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Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes. Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor κB ligand (RANKL) and its receptor (RANK). Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen. These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

It is well-known that breast cancer is hormone-dependent and that steroid hormones exert their mitogenic effects by binding to estrogen, progesterone and androgen receptors. Vital to our understanding and treatment of this malignancy, is the local metabolism of steroid hormones in breast cancer tissue. This review summarises our current knowledge on steroid producing pathways in the adrenal, ovary and breast, while focussing on the availability of specific circulating hormone precursors and steroidogenic enzymes involved in the local synthesis and metabolism of steroid hormones in the breast. Consequently, we highlight alternate pathways that may be instrumental in the etiology of breast cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A method for the quantitation of 22 urinary steroids (androgens, estrogens and the main pregnenolone and progesterone metabolites) by means of gas chromatography tandem mass spectrometry using a triple quadrupole analyzer has been developed. Two different enzymatic hydrolysis protocols were investigated; one capable of releasing steroids present as both sulfates and glucuronides (total fraction), and another with β-glucuronidase activity only. After selecting adequate internal standards and choosing the optimal instrumental parameters, i.e. chromatographic separation and ion transition conditions, the method was fully validated using both hydrolysis protocols. The method was shown to be linear (r >0.99) in the range of endogenous concentrations for all studied steroids with extraction recoveries higher than 80%. The use of labeled internal standards allowed for both a correct quantification and the evaluation of the rate of deconjugation for sulfates and glucuronides in every sample. In general, the sensitivity of the method was suitable for the detection of the endogenous levels, with limits of quantification ranging from 0.1 to 20ng/mL. Accuracies ranging from 80% to 120%, and relative standard deviations below 25% in intra- and inter- assay experiments were found for most of the analytes. The applicability of the validated method was tested by quantifying twenty-two metabolites in 24-h urine samples collected from healthy individuals. The ranges for the excretion of steroids in the total and glucuronide fractions obtained with the new method were compared with those available in the literature. By comparing the figures in both fractions, an estimation of the percentage that the sulfation represents for each steroid was also calculated. The presence of side enzymatic activities and the utility of the method for clinical studies as well as for doping control analysis is discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This work describes the development and validation of a method for the simultaneous determination of 13 estrogens and progestogens in honey by high performance liquid chromatography-tandem mass spectrometry. The hormones were preconcentrated by solid phase extraction. Pretreatment variables were optimized for a better compatibility with electrospray ionization interfaced mass spectrometry. The analytes were analyzed in multiple-reaction monitoring mode with two pairs of precursor product ion transitions. The proposed method was validated with method detection limits of 0.01-0.33ng/g and good linearities (r 2 >0.9901) throughout the studied concentration range. The recoveries of analytes at the spiking levels (5ng/g and 25ng/g) ranged from 71.2% to 99.7%, with relative standard deviations below 20%. The method was used to determine the target compounds in honey samples (orange blossom, clover and multiflower) obtained from supermarkets. Two samples of honey were found to contain trace amounts of estrone (

Synthetic and natural steroid hormones have attracted some attention in recent years as endocrine active substances (EAS) that interact or interfere with the endocrine system. Endogenous hormones occur naturally in food of animal origin, among which bovine milk represents an important source. This study was conducted to determine the occurrence of steroid hormones (oestrogens, androgens, progestogens and glucocorticoids) in cow's milk samples from three farms in Switzerland. An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of 12 hormones in milk. Some hormonal levels from individual cows showed large variations. The average levels of the hormones analysed (17α-estradiol = 31 ng kg(-)(1), 17β-estradiol = 6 ng kg(-)(1), estrone = 159 ng kg(-)(1), 4-androstenedione = 684 ng kg(-)(1), progesterone = 15486 ng kg(-)(1), 17-hydroxyprogesterone = 214 ng kg(-)(1), cortisone = 112 ng kg(-)(1), and cortisol = 235 ng kg(-)(1)) were comparable with literature data. Estriol, testosterone and androstenediols were not detected at their respective limit of quantification. No significant differences of hormonal content among milk from cows at different lactation/calving numbers were evidenced, except for progesterone and 4-androstenedione. Due to confounding parameters linked to the physiological stage of the animal, like pregnancy and gestational stage (pregnancy trimester), the causal correlation between the variation of the levels for these two hormones and the lactation/calving number could not be unambiguously demonstrated.

Aim: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue., Methods: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging., Results: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis., Conclusions: The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.

Both natural oestrogens and progesterone influence synaptic plasticity and neurogenesis within the female hippocampus. However, less is known of the impact of synthetic hormones on hippocampal structure and function. There is some evidence that the administration of the synthetic progestin, medroxyprogesterone acetate (MPA) is not as beneficial as natural progesterone and can attenuate oestrogen-induced neuroprotection. Although the effects of oestradiol have been well studied, little is known about the effects of natural and synthetic progestins alone and in combination with oestradiol on adult neurogenesis in females. In the present study, we investigated the effects of chronic oestradiol, progesterone, MPA and the co-administration of each progestin with oestradiol on neurogenesis within the dentate gyrus of adult ovariectomised female rats. Twenty-four hours after a bromodeoxyuridine (BrdU; 200 mg/kg) injection, female rats were repeatedly administered either progesterone (1 or 4 mg), MPA (1 or 4 mg), oestradiol benzoate (EB), progesterone or MPA in combination with EB (10 μg), or vehicle for 21 days. Rats were perfused on day 22 and brain tissue was analysed for the number of BrdU-labelled and Ki67 (an endogenous marker of cell proliferation)-expressing cells. EB alone and MPA + EB significantly decreased neurogenesis and the number of surviving BrdU-labelled cells in the dorsal region of the dentate gyrus, independent of any effects on cell proliferation. Furthermore, MPA (1 and 4 mg) and MPA + EB treated animals had significantly lower adrenal/body mass ratios and reduced serum corticosterone (CORT) levels. By contrast, progesterone + EB treated animals had significantly higher adrenal/body mass ratios and 1 mg of progesterone, progesterone + EB, and EB significantly increased CORT levels. The results of the present study demonstrate that different progestins alone and in combination with oestradiol can differentially affect neurogenesis (via cell survival) and regulation of the hypothalamic-pituitary-adrenal axis. These findings have implications for women using hormone replacement therapies with MPA for both neuroprotection and stress-related disorders., (© 2014 British Society for Neuroendocrinology.)

