Estrogen Regulates Duodenal Calcium Absorption Through Differential Role of Estrogen Receptor on Calcium Transport Proteins.

BACKGROUND AND AIMS: Intestinal calcium absorption from the diet plays important role in maintaining calcium homeostasis in the body. Estrogen exerts wide physiological and pathological effects in the human. Previous studies have shown that estrogen is involved in the intestinal calcium absorption. In this study, we made investigation on the mechanism of estrogen action on duodenal calcium absorption. METHODS: The experiments were performed in mice, human, and human duodenal epithelial cells, SCBN cells. Murine duodenal calcium absorption was measured by using single pass perfusion of the duodenum in vivo. The calcium absorption of SCBN cells was evaluated by calcium imaging system. The expression of calcium transport proteins, transient receptor potential cation channel (TRPV6) and plasma membrane calcium pump (PMCA1b), in the duodenum or SCBN cells were analyzed by western blot. RESULTS: The duodenal calcium absorption in ovariectomized mice was significantly decreased, compared with control female mice, which returned to control level after 17ß-estradiol replacement treatment. Estrogen regulated the expressions of TRPV6 and PMCA1b in murine and human duodenal mucosae and SCBN cells. The further results from SCBN cells showed that 17ß-estradiol regulated calcium influx through the respective effects of estrogen receptor (ER) ɑ and ß on TRPV6 and PMCA1b. CONCLUSION: Estrogen regulates duodenal calcium absorption through differential role of ERɑ and ERß on duodenal epithelial cellular TRPV6 and PMCA1b. The study further elucidates the mechanism of estrogen on the regulation of intestinal calcium absorption.

Quantitative in vitro-to-in vivo extrapolation (QIVIVE) of estrogenic and anti-androgenic potencies of BPA and BADGE analogues.

The goal of the present study was to obtain an in vivo relevant prioritization method for the endocrine potencies of different polycarbonate monomers, by combining in vitro bioassay data with physiologically based kinetic (PBK) modelling. PBK models were developed for a selection of monomers, including bisphenol A (BPA), two bisphenol F (BPF) isomers and four different bisphenol A diglycidyl ethers (BADGEs), using in vitro input data. With these models, the plasma concentrations of the compounds were simulated, providing means to estimate the dose levels at which the in vitro endocrine effect concentrations are reached. The results revealed that, whereas the in vitro relative potencies of different BADGEs (predominantly anti-androgenic effects) can be up to fourfold higher than BPA, the estimated in vivo potencies based on the oral equivalent doses are one to two orders of magnitude lower than BPA because of fast detoxification of the BADGEs. In contrast, the relative potencies of 2,2-BPF and 4,4-BPF increase when accounting for the in vivo availability. 4,4-BPF is estimated to be fivefold more potent than BPA in humans in vivo in inducing estrogenic effects and both 2,2-BPF and 4,4-BPF are estimated to be, respectively, 7 and 11-fold more potent in inducing anti-androgenic effects. These relative potencies were considered to be first-tier estimates, particularly given that the potential influence of intestinal metabolism on the in vivo availability was not accounted for. Overall, it can be concluded that both 2,2-BPF and 4,4-BPF are priority compounds.

The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

Of Mice and Women: A Laparoscopic Mouse Model for Endometriosis.

