Active feminization of the preoptic area occurs independently of the gonads in Amphiprion ocellaris.

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.

Feminizing Adrenocortical Carcinoma with Distinct Histopathological Findings.

We herein present a 60-year-old man with adrenocortical carcinoma who had gynecomastia. An endocrinological examination revealed increased levels of serum estradiol and dehydroepiandrosterone-sulfate (DHEA-S) and reduced levels of free testosterone. Magnetic resonance imaging showed an adrenal tumor with heterogeneous intensity. Iodine-131 adosterol scintigraphy showed an increased uptake at the same site. Because feminizing adrenocortical carcinoma was suspected, right adrenalectomy was performed; the pathological diagnosis was adrenocortical carcinoma. The results of immunostaining indicated a virilizing tumor. Aromatase activity was identified on RT-PCR. As disorganized steroidogenesis is pathologically present in adrenocortical carcinoma, this diagnosis should be made with caution.

A validated protocol to quantify severity of male urogenital feminization using the MOUSE (Mouse objective urethral severity evaluation).

BACKGROUND: Congenital abnormalities vary in presentation, yet studies using model organisms tend to focus on occurrence rather than severity of the defect. Scoring severity of abnormalities in model systems allows explicit hypothesis testing during basic, translational, and reverse translational studies. We developed and validated a protocol to quantify severity of male urogenital feminization (hypospadias) in the mouse model. Hypospadias is one of the most common birth defects in the world. METHODS: To induce genital feminization, pregnant mice were exposed to different concentrations of the antiandrogen vinclozolin. Genitalia were photographed at gestational age 18.5. A dichotomous scoring system to evaluate genital feminization was developed, and validated against histological measurements of urethral length. A training protocol was developed for novice scorers, and criteria were defined to evaluate precision and accuracy of scores. RESULTS: Vinclozolin induced variation in hypospadias severity. Severity scores were tightly correlated with histologically determined urethral length and both techniques showed similar dose-response relationships. Novice observers were trained to precisely and accurately score hypospadias severity. CONCLUSION: This standardized scoring system advances the mouse as a model to study urogenital development, and will facilitate research on the mechanisms driving genital feminization in males, and aid translational hypospadias research.

Pathologic Risk Factors in Pediatric and Adolescent Patients With Clinical Stage I Testicular Stromal Tumors.

BACKGROUND: Testicular stromal tumors (TSTs) are rare. In adult men with TSTs, various pathologic risk factors have been identified in patients with clinically localized disease that increase the risk of occult metastatic disease (OMD). We systematically reviewed existing literature to analyze the impact of these risk factors on OMD in prepubertal (0 to 12 y) and postpubertal (13 to 21 y) patients. METHODS: A literature search was conducted using the combination of terms: "testicular stromal tumors," "testicular leydig cell tumors," "testicular sertoli tumors," "testicular interstitial tumors," "testicular granulosa tumor," and "testicular sex cord tumors." Studies of patients 0 to 21 years with clinical stage I TSTs were included. RESULTS: A total of 100 patients from 31 publications were included with a median age at diagnosis of 5.7 years (range, 1.2 mo to 21 y). Seventy-nine patients were 12 years and below (median 7.2 mo) and 21 patients were 13 to 21 years (median 16 y). No patients in either group were identified to have OMD at retroperitoneal lymph node dissection or during follow-up surveillance (median follow-up 45.6 y; range, 4 to 360 mo). 99% of those 12 years and below versus 95% of those above 12 years had 0 to 1 pathologic risk factors, and 1% versus 5% had 2+ pathologic risk factors (P=0.38). CONCLUSIONS: Clinical stage I TSTs in adolescent, postpubertal patients appear to behave in a benign manner with few pathologic risk factors, similar to prepubertal patients. Given the low risk of relapse in this population, low-impact surveillance strategies are paramount. Prospective study of these patients is needed, and entry into a tumor registry such as the International Ovarian and Testicular Stromal Tumor Registry is important to learning more about this rare disease.

From the radiologic pathology archives: Adrenal tumors and tumor-like conditions in the adult: radiologic-pathologic correlation.