To review the criteria for the selection of estrogens and especially progestogens for optimizing Menopausal Hormone Therapy (MHT). The main criteria are primarily derived from the Women's Health Initiative (WHI)-trial, disclosing the main risks like endometrial cancer, coronary heart disease (CHD), stroke, venous tromboembolism (VTE) and breast cancer. In addition observational studies must be considered for individualizing MHT, because WHI has tested only one preparation and has a lot of problems like early opening of the hormone/placebo-code (i.e., loss of placebo control), in 60% MHT-initiation too late, and in 40% risk factors for cardiovascular diseases and breast cancer. Pharmacological properties should be considered, such as only oral, but not transdermal estradiol increases VTE-risk. The choice of progestogens could be dependent on the different "partial effects" on steroid receptors, e.g., use of anti-androgenic progestogens in metabolic syndrome, Polycystic Ovary Syndrome (PCOS) etc., taking advantage of the anti-mineralocorticoid effect of drospirenone to stabilize blood pressure and reduce the risk of stroke, selection of tibolone for patients with sexual dysfunctions because its androgenic properties etc. Most important for the selection of the progestogen is endometrial efficacy, primary indication for progestogens in MHT. Therefore regular endometrial monitoring is reommended, using sequential or continuous combined regimens; "hormonal curettage" and/or the progestogen challenge text to avoid endometrial hyperproliferation. Levonorgestrel-IUD as progestogen component can reduce progestogen-dependent risks, offering also contraception, but often with longer bleeding problems, in contrast to sequential regimens of MHT, which can be used to treat irregular bleedings. Other main indications are treatment of climacteric complaints and prevention of osteoporosis and possible other preventive options. Regarding contraindications, according to the general rules of "class-labeling", they are the same for every MHT despite there are differences in benefits and risks. Choice of the timing of MHT-initiation is crucial to whether cardiovascular prevention (early start) or (like in WHI) increased risk of CHD and stroke occurs. The increased risk of breast cancer can be reduced using progesterone or its isomer dydrogesterone. Since, however, this risk cannot been excluded with any MHT, recommendations for screening on the possible development of breast cancer are given, on the basis of own recent research. Criteria for the selection of MHT are mainly to reduce possible risks as seen in WHI since for every MHT efficacy is good and essentially the same. Often the best choice is estradiol combined with progesterone or dydrogesterone, but also other progestogens should be considered including LNG-IUD, to optimize and individualize MHT. [ABSTRACT FROM AUTHOR]

Hormone laboratories located "on-site" where field studies are being conducted have a number of advantages. On-site laboratories allow hormone analyses to proceed in near-real-time, minimize logistics of sample permits/shipping, contribute to in-country capacity-building, and (our focus here) facilitate cross-site collaboration through shared methods and a shared laboratory. Here we provide proof-of-concept that an on-site hormone laboratory (the Taboga Field Laboratory, located in the Taboga Forest Reserve, Costa Rica) can successfully run endocrine analyses in a remote location. Using fecal samples from wild white-faced capuchins (Cebus imitator) from three Costa Rican forests, we validate the extraction and analysis of four steroid hormones (glucocorticoids, testosterone, estradiol, progesterone) across six assays (DetectX® and ISWE, all from Arbor Assays). Additionally, as the first collaboration across three long-term, wild capuchin field sites (Lomas Barbudal, Santa Rosa, Taboga) involving local Costa Rican collaborators, this laboratory can serve as a future hub for collaborative exchange.

Background: In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users. Objective: To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety. Method: For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptives'. Results: Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman. Conclusion: Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the real‐world clinical practice of estrogen and progestogen prescriptions for menopausal women. Methods: Using a health care database in Japan, we conducted a cross‐sectional study on estrogen prescriptions and detailed analyses of newly initiated estrogens and concomitant prescriptions of progestogens. Data between January 2005 and December 2021 were analyzed. Results: In 2021, the proportion of women aged 45–49 years receiving estrogens was 25.8 [95% confidence interval (CI): 25.3, 26.3] per 1000 women, while it was 6.4 [95% CI: 6.0, 6.7] for those aged ≥60 years. The prescription of estrogens gradually increased in women aged 50–59 years after 2009. In women without a history of hysterectomy, transdermal estradiol was the primary form of estrogens prescribed for ≥180 days, in women aged <60 years. The proportion of transdermal estradiol gradually increased each year, whereas that of oral‐conjugated equine estrogens decreased. Among progestogen, the proportions of dydrogesterone and transdermal norethisterone acetate increased over time, while that of medroxyprogesterone acetate decreased. Approximately 30% of women prescribed estrogens for ≥180 days did not initiate progestogen concurrently. In women undergoing hysterectomy, progestogen was not initiated in >90% of cases, and transdermal estradiol was prescribed in approximately 80% of cases in 2021. Conclusions: This study reviewed the prescription of estrogens in menopausal women in Japan. A considerable number of women with a uterus are receiving estrogen therapy rather than estrogen‐progestogen therapy (EPT), despite the guidelines recommending the use of EPT in these women. [ABSTRACT FROM AUTHOR]

