Synthetic female gonadal hormones alter neurodevelopmental programming and behavior in F1 offspring.

The increased prevalence of neurodevelopmental disorders during the last half-century led us to investigate the potential for intergenerational detrimental neurodevelopmental effects of synthetic female gonadal hormones, typically used in contraceptive pills. We examined 3 separate cohorts of mice over the span of 2 years, a total of 150 female F0 mice and over 300 male and female rodents from their F1 progeny. We demonstrate that F1 male offsprings of female mice previously exposed to the synthetic estrogen 17α-ethinylestradiol (EE2) in combination with the synthetic progestin Norethindrone, exhibit neurodevelopmental and behavioral differences compared to control mice. Because the EE2 + Norethindrone administration resulted in gene expression changes in the exposed F0 mice ovaries persisting after the end of treatment, it is likely that the synthetic hormone treatment caused changes in the germline cells and that led to altered neurodevelopment in the offsprings. An altered gene expression pattern was discovered in the frontal cortex of male mice from the first offspring (F1.1) at infancy and an ADHD-like hyperactive locomotor behavior was exhibited in young male mice from the second offspring (F1.2) of female mice treated with contraceptive pill doses of EE2 + Norethindrone prior to pregnancy. The intergenerational neurodevelopmental effects of EE2 + Norethindrone treatment were sex specific, predominantly affecting males. Our observations in mice support the hypothesis that the use of synthetic contraceptive hormones is a potential environmental factor impacting the prevalence of human neurodevelopmental disorders. Additionally, our results indicate that contraceptive hormone drug safety assessments may need to be extended to F1 offspring.

Oral contraceptive and breast cancer: do benefits outweigh the risks? A case - control study from Jordan.

BACKGROUND: Oral contraceptives (OCs) use has been linked to increased risk of breast cancer (BC) in several reports from the world. Limited number of similar studies have been conducted in the Middle Eastern female population. This study aimed to explore any possible correlation between the contemporary and duration of OCs use among Jordanian women and the risk of breast cancer. METHODS: A case control study was conducted in 450 Jordanian women (225 as cases and 225 as controls), aged 18 to 65. Chi-square test was used to study the association between risk of breast cancer and different factors. Mann Whitney-U test was employed to evaluate the relation between time-dependent risk factor and breast cancer. RESULTS: Our results indicated that regular use of OCs exhibited association with increased risk of breast cancer (OR = 2.25, 95% CI 1.34-2.79; p = 0.002), while the duration of OCs use was not associated with the increased risk of breast cancer (p > 0.05). In addition, other factors demonstrated significant association with the increased risk of breast cancer such as age at puberty, age at menopause, previous pregnancies, menopausal status, and family history of cancer. CONCLUSIONS: regular use of OCs may be associated with increased risk of breast cancer in Jordanian women. A larger sample size in multi-center setting study is required to confirm this finding among the Jordanian female population.

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study.

Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary Funding Source: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk.

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium.

A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.

GPR30: a novel therapeutic target in estrogen-related disease.

Estrogen is a crucial hormone in human physiology that regulates a multitude of biological processes. It is also an important target in many diseases such as cancer and skeletal, neurological and immunological conditions. The actions of estrogen have traditionally been ascribed to one of two closely related classical nuclear hormone receptors, ERalpha and ERbeta, which are best characterized for regulating gene expression. Recent studies have revealed the contribution of a novel estrogen receptor GPR30, which belongs to the family of seven-transmembrane G-protein-coupled receptors, to many of the rapid biological responses to estrogen. Many drugs, such as tamoxifen and fulvestrant, which seem to selectively inhibit the activities of the classical estrogen receptors, are in widespread clinical use. However, recent results indicate that these same drugs activate multiple cellular-signaling pathways via GPR30. Unraveling the pharmacological profiles and specificities of ERalpha, ERbeta and GPR30 will be vital for understanding not only the physiological roles of each receptor but also for the development of the next generation of receptor-specific drugs.

