Differential Effects Of Estrogen Research Articles

Differential effect of estrogen and progesterone on <i>in vitro</i> growth of uterine leiomyoma cells with chromosome 7 deletions

BACKGROUND: The studies on how sex steroid hormones affect growth of uterine leiomyoma cells with chromosomal abnormalities is highly relevant for development of personalized tumor therapy.
 AIM: To study in vitro the isolated and combined effects of estrogen and progesterone on uterine leiomyoma cells with chromosomal aberrations — deletions in 7q.
 MATERIALS AND METHODS: The study was performed on 15 uterine leiomyomas, excised from 15 women of 26–44 years of age who were not treated with hormones. Uterine leiomyoma cells were cultured in hormone-free medium, in the medium supplemented with estrogen, progesterone or both hormones. The chromosome preparations were made and stained with QFH/AcD to perform conventional karyotyping and fluorescence in situ hybridization (FISH) to accurately describe chromosomal rearrangements. The frequency of uterine leiomyoma cells with chromosomal aberrations was assessed by interphase FISH.
 RESULTS: Deletions in 7q were identified in 6 out of 15 karyotyped uterine leiomyomas; four of them had one clone with deletion in 7q whereas two others comprised two clones with 7q deletions of different length. The frequency of cells carrying deletions in 7q greatly varied in uterine leiomyoma samples cultured in hormone-free medium: from 3.5% to 93.6%. Exposure of cell cultures to estrogen and progesterone resulted in a fold change frequency increase in some of the uterine leiomyomas and decrease in the others. The most significant changes in the frequency of cells with deletions in 7q were registered in response to the isolated estrogen and, to a lesser extent, to progesterone exposure; less significant changes were observed after combined hormonal effect.
 CONCLUSIONS: In uterine leiomyomas with deletions in 7q, the frequency of abnormal cells may either increase or decrease in response to estrogen and progesterone in vitro supplementation. The isolated effect of estrogen or progesterone on the frequency of uterine leiomyoma cells with deletion in 7q is more pronounced compared to the combined one.

ANMCO Position paper: Cardiovascular disease in women - prevention, diagnosis, treatment and organization of care

Cardiovascular diseases are still the main cause of death among women despite the improvements in treatment and prognosis achieved in the last 30 years of research. The determinant factors and causes have not been completely identified but the role of "gender" is now recognized. It is well known that women tend to develop cardiovascular disease at an older age than men, and have a high probability of manifesting atypical symptoms not often recognized. Other factors may also co-exist in women, which may favor the onset of specific cardiac diseases such as those with a sex-specific etiology (differential effects of estrogens, pregnancy pathologies, etc.) and those with a different gender expression of specific and prevalent risk factors, inflammatory and autoimmune diseases and cancer. Whether the gender differences observed in cardiovascular outcomes are influenced by real biological differences remains a matter of debate.This ANMCO position paper aims at providing the state of the research on this topic, with particular attention to the diagnostic aspects and to care organization.

1369-P: The Differential Effects of Estrogen on Determinants of Skeletal Muscle Bioenergetics with a High-Fat, High-Sucrose Diet in Rats

