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SUMMARY Introduction Wendler glottoplasty is a voice feminization surgical procedure designed to increase the fundamental frequency (F0) in male-to-female transsexual patients with gender dysphoria. On average, Wendler glottoplasty has the most significant effect on F0 among voice feminization surgical procedures. Case report We present the case of a young female patient with a testosterone-producing adrenocortical adenoma who underwent irreversible vocal changes secondary to virilization, which impacted her self-esteem and quality of life (QOL). Voice feminization surgery using Wendler glottoplasty was performed with significant improvement in F0 and QOL. Discussion Sex hormones have a profound impact on the voice. Increased testosterone and dihydrotestosterone are known to cause hypertrophy of the laryngeal muscles and ligaments, which leads to a drop in F0. However, women who present androphonia rarely require surgical management and improve with vocal therapy alone. Few cases of voice feminization procedures for the treatment of androphonia have been described in the literature. Our patient presented with severe masculinization of her voice with a F0 lower than the average adolescent male, which led to the requirement of surgical management. Conclusions Patients with severe androphonia that significantly affect their QOL and show no improvement after the management of the underlying pathology and intense vocal therapy are candidates for voice feminization surgeries. These procedures offer positive results both in terms of F0 and in improving patient's self-esteem and QOL.

Mefentrifluconazole (trade name: Revysol®) is an agrochemical active ingredient from the new sub-class of isopropanol-triazole fungicides, with high selective fungicide activity. A full program of toxicity testing conducted according to OECD guidelines has shown mefentrifluconazole (MFZ) to be non-genotoxic and non-carcinogenic. Repeated dose studies in rats, mice and dogs identified the liver as the main target organ. Prenatal developmental toxicity studies in rats and rabbits did not indicate treatment-related embryofetal toxicity or teratogenicity up to the highest dose levels tested. In a two-generation dietary study in rats, the high dose level resulted in reduced food consumption and body weight gain throughout the dosing-period. Mating performance and fertility, estrous cycles, gestation length and pre-and post-natal survival of offspring were essentially unaffected and there was no evidence of masculinization of female pups or feminization of male pups. The screening strategy that led to the selection of MFZ was aimed to identify candidates with both high fungicidal activity and minimal likelihood of adverse side effects thought to arise from aromatase inhibition. The success of the selection strategy has been illustrated for MFZ by the absence in toxicity studies of effects that would indicate an endocrine disrupting potential.

Sex differences in the anatomy and physiology of the vertebrate preoptic area (POA) arise during development, and influence sex-specific reproductive functions later in life. Relative to masculinization, mechanisms for feminization of the POA are not well understood. The purpose of this study was to induce sex change from male to female in the anemonefish Amphiprion ocellaris, and track the timing of changes in POA cytoarchitecture, composition of the gonads and circulating sex steroid levels. Reproductive males were paired together and then sampled after 3 weeks, 6 months, 1 year and 3 years. Results show that as males change sex into females, number of medium cells in the anterior POA (parvocellular region) approximately double to female levels over the course of several months to 1 year. Feminization of gonads, and plasma sex steroids occur independently, on a variable timescale, up to years after POA sex change has completed. Findings suggest the process of POA feminization is orchestrated by factors originating from within the brain as opposed to being cued from the gonads, consistent with the dominant hypothesis in mammals. Anemonefish provide an opportunity to explore active mechanisms responsible for female brain development in an individual with male gonads and circulating sex steroid levels.

Facial gender-affirming surgery can have significant impact on patient quality of life for some gender-dysphoric patients. Lower jaw contouring can be used to harmonize the face during facial gender-affirming surgery through masculinization or feminization. During feminization, the mandibular angle and body and chin are reduced in width and size. During masculinization, augmentation of the mandibular angle and body and chin are completed with alloplastic implants, fat, or bone. Complications are minimal. Further research is needed on outcomes of these procedures.

The expression profiles of key genes associated with sex differentiation in vertebrates, namely, amh, ar, cyp19, dmrt1, erα, erβ, foxl2, sox9, star, and vtg, were analyzed in the gonads, liver, muscle, and brain of Russian sturgeon (Acipenser gueldenstaedtii). The aims of this study were to determine in which tissue the signal for sex differentiation primarily occurs, and which factors are most important for gonadal differentiation. The sturgeons included in the study (180 days post-hatching; n = 20) were at the beginning of gonadal differentiation; five females, seven males, and eight individuals with disturbed germinal tissue development were identified. All of the examined genes except for star had diverse sex-related expression profiles in the brain. By contrast, in the gonads, only foxl2 expression was sex-dependent. With the exception of star and cyp19, all of the other genes were expressed in the muscle and liver, but there were no significant differences between sexes. The expression profiles of the analyzed genes in the brain were atypical, indicating feminization. This finding was in agreement with the high occurrence of individuals sharing female and male germinal tissue characteristics. The data presented here suggest that the sturgeon brain is the primary organ that stimulates other organs and tissues to differentiate into male or female, and that dmrt1 and foxl2 play major roles in sex differentiation in this species.

Using gender-disaggregated data on land operations from India, this paper contributes to the literature on agricultural feminization by showing a relationship between seasonal or short-term migration for work and feminization of farm management. Using a nationally representative data-set covering 35,604 rural Indian households in 2013, we identify if women are taking on the role of farm managers in households with short-term migrants. Our results show that women are less likely than men to be decision makers on farms, but this dynamic changes when there is short-term migration in the household; the probability of women being decision makers on farms increases. These results are robust to concerns over omitted variables, endogeneity and sample selection issues. Our study highlights the importance of unpacking the feminization process to better understand the role of women as farm managers and the need for supporting this transition to ensure women farmers realise their full potential.

Even after long-term hormone therapy, many transwomen still have challenges in the size and shape of their breasts and also of the contour of their trunk areas. Though distinct anthropomorphic differences in skeletal structure exist and pose limitations to an ideal result, considerable improvements can be obtained through breast augmentation and trunk feminization. There are challenges that are unique to the transfeminine chest and trunk, and important considerations for the priority of fat grafting to the buttocks and hips when grafted fat is in short supply.

Transfeminine individuals are treated with estradiol and anti-androgen agents to transition to a more feminine appearance. The physical changes that occur with estradiol therapy include breast development, body fat redistribution, and decreased muscle mass. Transfeminine treatment regimens require monitoring and dose adjustments to achieve appropriate physiologic targets to enhance feminization and decrease risk of adverse outcomes. Adverse effects associated with estradiol use include thromboembolic disease, macroprolactinoma, breast cancer, coronary artery disease, cerebrovascular disease, cholelithiasis, and hypertriglyceridemia. Benefits of hormonal treatment may include both an improvement in quality of life and a decrease in gender dysphoria.

