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PubMed1995

Estradiol and tamoxifen interactions with thyroid hormone in the ovariectomized-thyroidectomized rat.

Receptors for estrogens and thyroid hormone (T3) have related DNA-binding domains that interact with closely related DNA target sequences which enable transcriptional control. In vitro molecular studies have raised the possibility that estrogen and T3 receptors may compete for binding to certain DNA target sites (cross-talk). However, there have been no physiological studies evaluating the abilities of estrogens or T3 to mimic or inhibit each other in vivo in a manner consistent with a mechanism involving receptor cross-talk. To address this issue, the effects of estradiol, tamoxifen (an antiestrogen), and T3 were studied in an ovariectomized-thyroidectomized rat model designed to minimize hormone interplay occurring via neuroendocrine or pharmacokinetic mechanisms. The T3 responses examined included induction of GH, somatic growth, and hepatic malic enzyme, and suppression of TSH secretion. The estrogen responses examined included induction of pituitary kallikrein, PRL, and uterine weight; increases in serum triglycerides; and suppression of LH secretion. Estradiol and tamoxifen acted as partial T3 agonists on GH induction, with agonist or antagonist effects depending upon T3's presence. Estradiol and tamoxifen acted as pure T3 antagonists on T3 induction of somatic growth and malic enzyme. Similarly, estradiol blocked T3-evoked decreases in bone mineral density and had no effect on bone in T3's absence. In contrast, estradiol or tamoxifen did not alter T3 feedback inhibition of TSH release or T3 induction of PRL. T3 partially mimicked estrogen actions to suppress LH, but did not mimic or inhibit other estrogen responses. Interestingly, the effect of estradiol and tamoxifen to increase serum triglycerides was totally T3 dependent even though T3 tended to decrease triglyceride levels. The results indicate that physiological effects of estrogens on GH, somatic growth, bone, malic enzyme, and serum triglycerides exhibit properties suggestive of a mechanism involving cross-talk with T3 receptors. Tamoxifen fully mimicked the effects of estradiol arising by an apparent antagonism of T3 actions, but acted as an antiestrogen in other responses.

Animals↗
PubMed1995

Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe.

The follicular phase rise in circulating estradiol causes a suppression of GnRH pulse amplitude and an increase in pulse frequency before stimulation of the preovulatory GnRH surge in the ewe. Studies in which samples were collected at 10-min intervals were found unsuitable to determine whether GnRH secretion is exclusively pulsatile at this time or whether estradiol induces additional qualitative changes in the pattern of GnRH secretion that, combined with the quantitative changes, result in generation of the surge. To address these issues, GnRH was measured in pituitary portal blood and LH in peripheral blood collected at 1- and 10-min intervals, respectively, in ewes receiving no estradiol (n = 5), a luteal phase level of circulating estradiol (n = 5), or a peak follicular phase concentration of estradiol (n = 5). The results provide evidence that, in a dose-dependent manner, estradiol induces the secretion of significant amounts of GnRH between pulses and alters the shape of GnRH pulses by reducing the slope of the rising and falling phases of each pulse. These findings lead to the conclusion that during the presurge period in the ewe, estradiol induces qualitative change in the pattern of GnRH release in addition to stimulating GnRH pulse frequency and reducing pulse amplitude.

Animals↗
PubMed1995

Cellular localization of estradiol-induced c-fos messenger ribonucleic acid in the rat uterus: c-fos expression and uterine cell proliferation do not correlate strictly.

Estrogens stimulate DNA synthesis and cell proliferation in the uterus. All major uterine cell types (luminal and glandular epithelium, stroma, and myometrium) respond to 17 beta-estradiol in the immature animal, whereas primarily epithelial cells of the uterine endometrium respond in the mature animal. Rapid activation of the c-fos protooncogene by estrogen precedes the uterine growth, suggesting that c-fos plays a role in amplifying the hormonal signal. The specific uterine cell types in which estrogen induces c-fos messenger RNA (mRNA) expression, however, have not been identified in either mature or immature animals. In this study, in situ hybridization was used to determine the cell type-specific location of mRNA encoding c-fos in the uterus. In both immature and mature castrated rats at 3 h after 17 beta-estradiol administration, c-fos expression was detected primarily in uterine luminal and glandular epithelia. Expression of c-fos returned to baseline levels by 24 h post 17 beta-estradiol treatment. There was no apparent difference in the uterine cell type-specific pattern of c-fos expression stimulated by estradiol in mature vs. immature animals. Nuclear run-on transcription assay in isolated luminal epithelial cell nuclei showed that c-fos gene transcription increased rapidly in the uterus after estradiol stimulation. Treatment of adult rats with a single injection of 16 alpha-estradiol, a short-acting, nonmitogenic estrogen, induced c-fos primarily in the uterine glandular epithelia. Progesterone is known to modify the action of estrogen on the uterus by redirecting the proliferative response from epithelia to stroma. To determine if progesterone modulation of estrogen action involves shifting of c-fos expression to stromal cells, rats were treated with progesterone for 48 h and then killed 0, 3, 6, or 12 h after an estradiol injection. In situ hybridization analysis revealed that c-fos mRNA remained localized in the uterine luminal and glandular epithelia, and expression was not shifted to the stroma. Although these results support the idea that c-fos plays a role in proliferation of uterine epithelial cells, they also invite reassessment of the role played by c-fos in both epithelial and nonepithelial uterine cell types.