STUDY OBJECTIVE: To demonstrate how a novel laparoscopic approach allows the development of a mouse model for endometriosis after seeding menstrual endometrium from donor mice into the abdominal cavity of syngeneic recipient mice. DESIGN: A step-by-step video description of the techniques used to adapt the estrous cycle of mice towards a menstrual cycle and to subsequently induce endometriosis via laparoscopic seeding of menstrual endometrium. SETTING: University research institute. ETHICS: All animal experiments were ethically approved by KU Leuven, Belgium (ethical approval number: P031/2013). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Oophorectomized female C57BL/6JRj mice received a series of estrogen injections. Next, a progesterone pellet was administered, together with a second series of estrogen injections. In addition, decidualization of the endometrium was induced with an intrauterine sesame oil stimulus. Four days later the progesterone pellet was removed and menstruation started [1]. Five hours after the progesterone pellet was removal the uterus was harvested, and the menstrual endometrium was dissected and seeded into the abdominal cavity of syngeneic recipient mice to induce endometriosis [2] using a laparoscopic approach [3]. Uterus and lesions were removed from the recipient mice 1 week after induction, and tissues were immunohistochemically stained for H&E, vimentin, and cytokeratin. CONCLUSION: In this video we show a novel methodology to induce endometriosis in mice using laparoscopic inoculation of syngeneic menstrual endometrium, mimicking Sampson's theory of retrograde menstruation [4]. Compared with currently available rodent models, our model offers a less invasive and more physiologic way for fundamental and preclinical endometriosis research, with a high endometriosis incidence and lesion take rate.

In silico binding of 4,4'-bisphenols predicts in vitro estrogenic and antiandrogenic activity.

Bisphenols, anthropogenic pollutants, leach from consumer products and have potential to be ingested and are excreted in waste. The endocrine disrupting effects of highly manufactured bisphenols (BPA, BPS, and BPF) are known, however the activities of others are not. Here, the estrogenic and androgenic activities of a series of 4,4'-bisphenols that vary at the inter-connecting bisphenol bridge were determined (BPA, BPB, BPBP, BPC2, BPE, BPF, BPS, and BPZ) and compared to in silico binding to estrogen receptor-alpha and the androgen receptor. Bioassay results showed the order of estrogenicity (BPC2 (strongest) > BPBP > BPB > BPZ > BPE > BPF > BPA > BPS, r2 = 0.995) and anti-androgenicity (BPC2 (strongest) > BPE, BPB, BPA, BPF, and BPS, r2 = 0.996) correlated to nuclear receptor binding affinities. Like testosterone and the anti-androgen hydroxyflutamide, bisphenol fit in the ligand-binding domain through hydrogen-bonding at residues Thr877 and Asn705, but also interacted at either Cys784/Ser778 or Gln711 through the other phenol ring. This suggests the 4,4'-bisphenols, like hydroxyflutamide, are androgen receptor antagonists. Hydrogen-bond trends between ERα and the 4,4'-bisphenols were limited to residue Glu353, which interacted with the -OH of one phenol and the -OH of the A ring of 17ß-estradiol; hydrogen-bonding varied at the -OH of ring D of 17ß-estradiol and the second phenol -OH group. While both estrogen and androgen bioassays correlated to in silico results, conservation of hydrogen-bonding residues in the androgen receptor provides a convincing picture of direct antagonist binding by 4,4'-bisphenols.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Pharmacokinetic bioequivalence, safety and acceptability of Ornibel®, a new polymer composition contraceptive vaginal ring (etonogestrel/ethinylestradiol 11.00/3.474 mg) compared with Nuvaring® (etonogestrel/ethinylestradiol 11.7/2.7 mg).

OBJECTIVE: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). SUBJECTS AND METHODS: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire. RESULTS: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (Cmax: 96.81-112.20%; AUC0-504h: 98.71-108.61%; AUC0-t: 100.14-109.10%) and ethinylestradiol. (Cmax: 105.91-120.62%; AUC0-504h: 105.47-114.59%; AUC0-t: 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring®, with significantly higher level of ethinylestradiol (Cmax0-24h ratio: 78.34%, 94.12CI: 73.55-83.45%). Both products were well tolerated and accepted, without significant differences between them. CONCLUSION: Ornibel® is bioequivalent to Nuvaring® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

Interactions between plant-derived oestrogenic substances and the mycoestrogen zearalenone in a bioassay with MCF-7 cells.