Previous studies have reported that triclosan (TCS) could possess an androgenic activity. We aimed to investigate the effects of TCS on gonadal differentiation and development in the frog Pelophylax nigromaculatus, a sensitive amphibian species to androgenic chemicals. P. nigromaculatus tadpoles at stage 24 were exposed to TCS (3, 30, and 300nmol/L) to stage 46 in a semi-static exposure system. At the end of exposure, gonadal morphology and histology, sex ratio and gonadal expression of sex-biased genes were examined in P. nigromaculatus. In each TCS treatment group, we found several individuals whose gonads exhibited morphological and/or histological abnormalities. Gonadal histological abnormalities were characterized by few oocytes and many somatic cells. Although the percentage of the individuals with abnormal gonads was low (7.8%) among all animals treated with TCS, statistical test revealed the sex ratios in the 3 and 300nmol/L TCS treatment groups were significantly different from the solvent control. In the 30nmol/L TCS treatment group, abnormal gonads were also observed, although the sex ratio was not changed compared with the solvent control, which was possibly due to the smaller sample size in this group. In all the TCS treatment groups, the sex ratios were not obviously male-biased, but the expression levels of some sex-biased genes were significantly altered by TCS. Altogether, our results suggest that TCS, even at environmentally relevant concentrations, could disrupt gonadal differentiation and development in P. nigromaculatus, but we are not sure whether the disrupting effects were associated with masculinization or feminization.

Male Atlantic salmon (Salmo salar) display different sexual strategies, maturing either as parr during the freshwater phase (as sneaky spawners), or as post smolts following one or several years at sea. First sexual maturation (puberty) occurs at different times depending on environmental and genetic factors. To improve our knowledge on the timing (age and season) of first sexual maturation in Atlantic salmon male parr, we investigated pubertal activation in second generation farmed salmon from the Norwegian river Figgjo, reared under natural conditions of photoperiod and water temperature. Histological analysis, in combination with morphometric measurements, plasma androgen levels and pituitary gonadotropin gene expression analysis revealed that, as previously reported, some male parr initiated early sexual maturation in spring at one year of age. Interestingly, some male parr were observed to initiate sexual maturation already in autumn, six months after hatching (under-yearlings), much earlier than reported in previous studies. One-year old maturing males showed a low induction in gonadotropin levels, while under-yearling maturing males displayed a significant increase in fshb transcripts as compared to immature/early-maturing fish. Plasma testosterone, detectable also in immature/early-maturing males, increased constantly during testes development, while 11-ketotestosterone, undetectable in immature/early-maturing and early maturing males, increased during more advanced stages of maturation. A mild feminization of the testes (ovotestes) was detected in a subset of samples. This study brings new knowledge on the little investigated field of sexually maturing under-yearlings in Atlantic salmon. This is also the first study comparing the physiology of under-yearling vs one-year old maturing male parr, thus bringing new insights to the remarkable plasticity of Atlantic salmon puberty.

Male and female animals typically display innate sex-specific mating behaviors, which, in vertebrates, are highly dependent on sex steroid signaling. While estradiol-17β (E2) signaling through estrogen receptor 2 (ESR2) serves to defeminize male mating behavior in rodents, the available evidence suggests that E2 signaling is not required in teleosts for either male or female mating behavior. Here, we report that female medaka deficient for Esr2b, a teleost ortholog of ESR2, are not receptive to males but rather court females, despite retaining normal ovarian function with an unaltered sex steroid milieu. Thus, contrary to both prevailing views in rodents and teleosts, E2/Esr2b signaling in the brain plays a decisive role in feminization and demasculinization of female mating behavior and sexual preference in medaka. Further behavioral testing showed that mutual antagonism between E2/Esr2b signaling and androgen receptor-mediated androgen signaling in adulthood induces and actively maintains sex-typical mating behaviors and preference. Our results also revealed that the female-biased sexual dimorphism in esr2b expression in the telencephalic and preoptic nuclei implicated in mating behavior can be reversed between males and females by altering the sex steroid milieu in adulthood, likely via mechanisms involving direct E2-induced transcriptional activation. In addition, Npba, a neuropeptide mediating female sexual receptivity, was found to act downstream of E2/Esr2b signaling in these brain nuclei. Collectively, these functional and regulatory mechanisms of E2/Esr2b signaling presumably underpin the neural mechanism for induction, maintenance, and reversal of sex-typical mating behaviors and sexual preference in teleosts, at least in medaka.

This review is the first assembling information on intersexuality in aquatic invertebrates, from freshwater to estuarine and marine environments. Intersex is a condition whereby an individual of a gonochorist (separate sexes) species has oocytes or distinct stages of spermatogonia, at varying degrees of development, within the normal gonad of the opposite gender (i.e. spermatocytes in the ovary or oocytes in the testis), often involving alterations in the gonadal structure, reproductive tract or external genitalia. By the end of 2016 we found approximately 340 records of aquatic invertebrate species evidencing signs of intersexuality (or imposex), all comprised within the Phyla Mollusca and Arthropoda. Gastropod molluscs are by far the group with more examples documented (256 species), followed by crustaceans, i.e., decapods, copepods and amphipods. To our knowledge no further cases of intersexuality were known concerning other invertebrate taxa. Despite some reports suggesting that a baseline level of intersexuality may occur naturally in some populations, the causes are multifaceted and mostly linked with environmental contamination by estrogenic and organotin endocrine disrupting chemicals (EDCs), parasitism, and genetic/environmental sex determination abnormalities. A more comprehensive discussion about the origin of intersexuality, prevalence and causes, knowledge gaps and future research directions in the light of new omics scientific advances (genomics, proteomics and transcriptomics) is also provided. The lack of studies linking molecular responses of invertebrate intersex individuals to multiple stressors represents a true challenge to be further investigated in the future.

We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre- and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male- or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or OIL as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior.

Highlights • Evidence suggests neuroimaging-based sex differences in ASD are age-dependent. • Most studies collapse across age, possibly masking sex-by-diagnosis effects. • Sex-by-diagnosis effects overlap with regions showing typical sexual dimorphism. • Findings discussed in the context of genetic and endocrine sex effects on the brain. • Future research would benefit from a lifespan approach in large-sample studies., Females with autism spectrum disorder (ASD) have been long overlooked in neuroscience research, but emerging evidence suggests they show distinct phenotypic trajectories and age-related brain differences. Sex-related biological factors (e.g., hormones, genes) may play a role in ASD etiology and have been shown to influence neurodevelopmental trajectories. Thus, a lifespan approach is warranted to understand brain-based sex differences in ASD. This systematic review on MRI-based sex differences in ASD was conducted to elucidate variations across the lifespan and inform biomarker discovery of ASD in females We identified articles through two database searches. Fifty studies met criteria and underwent integrative review. We found that regions expressing replicable sex-by-diagnosis differences across studies overlapped with regions showing sex differences in neurotypical cohorts. Furthermore, studies investigating age-related brain differences across a broad age-span suggest distinct neurodevelopmental patterns in females with ASD. Qualitative comparison across youth and adult studies also supported this hypothesis. However, many studies collapsed across age, which may mask differences. Furthermore, accumulating evidence supports the female protective effect in ASD, although only one study examined brain circuits implicated in “protection.” When synthesized with the broader literature, brain-based sex differences in ASD may come from various sources, including genetic and endocrine processes involved in brain “masculinization” and “feminization” across early development, puberty, and other lifespan windows of hormonal transition. Furthermore, sex-related biology may interact with peripheral processes, in particular the stress axis and brain arousal system, to produce distinct neurodevelopmental patterns in males and females with ASD. Future research on neuroimaging-based sex differences in ASD would benefit from a lifespan approach in well-controlled and multivariate studies. Possible relationships between behavior, sex hormones, and brain development in ASD remain largely unexamined.