Advanced imaging often reveals adrenal tumors and tumor-like conditions in both symptomatic and asymptomatic patients. When adrenal disease is clinically suspected, cross-sectional imaging can be helpful in evaluating the etiology of the patient's symptoms. When adrenal disease is incidentally identified, what the clinician and patient really want to know is whether the findings are benign or malignant, as this ultimately will affect their next step in management. Using radiologic-pathologic correlation, we broadly classify common, uncommon, and rare tumors and tumor-like conditions that can occur in the adrenal as benign or malignant. This classification follows predominant trends in observed biologic behavior while acknowledging those tumors that may behave in the minority in an unpredictable manner. We review the clinical background and presentation of functional adrenal tumors including Conn syndrome, Cushing syndrome, and catecholamine-secreting tumors, as well as their relationship with adrenal anatomy. We discuss a variety of benign tumors, including adrenal cortical adenoma (including oncocytoma) and pheochromocytoma, as well as uncommonly and rarely encountered tumors such as myelolipoma, hemangioma, lymphangioma, schwannoma, ganglioneuroma, and adenomatoid tumor. A variety of tumefactive but nonneoplastic lesions are addressed, including adrenal cortical hyperplasia, adrenal hemorrhage, adrenal cysts, and infections. Malignant tumors discussed include adrenal cortical carcinoma, the rare malignant pheochromocytoma, lymphoma, metastases, and sarcomas. For each tumor and tumor-like lesion, the clinical presentation, epidemiology, key imaging findings, diagnostic differential considerations, and management options are briefly addressed. Finally, an approach to the workup of suspected or incidentally discovered tumors is presented based on a selected literature survey and our clinical experience. Radiologists play an important role in identification and diagnosis of adrenal tumors and tumor-like conditions in both symptomatic and asymptomatic patients.

The extreme male brain revisited: gender coherence in adults with autism spectrum disorder.

BACKGROUND: The 'extreme male brain' theory suggests that autism spectrum disorder (ASD) is an extreme variant of male intelligence. However, somewhat paradoxically, many individuals with ASD display androgynous physical features regardless of gender. AIMS: To assess physical measures, supposedly related to androgen influence, in adults with and without ASD. METHOD: Serum hormone levels, anthropometry, the ratio of 2nd to 4th digit length (2D:4D) and psychiatric symptomatology were measured in 50 adults with high-functioning ASD and age- and gender-matched neurotypical controls. Photographs of face and body, as well as voice recordings, were obtained and assessed with respect to gender coherence, blindly and independently, by eight assessors. RESULTS: Women with ASD had higher total and bioactive testosterone levels, less feminine facial features and a larger head circumference than female controls. Men in the ASD group were assessed as having less masculine body characteristics and voice quality, and displayed higher (i.e. less masculine) 2D:4D ratios, but similar testosterone levels to controls. Androgynous facial features correlated strongly and positively with autistic traits measured with the Autism-Spectrum Quotient in the total sample. In males and females with ASD dehydroepiandrosterone sulfate did not decrease with age, in contrast to the control group. CONCLUSIONS: Women with ASD had elevated testosterone levels and several masculinised characteristics compared with controls, whereas men with ASD displayed several feminised characteristics. Our findings suggest that ASD, rather than being characterised by masculinisation in both genders, may constitute a gender defiant disorder.

Soybean isoflavone exposure does not have feminizing effects on men: a critical examination of the clinical evidence.

OBJECTIVE: To critically evaluate the clinical evidence, and when not available, the animal data, most relevant to concerns that isoflavone exposure in the form of supplements or soy foods has feminizing effects on men. DESIGN: Medline literature review and cross-reference of published data. RESULT(S): In contrast to the results of some rodent studies, findings from a recently published metaanalysis and subsequently published studies show that neither isoflavone supplements nor isoflavone-rich soy affect total or free testosterone (T) levels. Similarly, there is essentially no evidence from the nine identified clinical studies that isoflavone exposure affects circulating estrogen levels in men. Clinical evidence also indicates that isoflavones have no effect on sperm or semen parameters, although only three intervention studies were identified and none were longer than 3 months in duration. Finally, findings from animal studies suggesting that isoflavones increase the risk of erectile dysfunction are not applicable to men, because of differences in isoflavone metabolism between rodents and humans and the excessively high amount of isoflavones to which the animals were exposed. CONCLUSION(S): The intervention data indicate that isoflavones do not exert feminizing effects on men at intake levels equal to and even considerably higher than are typical for Asian males.

Tumores suprarrenales feminizantes en España: aportación de un caso y revisión de los cinco pacientes descritos / Feminizing adrenal tumors in Spain: report of a case and review of the five previously published patients

Los tumores adrenales feminizantes son muy raros. Se presenta el estudio clínico y hormonal de un varón de 49 años hasta su fallecimiento, 6 años después del diagnóstico, junto con una revisión de los otros 5 casos descritos en España. El paciente consultó por ginecomastia y disminución de la libido; se halló gran elevación de estrógenos, testosterona en el límite bajo de la normalidad y un tumor suprarrenal derecho que, al extirparlo, se observó que era de histología benigna, informado como adenoma. Tres años después, reapareció la clínica junto con aumento de estrógenos, glucocorticoides y andrógenos; se objetivó recidiva tumoral en el polo superior del riñón derecho y metástasis peritoneales, hepáticas y pulmonares. Tratado con mitotano y aminoglutetimida, las concentraciones hormonales descendieron transitoriamente, pero volvieron a aumentar hasta su fallecimiento a los 6 años del diagnóstico inicial. Resalta en este caso el carácter aparentemente benigno y unisecretor del tumor para recidivar a los 3 años con carácter maligno y plurisecretor y metástasis generalizadas sin respuesta al tratamiento médico (AU)