Human and animal diets may contain several non-steroidal oestrogenic compounds which originate either from plants (phytoestrogens) or from fungi that infect plants (mycoestrogens such as zearalenone (ZEN)). Phytoestrogens may compete with ZEN in binding to the oestrogen receptor ß and thereby may counteract the oestrogenic activity of ZEN. Using a modified version of the E-screen assay, plant-derived oestrogenic substances were tested for their proliferative or anti-proliferative effect on oestrogen-dependent MCF-7 cells. The samples were additionally tested for their ability to influence the oestrogenic activity of ZEN (1 µM). Among the individual substances tested, 8-prenylnaringenin had the strongest effect, as cell proliferation was increased by 78% at the lowest concentration (0.23 µM), and by 167% at the highest concentration (29.4 µM). Coumestrol (5.83 µM) increased cell proliferation by 39%, and genistein (370 µM) by 61%, respectively. Xanthohumol and enterolactone did not stimulate cell proliferation significantly. In the co-incubation experiments with ZEN, none of the single substances was able to decrease the oestrogenic activity of ZEN. Only for 8-prenylnaringenin (14.7 and 29.4 µM) was a trend towards an increase in the ZEN-induced cell proliferation up to 72% observed. In conclusion, with the exception of 8-prenylnaringenin, no substantial interaction between phytoestrogens and the mycotoxin ZEN could be detected using a bioassays with MCF-7 cells.

Pharmacokinetics and tissue distribution of five active ingredients of Eucommiae cortex in normal and ovariectomized mice by UHPLC-MS/MS.

1. Pinoresinol di-O-ß-d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA) are the representative active ingredients in Eucommiae cortex (EC), which may be estrogenic. 2. The ultra high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of the five ingredients showed good linearity, low limits of quantification and high extraction recoveries, as well as acceptable precision, accuracy and stability in mice plasma and tissue samples (liver, spleen, kidney and uterus). It was successfully applied to the comparative study on pharmacokinetics and tissue distribution of PDG, GE, GA, AN and CA between normal and ovariectomized (OVX) mice. 3. The results indicated that except CA, the plasma and tissue concentrations of PDG, GE, GA in OVX mice were all greater than those in normal mice. AN could only be detected in the plasma and liver homogenate of normal mice, which was poorly absorbed in OVX mice and low in other measured tissues. PDG, GE and GA seem to be better absorbed in OVX mice than in normal mice proved by the remarkable increased value of AUC0-∞ and Cmax. It is beneficial that PDG, GE, GA have better plasma absorption and tissue distribution in pathological state.

Quantification of lipid modified estrogenic derivative (ESC8) in rat plasma by LC-MS: application to a pharmacokinetic study.

A lipid-conjugated, estrogenic derivative molecule, ESC8, compared with other estrogenic molecules, encourages cell death in both ER-positive and ER-negative breast cancer cells. A rapid and highly sensitive assay method has been developed and validated for the estimation of a ESC8 in rat plasma using liquid chromatography coupled with mass spectrometry under positive-ion mode with electrospray ionization. The sample process includes using methanol for precipitation of ESC8 and dextromethorphan (internal standard, IS) from plasma. Chromatographic separation was achieved with methanol-water-formic acid (70:30:0.1% v/v/v) pumped at a flow rate of 0.3mL/min and a C18 column (50 × 2.1 mm i.d., 1.7 µm particle size) with a total run time of 5 min. The m/z ions monitored were 568.5 and 272.1 for ESC8 and IS, respectively. The lower limit of quantitation achieved was 1.08 ng/mL and linearity was observed from 5 to 500 ng/mL. The intra- and inter-day precisions were <4%. The proposed method was successfully applied to a preliminary pharmacokinetic study of ESC8 liposomal formulation following an intraperitoneal administration of 3.67 mg/kg in rats. The concentrations of ESC8 in plasma were quantifiable up to 36 h. The peak concentration of ESC8 was found to be 110.72 ng/mL, the area under the concentration-time curve was 1625.23ng/mL h and the half-life was 11.72 h.

Comparative pharmacokinetics of purified flaxseed and associated mammalian lignans in male Wistar rats.