Sexual dimorphism in mouse reproductive tissues is observable in adult, post-natal, and embryonic stages. The development of sexually dimorphic tissues starts with an ambisexual structure. It is followed by sex-specific organogenesis as guided by different signaling pathways that occur from late embryonic stages. The measurement of the anogenital distance (AGD), and the observation of the external genitalia are practical ways to distinguish male and female pups at birth and thereafter. Careful observation of the morphological or histological features and the molecular signatures of the external genitalia and perineum enable identification of sex or feminization/masculinization of embryos. Aberrations in hormone signaling via castration or treatment with hormones or hormone disruptors result in dysmorphogenesis of reproductive tissues. Several hormone disruptors have been used to modulate different aspects of hormone action through competitive inhibition and exogenous hormone treatment. Concomitantly, the vast advancement of conditional mutant mouse analysis leads to the frequent utilization of Cre recombination technology in the study of reproductive/urogenital tissue development. Mouse Cre-lines that are tissue-specific and cell-specific are also effective tools in identifying the molecular mechanisms during sexually dimorphic development. Cre-lines applicable to different cell populations in the prostate, seminal vesicles, testis and ovaries, and mammary glands are currently being utilized. In the external genitalia and perineum, Cre lines that examine the signaling pathways of cells of endodermal, ectodermal, and mesenchymal origin reveal the roles of these tissues in the development of the external genitalia. The interaction of hormones and growth factors can be examined further through a variety of techniques available for researchers. Such cumulative information about various technologies is summarized.

Environmental estrogens and androgens can be present simultaneously in aquatic environments and thereby interact to disturb multiple physiological systems in organisms. Studies on interaction effects in fish of androgenic and estrogenic chemicals are limited. Therefore, the aim of the present study was to evaluate feminization and masculinization effects in zebrafish (Danio rerio) exposed to combinations of two synthetic steroid hormones detected in environmental waters: the androgen 17β-trenbolone (Tb) and the oestrogen 17α-ethinylestradiol (EE2). Juvenile zebrafish were exposed between days 20 and 60 post-hatch to different binary mixtures of Tb (1, 10, and 50 ng/L) and EE2 (2 and 5 ng/L). The endpoints studied were whole-body homogenate vitellogenin concentration at 40 days post-hatch, and sex ratio including gonad maturation at 60 days post-hatch. The feminizing potency of 5 ng/L of EE2, alone as well as in combination with Tb, was clear in the present study, with exposures resulting in almost all-female populations and females being sexually immature. Masculinization effects with male-biased sex ratios were observed when fish were exposed to 2 ng/L of EE2 in combination with Tb concentrations. Intersex fish were observed after exposure to mixtures of 2 ng/L EE2 with 50 ng/L Tb. Sexual maturity generally increased among males at increasing concentrations of Tb. The results of the present study show that exposure to environmentally relevant mixtures of an oestrogen and androgen affects the process of gonad differentiation in zebrafish and lead to sexual disruption.

Body feminization, as part of gender affirmation process of transgender women, decreases the volume of their cortical and subcortical brain structures. In this work, we implement a rat model of adult male feminization which reproduces the results in the human brain and allows for the longitudinal investigation of the underlying structural and metabolic determinants in the brain of adult male rats undergoing feminization treatments. Structural MRI and Diffusion Tensor Imaging (DTI) were used to non-invasively monitor in vivo cortical brain volume and white matter microstructure over 30 days in adult male rats receiving estradiol (E2), estradiol plus cyproterone acetate (CA), an androgen receptor blocker and antigonadotropic agent (E2 + CA), or vehicle (control). Ex vivo cerebral metabolic profiles were assessed by 1H High Resolution Magic Angle Spinning NMR (1H HRMAS) at the end of the treatments in samples from brain regions dissected after focused microwave fixation (5 kW). We found that; a) Groups receiving E2 and E2 + CA showed a generalized bilateral decrease in cortical volume; b) the E2 + CA and, to a lesser extent, the E2 groups maintained fractional anisotropy values over the experiment while these values decreased in the control group; c) E2 treatment produced increases in the relative concentration of brain metabolites, including glutamate and glutamine and d) the glutamine relative concentration and fractional anisotropy were negatively correlated with total cortical volume. These results reveal, for the first time to our knowledge, that the volumetric decreases observed in trans women under cross-sex hormone treatment can be reproduced in a rat model. Estrogens are more potent drivers of brain changes in male rats than anti-androgen treatment., This work was supported by Grants (PGC2018-094919-B-C1 to AG; PGC2018-094919-B-C2 to RF and SAF-2017-83043-R to SC) from Ministerio de Ciencia, Innovación y Universidades (Spain).

2,4-Dichlorophenol (2,4-DCP) is a ubiquitous contaminant of aquatic environments with an estrogenic effect on fish. However, the molecular mechanism underlying this effect remains elusive. To this end, the present study aimed to explore the effect of 2,4-DCP on sex differentiation and its relevant mechanism in zebrafish (Danio rerio). The results showed that a female-biased sex ratio was induced after exposing larval zebrafish to 2,4-DCP (0–160 μg/L) from 20 to 50 days post fertilization (dpf). The feminization of zebrafish was accompanied by decreased expression of male-related genes (sox9a, amh and dmrt1) under 2,4-DCP from 20 to 50 dpf. However, the expression of female-related genes (cyp19a1a, foxl2 and esr1) was also suppressed. Nevertheless, it is noteworthy that the methylation level of sox9a promoter was significantly increased, which may result in the significantly decreased expression of sox9a and ultimately the feminization effect of 2,4-DCP on zebrafish. In addition, 5-aza-2′-deoxycytidine (5-AZA), a methyltransferase inhibitor, significantly reduced the methylation level, increased the expression of sox9a, and partly impaired the feminization effect caused by 2,4-DCP, which further confirmed the importance of DNA methylation of sox9a in 2,4-DCP-induced feminization. These findings provide novel insights into the epigenetic mechanisms of DCP-induced estrogenic effect in fish.