Since the middle of the 20th century, synthetic sex hormones (estrogens and progestins) have been administered to millions of pregnant or not women worldwide, mainly to avoid miscarriage or for comfort, although their mode of action and their effects on the mother and fetus were ignored. Despite the alerts and the description of somatic and psychiatric disorders in children exposed in utero, synthetic estrogens were prohibited for pregnant women only in the 1970s and 1980s, but some progestins are still authorized. In this review, we summarize the psychiatric disorders described in children exposed in utero to such hormones, focusing particularly on schizophrenia, bipolar disorders, severe depression, eating disorders, suicide and suicide attempts. Moreover, only in 2017 the mechanism of action of these xenohormones has started to be deciphered. Some studies showed that in the fetus exposed in utero, they alter the DNA methylation profile (mainly hypermethylation), and consequently the expression of genes implicated in neurodevelopment and in regulating the sexual organ morphogenesis and also of the promoter of estrogen receptors, located in the amygdala. These deleterious effects may be transmitted also to the next generations, thus affecting the children directly exposed and also the following generations. [ABSTRACT FROM AUTHOR]

Since the middle of the 20th century, synthetic sex hormones (estrogens and progestins) have been administered to millions of pregnant or not women worldwide, mainly to avoid miscarriage or for comfort, although their mode of action and their effects on the mother and fetus were ignored. Despite the alerts and the description of somatic and psychiatric disorders in children exposed in utero, synthetic estrogens were prohibited for pregnant women only in the 1970s and 1980s, but some progestins are still authorized. In this review, we summarize the psychiatric disorders described in children exposed in utero to such hormones, focusing particularly on schizophrenia, bipolar disorders, severe depression, eating disorders, suicide and suicide attempts. Moreover, only in 2017 the mechanism of action of these xenohormones has started to be deciphered. Some studies showed that in the fetus exposed in utero, they alter the DNA methylation profile (mainly hypermethylation), and consequently the expression of genes implicated in neurodevelopment and in regulating the sexual organ morphogenesis and also of the promoter of estrogen receptors, located in the amygdala. These deleterious effects may be transmitted also to the next generations, thus affecting the children directly exposed and also the following generations.

The menopause is a significant event in a women's life that can potentially impact on her quality of life in several ways. It marks the end of the reproductive life cycle and the clinical manifestations of the menopause result from the eventual exhaustion of oocytes within the ovaries. The depletion of these oocytes results in chronic hypoestrogenic state, which in the short term can cause menopausal symptoms and over a longer period, may impact upon bone and cardiovascular health. This review summarises current understanding of pathophysiology of the symptoms of the menopause as well as reviewing the current recommendations for HRT use in symptomatic menopausal women. The benefits of HRT in improving the symptoms of menopause are discussed as well as a review of the evidence pertaining to the potential risks associated with HRT. [ABSTRACT FROM AUTHOR]

Menopause is a natural stage of hormonal aging in women, accompanied by a series of symptoms that reduce the quality of life of a fully active person. As no therapy is entirely satisfactory, the race for a better option is in full swing. Our study objective is to investigate the most recent menopause studies on pharmacological resources, emerging therapies, and the particularities of hormonal replacement therapy (HRT). For this purpose, a comprehensive search was conducted in two main databases (PubMed and Web of Science) guided by the specific keywords "menopause" and "therapy" or "estrogen" or "progesterone" or "hormone replacement" during the last ten years period. Studies were eligible if they met certain criteria: randomized controlled trials (RCT) in adult women with menopause and hormonal or non-hormonal therapies. We selected 62 RCTs, which are focused on four main topics: (a) epidemiology of menopause-related symptoms, (b) hormonal replacement therapy (HRT) selective estrogen receptor modulators, (c) emerging therapies, and (d) menopause. HRT has proven a real health benefit for menopausal women; besides, complementary interventions must be considered. Further studies are needed on menopause and menopause-related therapies. The continuous updating of clinical experience will strengthen the therapeutic benefit and the decision to treat patients safely. This goal will fully access all therapeutic resources to address an unresolved health issue of active adult women. [ABSTRACT FROM AUTHOR]

Menopausal hormone therapy (MHT) is used to treat menopausal complaints including the genitourinary syndrome of menopause, to prevent osteoporosis, and to treat bleeding problems. Since these can be the indications also in young women, especially with POI (premature ovarian insufficiency) or with surgical menopause (bilateral oophorectomy), also the old term “Hormone Replacement Therapy (HRT)” is still used. The effective component is the estrogen component without relevant difference in the efficacy of the various MHT-preparations. Additional preventive benefits are reduction of cardiovascular disease (including prevention of diabetes mellitus and metabolic syndrome), reduction of colon cancer, and perhaps also Alzheimer's disease, if started within a “window of opportunity”, i.e. in perimenopause or within 6–10 years after menopause.Primary indication for progestogen addition is to avoid the development of estrogen-dependent endometrial cancer, i.e. addition not recommended in hysterectomized women. Two main schedules, sequential- or continuous-combined estrogen/progestogen regimens, are used for treatment of bleeding problems. For this and for optimizing menstrual regulation detailed recommendations are given including proposed dosages for the available different progestogens if added to oral or transdermal estradiol in different estrogen dosages.The WHI-study demonstrated the main risks using MHT within a “worst-case scenario”, i.e. start of MHT in old women with high risk for breast cancer and cardiovascular diseases, whereby only “conjugated equine estrogens” and “medroxprogesterone acetate” have been tested. One main result was that the progestogen component is decisive for the risk of breast cancer, which according to own experimental research and observational studies may be reduced using the physiological progesterone or its isomer dydrogesterone. In addition we propose to push forward research for screening patients with increased breast cancer risk like we have done in the past decade demonstrating that certain membrane-bound receptors in breast cancer tissue or blood can increase this risk. To reduce the risk of venous thromboembolism and stroke, transdermal estradiol (gels, patches,) should be used, in free combination with progesterone or dydrogesterone as “golden standard” in patients with increased risk. To increase the compliance in our patients without special risks we mostly use the available fix-combinations of estradiol/dydrogesterone getting strong efficacy, good menstrual regulation or amenorrhea, respectively, but also other combinations may be indicated to take advantage of for example androgenic or antiandrogenic progestogens.