Liver dysfunction in Turner's syndrome: prevalence, natural history and effect of exogenous oestrogen.

OBJECTIVES: Raised liver enzymes are a common feature of Turner's syndrome (TS), but the cause remains unclear. We studied the hepatic function in a large cohort of women with TS and tested the effect of increasing doses of hormone replacement therapy (HRT) on liver function tests (LFTs). DESIGN AND PATIENTS: LFTs were assessed in three studies. A cross-sectional review of liver function of 125 women (median age: 31 years), a longitudinal study of 30 women (mean follow-up period: 8 years) and a dose-response study of 14 women with TS and 11 controls with hypogonadism, who received oral 17-beta-oestradiol (E(2)) 1, 2 and 4 mg daily in a cyclical formulation for 12 weeks each. MEASUREMENTS: Clinical features, oestrogen use and metabolic parameters were compared to liver enzymes (gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), albumin and bilirubin. LFTs were also measured during each treatment interval of the dose-response study. Hepatic autoimmunity was sought in the cross-sectional study. RESULTS: When compared to the control population, as opposed to reference ranges, 91% of women with TS demonstrated liver enzyme elevation, with a yearly incidence of 2.1%. LFTs correlated positively with cholesterol (P < 0.001), BMI (P = 0.004) and type of oestrogen therapy (P = 0.04). Increasing doses of HRT resulted in a significant decrease in GGT, ALT, bilirubin and albumin. No evidence of excessive hepatic autoimmunity was found. CONCLUSION: The prevalence of raised liver enzymes in TS may have been underestimated by the use of reference ranges rather than matched controls. Obesity and hyperlipidaemia are associated with raised LFTs, as well as the use of HRT compared to the oral contraceptive pill (OCP). Exogenous oestrogen both as OCP and HRT improves liver function. Liver dysfunction in TS is likely to be a form of hepatic steatosis and intervention trials are now indicated.

Oestrogens and Crohn's disease: the missed link.

Observational studies, sometimes, can not provide us with clear answers for very important questions. The answer for a question on whether sex hormones in general, and oestrogen in particular, play some role in inducing and development of Crohn's disease is uncertain. Study design, inclusion criteria, and different formulations of oral contraceptives may partly explain the conflict results of the published reports. But these may be due to the divergent effects of oestrogen, which are based on dose, tissue specificity and cellular environment. This paper is aimed at examining the influence of androgens on the prognosis of Crohn's disease.

Effects of Feminizing Hormones on Sperm Production and Malignant Changes: Microscopic Examination of Post Orchiectomy Specimens in Transwomen.

OBJECTIVE: To examine post-orchiectomy specimens of transgender individuals to better understand the reproductive implications of hormonal therapy and to look for potential malignant or premalignant changes. MATERIALS AND METHODS: A retrospective chart review was performed on the orchiectomy specimens from 135 TG individuals who underwent bilateral simple orchiectomy (54) or vaginoplasty with combined orchiectomy (81) at a single institution from 2014-2017. Factors examined included microscopic evidence of spermatogenesis, weight of specimens, evidence of malignant or premalignant changes, and patient demographic information. RESULTS: Four percent (6/135) of all orchiectomy specimens had normal spermatogenesis in both testicles. Twenty-one percent (28/135) demonstrated some stage of spermatogenesis, of which 61% (17/28) were in maturational arrest. The median patient age at surgery was 30 years (range 18-76). Median overall testicle weight was 24 g (range 10.4-71.1), compared with 24 g (range 10-71g) in testicles without evidence of spermatogenesis and 26 g (range 17.9-40.9) in testicles with normal spermatogenesis. None of the specimens demonstrated premalignant or malignant changes. CONCLUSION: Up to 21% of individuals undergoing a gender affirming surgery had microscopic evidence of spermatogenesis in varying stages. Furthermore, 4% of individuals had normal spermatogenesis. None of the specimens had malignant or premalignant changes. These findings may have implications for counseling transgender individuals on sexual and reproductive health and highlight the need for further research in this sector.