Environmental chemicals can disrupt endocrine signaling and adversely impact sexual differentiation in wildlife. Bisphenol A (BPA) is an estrogenic chemical commonly found in a variety of habitats. In this study, we used painted turtles (Chrysemys picta), which have temperature-dependent sex determination (TSD), as an animal model for ontogenetic endocrine disruption by BPA. We hypothesized that BPA would override TSD and disrupt sexual development. We incubated farm-raised turtle eggs at the male-producing temperature (26°C), randomly assigned individuals to treatment groups: control, vehicle control, 17β-estradiol (E2, 20ng/g-egg) or 0.01, 1.0, 100μgBPA/g-egg and harvested tissues at hatch. Typical female gonads were present in 89% of the E2-treated "males", but in none of the control males (n=35). Gonads of BPA-exposed turtles had varying amounts of ovarian-like cortical (OLC) tissue and disorganized testicular tubules in the medulla. Although the percentage of males with OLCs increased with BPA dose (BPA-low=30%, BPA-medium=33%, BPA-high=39%), this difference was not significant (p=0.85). In all three BPA treatments, SOX9 patterns revealed disorganized medullary testicular tubules and β-catenin expression in a thickened cortex. Liver vitellogenin, a female-specific liver protein commonly used as an exposure biomarker, was not induced by any of the treatments. Notably, these results suggest that developmental exposure to BPA disrupts sexual differentiation in painted turtles. Further examination is necessary to determine the underlying mechanisms of sex reversal in reptiles and how these translate to EDC exposure in wild populations.

Runoff from lands fertilized with animal manure from concentrated animal feeding operations (CAFOs) is a source of hormones to surface water. In this study we tested the hypothesis that larval fathead minnows exposed to sex steroids singly or in a “typical” CAFO mixture during sex differentiation would respond with changes in the expression of a set of target genes, leading to gonadal abnormalities later in life. In the first experiment, a static daily-renewal system was used to expose larvae during the period of 10–20 days post-hatch (dph) to either 5 ng/L 17β-trenbolone (17β-TRB) or 5 ng/L 17α-ethinylestradiol (EE 2 ). In a second experiment, fish were exposed from 0 to 45 dph in a flow-through system to a CAFO mixture composed of steroids and degradates (2–16 ng/L), atrazine and degradates (15–250 ng/L), and nitrate (3–11 mg/L). In the single hormone experiment, expression of genes involved in steroidogenesis ( cyp19a, cyp17 , and star ) was decreased in females. In contrast, no differences in gene expression were observed in fish exposed to the CAFO mixture. However, the majority (84%) of treated males had testes containing an ovarian cavity, indicative of feminization, compared to 0% in the control males. Overall, our results show that: (1) changes in gene expression after single hormone exposures are sex-specific, with females more responsive than males; and (2) phenotypic alterations in testicular development can be elicited by a simulated “CAFO” mixture when fathead minnows are exposed during the first 45 days of development. More research is needed to further discern the complex response of fish to steroid mixtures, especially those associated with runoff from land-applied CAFO waste.

Horses are characterized as having a greater rate of chromosomal abnormalities than other species, which are mainly related to the sex chromosome pair and produce a series of different anomalies known as disorders in sexual development (DSD). In the present study, three Pura Raza Española (PRE) and one Menorquín (MEN) horses were studied and an incompatibility in their genetic and phenotypic sex were detected. Animals were karyotyped by conventional and molecular cytogenetic analyses and characterized using genomic techniques. Although all individuals, were totally unrelated, these animals had the same abnormality (64,XY SRY negative DSD) despite having an anatomically normal external mare phenotype. Therefore, this syndrome could remain undiagnosed in a large percentage of cases because the physiological and morphological symptoms are rare. In the present study, a slight gonadal dysgenesis was observed only in older individuals. Interestingly this chromosomal abnormality has been previously reported less than twenty times, and never in the PRE or MEN horses. With the present research, it is demonstrated that the use of genetic and cytogenetic diagnostic tools in veterinary practice could be an important complementary test to determine the origin of unexplained reproductive failures among horses.

Background Feminization of animals derived from areas polluted by endocrine disrupting chemicals (EDCs) has been observed in all classes of vertebrates. However, feminization of artificially reared offspring by feeding of specific living organisms has never been reported. Methods Different food (including Limnodilus spp collected from the wild) and time treatment were applied to southern catfish. In addition, EDCs in Limnodilus spp., an annelid worm collected from wild contaminated small streams, was detected by LC–MS (Liquid chromatography-mass spectrometry). Serum estradiol-17β and vitellogenin (VTG) levels and gonadal Sf1, Dmrt1, Foxl2, Cyp19a1a expression levels in the catfish were measured through Estradiol/VTG EIA Kit and real-time PCR. Results Here we report that feeding of Limnodilus spp. resulted in complete feminization of southern catfish, which has a 1:1 sex ratio in wild conditions. Furthermore, HPLC analysis showed that the extraction of Limnodilus spp. contained EDCs, including bisphenol A (BPA), diethylstilbestrol (DES), 4-tert-octylphenol (4-t-OP) and 4-nonylphenol (4-NP), which were further confirmed by LC–MS. Feeding southern catfish using commercial diets sprayed with EDCs cocktail also resulted in 100% female, whereas the control fish displayed approximate 1:1 sex ratio. Limnodilus spp. fed fish displayed similar serum estradiol-17β and VTG levels and gonadal Sf1, Dmrt1, Foxl2, Cyp19a1a expression levels to those of female control. Conclusion These results demonstrated that EDCs in Limnodilus spp. cause southern catfish feminization by affecting aromatase expression and endogenous estrogen level. This is the first report showing that feeding of any living organism resulted in complete feminization of a vertebrate.

a b s t r a c t Plukenetia volubilis, whose seeds contain a high content of polyunsaturated fatty acids, produces approx- imately 60 male flowers but only 1-2 female flowers per inflorescence. Increasing the number of female flowers is critical for yield improvement of P. volubilis. In this study, we determined the effect of the plant growth regulator 6-benzyladenine (BA) on floral sex determination in P. volubilis. Exogenous application of BA converted male flowers on most of the inflorescences to female flowers, and approximately 8-20% of the induced female flowers further developed into fruits. Treatment with various concentrations of BA resulted in 3-41 female flowers per inflorescence, reaching the highest average of 23.9 at 160 mg/L BA treatment. There were 3-22 inflorescences with induced female flowers per branch on the trees treated with various concentrations of BA, and the highest average of 13.8 was observed at 20 mg/L of BA treat- ment. The average number of fruits per infructescence was 3.3 in the trees treated with the optimal concentration of BA (20 mg/L), compared with 1.3 for infructescences of the control trees. The results of this study show that BA is a plant growth regulator with the potential to induce floral feminization and promote fruiting of P. volubilis. © 2014 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

Given the complexities of the transitioning process, transgender individuals may face unique dermatologic needs in addition to routine care. Exogenous hormones affect hair and sebum production, gender-confirming surgeries often require dermatologic pre- and postoperative interventions, and postoperative anatomy may show unique presentations of routine skin conditions. Aesthetic techniques that are often used for rejuvenation may have a role in facial feminization and masculinization and unfortunately are too frequently performed by nonmedical personnel with negative consequences. Ultimately, physicians should strive to make their office a more accommodating environment for transgender individuals. Key words: transgender, dermatology, LGBT, skin, procedures