High-grade serous ovarian cancer (HGSOC) represents the most lethal subtype of ovarian cancer, largely due to being commonly diagnosed at advanced stages. The early molecular mechanisms underlying ovarian carcinogenesis remain poorly defined, posing challenges to the development of prevention and early detection strategies. Here we dissect the molecular mechanisms of sex steroid hormone signaling throughout the decades-long evolution of HGSOC precursor lesions, which predominantly originate from secretory epithelial cells of fallopian tubes (FT). We also discuss the prognostic significance of sex steroid receptor isoforms and steroid metabolizing enzymes in HGSOCs. Finally, we provide a comprehensive gene expression atlases of sex steroid receptors, steroidogenic, and steroid-metabolizing enzymes across different cell populations in pre- and postmenopausal FTs, and HGSOCs, using published single-cell RNA sequencing datasets. These atlases reveal that secretory epithelial cells and stromal populations in FTs express sex steroid receptors and enzymes responsible for the formation and inactivation of genotoxic estrogen metabolites. In HGSOC, epithelial cells express various HSD17B isoforms and steroid conjugating enzymes, suggesting an enhanced ability to finely regulate the levels of bioactive sex steroids. [Display omitted] • Sex steroids play an active role in the evolution of precursor lesions of high-grade serous ovarian cancer (HGSOC). • Progesterone receptor (isoforms A, B, and C) is strongly linked to platinum sensitivity and better survival in patients with HGSOC. • Sex steroid receptors and enzymes for catechol estrogen metabolism are present in secretory epithelial and stromal cells of FTs. • The cancerous epithelial population in HGSOCs expresses multiple HSD17B isoforms and steroid-conjugating enzymes, indicating its ability to regulate bioactive sex steroids. [ABSTRACT FROM AUTHOR]

Despite the invaluable role that assisted reproduction technologies (ARTs) play in conservation, pregnancy and parturition rates by embryo transfer (ET) are low for most endangered felids. Thus, efforts to expand the knowledge on pregnancy biology and ET are still required. In this context, we examined fecal sex steroid metabolites (i.e., estrogens, glucocorticoids, and progestogens) of eight ocelots submitted to natural fertilization (NF) and ET in 22 pregnancies (19 NF and 3 ET). Fecal samples were collected and assessed for each pregnancy from estrous cycle, pregnancy, and lactation, totaling 155 days. In short, progestogen levels remained high and unchanged (P < 0.05) from conception until parturition for females maintained under NF. On the other hand, females submitted to ET exhibited changes (P > 0.05) in progestogen levels from conception until parturition, with a significant decrease during pregnancy (480.72 ng/day; r2 = 0.81; P < 0.0001). Significant changes between NF and ET also were noted in estrogen levels between the first and last thirds of pregnancy (P < 0.05), in which estrogen levels exhibited a negative correlation (P < 0.01) between themselves. Regarding glucocorticoids, significant changes (P < 0.01) were observed only in the first third of pregnancy between NF and ET, which we believe may be related to the handling for ovarian synchronization and ET. Besides hormonal changes, the pregnancy was more prolonged (2.5 days) and more prone to dystocia in ET than NF. Overall, 24 embryos were transferred into eight females (3/1), with three kittens being born from three distinct deliveries (i.e., 12.5% of embryos and 37.5% of females). Our findings have supported the great potential of production and transfer of long-term frozen embryos in ocelot conservation. However, they reveal possible effects of these biotechnologies on hormonal levels during pregnancy linked with low conception and parturition rates and dystocic cases in felids. • Embryo recipients exhibit altered fecal steroid profiles during pregnancy • The progestogen level does not remain high during pregnancy for embryo recipients • The estrogen levels do not substantially increase in the last third of pregnancy in embryo recipients. [ABSTRACT FROM AUTHOR]

Background: Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT.Objective and Rationale: The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms.Search Methods: A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause.Outcomes: HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity.Wider Implications: In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks. [ABSTRACT FROM AUTHOR]

This paper describes a methodology for simultaneous determination of 19 steroid hormones, viz. estrone, estradiol, estriol, testosterone, 5α-dihydrotestosterone, androstenedione, androstenediol, dehydroepiandrosterone, progesterone, pregnenolone, 17α-OH-progesterone, 17α-OH-pregnenolone, cortisone, cortisol, 11-deoxycortisol, 11-deoxycorticosterone, 11-dehydrocorticosterone, aldosterone, and corticosterone, in 500-µL of urine or serum/plasma. The method was optimized using isotopically labeled internal standards and liquid-liquid extraction followed by detection using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS). Dansylation of estrogens significantly improved their sensitivities (~11- to 23-fold) and chromatographic separation. The respective limit of detection (LOD) and limit of quantification (LOQ) of all analytes were 0.04–0.28 and 0.14–0.92 ng/mL in human urine, and 0.11–0.35 and 0.38–1.18 ng/mL in human serum/plasma. Recoveries of all analytes (except for progesterone) fortified at 10, 20, and 200 ng/mL in urine and serum were 80–120%, with standard deviations ranging from 0 to 17.3%. Repeated analysis of similarly fortified urine and serum samples yielded intra-day and inter-day variations of 0–21.7% and 0.16–11.5%, respectively. All analytes except cortisone exhibited weak matrix effects in urine and serum (−13.9–18.2%). The method was further validated through the analysis of the National Institute of Standards and Technology (NIST) plasma Standard Reference Material (SRM1950) with certified concentrations for cortisol, progesterone, and testosterone (coefficient of variation: 3–11%). The developed method was applied in the analysis of urine samples from 20 volunteers, which revealed the occurrence of 16 analytes with detection frequencies (DFs) > 80%. Furthermore, 15 analytes were found in plasma SRM1950, indicating the feasibility of our method in the analysis of steroid hormones in urine and serum/plasma. This method will facilitate analysis of steroid hormones in population-based biomonitoring studies.