Animals↗
PubMed1996

Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol.

Estrogens increase the proliferative response of estrogen-responsive breast cancer cells to insulin-like growth factors (IGFs). The mechanisms involved are unclear, but the observation that estradiol increases type I IGF receptor levels in MCF-7 breast cancer cells has suggested that the increased response may be due to increased expression of type I IGF receptor. The purpose of this study was to investigate this hypothesis by using a retroviral expression vector to constitutively over-express the type I IGF receptor in estrogen-responsive breast cancer cells. We isolated clones of infected MCF-7 cells that expressed up to 4.5-fold more receptor than the estradiol-induced level in cells infected with a control vector. Hybridization of a type I IGF receptor complementary DNA probe to RNA extracted from these clones showed that most of the receptor RNA was transcribed from the retroviral provirus. Estrogen receptor continued to be expressed in clones overexpressing type I IGF receptor, and overexpression had little effect on the induction of an estrogen-regulated gene by estradiol and the proliferative response to IGFs alone or estradiol alone. Overexpression did, however, alter the proliferative response to IGFs in the presence of estradiol. The three clones analyzed showed an increased sensitivity to low IGF-I concentrations and a paradoxical attenuation of the synergistic effect between estradiol and IGF-I at high IGF-I concentrations. Collectively, these experiments show that the level of expression of the type I IGF receptor is an important determinant in the responsiveness of breast cancer cells to estrogen, but the observation that the response of cells to estradiol alone is not affected by constitutive overexpression of the type I IGF receptor suggests that estrogens stimulate the proliferation of breast cancer cells by regulating the expression of genes in addition to the type I IGF receptor.

Breast Neoplasms↗
PubMed1998

Mediators of estradiol-stimulated mitosis in the rat uterine luminal epithelium.

The effects of estradiol treatment, which stimulates cell division in rat uterine epithelial cells, on the in vivo expression of heparin-binding epidermal growth factor (HB-EGF), cyclin D1, and cyclin B1 messenger RNA (mRNA) in these cells have been examined using ribonuclease protection assays. Estradiol gave rise to significant increases in steady state levels of HB-EGF 2 and 24 h after treatment. Cyclin D1 mRNA levels were elevated 8 and 10 h after estradiol administration, corresponding to the G1 phase of the mitotic cycle, and cyclin B1 mRNA was only expressed 16-24 h after estradiol treatment, which corresponds to the G2 and M phases of the rat uterine epithelial cell cycle. Estradiol-stimulated increases in HB-EGF mRNA were not affected by treatment with cycloheximide, but were inhibited by the estrogen antagonist compound, ICI 164,384, demonstrating that the estrogen-stimulated increase in HB-EGF mRNA is a primary, estrogen receptor-mediated response of rat uterine epithelium to estradiol. Progesterone treatment, which blocks epithelial cells in G1 of the cycle, suppressed levels of HB-EGF mRNA below those observed in ovariectomized rats. These results indicate that HB-EGF mediates the regulatory effects of both estradiol and progesterone on rat uterine epithelial cell proliferation through an effect on the production of G1 phase molecules such as cyclin D1.

Animals↗
PubMed1999

The expression of interleukin-6 (IL-6), IL-6 receptor, and gp130-kilodalton glycoprotein in the rat decidua and a decidual cell line: regulation by 17beta-estradiol and prolactin.