In the majority of species in which monosex culture is practised, the female is more economically attractive than the male because of its faster growth rate (Beardmore et al., 2001). Due to the profitability surrounding commercial shrimp farming, a study was conducted to determine the effect of estrogen hormone, 17ß-estradiol (E2) on the feminization and also to identify the age of external sex differentiation of banana shrimp, Penaeus merguiensis postlarvae (PL), starting from the first day of PL. From the results of feminization via a lower E2 hormone (0–1000 mg/kg) application revealed that, a concentration of 800 mg/kg was able to produce 79.3% females, while a 1000 mg/kg concentration would produce 85.3% PL shrimps with a 19.16% to 45.6% survival rate. By applying a higher E2 hormone concentration (1000–1800 mg/kg) of 1200 mg/kg to the shrimps’ feeding, 99% females were produced, while an application of between 1400 and 1800 mg/kg concentration was identified to produce 100% female PL shrimps with a 45.6% to 60.17% survival rate. The optimum concentration for application was identified at a higher dosage, which was at 1600 mg/kg, with a 100% feminization results followed by good weight and length growth rate compared to the results from other dosage applications. From the sex identification, the shrimp’s sex organ appeared at 50 days of culture (PL50) for both male and female shrimps. For the male shrimp PL, an Appendix Masculine was identified at its second pleopod; Male Gonophores at the fifth pereiopods and an Early Male Petasma was identified at the first pleopod. For the female, a Sharp Ridge Thelycum was identified at the fifth pereiopod of the shrimp. As a conclusion, even though the concentration to produce 100% females could be identified, further studies should be carried out to improve the survival rate of the PL shrimps, possibly by the use of hormone treatments in the future. Keywords: Estrogen hormone, Monosex, Sex identification, Banana shrimp, Penaeus merguiensis

This article is part of a Special Issue "Puberty and Adolescence". Sexual differentiation is the process by which the nervous system becomes structurally and functionally dissimilar in females and males. In mammals, this process has been thought to occur during prenatal and early postnatal development, when a transient increase in testosterone secretion masculinizes and defeminizes the developing male nervous system. Decades of research have led to the views that structural sexual dimorphisms created during perinatal development are passively maintained throughout life, and that ovarian hormones do not play an active role in feminization of the nervous system. Furthermore, perinatal testosterone was thought to determine sex differences in neuron number by regulating cell death and cell survival, and not by regulating cell proliferation. As investigations of neural development during adolescence became more prominent in the late 20th century and revealed the extent of brain remodeling during this time, each of these tenets has been challenged and modified. Here we review evidence from the animal literature that 1) the brain is further sexually differentiated during puberty and adolescence; 2) ovarian hormones play an active role in the feminization of the brain during puberty; and 3) hormonally modulated, sex-specific addition of new neurons and glial cells, as well as loss of neurons, contribute to sexual differentiation of hypothalamic, limbic, and cortical regions during adolescence. This architectural remodeling during the adolescent phase of sexual differentiation of the brain may underlie the known sex differences in vulnerability to addiction and psychiatric disorders that emerge during this developmental period.

Feminizing parasites enhance their vertical transmission to the host offspring by converting genetic male hosts into phenotypic females. Crustacea are the only invertebrates where sexual differentiation is controlled by a specialised endocrine organ, the androgenic gland, rather than by the gonads. We showed that a feminizing microsporidian Microsporidium sp. inhibits androgenic gland differentiation. We investigated the effect of Microsporidium sp. and a second feminizing microsporidium, Nosema granulosis, on the masculinizing function of the androgenic gland in Gammarus duebeni. Androgenic gland implants had a masculinizing effect on the sexual characteristics and sexual behaviour of recipient female hosts, reflecting the masculinizing function of the androgenic gland. Individuals that had received androgenic glands showed changed morphology in comparison with controls; they were bigger overall, they lost their oostegite marginal setae, developed calceoli and acquired a male-like behaviour. This effect was observed in uninfected females, as well as in females infected with the Microsporidium sp. The masculinizing effect of androgenic gland implants was smaller in N. granulosis infected individuals. N. granulosis and Microsporidium sp. fall into distinct clades of the Microspora. It appears that these divergent parasites both act by inhibiting the development of the androgenic gland. However, they differ in their ability to inhibit the host's response to the hormone that controls male sexual differentiation.

Several studies have shown that exposure of amphibians, including the African clawed frog (Xenopus laevis), to potent estrogens at critical times during development results in feminization and/or demasculinization. However, genotyping of X. laevis has only recently become possible, so studies performed in the past were rarely able to make explicit linkages between genetic and phenotypic sex. Therefore, to further characterize this relationship, X. laevis tadpoles were exposed during development to 0.09, 0.84, or 8.81 μg/L 17α-ethynylestradiol (EE2), which is the estrogen analog commonly used in oral contraceptives. Exposure to all concentrations of EE2 tested resulted in significant delays in time to metamorphosis. Genotyping showed that genetic sex ratios were similar among treatments. However, morphological evaluation revealed that a significant number of individuals with a male genotype displayed mixed sex and abnormal phenotypes. Additionally, both genetic males and females exposed to EE2 exhibited greater presence of vitellogenin protein relative to the respective controls. Since estrogens function downstream of the initial molecular signals of sexual differentiation, it is likely that genetic male animals received mixed endogenous male and exogenous female signals that caused disordered sexual development. The production of vitellogenin was probably temporally separated and independent from primary effects on sexual differentiation, and might have contributed to delays in metamorphosis observed in individuals exposed to EE2.

An integrated approach, combining biological and chemical methods, was used to assess potential exposure to exogenous estrogens and their possible interference with the endocrine system of male goldfish (Carassius auratus) in Taihu Lake. A suite of biomarkers in caged fish after in situ exposure for 28 days, coupled with six selected exogenous estrogens in water, were determined at eight biomonitoring stations. The compounds estrone, 17β-estradiol (E2), estriol, 17α-ethinylestradiol (EE2), bisphenol-A and diethylstilbestrol were detected in most of the samples and the concentrations of total estradiol equivalent (EEQ) ranged between 5.69 and 17.8 ng/L. E2 and EE2 were thought to be the major causal agents responsible for the estrogenic activities. Elevated serum vitellogenin and E2, gonadal DNA damage and reduced gonadosomatic index were observed in fish collected from most stations. The integrated biomarker response (IBR) index showed good agreement with the observed total EEQ levels in water, and feminization risk in fish may be present in northern Taihu Lake, especially in Meiliang Bay and Zhushan Bay.