Estrogen is a powerful, beneficial regulator of skeletal muscle mitochondria. Premenopausal women with type 2 diabetes (T2D) have relatively greater complications associated with their T2D compared with the effect of the disease in men. We hypothesize that this impact of T2D in women is in part due to the impairment of estrogen-mediated regulation of skeletal muscle mitochondrial content and function. To explore the interaction between estrogen, diabetes and mitochondrial biogenesis in a rat model, 4-week-old, female Wistar Rats were fed a chow or a high fat/high sugar diet (HFHS) . At 8 weeks all mice underwent an ovariectomy (OVX) and randomized to estradiol (E2) replacement or none. One week prior to sacrifice, deuterium oxide was administered to determine skeletal muscle mitochondrial biogenesis. OVX +/- E2, animals were sacrificed 6 weeks post-randomization. Endpoints: body weight, gonadal fat mass, blood glucose and insulin levels, and gastrocnemius (mitochondrial biogenesis and function) . OVX+E2 rats had lower body mass compared with OVX (P = 0.0028) . HFHS fed rats had greater relative fat mass independent of E2 status (P = 0.0007) , and the OVX+E2 fed the HFHS diet were hyperglycemic (P = 0.00for the diet x E2 interaction) . State 3 mitochondrial respiration with carbohydrate-linked substrates was elevated in chow fed animals with E2, and this response was absent in HFHS animals (P = 0.0138 for the diet x E2 interaction) . Contrary to our hypothesis, there was no effect of diet or E2 on mitochondrial biogenesis measured with deuterium oxide (P > 0.4) . These data support the hypothesis that, in the context of a HFHS diet, the beneficial effect of E2 on skeletal muscle mitochondrial function is impaired. However, mitochondrial biogenesis does not appear to mediate this interaction of diet and E2. Future studies will focus on the E2-mediated regulation of mitochondrial quality to determine their role in the impairment of mitochondrial function. Disclosure N.A.Hulett: None. S.Hull: None. L.Knaub: None. G.Pott: None. B.F.Miller: None. J.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None. Funding Veterans Affairs (BX004533)

Differential Effects of Estrogen and Progestin on Apolipoprotein B100 and B48 Kinetics in Postmenopausal Women.

The distinct effects of the estrogen and progestin components of hormonal therapy on the metabolism of apolipoprotein (apo) B-containing lipoproteins have not been studied. We enrolled eight healthy postmenopausal women in a placebo-controlled, randomized, double-blind crossover study. Each subject received placebo, conjugated equine estrogen (CEE, 0.625 mg/day) and CEE plus medroxyprogesterone acetate (MPA, 2.5 mg/day) for 8 weeks in a randomized order, with a 4-week washout between phases. Main outcomes were the fractional catabolic rate (FCR) and production rate (PR) of apo B100 in triglyceride-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low -density lipoprotein (LDL) and of apo B48 in TRL. Compared to placebo, CEE increased TRL apo B100 PR (p = 0.04). CEE also increased LDL apo B100 FCR (p = 0.02), but this effect was offset by a significant increase in LDL apo B100 PR (p = 0.04). Adding MPA to CEE negated the CEE effects resulting in no significant changes in TRL apo B100 PR and LDL apo B100 FCR and PR relative to placebo. Relative to placebo, during CEE there was a trend toward a reduction in plasma apo B48 concentrations and PR (p = 0.07 and p = 0.12, respectively). Compared with CEE, CEE + MPA significantly increased TRL apo B48 FCR (p = 0.02) as well as apo B48 PR (p = 0.01), resulting in no significant changes in apo B48 concentration. Estrogen and progestin have independent and opposing effects on the metabolism of the atherogenic apo B100- and apo B48-containing lipoproteins.

Differential Effects of Estrogen on Corticosteroid-Binding Globulin Forms Suggests Reduced Cleavage in Pregnancy.

Corticosteroid-binding globulin (CBG) is secreted as high-affinity CBG (haCBG), which may be cleaved by tissue proteases to low-affinity CBG (laCBG), releasing free cortisol. Pregnancy and the estrogen-based combined oral contraceptive pill (COCP) increase CBG concentrations twofold to threefold. The relative effects of these two hyperestrogenic states on the CBG affinity forms are unknown. We performed an observational study in 30 pregnant women, 27 COCP takers and 23 controls. We analyzed circulating total CBG, haCBG, laCBG, and free and total cortisol concentrations. In pregnancy, total CBG and haCBG were increased compared to controls (both P < 0.0001); however, laCBG concentrations were similar. In COCP takers, total CBG and haCBG were increased [802 ± 41 vs compared to controls (both P < 0.0001)], but laCBG was also increased (P = 0.03). Pregnancy and use of COCP were associated with a comparable rise in haCBG, but laCBG was lower in pregnancy (P < 0.0001). These results were consistent with an estrogen-mediated increase in CBG synthesis in both hyperestrogenemic states but with reduced CBG cleavage in pregnancy relative to the COCP, perhaps due to pregnancy-induced CBG glycosylation. Speculatively, increased circulating haCBG concentrations in pregnancy may provide an increased reservoir of CBG-bound cortisol to prepare for the risk of puerperal infection or allow for cortisol binding in the face of competition from increased circulating progesterone concentrations.