Consumption of flaxseed lignans is associated with various health benefits; however, little is known about the bioavailability of purified lignans in flaxseed. Data on their bioavailability and hence pharmacokinetics (PK) are necessary to better understand their role in putative health benefits. In the present study, we conducted a comparative PK analysis of the principal lignan of flaxseed, secoisolariciresinol diglucoside (SDG), and its primary metabolites, secoisolariciresinol (SECO), enterodiol (ED) and enterolactone (EL) in rats. Purified lignans were intravenously or orally administered to each male Wistar rat. SDG and its primary metabolites SECO, ED and EL were administered orally at doses of 40, 40, 10 and 10 mg/kg, respectively, and intravenously at doses of 20, 20, 5 and 1 mg/kg, respectively. Blood samples were collected at 0 (pre-dose), 5, 10, 15, 20, 30 and 45 min, and at 1, 2, 4, 6, 8, 12 and 24 h post-dosing, and serum samples were analysed. PK parameters and oral bioavailability of purified lignans were determined by non-compartmental methods. In general, administration of the flaxseed lignans SDG, SECO and ED demonstrated a high systemic clearance, a large volume of distribution and short half-lives, whereas administration of EL at the doses of 1 mg/kg (intravenously) and 10 mg/kg (orally administered) killed the rats within a few hours of dosing, precluding a PK analysis of this lignan. PK parameters of flaxseed lignans exhibited the following order: systemic clearance, SDG < SECO < ED; volume of distribution, SDG < SECO < ED; half-life, SDG < ED < SECO. The percentage of oral bioavailability was 0, 25 and < 1 % for SDG, SECO and ED, respectively.

Serum estradiol level during withdrawal bleeding as a predictive factor for intermittent ovarian function in women with primary ovarian insufficiency.

The objective of this study was to assess the potential predictive factors for follicle growth, ovulation, and pregnancy rate in patients with primary ovarian insufficiency/premature ovarian failure (POI/POF). We enrolled 25 POI patients with desired fertility who were treated and monitored for a minimum of 7 months between the years of 2000-2009 into this retrospective study. The clinical, endocrinologic, chromosomal, and autoimmunologic parameters of these patients were collected. Furthermore, hormonal backgrounds on each of 620 treatment cycles were investigated. The main outcome measures were follicle growth, ovulation, and pregnancy rate. Four of 25 patients (16%) conceived while being monitored and undergoing treatment. Follicle growth, ovulation, and pregnancy rate were not significantly different as a function of parity, iatrogenic history (e.g., chemotherapy), age of disease onset, serum estradiol (E(2))/follicle stimulating hormone (FSH) level at the time of diagnosis, chromosomal abnormality, and positive autoantibody titer. The serum E2 levels on days 1-5 of withdrawal bleeding (Day 1-5 E(2)) were significantly higher in the cycles with successful follicle growth and ovulation than unsuccessful cycles (P<0.05). Receiver-operator characteristic curve analysis revealed the cut-off value of the Day 1-5 E(2) to be 15.5 pg/mL, and an area under the curve (AUC) value of 0.674 for follicle growth and 0.752 for ovulation. The results suggest that cycles with a Day 1-5 E(2)≥15.5 pg/mL have a higher rate of follicle growth and ovulation in patients with POI.

Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps.

Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse and non-adverse effects following human exposure to low doses of estrogen active chemicals (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly understood. This review summarizes our current understanding of the pharmacological action with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmacological characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health.

Trenbolone acetate metabolite transport in rangelands and irrigated pasture: observations and conceptual approaches for agro-ecosystems.