To produce all male Giant river prawn (Macrobrachium rosenbergii De Man, 1879) neofemales are produced by removing the androgenic glands of young post larvae (PL). Key to the success of sex change is having suitable PL stages which were formerly recommended according to size (carapace length, CL) or age. This study aimed at understanding the relationship between developmental stages of androgenic glands and size of M. rosenbergii and success rate of sex change after removal of androgenic glands in different size groups of PL. This is the first report on developmental stages of androgenic glands of juvenile M. rosenbergii based on histology of 30 PL/age-class (240 individuals) between 10 to 80 days after metamorphosis. The five stages of androgenic gland development are described. At a stocking density of 2500 PL/1500 l, development of androgenic glands depended on size and age. We found that the optimal PL stage for andrectomization was before development of appendix masculinae, regardless of size and age. Stocking PL at high density (e.g. 5000 PL/1500 l) extended the optimal stage for andrectomization up to PL105 compared to PL95 in the low density group. Only 84.86 ± 8.19 and 90.92 ± 17.78% (for the high and low stocking densities, respectively) of the presumed neofemales (identified by absence of appendix masculinae), developed ovaries.

Previous studies have shown that women with higher maternal tendencies are shorter and have lower testosterone levels than those with lower maternal tendencies. Here we report two studies that investigated the relationships between maternal tendencies and two further measures of physical masculinization/feminization; urinary estrogen metabolite (estrone-3-glucuronide: E1-3G) levels (Study 1) and rated facial femininity (Study 2). In Study 1, nulliparous women reported both their ideal number of children and ideal own age at first child and also provided urine samples. There was a significant positive correlation between measured late-follicular estrogen levels and reported ideal number of children. In Study 2, analyses of facial cues in two independent samples of women showed that the average facial characteristics of women who reported desiring many children were rated as more feminine than those desiring fewer children. Collectively, these results support the proposal that maternal tendencies are related to physical feminization and that this effect may, at least in part, reflect the influence of the hormone estrogen.

Transsexualism is a gender identity disorder in which there is a strong and ongoing desire to live and be accepted as a member of the opposite sex. In male-to-female transsexuals with strong masculine facial features facial feminization surgery can be performed as part of gender reassignment. The male forehead has extensive supraorbital bossing, and above this there is often a flat area before the convex curvature of the upper forehead begins. In the female, the supraorbital bossing is considerably less, often nonexistent, and above this the flattening is usually less marked and more of a continuous mild curvature. The female nose is relatively smaller than the male nose. The glabellar and the nasolabial angle are less acute. The female nose is regarded as attractive if it shows a straight or mildly concave dorsum and an accented tip. We present a case of treatment of a 26-year-old male-to-female transsexual to demonstrate that contouring the forehead combined with a rhinoplasty can lead to significant feminization of the face. The procedures described seem to be safe and reliable.

Wolbachia is one of the most prevalent endosymbiontic bacteria of arthropods. The bacterium induces sex ratio distortions in various host insects through processes such as cytoplasmic incompatibility, feminization, male killing, and parthenogenesis. We investigated if the Korean endemic firefly, Luciola unmunsana was infected with the bacterium because the species had an abnormal sex ratio in the field. The results show that some individuals are infected with the bacterium. Phylogenetic analyses showed that the bacterial strain infecting the firefly is closely related to strains that infect phylogenetically distant hosts.

We systematically investigated the feminization of bluegill Lepomis macrochirus by oral administration of various doses of estradiol-17β (E 2 ) and evaluated their effects on the growth performance, production and gonadal structure of sex-reversed female bluegill at both sex ratio and histological levels. With positive control treatment, 30-day-old fry were fed with E 2 at 50, 100, 150 and 200 mg kg − 1 diet for 60 days. The survival of fish in the E 2 treated and control groups was not significantly different ( P > 0.05). The growth of the treated fish was significantly retarded during the period of treatment, while there was no side effect detected post-treatment and the retarded fish caught up during 120 days of culture after E 2 treatment. All the treated groups produced 100% monosex female populations based on the macroscopic shape of gonads, and there were no significant differences detected between any E 2 treatment and control group in the mean GSI of females during the spawning season from June to October ( P > 0.05). Histologically, 13.3% and 5.0% of the intersex fish were determined to come from the 50 and 100 mg kg − 1 E 2 treatment groups, respectively, with 6.9% and 4.1% of the gonadal area containing spermatocytes. Most of genotypical male fish treated with exogenous E 2 developed gonadal structures histologically indistinguishable from the gonads of females. This study suggests that 150 mg kg − 1 E 2 is the optimal dosage for feminization in bluegill, with 50 and 100 mg kg − 1 E 2 being sub-optimal and 200 mg kg − 1 E 2 being over-optimal.

The gilthead seabream is a protandrous hermaphrodite seasonal breeding teleost with a bisexual gonad that offers an interesting model for studying the two first reproductive cycles (RCs), in which the specimens develops as males. During the first RC (RC1), 11-ketotestosterone (11-KT) and testosterone (T), the main androgens in fish, play different and specific roles in the testicular physiology as they peak at different stages of RC1. Moreover, the profiles of T serum levels during the second RC (RC2) demonstrated that this androgen is not essential in the testicular regression process that occurs during this cycle. However, changes in serum levels suggest that 17beta-estradiol (E2) orchestrates this process during both RCs. Moreover, the E2 serum levels recorded during RC2 indicate that there is a threshold level that determines the initiation of ovarian development during this cycle without promoting complete feminization. We analysed triglyceride, protein, glucose and lactate serum levels in order to establish a relationship between the mobilization and transfer of nutrients, the hormonal changes that take place during the RC and body composition, finding that in vivo serum levels of metabolites change significantly throughout the first two RCs, although the physiological relevance of such changes is still unknown. Triglyceride levels seem to be affected by the beginning of ovary development during RC2 but not by testicular recrudescence during RC1. Moreover, glucose and lactate might be important sources of energy during the resting and testicular involution stages.

Feminization of fish has been reported throughout the world in freshwater and marine systems. While the population impacts are conflictive, enough negative effects warrant additional research into causation. In order to ascertain the identities of specific feminizing agents, variants of toxicity identification evaluations (TIEs) have been employed. The majority of these evaluations have utilized in vitro estrogen receptor-based cell-lines to identify chromatographic fractions that possess biological activity from predominately wastewater derived from municipal treatment facilities and have concluded that synthetic and natural estrogens are the primary cause for feminization of fish. This paper will focus on three aquatic systems impacted by wastewater originating from purely domestic, and industrial/domestic secondary treatment systems. Wastewater and sediment extracts were evaluated by in vitro and in vivo biological responses in a TIE fractionation design. While in vitro responses tended to mirror in vivo responses in purely domestic wastewater systems, in vitro responses tended to severely underestimate in vivo estrogenic activity when normalized to estradiol equivalents in more complex systems. TIE fractionation schemes using in vivo biological responses failed to indicate any relationship to steroids in either wastewater or sediment extractions. These data consistently support the view that mechanisms other than direct ER binding and activation by toxicants may be important in the feminization of fish particularly residing in habitats that receive complex wastewater or agricultural effluents.