Differential Effects of Estrogen and Progesterone on Genetic and Environmental Risk for Emotional Eating in Women.

Recent data show shifts in genetic and environmental influences on emotional eating across the menstrual cycle, with significant shared environmental influences during pre-ovulation, and primarily genetic effects during post-ovulation. Factors driving differential effects are unknown, although increased estradiol during pre-ovulation and increased progesterone during post-ovulation are thought to play a role. We indirectly investigated this possibility by examining whether overall levels of estradiol and progesterone differentially impact genetic and environmental risk for emotional eating in adult female twins (N = 571) drawn from the MSU Twin Registry. Emotional eating, estradiol levels, and progesterone levels were assessed daily and then averaged to create aggregate measures for analysis. As predicted, shared environmental influences were significantly greater in twins with high estradiol levels, whereas additive genetic effects increased substantially across low versus high progesterone groups. Results highlight significant and differential effects of ovarian hormones on etiologic risk for emotional eating in adulthood.

Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro.

What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre-antral to early antral stage? In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health. Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure. Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (≥750 µm) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Müllerian hormone (AMH). In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles. This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles. This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates. NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest.

Gender differences in Crohn's disease are mediated by differential effects of estrogen on T cell function (MUC2P.825)

Abstract Inflammatory bowel disease (IBD) is one of several autoinflammatory diseases for which a female gender bias has been reported. We hypothesized that hormonal signaling may alter T cell function in IBD, since chronic activation of pathogenic T cells drive intestinal inflammation and symptoms of female patients often change during times of altered hormone signaling, such as puberty and pregnancy. We studied the function of regulatory T cells in experimental murine models of ileitis (SAMP1/YitFc) and colitis (CD45RB transfer model), as well as in human IBD patients. In the CD45RB colitis model, CD45RBlow cells (enriched for Treg cells) from WT female mice were less effective at dampening colitis compared to their male counterparts (p&amp;lt;0.001, n=6/group). Consistent with this finding, female SAMP (SAMP-F) mice developed accelerated, worsened ileitis compared to SAMP-M beginning at 6 weeks of age (p&amp;lt;0.01, n=6/group), and displayed reductions in Foxp3 expression and Treg function in vitro. SAMP-F Tregs were non-responsive to estrogen-mediated increases in Foxp3 expression, suggesting that hormone signaling may influence Treg function in ileitis. Lastly, female IBD patients displayed a reduction in Foxp3 expression by FACS compared to males (p≤0.05, n=3/group); this was in contrast to Foxp3 expression in healthy female controls, which exceeded that of healthy males (p&amp;lt;0.01, n=5/group). Together, these data suggest that hormone signaling may directly influence Treg function in IBD.

Differential effects of estrogen and testosterone on auditory sensory gating in rats

Estrogen has been shown to have beneficial effects in patients with schizophrenia. However, the mechanisms involved in this protective effect are unclear. Schizophrenia is associated with deficits in sensory gating, a filtering mechanism which normally prevents sensory overload. In rodent models, acute treatment with drugs such as the dopamine D1/D2 receptor agonist, apomorphine; the dopamine releaser, amphetamine; and the glutamate NMDA receptor antagonists, phencyclidine or MK-801, can induce a phenotype similar to that seen in schizophrenia. Given the putative protective action of estrogen in schizophrenia, here we investigated the effect of ovariectomy (OVX) and estrogen replacement in female rats on drug-induced auditory gating deficits. For comparison, we also assessed the effects of castration (CAST) and dihydrotestosterone (DHT) replacement in male rats. Rats were instrumented with cortical surface electrodes. Test sessions comprised of 150 presentations of paired clicks, 500 ms apart (S1 and S2). Administration of all drugs increased the ratio of responses to S2/S1 in sham-operated female and male rats. OVX reduced event-related potential amplitudes but did not alter S2/S1 ratio or drug effects. In OVX rats with 17β-estradiol implants, the effect of apomorphine was abolished, but there was no change in that of amphetamine and phencyclidine. There were no effects of CAST or DHT replacement in male rats. Chronic estrogen replacement in OVX rats protected against sensory gating deficits caused by direct dopamine D1/D2 receptor stimulation. These data could indicate a possible mechanism by which estrogen exerts a protective action in schizophrenia.