Drug-induced lupus associated with synthetic conjugated estrogens.

OBJECTIVE: To report a case of drug-induced lupus (DIL) in a patient taking Cenestin, a combination product of synthetic conjugated estrogens. CASE SUMMARY: A 54-year-old white female presented with a 4 month history of bilateral arm pain that developed and progressively worsened after initiating Cenestin 0.625 mg daily. The patient's symptoms, findings on physical examination (eg, degenerative changes of the acromioclavicular joint), and laboratory test results (eg, antinuclear antibody titer 1-640 [normal <1-40]) were suggestive of DIL. Her symptoms rapidly resolved with discontinuation of Cenestin and promptly resumed with reinitiation of the drug. Laboratory test values also improved significantly with discontinuation of Cenestin. Based on these findings and the Naranjo probability scale score, this reaction was probably associated with Cenestin. DISCUSSION: DIL differs from systemic lupus erythematosus in that it is caused by prolonged exposure at adequate doses to a drug rather than being an autoimmune reaction. The most commonly reported and studied medications are hydralazine, quinidine, and procainamide. Other medications have been associated with DIL; however, data are limited in these reports, especially with estrogen. There have been no previous reports in the literature of synthetic estrogen products associated with DIL. CONCLUSIONS: A diagnosis of DIL can be very challenging to make, especially since there are no clear criteria on which to base it. While estrogen has rarely been reported to be associated with DIL, it may be considered as a possible cause.

Breast cancer: are oestrogen metabolites carcinogenic?

The World Health Organization (WHO) classified oestrogens as carcinogenic in humans. One of the main arguments has been that oestrogens not only can promote cancers but also may initiate mutations caused by certain oestrogen metabolites. Indeed there is evidence that they can have biological properties even at very low concentrations which can exceed manifold those of their parent substance. Highly sophisticated laboratory methods will allow us to understand oestrogenic effects as a net effect of the corresponding metabolite pattern. Current research focuses on the possible carcinogenic properties of 4-hydroxyoestrogens and 16-alpha-hydroxyoestrone, but also on the anticancerogenic effects particularly of 2-methoxyoestradiol. Thus, potential toxic secondary metabolites like 4-quinones can be eliminated, e.g. by methylation. 2-methoxyoestradiol is a potent antiproliferative and antiangiogenic metabolite, and is currently tested in patients with refractory metastatic breast cancer. Observational trials have demonstrated that the ratio of 2- to 16-alpha-hydroxyoestrone is decreased in women with breast cancer. We have been able to demonstrate that oestradiol metabolism during HRT can be influenced by administration route, possibly also by certain progestogens. In in vitro and animal experiments certain oestrogen metabolites indeed can act as carcinogens. However, since for the formation of these metabolites the appearance of very special conditions is a prerequisite and also various protective mechanisms are present, this might only contribute to breast carcinogenesis in very rare cases. However, the clinical relevance remains unclear and it appears to be important to ascertain this issue.

Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES).

BACKGROUND: In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES. METHODS: Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure. RESULTS: Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers' DES exposure and daughters' infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005). CONCLUSIONS: The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.

Human exposure to bisphenol A.

Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl)propane, is made by combining acetone and phenol. It has estrogenic activity and is acutely toxic to aquatic organisms. BPA is used mainly as a material for the production of epoxy resins and polycarbonate plastics. Due to an increase in products based on epoxy resins and polycarbonate plastics, human exposure to BPA has increased. The environment (aquatic environment, air and soil) can be one source of human BPA exposure, but the primary route of human exposure is foods. The daily human intake of BPA is <1 microg/kg body weight/day on the basis of several studies, and whether these doses can have an adverse endocrine disruptive effect on humans, especially fetuses, needs to be studied carefully.

Biphasic versus monophasic oral contraceptives for contraception.