Adrenocortical tumors are rare and mostly non-secreting; their discovery is incidental. When secreting, they produce steroid excess and result in a clinical presentation such as the Cushing syndrome, primary aldosteronism, virilization or feminization syndrome. Such tumors are mostly sporadic but can belong to hereditary syndromes predisposing to tumors. The diagnosis of secreting adrenocortical tumors is based upon clinical presentation and biological data associated with specific biological assessments. Adrenal imaging has been considerably improved with the development of CT scan, which can be completed by MRI if necessary. Most of adrenocortical tumors are adenoma, nevertheless some of them can be malignant and the prognosis of such carcinomas is poor. Management of secreting adrenocortical tumors requires surgery in most of the cases and laparoscopic access is now widely used and provides good results in the treatment of benign tumors.

Anogenital distance (AGD) in rodents is a useful indicator of masculinization or feminization due to prenatal hormonal effects. If such cues convey useful information about both 'maleness' and more importantly mate quality, then females may select males based on this cue or other cues related to it. We tested this hypothesis by asking if female prairie voles (Microtus ochrogaster) preferred males with relatively longer AGDs and if AGD correlated with fitness enhancing characteristics such as sperm count, sperm size, and gonad size. Not only did preferred males have significantly longer AGD and larger testes than nonpreferred males, but AGD was directly related to the testes size, seminal vesicle size, and the number of sperm stored. We re-evaluated data collected in semi-natural field enclosures and discovered that males that were members of a pairbond had longer AGD than single males. This later result, taken under semi-natural conditions, was consistent with results we obtained in the laboratory. Taken together these data indicate that AGD serves as a useful cue of male potency and that females preferentially associate with males that demonstrate this masculinized phenotype. Moreover, these data imply that females may select mates based on their potential to effectively fertilize ova, a potentially important trait for a species that forms life-long pairbonds.

This review assesses the effects of environmental concentrations of bisphenol-A (BPA) on wildlife. Water concentrations of BPA vary tremendously due to proximity to point and non-point sources, but reported concentrations in stream/river water samples are less than 21 microg/L, and concentrations in landfill leacheate are less than 17.2mg/L. Extensive evidence indicates that BPA induces feminization during gonadal ontogeny of fishes, reptiles, and birds, but in all cases the amount of BPA necessary to cause such ontogenetic disruption exceeds concentrations in the environment. Extensive evidence also exists that adult exposure to environmental concentrations of BPA is detrimental to spermatogenetic endpoints and stimulates vitellogenin synthesis in model species of fish. Most of the reported effects of BPA on vertebrate wildlife species can be attributed to BPA acting as an estrogen receptor agonist, but mechanisms of disruption in invertebrates are less certain. A comparison of measured BPA environmental concentrations with chronic values suggests that no significant margin of safety exists for the protection of aquatic communities against the toxicity of BPA. Further studies should examine the most vulnerable vertebrate and invertebrate species.

Ageing affects drugs metabolism influencing the therapeutic efficacy and safety of drugs. By using the experimental model of aged male rats, we investigated the influence of ageing on some CYP2C isoforms, the most important CYP450 sub-family in rats. The activity of the male specific CYP2C11 is decreased by 55% in senescent male rats. This correlates with a significant reduction of both protein content (80%) and mRNA (60%) indicating a demasculinization process. The expression of CYP2C12, a female specific isoform, is induced in senescent male rats indicating a feminization process. Neither the activity nor the expression of CYP2C6, a female predominant isoform, is modified in senescent male rats. Thereafter, certain putative GH mediators like some liver enriched transcription factors (LETFs) or STAT5b were investigated. The amount of HNF3beta mRNA, a transcription factor involved in the up-regulation of CYP2C12, has been shown to increase by about three-fold in senescent male rats. With regard to STAT5b, which has been reported to be involved in the male specific regulation of CYP2C11, large amounts of phosphorylated STAT5 were observed in the liver of senescent male rats. These results indicate that while the induction of CYP2C12 during ageing could be due, at least partially, to the enhanced HNF3beta expression, the decline of CYP2C11 is unlikely related to a decrease of STAT5 activation.

Many hormone preparations are available for the induction of puberty. We present arguments and evidence that favor the use of physiologic hormone replacement regimens with estradiol and progesterone that mimic the normal changes in production of these natural hormones across puberty. Delaying estrogen therapy until 15 years of age to optimize height potential, as previously recommended, seems unwarranted. This emphasis on stature tends to undervalue the psychosocial importance of age-appropriate pubertal maturation and may be deleterious to bone and other aspects of the child's health. It is now clear that puberty induction can be initiated as early as 12 years of age with very low-dose estradiol (starting doses of one-tenth to one-eighth of the adult dose) without compromising enhancement of growth potential by growth hormone (GH). We give suggestions and recommendations for the induction of puberty in Turner syndrome on the basis of existing data from prospective clinical trials. However, such data are sparse, and there are unanswered questions about optimal treatment schedules for stature, feminization, and uterine and bone development since estradiol percutaneous preparations have only recently become available by prescription in sufficiently low dosages to initiate puberty.

Maternally inherited, cellular endosymbionts can enhance their fitness by biasing host sex ratio in favor of females. Male killing (MK), an extreme form of sex-ratio manipulation, is selectively advantageous, if the death of males results in increased microbe transmission through female siblings. In live-bearing hosts, females typically produce more embryos than are brought to term, and reproductive compensation through maternal resource reallocation from dead male embryos to female siblings provides a direct, physiological mechanism that could increase the number of daughters born to infected females, thereby promoting MK endosymbiont spread. In this study, a Wolbachia-infected line and an uninfected line of the viviparous pseudoscorpion, Cordylochernes scorpioides were genetically homogenized for nuclear DNA by repeated backcrossing of the infected line with the uninfected, laboratory population. Photomicroscopy of early-stage embryos demonstrated that female C. scorpioides invariably produced an excess of embryos, with Wolbachia-infected females producing as many early-stage embryos as uninfected female controls. However, Wolbachia-infected females that successfully carried broods to term gave birth to significantly fewer offspring, indicating that the extreme female bias characteristic of their broods results from the killing rather than the feminization of male embryos. Infected females that carried broods to term gave birth to significantly larger nymphs and did produce 10% more female offspring than uninfected females. However, the slight transmission advantage that the MK Wolbachia accrued from this reproductive compensation appears to be heavily outweighed by the high rate of spontaneous brood abortion suffered by infected females.