Sex Differences in Hypertension: Contribution of the Renin–Angiotensin System

Numerous studies have shown that female human beings exhibit lower blood pressure levels over much of their life span compared with their age-matched counterparts. This sexual dimorphism is apparent in human beings as well as most, if not all, mammals. However, after the onset of menopause blood pressure levels in women increase and become similar to those in men, suggesting an important role of sex hormones in the regulation of blood pressure. The lower blood pressure levels in premenopausal women are associated with a lower risk of development and progression of cardiovascular disease and hypertension compared with age-matched men. This clear female advantage with respect to lower incidence of cardiovascular disease no longer exists after menopause, again highlighting the importance of sex hormones in the pathophysiology of cardiovascular disease in both men and women. In fact, both estrogens and androgens have been implicated in the development of cardiovascular disease and hypertension, with estrogens, in general, being protective and androgens being detrimental. Although the exact mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated, there is increasing evidence that modulating the activity of locally active hormonal systems is one of the major mechanisms of sex hormone actions in target organs, including the vasculature and kidneys. Indeed, several studies have demonstrated the importance of the interaction between sex hormones and the renin-angiotensin system in regulating cardiovascular function and blood pressure. Furthermore, the differential effects of estrogens and androgens on the expression and activity of the components of the renin-angiotensin system could possibly explain the sex differences in blood pressure levels and the development and progression of cardiovascular disease and hypertension.

Estrogen Receptor-α and Estrogen Receptor-β in the Uterine Vascular Endothelium during Pregnancy: Functional Implications for Regulating Uterine Blood Flow

The steroid hormone estrogen and its classical estrogen receptors (ERs), ER-α and ER-β, have been shown to be partly responsible for the short- and long-term uterine endothelial adaptations during pregnancy. The ER-subtype molecular and structural differences coupled with the differential effects of estrogen in target cells and tissues suggest a substantial functional heterogeneity of the ERs in estrogen signaling. In this review we discuss (1) the role of estrogen and ERs in cardiovascular adaptations during pregnancy, (2) in vivo and in vitro expression of ERs in uterine artery endothelium during the ovarian cycle and pregnancy, contrasting reproductive and nonreproductive arterial endothelia, (3) the structural basis for functional diversity of the ERs and estrogen subtype selectivity, (4) the role of estrogen and ERs on genomic responses of uterine artery endothelial cells, and (5) the role of estrogen and ERs on nongenomic responses in uterine artery endothelia. These topics integrate current knowledge of this very rapidly expanding scientific field with diverse interpretations and hypotheses regarding the estrogenic effects that are mediated by either or both ERs and their relationship with vasodilatory and angiogenic vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion observed during normal pregnancy.

Differential effects of estrogen and micronized progesterone or medroxyprogesterone acetate on cognition in postmenopausal women

To investigate possible differential effects of the coadministration of conjugated equine estrogen (CEE) and a placebo (CEE + PL), CEE and medroxyprogesterone acetate (CEE + MPA), or CEE and micronized P (CEE + MP) on aspects of cognitive functioning in naturally postmenopausal women. Double-blind, randomized, controlled trial. Gynecologic screening occurred at a university hospital, and neuropsychological testing took place in a university laboratory. Twenty-four naturally menopausal women with an intact uterus who had never used hormone therapy were recruited by means of newspaper advertisements. All completed the study. A battery of mood and neuropsychological tests was administered. Women were randomly assigned to receive CEE + PL (n = 7), CEE + MPA (n = 9), or CEE + MP (n = 8). The tests were readministered 12 weeks later. Standardized tests of mood, verbal memory, working memory, spatial abilities, and visual-spatial sequencing, and assays of serum sex hormone levels. Mood improved after treatment in all groups. No changes in scores occurred over time in any cognitive test in the group that received CEE + PL. Only the CEE + MP group had a significant decrease in their delayed verbal memory scores from baseline to after treatment. The CEE + MP-treated women performed significantly better on a test of working memory than women in the other two groups. Coadministration of CEE with MPA or MP caused differential effects on aspects of memory in postmenopausal women. These findings need to be replicated with a larger sample size before their potential clinical implications can be determined.

