and caspase-3 activity also increased following exposure to 6-OHDA. Inhibition of CD and caspase-3 with pepstatin A (PA) and DEVD-Cho, respectively, attenuated the 6-OHDA induced cell death at 48 and 72 h. However, the CB inhibitor CA-074 Me failed to protect cells. Additionally, poly-ADP-ribose polymerase (PARP) cleavage was evaluated after exposure to 6-OHDA and PA, CA-074 Me, and DEVD-Cho. Only DEVD-Cho significantly decreased PARP cleavage following exposure to 6-OHDA. Hence, caspase-3 mediated PARP cleavage following exposure to 6-OHDA appears independent of CB and CD alterations. These studies suggest alternate pathways and potential therapeutic targets of cell death associated with oxidative stress, CC, and lysosomal dysregulation.

Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis.

OBJECTIVE: To perform a meta-analysis of case-control studies that addressed whether prior oral contraceptive (OC) use is associated with premenopausal breast cancer. METHODS: We searched the MEDLINE and PubMed databases and bibliography reviews to identify case-control studies of OCs and premenopausal breast cancer published in or after 1980. Search terms used included breast neoplasms, oral contraceptives, contraceptive agents, and case-control studies. Studies reported in all languages were included. Thirty-four studies were identified that met inclusion criteria. Two reviewers extracted data from original research articles or additional data provided by study authors. We used the DerSimonian-Laird method to compute pooled odds ratios (ORs) and confidence intervals (CIs) and the Mantel-Haenszel test to assess association between OC use and cancer. RESULTS: Use of OCs was associated with an increased risk of premenopausal breast cancer in general (OR, 1.19; 95% CI, 1.09-1.29) and across various patterns of OC use. Among studies that provided data on nulliparous and parous women separately, OC use was associated with breast cancer risk in both parous (OR, 1.29; 95% CI, 1.20-1.40) and nulliparous (OR, 1.24; 95% CI, 0.92-1.67) women. Longer duration of use did not substantially alter risk in nulliparous women (OR, 1.29; 95% CI, 0.85-1.96). Among parous women, the association was stronger when OCs were used before first full-term pregnancy (FFTP) (OR, 1.44; 95% CI, 1.28-1.62) than after FFTP (OR, 1.15; 95% CI, 1.06-1.26). The association between OC use and breast cancer risk was greatest for parous women who used OCs 4 or more years before FFTP (OR, 1.52; 95% CI, 1.26-1.82). CONCLUSION: Use of OCs is associated with an increased risk of premenopausal breast cancer, especially with use before FFTP in parous women.

Somatostatin affects morphology and secretion of pituitary luteinizing hormone (LH) cells in male rats.

The somatostatin peptides (SRIH-14, SRIH-28) and their multiple receptors are generally associated with anti-proliferative and anti-secretory actions. This study compared, using standard morphometric measurements and terminal serum LH concentrations, effects of intracerebroventricular (icv) SRIH-14 and SRIH-28 in nanomolar amounts on immunohistochemically identified LH cells in pituitary glands of male rats. Rats received l microg/5 microl of SRIH-14 or SRIH-28 icv on days 1,3, and 5, whereas control rats received only icv saline. Animals were killed 5 days later for serum LH assays. Pituitarys were harvested for PAP immunohistochemistry and morphometry. Morphometric measurements were made by an observer blinded to the treatment group. Histochemically identified LH cells from both SRIH groups appeared smaller, often pycnotic and darkly stained compared to those from saline-treated rats. Both SRIH treatments reduced (p < 0.05) the quantitative morphometric measurements for cell volume, nuclear volume, and relative volume density. Both SRIH treatments also reduced serum LH concentration (p < 0.05), supporting the hypothesis that systemic physiology was altered. Collectively, the data support the opinion that nanomolar amounts of either SRIH peptide, acting on receptors reached from cerebrospinal fluid, exert an anti-secretory effect on LH cells of male rats. Modifications of central SRIH receptors may provide an approach for treatment of male sexual dysfunction and/or be of pathophysiologic significance in these disturbances.