The cytokine interleukin 6 (IL-6), a major mediator of immune and acute phase responses of the liver, has been implicated in the termination of pregnancy once expressed in the uterus. This study was undertaken to investigate the expression and regulation of genes encoding IL-6 and IL-6 receptor (IL-6R) in rat decidual tissue. Total RNA obtained from rat decidual tissue on different days of pseudopregnancy was analyzed by RT-PCR using specific primers for IL-6, IL-6R, and 130-kDa glycoprotein (gp130). Ribosomal L19 primers served as an internal control. IL-6R and gp130 were found to be expressed in the decidua throughout development, while no messenger RNA (mRNA) for IL-6 was detected. Interestingly, within several hours of culture, decidual explants acquired the ability to express IL-6. The apparent ability of decidual cells to express IL-6 and its lack of expression in vivo led us to examine whether the IL-6 gene is actively inhibited. Primary decidual cells were cultured in the presence of estradiol, progesterone, or PRL. Progesterone showed no effect, whereas estradiol and PRL reduced the level of IL-6 mRNA expression. To examine the mechanism by which these hormones inhibit IL-6 expression, we used a simian virus 40-transformed decidual cell line (GG-AD), which expresses only estrogen receptor-beta (ERbeta). Like primary decidual cells in culture, GG-AD cells express IL-6, IL-6R, and gp130 mRNA. When cultured in the presence of estradiol (0-100 ng/ml), mRNA for IL-6 and its receptor components were down-regulated in a dose-dependent manner. Estradiol also caused a dose-dependent decrease in IL-6 protein secretion into the culture medium. The inhibitory effect of estradiol on IL-6 mRNA expression was reversed by the antiestrogen ICI-164,384. Similar inhibition of IL-6 and gp130 mRNA expression was observed with PRL treatment. However, PRL had no effect on IL-6R mRNA levels. PRL inhibition of IL-6 expression was totally reversed by tyrphostin AG490, a JAK2 inhibitor. In summary, the results of this investigation indicate that IL-6 expression, which is detrimental to the maintenance of pregnancy, is inhibited in the rat decidual tissue. This inhibition is induced by PRL and estradiol, which down-regulate not only IL-6 expression, but also the expression of IL-6 receptor and signaling proteins. The results also suggest that PRL signaling to the IL-6 gene is mediated through the long form of PRL receptor and involves JAK2 activation, whereas that of estradiol can be transduced by estrogen receptor-beta.

Animals↗
PubMed1999

Estradiol increases proliferation and down-regulates the sodium/iodide symporter gene in FRTL-5 cells.

Goiter (increased thyroid gland size) is more prevalent in women than men, even in areas where iodine levels in the diet are sufficient. We investigated a possible role of estrogen on thyroid follicular cell growth using rat FRTL-5 thyroid follicular cells as a model. Estrogen receptor-alpha (ERalpha) messenger RNA was present in FRTL-5 cells using a RT-PCR assay and was confirmed by Western blot analysis. An estrogen-responsive reporter gene was transfected into FRTL-5 cells to test the functionality of the endogenous ERs. Estradiol increased the activity of the reporter gene, and the antagonist, ICI182780, inhibited ER-dependent transcription. To extend this analysis, we examined the effect of estradiol on FRTL-5 cell growth. Estradiol increased FRTL-5 cell growth in a time- and concentration-dependent manner in either the absence or presence of TSH. Because iodine is known to inhibit thyroid cell growth, the effect of estradiol on the expression of the sodium/iodide symporter (NIS) was assessed as a potential target of estrogen action. Estradiol blocked TSH-induced NIS expression, and treatment of cells with estradiol and ICI182780 restored TSH-induced NIS expression to normal levels. These data demonstrate that FRTL-5 cells contain functional ERs that enhance cell growth and inhibit expression of the NIS. The demonstration of a direct effect of estradiol on thyroid follicular cells raises the possibility that it may play a role in the sexually dimorphic prevalence of goiter.

Animals↗
PubMed2000

Androstenedione treatment of pregnant baboons at 0.7-0.8 of gestation promotes a premature forward shift in the nocturnal maternal plasma estradiol surge relative to progesterone and increases myometrial contraction activity.