Differential Effects of Estrogen on Memory Processes and Learning Strategies: A Selective Review of Animal Studies

&#x0D; &#x0D; &#x0D; estrogen has differential effects on learning and memory. The direction of these effects depends on a variety of factors including the type of memory process, task specific demands, dose and time course of treatment. While some processes, including working memory, spatial memory and place learning, are improved in high estrogen conditions, other processes such as amygdala-dependent associative memory, reference memory and response learning are impaired. Furthermore, learning strategy is sensitive to the effects of estrogen. specifically, high estrogen conditions promote the use of a hippocampus-dependent strategy, while low estrogen levels bias learning towards a response strategy. In humans, the evidence for effects of estrogen on cognitive function is controversial and the mechanisms of action are not fully understood. This review will discuss major findings from animal studies, highlighting the modulatory effects of estrogen on learning and memory, possible neurobiological mechanisms underlying these effects and the implications of these findings for future investigations of the cognitive effects of estrogen in humans.&#x0D; &#x0D; &#x0D;

Differential effects of estrogen and progesterone on potassium channels expressed in Xenopus oocytes

Hypothesis Potassium (K +) channel activation contributes in part to estrogen-mediated vasorelaxation. However, the underlying mechanism is still unclear. We hypothesize that estrogen increases K + currents via membrane-associated, non-genomic interaction and that steroid hormones have differential effects on different types of K + channels. Experimental Human large-conductance Ca 2+-activated K + channels (BK Ca) and human voltage-gated K + channels (K V1.5) were expressed in Xenopus oocytes, and K + currents elicited by voltage clamp were measured. Results Both 17β-estradiol and BSA-conjugated 17β-estradiol increased the BK Ca current in a concentration-dependent manner and this effect was abolished by tetraethylammonium ions and iberiotoxin (putative BK Ca channel blockers). 17β-estradiol-stimulated increase in the BK Ca current was unaffected by treatment with ICI 182,780 (classic estrogen receptor antagonist), tamoxifen (estrogen receptor agonist/antagonist), actinomycin D (RNA synthesis inhibitor), or cycloheximide (protein synthesis inhibitor). In contrast, progesterone reduced the BK Ca current in the absence or presence of NS 1619 (BK Ca channel activator). Progesterone also inhibited 17β-estradiol-stimulated increase in the BK Ca current. Finally, progesterone but not 17β-estradiol reduced the K V1.5 current. Conclusions The present results show that 17β-estradiol stimulates BK Ca channels without affecting K V1.5 channels. This effect is ICI 182,780-insensitive and is likely mediated via a membrane-bound binding site. Progesterone inhibits both BK Ca- and K V1.5-encoded currents. The present results suggest that inhibition of K + channels may contribute in part to its reported antagonism against 17β-estradiol-mediated vascular relaxation via BK Ca channels.

Proteomic analysis of the differential effects of estrogens on human breast cancer cells

Proteomic analysis of the differential effects of estrogens on human breast cancer cells

The differential effect of estrogen, estrogen–progestin and tibolone on coagulation inhibitors in postmenopausal women