BACKGROUND: Side effects caused by oral contraceptives discourage compliance with, and continuation of, oral contraceptives. Three approaches have been used to decrease these adverse effects: reduction of steroid dose, development of new steroids, and new formulas and schedules of administration. The third strategy led to the biphasic oral contraceptive pill. OBJECTIVES: To compare biphasic with monophasic oral contraceptives in terms of efficacy, cycle control, and discontinuation due to side effects. Our a priori hypotheses were: (a) biphasic oral contraceptives are less effective than monophasic oral contraceptives in preventing pregnancy; (b) biphasic oral contraceptives cause more side effects, give poorer cycle control, and have lower continuation rates. SEARCH STRATEGY: We searched the computerized databases MEDLINE, EMBASE, POPLINE, LILACS and CENTRAL. In addition, we searched the reference lists of all potentially relevant articles and book chapters. We also contacted the authors of relevant studies and pharmaceutical companies in Europe and the USA. SELECTION CRITERIA: We included randomized controlled trials comparing any biphasic with any monophasic oral contraceptive when used to prevent pregnancy. DATA COLLECTION AND ANALYSIS: We examined the studies found during the various literature searches for possible inclusion and assessed their methodology using Cochrane guidelines. We contacted the authors of all included studies and possibly randomized studies for supplemental information about methodology and outcome. We entered the data into RevMan, and calculated Peto odds ratios for the incidence of intermenstrual bleeding, absence of withdrawal bleeding, and study discontinuation due to intermenstrual bleeding. MAIN RESULTS: Only one trial of limited quality compared a biphasic and monophasic preparation. Percival-Smith 1990 examined 533 user cycles of a biphasic pill (500 microg norethindrone/35 microg ethinyl estradiol for 10 days, followed by 1000 microg norethindrone/35 microg ethinyl estradiol for 11 days; Ortho 10/11) and 481 user cycles of a monophasic contraceptive pill (1500 microg norethindrone acetate/30 microg ethinyl estradiol daily; Loestrin). The study found no significant differences in intermenstrual bleeding, amenorrhea and study discontinuation due to intermenstrual bleeding between the biphasic and monophasic oral contraceptive pills. AUTHORS' CONCLUSIONS: Conclusions are limited by the identification of only one trial, the methodological shortcomings of that trial, and the absence of data on accidental pregnancies. However, the trial found no important differences in bleeding patterns between the biphasic and monophasic preparations studied. Since no clear rationale exists for biphasic pills and since extensive evidence is available for monophasic pills, the latter are preferred.

Increase in cancer of the corpus uteri in the San Francisco-Oakland standard metropolitan statistical area, 1960--75.

A significant rise in the incidence of carcinoma of the corpus uteri in women of the San Francisco-Oakland standard metropolitan statistical area (SMSA) was reported by the Resource for Cancer Epidemiology. The incidence among white females increased by over 50% in the 6 years between 1969 and 1975. The increase was limited to the groups over 50 years old and to invasive cancers of the endometrial lining. The increase occurred in all five of the SMSA counties and, in white women in Aalmeda County, the average annual incidence for the 50- to 74-year age group tripled in 15 years. The rise was greatest in the areas of most affluence. Possible spurious causes of increase, such as changing diagnostic criteria, better case finding, or better reporting were examined and ruled out. The data suggested that the increase was due to the recent introduction of a potent endometrial carcinogen to the population group affected.

Exogenous estrogens and other risk factors for breast cancer in women with benign breast diseases.

A group of 1,439 white women who were initially treated for biopsy-proved benign breast diseases from 1942 to 1975 in a single private surgery practice were followed through 1976 for development of breast cancer. Information on age, parity, and use of noncontraceptive estrogens was collected on all women at the time of their initial benign lesions. At follow-up, ages at menarche, menopause, and birth of first child were obtained, as was information on use of estrogens after the initial lesion. Slides from the initial lesion were reinterpreted and classified by a panel of pathologists. The influence of gross and microscopic features of the initial benign conditions on subsequent risk of breast cancer was ascertained and reported previously. This paper presents results of additional analyses based largely on Cox's proportional hazards model. Risk of breast cancer was related to nulliparity and ages at menarche and birth of first child and to a lesser extent to age at artificial menopause. Exogenous estrogen taken prior to the initial benign lesion did not alter risk of breast cancer. Subsequent use, primarily of conjugated estrogens, eliminated the protective effect of an artificial menopause and appeared to act synergistically with epithelial hyperplasia or papillomatosis in the initial lesion and calcification of that lesion to increase the risk of breast cancer. A marked increase in risk of breast cancer in succeeding birth cohorts was unexpectedly found that could not be explained by temporal changes in any of the other risk factors considered.