Recently, male urogenital papilla feminization (UGPF) in the sand goby Pomatoschistus minutus was reported in several UK estuaries with high levels of estrogenic compounds. The fact that this species is also common in southern European estuaries, together with its life-cycle characteristics, prompted us to investigate P. minutus UGPF in the northwestern of Iberian Peninsula. Specimens of P. minutus were periodically sampled during 2004 at several locations in two estuaries (Minho and Lima). Evidence for UGPF was recorded in both estuaries, the highest incidence being observed in the Lima estuary (50%). Estrogen levels (17beta-estradiol and estrone) above 100 pg/l were observed in both estuaries, the higher concentrations being found in the Lima estuary. Overall, the results suggest a relationship between the feminization of male P. minutus urogenital papilla and the presence of estrogenic compounds. In the future, more in-depth studies are required in order to use P. minutus as a sentinel species for estrogenic compound monitoring in estuaries.

Genital malformations constitute the most common birth defects in man and domestic animals and occur frequently in males since the participation of many genes is required for sex differentiation to proceed in the male direction. The precise dose, timing, and coordination needed for their expression add to the proneness of various stages in male sex differentiation to external influences. The emerging insight, through the identification of genes involved in the sex differentiation cascade, is that over 85% of sex anomalies in human and domestic animal populations are not attributable to chromosome aberrations or to mutations in a known gene. Since a majority of severely malformed individuals are incapable of reproduction, the high rates of these defects have to be results either of new mutations or of collaboration of environmental factors with genes. Increase in specific malformations in domestic animals often indicates increased concentration of liability genes brought together in the conceptus by inbreeding. However, in human populations where inbreeding is not the norm such increases may reflect environment-induced new mutations or interaction of environmental agents with hormone-sensitive genes. This review summarizes the information currently available on the genetics of major events in male sex differentiation and briefly discusses the collaborative role that environment may play in disrupting different components of this process.

Fetal male sex development proceeds along an orderly sequence of events coordinated by an interplay of genetic and hormonal events. These operate in a time- and concentration-dependent manner. Once a testis is formed (the female sex being constitutive in nature), differentiation of the internal and external male genitalia is androgen dependent. A number of genetic syndromes of sex reversal are well characterized at the biochemical and molecular levels. They fall into three principal categories: defects in formation of the testis, defects in production of androgens, and defects in the action of androgens. In many instances, the precise cause is not established, although the investigative evidence points in the direction of one of the three stated classifications. Polymorphic variants in several of the genes involved in male development are associated with certain degrees of male undermasculinization. While the genetic background is essentially static, it is plausible that the effect of endocrine disruptors during fetal life acting through epigenetic mechanisms may partly explain the observed changing trends in male reproductive tract disorders.

This study was undertaken to determine if prenatal exposure to therapeutic drugs contributes to variations in sexual orientation. Especially suspect were drugs that could affect the delicate balance of sex hormone levels that appear to guide the sexual differentiation of the fetal brain. The recollections of 5102 mothers concerning their use of therapeutic drugs during pregnancy were linked to reports of the sexual orientation of their offspring (as provided by either the offspring themselves or by their mothers). About 14% of the mothers recalled having taken at least one of 19 prescription drugs (or classes of drugs) during their pregnancy. Regarding male offspring, little evidence was found that prenatal exposure to any of these medications was associated with variations in sexual orientation. However, even after controlling for age, education, and self-rated recall ability of the mothers, exposure to two types of drugs was significantly related to sexual orientation among female offspring. One type consisted of amphetamine-based diet pills and the other was comprised of synthetic thyroid medications. A month-by-month analysis revealed that during the first trimester consumption of all prescription drugs was unusually high for mothers of female homosexual offspring. Prescription medications that affect the mother’s and/or the female fetuses’ developing immune system may alter the feminization/demasculinization of the brain in ways that cause variations in the offspring’s adult sexual orientation.

Testicular descent as a prerequisite for the production of mature spermatozoa and normal external genitalia morphogenesis, and therefore facilitating copulation and internal fertilization, are essential developmental steps in reproduction of vertebrate species. Cryptorchidism, the failure of testis descent, and feminization of external genitalia in the male, usually in the form of hypospadias, in which the opening of the urethra occurs along the ventral aspect of the penis, are the most frequent pediatric complications. Thus, elucidating the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia merits a special focus. Natural and transgenic rodent models have demonstrated both morphogenic processes to be under the control of a plethora of genetic factors with complex time-, space-, and dose-restricted expression pattern. The review elucidates the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia and, wherever possible, assesses the differences between these rodent animal models and other mammalian species, including human.

A mathematical model is presented which combines genetic XX-female/XY-male sex determination with environmental pressure for phenotypic sex reversal. This may occur when fishes are exposed to endocrine disrupters, specifically masculinization by exposure to androgens and feminization by exposure to estrogens. A generic model is derived for the sex ratio in successive generations and three special cases, with chronic and constant pressure to sex reverse, are discussed in detail. These show that, with extreme environmental pressure to masculinize, the male genotype is at risk of dying out but with less extreme pressure, masculinization will not be detectable since the proportion of phenotypic males becomes one-half. With feminization at any pressure to sex reverse, the male and female genotypes will be maintained in a stable sex ratio in which the proportion of genotypic males exceeds one-half and is close to one-half if YY offspring (eggs) are not viable. In converse, the model is also applicable to the genetic ZZ-male/ZW-female system of sex determination in fish. At present suitable data are not available with which to validate the model, but proposals are made for relevant experimental studies.

To evaluate possible estrogenic effects of bisphenol A (BPA) in an amphibian model, Xenopus laevis tadpoles were exposed to BPA and 17beta-estradiol (E2) during larval development. After metamorphosis, the gonadal phenotype was determined by gross morphology, and testes were further examined histologically to validate the results. BPA treatment altered the normal sex ratio toward females depending on the BPA concentrations added. Chemical analysis showed a time-dependent decline of BPA during semistatic exposure, indicating that BPA is taken up and metabolized to some extent by tadpoles. In addition, tadpoles were exposed to BPA and E2 for 2 weeks during sensitive stages of sexual differentiation. Afterward, the expression of an estrogenic biomarker, estrogen receptor (ER) mRNA, was assessed by semiquantitative RT-PCR. Both BPA and E2 up-regulated ER mRNA significantly. In conclusion, these results show clear evidence that BPA induces feminization in X. laevis tadpoles, revealing an estrogenic potency of BPA that influences sexual development in amphibians.

Atlantic halibut (Hippoglossus hippoglossus L.) females grow larger and mature later than males, making monosex (all-female) culture economically advantageous. The objective of this research was to develop methods for the production of monosex populations of halibut through the use of sex steroids. Six hundred postlarval halibut, mean size 30.0 mm fork length (FL), were divided evenly among eight tanks and fed a formulated diet supplemented with either 17α-methyldihydrotestosterone (MDHT; 1 and 5 ppm) or 17β-estradiol (E2; 10 ppm) for 45 days. Fish were then further reared on a standard halibut diet until sex ratios could be determined through histological and macroscopic observations. The MDHT treatments yielded 97–100% males, while the E2 treatment yielded a 70–74% female population. This demonstrates that the direct feminization of halibut can be achieved, and also allows for the evaluation of indirect feminization through the crossing of hormonally masculinized females (“neomales”) to normal females.