Objectives Hormone therapy increases the risk of venous thromboembolism, possibly through a negative effect on coagulation inhibitors. The aim of the study was to assess the effect of conjugated equine estrogens alone or in combination with medroxyprogesterone acetate, low-dose 17β-estradiol combined with norethisterone acetate and tibolone on inhibitors of coagulation.Methods Two hundred and sixteen postmenopausal women received orally either conjugated equine estrogens 0.625 mg (CEE, n = 24) or tibolone 2.5 mg (n = 24) or CEE + medroxyprogesterone acetate 5 mg (CEE/MPA, n = 34) or 17β-estradiol 1 mg + norethisterone acetate 0.5 mg (E2/NETA, n = 66) or no therapy (control, n = 68) for 12 months. Plasma antithrombin, protein C and total protein S were measured at baseline and at 12 months.Results CEE, CEE/MPA and E2/NETA treatment were associated with a significant decrease in antithrombin levels (CEE: baseline 235.6 ± 47.6 mg/l, follow-up 221.3 ± 48.3 mg/l, p = 0.0001; CEE/MPA: baseline 251.1 ± 38.6 mg/l, follow-up 225.0 ± 42.6 mg/l, p = 0.009; E2/NETA: baseline 257.1 ± 59.4 mg/l, follow-up 227.1 ± 50.4 mg/l, p = 0.007; tibolone: baseline 252.6 ± 62.4 mg/l, follow-up 261.9 ± 59.1 mg/l, p = 0.39). Protein C decreased significantly in the CEE and CEE/MPA groups (CEE: baseline 3.64 ± 1.17 mg/l, follow-up 2.48 ± 1.47 mg/l, p = 0.004; CEE/MPA: baseline 3.24 ± 1.23 mg/l, follow-up 2.61 ± 1.38 mg/l, p = 0.001; E2/NETA: baseline 3.24 ± 1.10 mg/l, follow-up, 3.15 ± 1.11 mg/l, p = 0.08; tibolone: baseline 3.26 ± 1.25 mg/l, follow-up 3.09 ± 1.32 mg/l, p = 0.37). Protein S decreased significantly only in the CEE/MPA group (CEE: baseline 19.4 ± 2.76 mg/l, follow-up 18.0 ± 2.45 mg/l, p = 0.56; CEE/MPA: baseline 18.4 ± 3.42 mg/l, follow-up 14.5 ± 3.43 mg/l, p = 0.005; E2/NETA: baseline 19.0 ± 3.11 mg/l, follow-up 19.5 ± 3.43 mg/l, p = 0.18; tibolone: baseline 18.5 ± 3.09 mg/l, follow-up 18.0 ± 4.09 mg/l, p = 0.32).Conclusions Estrogen and estrogen–progestin therapy are associated with a reduction in coagulation inhibitors, the extent of which depends on the regimen administered. Tibolone appears to have no effect on inhibitors of coagulation.

Differential effects of estrogen on hippocampal- and striatal-dependent learning

Estrogen’s role in learning and memory may be to predispose animals to use specific cognitive strategies ( Korol & Kolo, 2002). Specifically, estrogen may facilitate hippocampal-dependent learning, while at the same time attenuate striatal-dependent learning. As a stringent test of this hypothesis, place or response learning on an eight-arm radial maze was compared between ovariectomized (OVX) female Long–Evans rats and rats with chronic estrogen replacement (OVX + E; 5 mg 17-β estradiol 60-day release tablet). Reference and working memory errors were monitored separately for both place and response learning tasks. OVX + E rats learned the place task significantly faster than the response task, and faster than OVX rats. OVX rats required fewer days to reach criterion on the response task than OVX + E rats. Estrogen selectively enhanced reference memory performance, but only during place learning. The specific pattern of estrogen effects on learning suggests that future studies include verification of cognitive strategies used by animals.

Differential effects of estrogen on DNA synthesis in human periodontal ligament and breast cancer cells