To assess the relative ecological risks of trenbolone acetate (TBA) use in agro-ecosystems, we evaluated the spatiotemporal dynamics of TBA metabolite transport during irrigation and rainfall events. Within a pasture, TBA-implanted heifers (40 mg TBA, 8 mg estradiol) were briefly penned (24 h) at high stocking densities (500 animal units (AU)/ha), prior to irrigation. Irrigation runoff concentrations of 17α-trenbolone (17α-TBOH) 0.3 m downslope were 11 ng/L in the wetting front, but quickly decreased to ∼0.5 ng/L, suggesting mass transfer limitations to transport. At 3 and 30 m downslope, efficient attenuation of 17α-TBOH concentrations is best explained by infiltration and surface partitioning. At plot scales, transport through vegetated filter strips resulted in <0.5-7 ng/L 17α-TBOH concentrations in rainfall-induced runoff with partial subsequent attenuation. Thus, even under intense grazing scenarios, TBA-metabolite transport potential is expected to be low in rangelands, with ecological risks primarily arising from uncontrolled animal access to receiving waters. However, 17α-TBOH concentrations in initial runoff were predicted to exceed threshold levels (i.e., no observed adverse effect levels [NOAELs]) for manure concentrations exceeding 2.0 ng/g-dw, which occurs throughout most of the implant life. For comparison, estrone and 17ß-estradiol were modeled and are likely capable of exceeding NOAELs by a factor of ∼2-5 in irrigation runoff, suggesting that both endogenous and exogenous steroids contribute to endocrine disruption potential in agro-ecosystems.

Characterization of estrogen-receptor-targeted contrast agents in solution, breast cancer cells, and tumors in vivo.

The estrogen receptor (ER) is a major prognostic biomarker of breast cancer, currently determined in surgical specimens by immunohistochemistry. Two new ER-targeted probes, pyridine-tetra-acetate-Gd chelate (PTA-Gd) conjugated either to 17ß-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd), were explored as contrast agents for molecular imaging of ER. In solution, both probes exhibited a micromolar ER binding affinity, fast water exchange rate (∼10(7) s(-1)), and water proton-relaxivity of 4.7-6.8 mM(-1) s(-1). In human breast cancer cells, both probes acted as estrogen agonists and enhanced the water protons T1 relaxation rate and relaxivity in ER-positive as compared to ER-negative cells, with EPTA-Gd showing a higher ER-specific relaxivity than TPTA-Gd. In studies of breast cancer tumors in vivo, EPTA-Gd induced the highest enhancement in ER-positive tumors as compared to ER-negative tumors and muscle tissue, enabling in vivo detection of ER. TPTA-Gd demonstrated the highest enhancement in muscle tissue indicating nonspecific interaction of this agent with muscle components. The extracellular contrast agents, PTA-Gd and GdDTPA, showed no difference in the perfusion capacity of ER-positive and -negative tumors confirming the specific interaction of EPTA-Gd with ER. These findings lay a basis for the molecular imaging of the ER using EPTA-Gd as a template for further developments.

Effect of estrogen and testosterone replacement therapy on cognitive fatigue.

Both estrogen and testosterone insufficiency has been associated with reduced psychological well-being including fatigue. However, hormonal replacement studies on fatigue are rare. Therefore, we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women. Fifty women with surgically induced menopause (mean age: 54.0 ± 2.9 years) were randomly assigned to treatment with estradiol valerate in combination with testosterone undecanoate or placebo for 24 weeks in a double-blind cross-over study. Neuropsychological tests and questionnaires were used to assess cognitive fatigue and psychological well-being. Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels. Treatment with testosterone + estrogen had no significant effect on cognitive fatigue but the results indicated a curvilinear relation for hormonal levels. The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se. We found that cognitive fatigue is frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI. A well-balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue.

Pharmacokinetics and ovarian suppression during use of a contraceptive vaginal ring in normal-weight and obese women.