The most common treatment for menopausal syndrome is menopausal hormone therapy (MHT), however, the safety of MHT, due to the risk of developing and recurrent breast cancer (BC), is still a matter of debate. The review presents the results of randomized cohort studies of this issue. It has been shown that MHT increases the risk of developing breast cancer and disease recurrence after treatment. The risk of breast cancer developing in women receiving MHT depends on body mass index (BMI), duration of hormone use, and dose of drugs, and is greater in thin women compared with women with increased BMI, and also greater in estrogen–progestin combined MHT users compared with estrogen-only users. It was found that hormone-dependent forms of cancer developed more often in women using MHT, but by the time of diagnosis, the disease was found in more advanced stages and metastases in lymph nodes were found more often when compared with patients who did not use MHT. Risk of breast cancer recurrence is less with low doses of vaginal estrogen. An alternative option for the relief of menopausal disorders in breast cancer patients during and after treatment is using of pineal gland hormone melatonin, since, along with its anti-aging properties, it is able to suppress cancer at the stages of initiation, progression, and metastasis and has the ability to reduce the toxic effects of anticancer drugs simultaneously increasing their effectiveness. [ABSTRACT FROM AUTHOR]

Hormone therapy is widely used in obstetric practice for the treatment of miscarriage, but, despite the known facts about the decisive influence of hormones on the sexual differentiation of the brain, long-term effects of intrauterine exposure to steroid drugs (drugs) on the formation of sexual behavior insufficiently studied. Therefore, the purpose of the study was to assess the performance of psychosexual development of children whose mothers received hormonal drugs during pregnancy. The cross-sectional study included 148 children whose mothers took estrogens and/or progestogens, and/or glucocorticoids, or did not take steroids (control group). The evaluation of indicators of mental development of children using the methods of «Age and gender identification», «Figure-posture-clothing», «Picture yourself», «Drawing the human behind the front» has been held.Results. Most of the children's sexual development was in line with the norm, gender and age identification formed by age and without features, elements of sexual dysontogenesis observed in isolated cases. Deviations were more common in girls whose mothers took estrogens and progestogens, and boys whose mothers received corticosteroids, but the proportion of these children were not significantly different from the proportion of children in the group of women who did not receive hormone therapy.Conclusion. The data obtained refute assumptions about the relationship of hormonal drugs during pregnancy with the development of disorders of puberty and sexual behavior anomalies in the offspring.

Monitoring complex endocrine pathways is often limited by indirect measurement or measurement of a single hormone class per analysis. There is a burgeoning need to develop specific direct-detection methods capable of providing simultaneous measurement of biologically relevant concentrations of multiple classes of hormones (estrogens, androgens, progestogens, and corticosteroids). The objectives of this study were to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for multi-class steroid hormone detection using biologically relevant concentrations, then test limits of detection (LOD) in a high-background matrix by spiking charcoal-stripped fetal bovine serum (FBS) extract. Accuracy was tested with National Institute of Standards and Technology Standard Reference Materials (SRMs) with certified concentrations of cortisol, testosterone, and progesterone. 11-Deoxycorticosterone, 11-deoxycortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, adrenosterone, androstenedione, cortisol, corticosterone, dehydroepiandrosterone, dihydrotestosterone, estradiol, estriol, estrone, equilin, pregnenolone, progesterone, and testosterone were also measured using isotopic dilution. Dansyl chloride (DC) derivatization was investigated maintaining the same method to improve and expedite estrogen analysis. Biologically relevant LODs were determined for 15 hormones. DC derivatization improved estrogen response two- to eight-fold, and improved chromatographic separation. All measurements had an accuracy ≤14 % difference from certified values (not accounting for uncertainty) and relative standard deviation ≤14 %. This method chromatographically separated and quantified biologically relevant concentrations of four hormone classes using highly specific fragmentation patterns and measured certified values of hormones that were previously split into three separate chromatographic methods. [ABSTRACT FROM AUTHOR]

• We introduce an "on-site laboratory", the Taboga Field Laboratory, established outside the Taboga Forest Reserve in Costa Rica. • This manuscript is the first collaboration across three long-term field sites on the behavior and biology of wild white-faced capuchins (Cebus imitator). • We validate six steroid hormone assays for use on wild capuchin fecal samples (glucocorticoids, androgens, estrogens, and progestogens). Hormone laboratories located "on-site" where field studies are being conducted have a number of advantages. On-site laboratories allow hormone analyses to proceed in near-real-time, minimize logistics of sample permits/shipping, contribute to in-country capacity-building, and (our focus here) facilitate cross-site collaboration through shared methods and a shared laboratory. Here we provide proof-of-concept that an on-site hormone laboratory (the Taboga Field Laboratory, located in the Taboga Forest Reserve, Costa Rica) can successfully run endocrine analyses in a remote location. Using fecal samples from wild white-faced capuchins (Cebus imitator) from three Costa Rican forests, we validate the extraction and analysis of four steroid hormones (glucocorticoids, testosterone, estradiol, progesterone) across six assays (DetectX® and ISWE, all from Arbor Assays). Additionally, as the first collaboration across three long-term, wild capuchin field sites (Lomas Barbudal, Santa Rosa, Taboga) involving local Costa Rican collaborators, this laboratory can serve as a future hub for collaborative exchange. [ABSTRACT FROM AUTHOR]