Androstenedione treatment of pregnant monkeys at 0.8 of gestation reproduces endocrine, biophysical, and biochemical changes similar to those measured during spontaneous, term labor in the pregnant monkey. In the pregnant baboon, the spontaneous onset of labor at term has been attributed to a forward shift in the nocturnal estradiol surge relative to that of progesterone in maternal plasma. This study investigated whether androstenedione treatment of the pregnant baboon at 0.7-0.8 of gestation promotes a premature forward shift in the nocturnal surge of maternal plasma estradiol relative to progesterone and whether this shift is associated with premature increases in nocturnal myometrial activity. Eight pregnant baboons were prepared surgically under general anesthesia with vascular catheters and myometrial electromyogram electrodes between 121 and 139 days of gestation (term is ca. 185 days). Catheters were maintained patent by continuous infusion of heparinized saline from the time of surgery until one of two treatments began following at least 9 days of postoperative recovery. In four baboons (Group I), the saline administration was replaced by a continuous infusion of 10% intralipid vehicle during Day 1 of the experimental protocol. During Day 2 and Day 3, the intralipid infusion was switched for a continuous infusion of androstenedione dissolved in intralipid set at a low (0.8 mg x kg(-1) x h(-1)) and at a high (1.6 mg x kg(-1) x h(-1)) dose, each delivered for 24 h. The other four pregnant baboons (Group II) received 10% intralipid vehicle for Days 1, 2, and 3 of the experimental protocol. One baboon from Group I received an additional dose of 0.4 mg x kg(-1) x h(-1) for 24 h before the low and the high dose of androstenedione. In each baboon, during each experimental day, maternal arterial blood samples (1 ml) were taken at 1 h intervals for 12 h, starting 3 h before the onset of darkness in the animal's environment, for measurement of maternal plasma estradiol and progesterone concentrations via RIA. Myometrial contractions were counted during each night-time period of the experimental protocol. All pregnant baboons demonstrated increases in maternal plasma estradiol and progesterone concentrations at night-time. Androstenedione had a dose-dependent effect in elevating day-time maternal plasma estradiol concentrations and in promoting a forward shift in the nocturnal surge of maternal plasma estradiol without affecting the nocturnal progesterone profile in maternal plasma. Maternal treatment with androstenedione also led to an increase in nocturnal myometrial contraction activity. We conclude that androstenedione treatment of the pregnant baboon at 0.7-0.8 of gestation promotes a premature forward shift in the nocturnal estradiol surge relative to that of progesterone in maternal plasma and that this shift is associated with an increase in nocturnal myometrial contraction activity, in a similar way to that measured during spontaneous onset of labor at term in this species.

Androstenedione↗
PubMed2002

Antigen presentation by vaginal cells: role of TGFbeta as a mediator of estradiol inhibition of antigen presentation.

Estradiol is known to inhibit antigen presentation in the vagina. We report here that TGFbeta mediates the action of estradiol on vaginal antigen presenting cells (APC). When vaginal APC from ovariectomized rats were incubated with increasing concentrations of TGFbeta1 and TGFbeta2 in the presence of ovalbumin-specific T cells and ovalbumin, both TGFbeta1 and TGFbeta2 inhibited vaginal cell antigen presentation, whereas IL-6, IL-10, and TNFalpha had no consistent effect. In other experiments, estradiol-induced inhibition of antigen presentation by vaginal cells was partially reversed when vaginal APC were incubated with anti-TGFbeta antibody. In contrast, anti-TNFalpha, anti-IL-6, and anti-IL-10 had no effect on antigen presentation. The effect of anti-TGFbeta was seen with vaginal APC from ovariectomized rats treated with estradiol for 1 d as well as 3 d. Finally, analysis of TGFbeta in the culture media of vaginal cells from saline- and estradiol-treated rats indicated that the TGFbeta produced is biologically active. In response to estradiol, vaginal cell production of TGFbeta was significantly greater than that seen with control cells. These studies suggest that estradiol regulation of antigen presentation by vaginal cells is mediated through the local production of TGFbeta by vaginal cells.

Animals↗
PubMed2002

17Beta-estradiol up-regulates vascular endothelial growth factor receptor-2 expression in human myometrial microvascular endothelial cells: role of estrogen receptor-alpha and -beta.

Estrogen has a cardiovascular protective role in women due in part to its effect on the vasculature. The roles of the two estrogen receptors (ERs), ERalpha and ERbeta, in the vascular actions of estrogen are unclear, as are effects of estrogen on microvascular endothelial cells (MEC) derived from sex steroid-responsive tissues. The present study demonstrates that 17beta-estradiol, but not progesterone, increases vascular endothelial growth factor (VEGF) receptor (VEGFR) expression on human myometrial MEC measured using biotin-recombinant human (rh) VEGF(165) and flow cytometry. This response occurred in a time- and dose-dependent manner, with significantly increased rhVEGF(165) binding at 3 h and maximal responses between 0.1 and 10 nmol/liter 17beta-estradiol, which was blocked by the antiestrogen ICI 182,780. Approximately 60% of samples demonstrated this response to 17beta-estradiol. All samples of myometrial MEC expressed both ERbeta mRNA and protein demonstrated by semiquantitative RT-PCR and Western blotting. However, ERalpha mRNA and protein were expressed in only 13 of 21 MEC samples. There was a significant association between ERalpha expression in myometrial MEC and their ability to respond to 17beta-estradiol by increasing rhVEGF(165) binding. 17beta-estradiol increased VEGFR-2 expression in ERalpha-expressing MEC isolates, which also demonstrated increased rhVEGF(165) binding, but failed to have these effects on ERalpha negative samples. Similarly, 17beta-estradiol augmented VEGF-induced MEC proliferation in ERalpha-expressing MEC samples, which was blocked by ICI 182,780. These observations suggest that 17beta-estradiol increases VEGFR-2 expression on human myometrial MEC promoting endothelial cell proliferation, an effect that varies between subjects and appears to be mediated primarily by ERalpha.