OBJECTIVE: Many observational studies indicate higher oral contraceptive failure among obese women, but most clinical trials and physiologic studies do not support these differences. Limited data indicate higher failure rates among obese contraceptive patch users. Data regarding contraceptive vaginal ring performance in obese women are needed. STUDY DESIGN: Twenty normal weight (body mass index [BMI] 19.0-24.9; median, 21.65) and 20 obese (BMI 30.0-39.9; median, 33.7) women enrolled in a prospective study of ethinyl estradiol (EE(2)) and etonorgestrel pharmacokinetics and of ovarian follicle development, endometrial thickness, and bleeding patterns, all measured biweekly during the second cycle of contraceptive vaginal ring use. RESULTS: Thirty-seven women completed follow-up. Mean day 0-21 EE(2) concentrations were lower among obese vs normal weight women (15.0 vs 22.0 pg/mL, respectively, P = .004), whereas etonorgestrel concentrations were similar (1138 vs 1256 pg/mL, respectively, P = .39). Follicular development was minimal in both groups, with only 5 women achieving a maximum follicle diameter >13 mm at any time during 3 weeks follow-up (3 normal weight and 2 obese women); these women had serum progesterone levels <1.0. Obese women reported more bleeding or spotting than normal weight women (3.6 vs 1.4 days, respectively, P = .01). CONCLUSION: Although obese women had lower EE(2) levels during contraceptive vaginal ring use, they had excellent suppression of ovarian follicle development, similar to normal weight women. This predicts that contraceptive vaginal ring effectiveness will be similar in women with a BMI up to 39.9. The lower serum EE(2) levels in the obese women may explain the greater reported bleeding or spotting days.

Estrogen therapy in Turner syndrome: does the type, dose and mode of delivery matter?

The best type, dose and route of estrogen replacement in hypogonadal females has not been fully elucidated and is the subject of this brief review. When feminizing girls with different forms of hypogonadism micronized 17betaE2 should be considered the first choice as it is the most physiological and can be accurately measured in plasma. Most studies of the metabolic effects of the different routes have also used different types of estrogen making comparisons difficult. However, when using the same estradiol compound, 17betaE2 transdermal results in E2, E1 and bioestrogen concentrations closer to normal as compared to oral and achieves greater suppression of LH/FSH but similar IGF-I and lipid concentrations. Whether this translates into better body composition and metabolic outcomes in girls with hypogonadism is being actively investigated and data will soon be available.

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women.

AIMS: Oral contraceptives such as norgestimate-ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate-ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. METHODS: In each of two periods, nineteen healthy women established on norgestimate-ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1-21. Pharmacokinetics were analysed on day 21 of each period. RESULTS: The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate-ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93-1.04) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); the GMR (90% CI) for the NGMN component of norgestimate-ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08-1.21) for AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS: Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.

The effect of circulating estradiol concentrations on gonadotropin secretion in young and old castrated male-to-female transsexuals.

CONTEXT: In aging men, circulating testosterone (T) declines which is associated with an increase in the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) , albeit insufficient to maintain T at its original level. It has been speculated that a higher sensitivity of the hypothalamus and/or pituitary for the feedback effect of circulating sex hormones in older men is responsible. OBJECTIVE: To compare the effect of experimentally varied plasma levels of estradiol on the LH and FSH secretion in young and old castrated male-to-female transsexuals, in almost absence of T. DESIGN, SUBJECTS, AND INTERVENTIONS: In 10 healthy, young (mean age 37.6 ± 6.2 years) and 11 healthy, old (mean age 68.1 ± 7.0) male-to-female transsexuals after gonadectomy plasma estradiol levels were experimentally varied with estradiol patches (the first week 100 µg/day patches, the second week 50 µg/day, the third week 25 µg/day and the fourth week no patch was applied) and plasma levels of LH and FSH were monitored after every week. RESULTS: Mean plasma bioavailable estradiol (E2) levels in the two groups ranged between 13.6 and 104 pmol/l. LH and FSH were inversely related to peripheral estradiol levels, were lower in the old group at all time points reaching statistical significance in the last week of the study when no patch was applied and estradiol levels were extremely low. CONCLUSIONS: The results of this study do not support the hypothesis of an age related increasing sensitivity of the hypothalamo-pituitary compartment for the negative feedback of E2, but suggest a deficient feed-forward drive in older male-to-female transsexuals.