Inflammatory breast carcinoma (IBC) is a special type of breast cancer with a poor survival rate. Though several IBC cell lines have been established, recently a first IMC cell line was established. The aims of this study were: (1) to validate a highly sensitive, reliable, accurate and direct amplified enzyme immunoassay (EIA) to measure several cell-secreted steroid hormones: progesterone (P4), androstenedione (A4), testosterone (T), 17β-estradiol (E2) and estrone sulfate (SO4E1) in the culture medium. (2) To assess whether hormone production profile by IPC-366 cells validates the IMC model for human IBC. We validated a non-competitive amplified EIA for inflammatory breast cancer cell lines based on the results of accuracy, precision, sensitivity and parallelism. The low detection limits of the technique were: P4 = 13.2 pg/well, A4 = 2.3 pg/well, T = 11.4 pg/well, E2 = 1.9 pg/well and SO4E1 = 4.5 pg/well. Intra- and inter-assay coefficient of variation percentages were < 10%. The mean recovery rate of hormone added to the culture medium was > 90%. In all hormones studied SUM149 have higher levels (1.4 times, but not significant) than IPC-366, and the correlation index between SUM149 and IPC-366 concentrations were > 97%. We can coclude that cells of both cell lines, IPC-366 and SUM149, are capable to produce steroid hormone in culture media. The presented EIA methodology is very valuable for the detection of steroid production in culture media and could be used in hormone regulation studies and therapeutic agents in cell lines of inflammatory and non-inflammatory mammary carcinoma or other cancer cell lines in preclinical studies. [ABSTRACT FROM AUTHOR]

Introduction: Women using oral hormonal contraceptives are exposed to an increased risk of venous thromboembolism. The incidence of venous thromboembolism in women is difficult to quantify but figures suggest it is in the range of 2 per 10,000 women in 1 year. However, it causes significant cause of morbidity and mortality. Aim: This study aims to provide a comprehensive overview of the risk of venous thrombosis in women using oral hormonal contraceptives. Methods: Extensive literature search in the electronic database “Pubmed”, “Google Scholar”, the website of the center for Disease Control and Prevention (CDC) and in scientific journals via search engine. There was a time restriction, the last fifteen years. Exclusion criteria of articles were articles related to the other side effects of hormonal contraception. Finally, 47 articles were included in the study. Results: Use of hormonal contraceptives increases the risk of venous thrombosis, especially in women with a similar predisposition. Epidemiological studies have shown that combined oral contraceptives increase the risk of venous thromboembolism significantly. The progestogen-only pills are not associated with an increased risk of venous thromboembolism. Thus, the risk of venous thrombosis of oral contraceptives is dependent on the dose of ethinylestradiol and the type of progestin. The risk is increased during the first year of their use or when restarting after a break of at least one month. Risk factors for venous thrombosis can be genetic or acquired, permanent or transient, such as current or previous venous thrombosis, family history, known thrombogenic mutations, post-pregnancy use, obesity, smoking, surgery and other conditions leading to immobilization. Conclusions: The management of women taking hormonal contraceptives should include disclosure of risk factors to prevent events related to thrombosis and with other harmful situations generally. [ABSTRACT FROM AUTHOR]

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Deep vein thrombosis is a clinical diagnosis serious, which is characterized by the formation of thrombus in deep veins. Being a part of normal hemostasis, pathological occurs to the formation of a blood clot within vessels intact, that effect this connected directly to blood, turbulence injuries in the endothelium and hypercoagulable States. Within the State of hypercoagulability register the use of oral contraceptives as one of the causes that might induce the development of thrombotic State. The contraceptive pills are from derived from progesterone, that are known as estrogens and progestagens. At the progestogens lies in its synthetic class division that have structural changes that may cause differences in the activity of each one, and can climb the hormones with smaller or larger androgenic effect, seeking a masquerading in users who have a predisposition to develop a framework of thrombosis. [ABSTRACT FROM AUTHOR]

Abstract: To screen for hormonal activity in water samples, highly sensitive in vitro CALUX bioassays are available which allow detection of estrogenic (ERα), androgenic (AR), progestagenic (PR), and glucocorticoid (GR) activities. This paper presents trigger values for the ERα, AR, PR, and GR CALUX bioassays for agonistic hormonal activities in (drinking) water, which define a level above which human health risk cannot be waived a priori and additional examination of specific endocrine activity may be warranted. The trigger values are based on 1) acceptable or tolerable daily intake (ADI/TDI) values of specific compounds, 2) pharmacokinetic factors defining their bioavailability, 3) estimations of the bioavailability of unknown compounds with equivalent hormonal activity, 4) relative endocrine potencies, and 5) physiological, and drinking water allocation factors. As a result, trigger values of 3.8ng 17β-estradiol (E2)-equivalents (eq)/L, 11ng dihydrotestosterone (DHT)-eq/L, 21ng dexamethasone (DEX)-eq/L, and 333ng Org2058-eq/L were derived. Benchmark Quotient (BQ) values were derived by dividing hormonal activity in water samples by the derived trigger using the highest concentrations detected in a recent, limited screening of Dutch water samples, and were in the order of (value) AR (0.41)>ERα (0.13)>GR (0.06)>PR (0.04). The application of trigger values derived in the present study can help to judge measured agonistic hormonal activities in water samples using the CALUX bioassays and help to decide whether further examination of specific endocrine activity followed by a subsequent safety evaluation may be warranted, or whether concentrations of such activity are of low priority with respect to health concerns in the human population. For instance, at one specific drinking water production site ERα and AR (but no GR and PR) activities were detected in drinking water, however, these levels are at least a factor 83 smaller than the respective trigger values, and therefore no human health risks are to be expected from hormonal activity in Dutch drinking water from this site. [Copyright &y& Elsevier]