Adult↗
PubMed2002

Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women.

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of NF kappa B ligand. OPG has been shown to be an important inhibitor of osteoclast differentiation and activation in rodent models. Estrogen is known to suppress bone resorption, and the action of estrogen on bone may be mediated by OPG. The relationship between endogenous estrogen and circulating OPG levels and bone status in human populations is unclear. Thus, the aim of this study was to investigate the relationship between biochemical markers of bone turnover and bone density and circulating OPG and endogenous estradiol levels in a population-based cohort of postmenopausal women. Subjects were 180 women ages 55-91 yr (mean age, 67 yr). Serum estradiol was measured using an auto-analyzer. Serum concentrations of OPG were determined by ELISA. Markers of bone formation and resorption were measured by standard methods. Bone mineral density at total body, total hip, femoral neck, and lumbar spine was measured by dual energy x-ray absorptiometry. There was a significant inverse relationship between estradiol and all bone turnover markers (r-values from -0.46 to -0.23; P < 0.05). Serum estradiol was positively related to absolute bone density at all sites and to change in bone density at the hip and femoral neck by univariate analysis (r-values from 0.15-0.29; P < 0.05). We observed a weak inverse association between OPG and serum-based bone turnover markers (r-values -0.18 and -0.16; P < 0.05). There was a significant positive relationship between OPG and bone mineral density at total body, total hip, and femoral neck (r-values from 0.17-0.2; P < 0.05) by univariate analysis, which was lost after adjustment for age and body mass index. There was a significant weak positive relationship between circulating OPG and serum estradiol (r = 0.18; P < 0.02). We observed no significant relationships between OPG and bone turnover markers measured in urine. We conclude that the variation in circulating endogenous estradiol levels is an important factor contributing to levels of bone turnover and bone density at the menopause. Our observations also suggest that circulating levels of OPG may reflect OPG activity in bone and are related to circulating endogenous levels of estradiol. We have previously reported high levels of variability in urine markers of bone resorption, and we suggest that this could account for the absence of a significant association between these markers and circulating OPG.

Aged↗
PubMed2005

Effects of selective testosterone and estradiol withdrawal on skeletal sensitivity to parathyroid hormone in men.

CONTEXT: Gonadal steroid withdrawal increases bone turnover and causes bone loss in men, but the underlying mechanisms have not been defined. We previously reported that gonadal steroid deprivation increases the skeletal sensitivity to the bone resorbing properties of PTH infusion in men, but it is not known whether this effect is mediated by the absence of androgens, estrogens, or both. OBJECTIVE: The objective of the study was to determine the selective effects of testosterone and estradiol withdrawal on the skeletal sensitivity to PTH infusion in healthy adult men. DESIGN AND SETTING: We randomly assigned 58 healthy men between the ages of 20 and 45 yr to receive treatment with combinations of a GnRH analog, an aromatase inhibitor, and hormone add-back therapy to produce the following treatment groups: group 1 (testosterone and estradiol deficient, n = 16); group 2 (testosterone sufficient but estradiol deficient, n = 12); group 3 (testosterone deficient but estradiol sufficient, n = 14); and group 4 (testosterone and estradiol sufficient, n = 16). Twenty-four-hour PTH infusions were performed at baseline and after 6 wk of therapy. Serum N-telopeptide (NTX), C-telopeptide (CTX), osteocalcin (OC), and amino-terminal propeptide of type I procollagen (P1NP) were measured every 6 h during the PTH infusions. RESULTS: Serum testosterone levels fell into the castrate range in groups 1 and 3, whereas estradiol levels were similarly reduced in groups 1 and 2. Gonadal steroid levels in the replaced groups were unchanged from baseline. Serum NTX levels measured before PTH infusion did not change in group 4 (+T, +E) but increased significantly in all other groups. A similar pattern was observed in serum CTX, although the increase in group 2 (+T, -E) was not significant (P = 0.12). Preinfusion concentrations of both OC and P1NP fell in most groups, but these changes were significant in group 2 (+T, -E) for both OC and P1NP and group 4 (+T, +E) for P1NP only. Serum NTX and CTX increased during PTH infusions in all groups at all time points (P < 0.001). In the eugonadal group (group 4 +T+E), the increase in NTX was the same at wk 0 and 6, whereas in all the other groups, the PTH-induced increase in serum NTX was significantly greater at wk, 6 compared with wk 0. The same pattern emerged for CTX, although the difference in group 3 (-T,+E) was not significant (P = 0.12). Serum OC and P1NP levels fell during PTH infusions in all groups and at all time points (P < 0.001), but no significant differences were observed between wk 0 and 6 in any group. CONCLUSIONS: These results demonstrate that the selective suppression of testosterone, estradiol, or both hormones increases the skeletal responsiveness to the bone-resorbing effects of PTH in men. These findings underscore the importance of both androgens and estrogens in male skeletal homeostasis and suggest that changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.