Estrogen exposure during gestation and risk of testicular cancer.

In this case--control study of 108 cases of testicular cancer in men under 30 years of age, cryptorchidism was a major risk factor [relative risk (RR) = 9.0]. Low birth weight was also associated with increased risk (RR = 3.2). Having severe acne at puberty was protective (RR = 0.37). Interviews with mothers of cases revealed that exposure of the mother to exogenous estrogen during pregnancy created a significant risk in the son (RR = 8.0). In first pregnancies, excessive nausea indicated an increased risk of testicular cancer (RR = 4.2). Increased body weight in the mother also increased the risk. The relation between these factors and testicular hypoplasia is discussed. Severe perimenopausal menorrhagia was a factor in the mother associated with reduced risk of testicular cancer in the son (RR = 0.10). A modified hormonal milieu in the mother appears to be important in the later development of testicular cancer in her sons.

Steroid hormones and endometrial cancer.

The factors that increase the risk of development of endometrial cancer are reviewed. Many of these conditions are frequently associated with an elevated production of estrone in peripheral (nonendocrine) tissues from circulating androstenedione. Elevated estrone production may occur in young, anovulatory or postmenopausal women whose ovaries secrete higher than normal amounts of androstenedione. Alternatively, conditions such as obesity and liver disease are associated with higher than normal rates of conversion of androstenedione to estrone, resulting in high estrone levels. Neither the exact tissue site(s) of conversion nor the normal function of this process has yet been established. Much less information concerning steroid hormone receptor measurements in endometrial cancer than in breast cancer is available. However, it seems certain that measurement of progesterone receptors will provide a useful guide in the selection of progestational therapy.

Role of exogenous female hormones in altering the risk of benign and malignant neoplasms in humans.

The epidemiological and clinical evidence for various forms of exogenous estrogens altering the risk of neoplasms of the female genital system, breast, and liver are reviewed and evaluated. It is virtually certain that in utero exposure to diethylstilbestrol can cause clear cell adenocarcinomas of the vagina and cervix. There is strong evidence that various estrogens given for treatment of menopausal symptoms can cause endometrial carcinoma and that sequential oral contraceptives probably also do so. Oral contraceptives very probably reduce the risk of both cystic disease and fibroadenoma of the breast and increase the risk of liver cell adenomas. Studies to date do not provide consistent and convincing evidence that any form of exogenous estrogen alters the risk of cancers of the breast or ovary or that oral contraceptives alter the risk of cervical neoplasia or focal nodular hyperplasia of the liver, although recent reports suggest that continued vigilance is warranted. Specific topics requiring further epidemiological investigation are suggested.

Regulation of the synthetic estrogen 17α-ethinylestradiol in water bodies in Europe, the United States, and Brazil.

The synthetic estrogen 17α-ethinylestradiol, the principal component of oral contraceptives, has been identified as one of the main compounds accounting for adverse effects on the endocrine system in various species. This study aimed to analyze the state-of-the-art in legislation and guidelines for the control of this synthetic estrogen in water bodies in Europe and the United States and to draw a parallel with the Brazilian reality. Countries have generally attempted to expand the regulation and monitoring of certain emerging micropollutants not previously covered by legislation. Europe is more advanced in terms of water quality, while in the United States this estrogen is only regulated in water for human consumption. Brazil still lacks legal provisions or standards for this estrogen, which can be explained by the relatively limited maturity of the country's system for controlling water pollutants.