The bioformation and transformation of estrogens and other hormones in the breast tissue as a result of the activity of the various enzymes involved attract particular attention for the role they play in the development and pathogenesis of hormone-dependent breast cancer. The enzymatic process concerns the aromatase, which transforms androgens into estrogens; the sulfatase, which hydrolyzes the biologically inactive sulfates to the active hormone; the 17β-hydroxysteroid dehydrogenases, which are involved in the interconversion estradiol/estrone or testosterone/androstenedione; hydroxylases, which transform estrogens into mitotic and antimitotic derivatives; and sulfotransferases and glucuronidases, which, respectively convert into the biologically inactive sulfates and glucuronides. These enzymatic activities are more intense in the carcinoma than in the normal tissue. Concerning aromatase, the application of antiaromatase agents has been largely developed in the treatment of breast cancer patients, with very positive results. Various studies have shown that the activity levels of these enzymes and their mRNA can be involved as interesting prognostic factors for breast cancer. In conclusion, the application of new antienzymatic molecules can open attractive perspectives in the treatment of hormone-dependent breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: In this study, a method employing ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was developed to simultaneously screen for 36 endocrine-disrupting chemicals (EDCs; e.g., estrogens, progestogens, phenols, and their metabolites) both in potable and river water. From the selected compounds, 21 target compounds, for which reference standards were available, were used as model compounds for method development and optimization. The other target compounds, for which reference standards were unavailable, were investigated in post-target analysis on the basis of their theoretical molecular masses. The solid-phase extraction and chromatographic separation steps were optimized. For this method, limits of detection for the target compounds were less than 0.72ngL−1, and the overall recoveries varied between 46% and 134% with relative standard deviations ranging from 7% to 35%. The mass errors between theoretical and experimental mass for all resulting precursor and characteristic fragment ions ranged from −1.9 to 2.8mDa. The method developed was successfully used to analyze the composition of potable and river water in Shanghai City; in addition, some compounds of interest (estriol, estrone, and bisphenol A) were identified accurately. Further, a post-target analysis was performed and an estrogen metabolite was hypothesized in the water samples due to the excellent sensitivity of the method in full-spectrum acquisition mode and the valuable accurate mass information in MS and tandem MS mode. Therefore, UPLC-Q-TOF-MS has proven to be a powerful technique for wide-scope screening and identification of relevant EDCs in environmental water sources. [Copyright &y& Elsevier]

Primates are unusual in that many females display sexual signals, such as sex skin swellings/colorations and copulation calls, without any sex role reversal. The adaptive function of these signals remains largely unclear, although it has been suggested that they provide males with information on female reproductive status. For sex skin swellings, there is increasing evidence that they represent a graded signal indicating the probability of ovulation. Data on the functional significance of copulation calls are much scarcer. To clarify the information content of such calls, we recorded copulation calls in wild long-tailed macaques ( Macaca fascicularis) and analysed the structure of these calls during the ovarian cycle. Specifically, we correlated selected call parameters with the female oestrogen to progestogen ratio (obtained from faecal samples), which are known to be elevated during the female's fertile phase. In addition, we ran a general linear mixed model for these call parameters, testing factors (cycle phase, occurrence/absence of ejaculation, male dominance status, occurrence/absence of mate guarding) which potentially influence female copulation calls in primates. Our results show that copulation calls of female long-tailed macaques signal mating outcome and rank of the mating partner, but not female reproductive status. They also show for the first time on primates that copulation calls can convey information on whether a female is mate guarded or not. We suspect that the function of these calls is manipulation of male mating and mate-guarding behaviour and that in this way the degree of sperm competition and ultimately male reproductive success is influenced. [ABSTRACT FROM AUTHOR]

Background: Tibolone (Org-OD14) is the active substance of Livial®, a synthetic steroid with the structure 7α,17α-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, possessing weak tissue-specific estrogenic, progestogenic, and androgenic properties, used to treat menopausal complaints. After oral administration, tibolone is extensively metabolized into the 3α-(Org-4904) and 3β-(Org-30126) hydroxy derivatives with estrogenic properties, its 4-ene (Org-OM38) isomer with progestogenic/androgenic activities, and the 3α-sulfate (Org-34322) derivative, a major biologically inactive circulating form. We compared the dose response of tibolone and its metabolites on estrone sulfatase activity [conversion of estrone sulfate (E1S) to estrone (E1)] in normal and cancerous human breast tissues. Materials and methods: Tissue minces were incubated with physiological concentrations of [3H]-E1S (5×10-9M) alone or in the presence of tibolone and its metabolites (concentration range: 5×10-7to 5×10-5M) for 4 h. Tritiated E1, estradiol (E2), and E1S were separated and evaluated quantitatively by thin-layer chromatography. Results: The sulfatase activity was significantly higher in cancerous breast but strongly inhibited by tibolone and the different metabolites, whereas 3α- and 3β-hydroxy derivatives were the most potent inhibitors. Conclusion: This very significant inhibitory effect of tibolone and its principal metabolites on the enzyme involved in E2biosynthesis in the human breast provides interesting perspectives to study the biological responses of these compounds in trials with breast cancer patients. [ABSTRACT FROM AUTHOR]