Adult↗
PubMed1975

Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. I. Effects of varying duration of estradiol administration.

This study was designed to investigate the effects of increased serum concentrations of estradiol of varying durations upon the gonadotropin responses to synthetic gonadotropin-releasing hormone (GnRH or LRF). Beginning at 8:00 PM on the first day of the menstrual cycle, subjects received im injections of estradiol benzoate (E2B), 5 mug/kg initially, followed by 2.5 mug/kg every 12 h for a total of 3, 5, 7, 9, or 11 injections. Twelve h after the last E2B injection, or 36, 60, 84, 108, or 132 h after the first injection of E2B (2 subjects at each time interval), each subject received 100 mug GnRH, iv. In addition, each subject received 100 mug GnRH iv during one of the seven days of the antecedent (control) menstrual cycle during which no exogenous estradiol was administered. When GnRH was infused 36 h after the initiation of E2B pretreatment, there was no significant LH or FSH increase. In contrast, LH and FSH responses were augmented and prolonged when compared with control cycles when GnRH was administered at 84, 108, or 132 h. At 60 h, responses of LH were augmented, although not to as great a degree. FSH responses were not augmented at 60 h. Expressed as maximal increase from baseline, gonadotropin responses following E2B were 1 1/2 to 9 times those achieved during control cycles (without E2B). Since mean serum estradiol concentrations at 36 h (185.9 +/- 20.0), when gonadotropin responses were absent, were similar to those at 60 (157.7 +/- 31.6), 84 (186.2 +/- 38.1), 108 (181.3 +/- 46.7), and 132 h (128.0 +/- 43.0 pg/ml), when responses were augmented, these results support the concept that the modulating effect of estradiol on pituitary response is dependent upon the duration of exposure of the hypothalamic-pituitary system to increased concentrations of estradiol. It is probable that the duration of the late follicular phase rise in serum estradiol is responsible, at least in part, for the augmented gonadotropin response seen at midcycle.

Estradiol↗
PubMed1981

Free estradiol in postmenopausal women with and without endometrial cancer.

To assess the role of biologically active estradiol in the development of endometrial cancer, 25 patients with endometrial tumors and a similar number of control subjects matched for age and body size were studied. No differences between the 2 groups were found for levels of total estradiol, sex hormone-binding globulin (SHBG), non-SHBG-bound estradiol, and absolute free estradiol. Body size correlated positively with levels of total, non-SHBG-bound, and absolute estradiol and negatively with SHBG levels. The obese postmenopausal women had higher total circulating levels and proportionally greater concentrations of free estradiol than nonobese subjects, suggesting a dual risk for the cellular action of circulating estradiol. These factors could contribute to the association of obesity and the occurrence of this tumor in susceptible women.

Body Weight↗
PubMed1993

Estradiol amplifies the amount of luteinizing hormone (LH) secreted in response to increasing doses of gonadotropin-releasing hormone by specifically augmenting the duration of evoked LH secretory events and hence their mass.

Amplification of LH release during the preovulatory LH surge could result from increased GnRH secretion and/or estradiol's facilitation of the dose-dependent actions of GnRH. We have investigated the mechanisms of estrogen's enhancement of GnRH action by evaluating LH release in response to four consecutive iv doses of GnRH (7.5, 25, 75, and 250 ng/kg) administered in randomized order followed by a fifth (maximal) dose of 750 ng/kg GnRH. The GnRH dose-response study was carried out before and after 10 days of estradiol treatment (0.2 mg/day percutaneously) in nine healthy postmenopausal women. Deconvolution analysis was used to quantitate specific measures of GnRH-stimulated LH secretion as well as estimate the half-life of endogenous LH. We found that 10 days of estradiol delivery did not alter the calculated half-life of immunoradiometric LH (126 +/- 10 min basally vs. 135 +/- 14 min during estrogen), but amplified the total mass of LH secreted in response to the five doses of GnRH; viz. 201 +/- 29 (control) vs. 406 +/- 58 IU/L (estrogen) (P < 0.001). Estradiol specifically enhanced the maximal value of the GnRH dose-LH secretory response curve; viz. from a mass of LH secreted of 46 (41-51) IU/L (basal) vs. 113 (93-139) IU/L (estrogen) (P < 0.001). Estradiol did not induce a significant leftward shift of the GnRH dose-LH secretory response curve, since the half-maximally effective dose of GnRH (ED50) was 9 (3.6-18) (control) vs. 19 (10-31) ng/kg (estradiol). The increased mass of LH secreted in the estrogen-rich milieu was due to a doubling of LH secretory burst duration, with no change in amplitude. We conclude that amplified LH secretory burst duration constitutes a novel neuroendocrine mechanism by which estradiol can promote GnRH self-priming of LH release by the previously estrogen-deprived human anterior pituitary gland in vivo.