It is important to clarify the biological function of the female sex hormones estrogen and progesterone in periodontal ligament cells, as these hormones may affect periodontal health. We have previously shown that human periodontal ligament cells express estrogen receptor beta (ERbeta) but not ERalpha, whereas human breast cancer cells (MCF7) express both ERalpha and ERbeta. Data on progesterone receptor (PgR) expression in human periodontal ligament cells have not been reported. Determine PgR expression in human periodontal ligament and MCF7 cells and to investigate how estrogen affects DNA and collagen synthesis in these two cell types showing different pattern of expression for ERalpha and beta. Periodontal ligament cells were obtained from the periodontal ligament of premolars extracted for orthodontic reasons and MCF7 cells from the American Type Culture Collection (ATCC). PgR expression was determined by immunocytochemistry. DNA and collagen synthesis was determined by [(3)H]thymidine and L-[(3)H]proline incorporation, respectively. PgR immunoreactivity was observed in nuclei of MCF7 but not periodontal ligament cells. Treatment with estrogen (17beta-estradiol, E(2)) at physiological concentrations for 24 h stimulated DNA synthesis by more than two times in MCF7 cells, whereas there was no effect on periodontal ligament cell DNA synthesis. The ER blocker ICI 182780 fully reversed the stimulatory effect of E(2). Not only short-term (24 h) but also long-term (5 days) treatment with E(2) lacked effect on DNA synthesis in periodontal ligament cells. Neither periodontal ligament cell viability nor collagen synthesis was affected by E(2) treatment. Identical results were observed in periodontal ligament cells from male and female subjects. Human MCF7 but not periodontal ligament cells express PgR, suggesting that progesterone via PgR affects MCF7 but not periodontal ligament cells. Further, estrogen stimulates breast cancer MCF7 cell proliferation, whereas it has no effect on proliferation of periodontal ligament cells, probably reflecting cell type specific ER expression pattern in these two cell types.

Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat

Oral contraceptives (OC) and postmenopausal hormone therapy (HT) modulate plasma levels of proteins that regulate blood coagulation. It remains unclear whether the progestin component contributes to these changes. The present study was designed to determine whether progestins modulate two essential plasma anticoagulants, antithrombin (AT) and tissue factor pathway inhibitor (TFPI), in an animal model. Ovariectomized rats were treated orally with three progestins, norethindrone acetate (NETA), trimegestone (TMG), or drospirenone (DSP), either alone or combined with 17α-ethyinylestradiol (EE). Plasma AT levels were unchanged. However, TFPI activity was reduced by EE alone (10–100 μg/kg/day) in a dose-dependent manner; NETA (3 or 10 mg/kg/day) reduced TFPI by ∼40 or ∼80%, respectively, while TMG and DSP had no effect. NETA and EE effects were blocked by co-administration of ICI-182,780, an estrogen receptor antagonist, suggesting that both responses were likely estrogen receptor-mediated. Reduced TFPI after NETA or EE treatment was not accompanied by changes in TFPI mRNA levels in tissues that express TFPI, but there was a positive correlation between plasma TFPI and total cholesterol. Sex hormone effects on TFPI in this model and as reported in women may help to shift the coagulation balance to a more prothrombotic state. Progestins such as TMG and DSP that lack estrogenic activity could potentially have an improved clinical profile.

Differential Effects of Estrogen and Raloxifene on Messenger RNA and Matrix Metalloproteinase 2 Activity in the Rat Uterus

A detailed analysis of the differential effects of estrogen (E) compared to raloxifene (Ral), a selective estrogen receptor modulator (SERM), following estrogen receptor (ER) binding in gynecological tissues was conducted using gene microarrays, Northern blot analysis, and matrix metalloproteinase (MMP) 2 activity studies. We profiled gene expression in the uterus following acute (1 day) and prolonged daily (5 wk) treatment of E and Ral in ovariectomized rats. Estrogen regulated twice as many genes as Ral, largely those associated with catalysis and metabolism, whereas Ral induced genes associated with cell death and negative cell regulation. Follow-up studies confirmed that genes associated with matrix integrity were differentially regulated by Ral and E at various time points in uterine and vaginal tissues. Additional experiments were conducted to determine the levels of MMP2 activity in uterus explants from ovariectomized rats following 2 wk of treatment with E, Ral, or one of two additional SERMs: lasofoxifene, and levormeloxifene. Both E and lasofoxifene stimulated uterine MMP2 activity to a level twofold that of Ral, whereas levormeloxifene elevated MMP2 activity to a level 12-fold that of Ral. These data show that one of the significant differences between E and Ral signaling in the uterus is the regulation of genes and proteins associated with matrix integrity. This may be a potential key difference between the action of SERMs in the uterus of postmenopausal women.