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Abstract: The multiwall carbon nanotubes (MWCNTs)-based matrix solid phase dispersion (MSPD) was applied for the extraction of hormones, including 17-α-ethinylestradiol, 17-α-estradiol, estriol, 17-β-estradiol, estrone, medroxyprogesterone, progesterone and norethisterone acetate in butter samples. The method includes MSPD extraction of the target analytes from butter samples, derivatization of hormones with heptafluorobutyric acid anhydride–acetonitrile mixture, and determination by gas chromatography–mass spectrometry. The mixture containing 0.30g graphitized MWCNTs and 0.10g MWCNTs was selected as absorbent. Ethyl acetate was used as elution solvent. The elution solvent volume and flow rate were 12mL and 0.9mLmin−1, respectively. The recoveries of hormones obtained by analyzing the five spiked butter samples were from 84.5 to 111.2% and relative standard deviations from 1.9 to 8.9%. Limits of detection and quantification for determining the analytes were in the range of 0.2–1.3 and 0.8–4.5μgkg−1, respectively. Compared with other traditional methods, the proposed method is simpler in the operation and shorter in the sample pretreatment time. [Copyright &y& Elsevier]

The decline in sex hormone levels that accompanies the menopause has substantial effects on the tissues of the urogenital system, leading to atrophic changes. These changes can have negative effects on sexual and urinary function. The authors evaluate the repercussion of hypoestrogenism and sexual steroids on some elements of the pelvic floor and lower urinary tract. They summarize their research work and review significant published papers. They emphasize the changes in urinary mucosae, periurethral vessels, muscular layer, connective tissue, gene expression, autonomic nervous system receptors, as well as the main clinical aspects involved. [ABSTRACT FROM AUTHOR]

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Abstract: Research has shown that exposure to androgens and progestogens can cause undesirable biological responses in the environment. To date, however, no detailed or direct study of their presence in wastewater treatment plants has been conducted. In this study, nine androgens, nine progestogens, and five estrogens were analyzed in influent and final effluent wastewaters in seven wastewater treatment plants (WWTPs) of Beijing, China. Over a period of three weeks, the average total hormone concentrations in influent wastewaters were 3562 (Wujiacun WWTP)–5400ng/L (Fangzhuang WWTP). Androgens contributed 96% of the total hormone concentrations in all WWTP influents, with natural androgen (androsterone: 2977±739ng/L; epiandrosterone: 640±263ng/L; and androstenedione: 270±132ng/L) being the predominant compounds. The concentrations of synthetic progestogens (megestrol acetate: 41±25ng/L; norethindrone: 6.5±3.3ng/L; and medroxyprogesterone acetate: 6.0±3.2ng/L) were comparable to natural ones (progesterone: 66±36ng/L; 17α,20β-dihydroxy-4-progegnen-3-one: 4.9±1.2ng/L; 21α-hydroxyprogesterone: 8.5±3.0ng/L; and 17α-hydroxyprogesterone: 1.5±0.95ng/L), probably due to the wide and relatively large usage of synthetic progestogens in medical therapy. In WWTP effluents, androgens were still the dominant class accounting for 60% of total hormone concentrations, followed by progestogens (24%), and estrogens (16%). Androstenedione and testosterone were the main androgens detected in all effluents. High removal efficiency (91–100%) was found for androgens and progestogens compared with estrogens (67–80%), with biodegradation the major removal route in WWTPs. Different profiles of progestogens in the receiving rivers and WWTP effluents were observed, which could be explained by the discharge of a mixture of treated and untreated wastewater into the receiving rivers. [ABSTRACT FROM AUTHOR]

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Using information based on the steroid metabolome in maternal and fetal body fluids, we attempted to ascertain whether there is a common mechanism, which is based on the placental distribution of various isoforms of 17β-hydroxysteroid dehydrogenases and aldo-keto reductases. This system simultaneously provides a higher proportion of active progestogens in fetal circulation and a higher proportion of active estrogens and GABAergic steroids in the maternal compartment. The data obtained using gas chromatography-mass spectrometry completely support the aforementioned hypothesis. We confirmed a common trend to higher ratios of steroids with hydroxy-groups in the 3α-, 17β-, and 20α-positions to the corresponding 3-oxo-, 17-oxo-, and 20-oxo-metabolites, respectively, in the maternal blood when compared with the fetal circulation, and the same tendency was obvious in the 3α-hydroxy/3β-hydroxy steroid ratios. A decreasing trend was observed in the ratios of active estrogens and neuro-inhibitory steroids to their inactive counterparts in fetal and maternal body fluids. This was probably associated with a limited capacity of placental oxidoreductases in the converting of estrone to estradiol during the transplacental passage. Although we observed a decreasing trend in pregnancy-sustaining steroids with increasing gestational age, we recorded rising levels of estradiol and particularly of estriol, regardless of the limited capacity of placental oxidoreductases. Besides the estradiol, which is generally known as an active estrogen, estriol may be of importance for the termination of pregnancy with respect to its excessive concentrations near term which allows its binding to estrogen receptors. [ABSTRACT FROM AUTHOR]

Regarding estrogen replacement therapy, two main mechanisms have to be considered for it to be discussed as a potential carcinogen in the breast, and also considering the World Health Organization definition of estrogens and estrogen/progestogen combinations as 'carcinogenic': (i) the proliferative/apoptotic effects on already pre-existing estrogen-sensitive cancer cells and (ii) the production of possible genotoxic estrogen metabolites. By addition of the progestogen component, as is usual in non-hysterectomized women, both mechanisms can lead to an increased risk compared to estrogenonly therapy. The detailed mechanisms underlying the development of the benign breast epithelial cell into clinically relevant breast cancer cells are very complicated. Based on these mechanisms, the following simplified summary of the main steps explains that: (i) an increased risk cannot be excluded, (ii) especially when estrogens are combined with progestogens, but (iii) there are differences between the preparations used in therapy; (iv) the risk seems to be very rare, needing very special cellular and extracellular conditions, (v) and could even be decreased in special situations of estrogen therapy. It is concluded that when critically reviewed, an increased risk of breast cancer during hormone replacement therapy cannot be excluded in very rare cases. Definitive mechanistic evidence for a possible causal relationship with carcinogenesis still remains open. [ABSTRACT FROM AUTHOR]