Analysis of Variance↗
PubMed1996

A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea.

Premature ovarian failure is classically defined as menopause occurring before age 40 and is associated with elevated serum FSH levels. If elevated FSH levels indicate lack of ovarian feedback and depletion of primordial follicles, women with prematurely elevated FSH levels should have infertility. However, there are many reports of pregnancies in affected women occurring during estrogen therapy leading to the hypothesis that estrogen may have a salutary effect on folliculogenesis and conception. This randomized, controlled trial was designed to investigate whether estrogen replacement therapy offered a significant therapeutic benefit in hypergonadotropic amenorrhea and to evaluate the potential pathophysiologic mechanisms that would explain the reported pregnancies. Thirty seven women, aged 16 to 40, with menstrual dysfunction and documented FSH levels elevated above the 95% confidence limits of the mid-cycle gonadotropin peak of the normal menstrual cycle (> 40 IU/L 2nd IRP hMG in our RIA) on at least two occasions, entered the study. The average duration of their amenorrhea was 15.9 months (range 2-96 months). Subjects were randomized to begin estradiol replacement (micronized estradiol [Estrace TM], 2 mg orally each day) or no therapy for 6 weeks in a 12-week, cross-over design with weekly monitoring by both pelvic ultrasonography and serum hormone levels. Thirty-one women completed the entire randomized study. As expected, estradiol therapy increased mean serum estradiol levels by 98 pg/mL and was associated with a significant decrease in mean LH and FSH levels (LH: 45.4 IU/L 2nd IRP hMG vs. 37.1 IU/L, FSH: 63.4 IU/L vs. 40.6 IU/L, geometric means). However, there was no effect of estradiol replacement on mean ovarian volume, the number or size of new follicles, or the ovulation rate in all subjects or in the subset with no identified cause for their hypergonadotropic hypogonadism (n = 20). Two pregnancies occurred during the randomized trial, one on and one off estradiol. In both arms of the study, the majority of subjects developed cystic ovarian structures by ultrasound that were temporally associated with increasing serum estradiol levels, indicating functional ovarian follicles. Seventy-eight percent of all subjects grew at least one new follicle over 10 mm in diameter and 46% ovulated at least once, as determined by a serum progesterone level more than 4 ng/mL. Although ovulations were significantly more common in the 10 women subjects who had less than 3 months of amenorrhea (all of whom ovulated) than in the 27 with greater than 3 months of amenorrhea (only 7 of whom ovulated (26%), P < 0.001), there was no significant difference in eventual pregnancies (2 of the 10 women with less than 3 months of amenorrhea vs. 3 of the 27 with greater than 3 months of amenorrhea, P = 0.47). We conclude that in hypergonadotropic women with amenorrhea: 1) folliculogenesis occurs often but is less frequently followed by ovulation and rarely by pregnancy, suggesting that elevated FSH is a marker of oocyte dysfunction occurring distinct from and earlier than granulosa cell or follicular dysfunction; and 2) estrogen therapy does not improve the rate of folliculogenesis or ovulation.

Adolescent↗
PubMed1997

Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate.

Increased incidence of cardiovascular disease in postmenopausal women (PMW) is accompanied by ovarian dysfunction; hormone replacement therapy (HRT) can have cardioprotective effects. Because hypertension and atherosclerosis are associated with impaired release of endothelium-derived nitric oxide (NO) and increased levels of low-density lipoproteins (LDL), we investigated whether HRT augments NO release, and whether these increases are accompanied by a decrease in LDL levels in PMW. We determined serum nitrite/ nitrate (NO2-/NO3-) and LDL levels at baseline (before initiation of HRT) and during the 6th and 12th months of the study. The PMW (n = 26) received continuous oral administration of estradiol valerate (Progynova, 2 mg daily) for 21 days supplemented with either oral cyproterone acetate (CPA; 1 mg; n = 11) or medroxyprogesterone acetate (MPA; 5 mg; n = 15) on days 12-21 of each treatment cycle. Blood samples in the PMW receiving HRT were collected at times while the subjects were taking estradiol valerate alone and estradiol valerate plus CPA or MPA. Compared with the samples collected at baseline, serum NO2-/NO3- levels increased significantly from 20.1 +/- 1.58 mumol/L at baseline to 30 +/- 3.7 mumol/L (P < 0.01) in samples collected after 12 months of HRT while the PMW were not taking progestins (CPA or MPA), and to 25.4 +/- 2 mumol/L (P < 0.05) when all the samples, regardless of the treatment with CPA or MPA, were included in the analysis. Moreover, > 30% increase in serum NO2-/NO3- levels were observed only in 13 (responders) out of 26 PMW substituted with estradiol valerate, suggesting that estradiol may improve endogenous NO synthesis in a differential fashion. Compared with baseline, no significant increases in serum NO2-/NO3- were observed in samples collected while the estradiol-treated responders were taking either CPA or MPA. In contrast to NO2-/NO3- serum LDL levels were significantly reduced in samples collected after 12 months of HRT (P < 0.05 vs. baseline). Furthermore, levels of NO2-/NO3 showed a significant negative correlation with the levels of LDL (r2 = 0.17; P < 0.05) in the responders but not in nonresponders. These results indicate that oral administration of estradiol valerate in PMW for HRT increases circulating NO levels, an effect that may contribute to the cardioprotective effects of HRT in PMW. In addition, our data suggests but does not prove that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release. Finally, our data provides evidence for the existence of responders and nonresponders to postmenopausal estrogen treatment with respect to improvement of endogenous NO levels, suggesting that a significant number, but not all, of the hormonally substituted PMW profit fully from the beneficial properties of a HRT.

Estradiol↗
PubMed1997

Tonic support of luteinizing hormone secretion by adrenal progesterone in the ovariectomized monkey replaced with midfollicular phase levels of estradiol.

Although it is known that progesterone facilitates the estradiol-induced gonadotropin surge at midcycle, its effect on LH secretion at other times of the follicular phase remains to be investigated. In this study, we investigate the role of progesterone on tonic LH secretion in the ovariectomized primate replaced with estradiol at levels representative of the follicular phase. The experiments were performed in nine ovariectomized rhesus monkeys, either unreplaced with estradiol or after a 5-day estradiol therapy to mimic early follicular (10-36 pg/mL; low dose) and midfollicular (medium dose; 40-75 pg/mL) concentrations. We used two antiprogesterone compounds, RU-486 (5 mg) and ORG-31806 (1 mg), to antagonize endogenous progesterone activity and studied their acute effects on LH secretion in each group. LH concentrations were measured at 15-min intervals for a 3-h baseline period and during a 5-h period after antagonist administration. LH concentrations remained unchanged after either antiprogesterone compound or diluent (ethanol) administration in the estrogen-unreplaced monkeys or after low dose estradiol replacement. However, both antiprogesterone compounds significantly decreased LH secretion in monkeys pretreated with the medium dose of estradiol; by 5 h, the mean (+/-SE) areas under the LH curve were 54.8 +/- 4.1% and 64.0 +/- 4.2% after RU-486 and ORG-31806, respectively (P < 0.05 vs. unreplaced and low dose estrogen-replaced groups). To exclude the possibility that the LH response reflects an agonist action of the progesterone antagonist, LH responses to progesterone infusions (at three doses to reproduce preovulatory, luteal, and pharmacological levels) were also examined in monkeys pretreated with midfollicular levels of estradiol. In none of these was there a decrease in LH; rather, progesterone infusions resulted in an increase in LH secretion in all three groups (to 115-194% of baseline in seven of eight monkeys). Finally, we determined that at the dose used in our protocol, neither of the two progesterone antagonists was able to prevent dexamethasone-induced cortisol suppression, thus excluding the possibility that results after progesterone antagonist administration may reflect a putative antiglucocorticoid activity of these compounds. When the doses of the antiprogesterone compounds were increased 6 times, only RU-486 counteracted the effect of dexamethasone on cortisol. In summary, our data indicate support by progesterone of tonic LH secretion in the nonhuman primate under estrogenic conditions similar to the midfollicular phase of the menstrual cycle. Significantly, because the experiments were performed in ovariectomized monkeys, and endogenous progesterone was most probably of adrenal origin, the data also demonstrate a role of the hypothalamo-pituitary-adrenal axis in support of gonadotropin secretion.

Adrenal Glands↗