Feminizing adrenal tumours are very rare. We report the clinical and hormonal study of a case, a 49 years old male, since his first consultation until his death 6 years after the initial diagnosis, and a review of the other 5 Spanish patients previously published. His initial symptoms were gynecomastia and libido decrease, with increase of plasmatic and urinary oestrogen levels, plasma testosterone near low normal level and a right adrenal gland tumour that, after its removal, showed a benign histology and was classified as an adrenocortical adenoma. Three years after, initial symptoms returned, with oestrogen, glucocorticoid and androgen hypersecretion, tumour local relapse and peritoneal, liver and lung metastasis. After mitotane and aminoglutethimide therapy, hormonal concentrations fell temporary and then raised again until his death 3 years later. The main special feature of this case is the apparently benign initial adrenal tumour with only oestrogen hypersecretion, and its relapse 3 years later with secretion of several steroid hormones, generalized metastasis and no response to medical therapy (AU)

Prevalence of low bone mass in relation to estrogen treatment and body composition in male-to-female transsexual persons.

Bone health is a parameter of interest in the daily follow-up of male-to-female (M --> F) transsexual persons both before and after sex reassignment surgery (SRS) due to an intensely changing hormonal milieu. We have studied body composition, areal, geometric, and volumetric bone parameters, using DXA and peripheral quantitative computed tomography at different sites in 50 M --> F transsexual persons, at least 3 yr after the start of the hormonal treatment and 1 yr after SRS. In this cross-sectional study, hormone levels and markers of bone metabolism were assessed using immunoassays. Prevalence of low bone mass as defined by a Z-score < or = -2.0 according to DXA criteria was 26% at lumbar spine and 2% at the total hip. We found no major differences in hormonal parameters between participants with a Z-score < or = or > -2.0. Markers of bone turnover were comparable between subjects with or without low bone mass, indicating a stable bone turnover at the time of investigation. No significant differences in bone size or density were observed between patients on transdermal vs. oral estrogens. Low bone mass is not uncommon in M --> F transsexual persons. Smaller bone size, and a strikingly lower muscle mass compared with men appear to underlie these findings.

[Feminizing adrenal tumours in Spain: report of a case and review of the five previously published patients]. / Tumores suprarrenales feminizantes en España: aportación de un caso y revisión de los cinco pacientes descritos.

Feminizing adrenal tumours are very rare. We report the clinical and hormonal study of a case, a 49 years old male, since his first consultation until his death 6 years after the initial diagnosis, and a review of the other 5 Spanish patients previously published. His initial symptoms were gynecomastia and libido decrease, with increase of plasmatic and urinary oestrogen levels, plasma testosterone near low normal level and a right adrenal gland tumour that, after its removal, showed a benign histology and was classified as an adrenocortical adenoma. Three years after, initial symptoms returned, with oestrogen, glucocorticoid and androgen hypersecretion, tumour local relapse and peritoneal, liver and lung metastasis. After mitotane and aminoglutethimide therapy, hormonal concentrations fell temporary and then raised again until his death 3 years later. The main special feature of this case is the apparently benign initial adrenal tumour with only oestrogen hypersecretion, and its relapse 3 years later with secretion of several steroid hormones, generalized metastasis and no response to medical therapy.

Use of intralesional oestradiol concentration to identify a functional pulmonary metastasis of canine sertoli cell tumour.

A seven-year-old, 31 kg male neutered Labrador was investigated for signs of feminisation syndrome and prostatic disease four years after castration and removal of a testicular sertoli cell tumour (SCT). Investigations revealed an elevated serum oestradiol-17beta concentration, a pulmonary mass containing fluid high in oestradiol-17beta and cystic changes in the prostate gland. The pulmonary mass was surgically excised and histologically confirmed to be a SCT metastasis. To the authors' knowledge, this is the first reported case of a proven functional extranodal SCT metastasis and the first to be diagnosed by oestradiol-17beta measurement of intralesional fluid.

Assessment of feminization of male fish in English rivers by the Environment Agency of England and Wales.

In recent years there has been considerable concern over the ability of substances discharged into the environment to disrupt the normal endocrine function of wildlife. In particular, the apparent widespread feminization of male fish in rivers has received significant attention from regulators in the United Kingdom, the United States, Europe, and Japan. The U.K. and European epidemiological data sets have demonstrated that the occurrence of feminized fish is associated with effluent discharges and that the incidence and severity is positively correlated with the proportion of treated sewage effluent in receiving waters. Although weakly estrogenic substances may contribute to the overall effect, studies have concluded that steroid estrogens are the principal and most potent estrogenic components of domestic sewage. Extensive laboratory data sets confirm that steroid estrogens are capable of eliciting the effects observed in wild fish at concentrations that have been measured in effluents and in the environment. Based on evaluation of the available information, the Environment Agency (England and Wales) has concluded that the weight of evidence for endocrine disruption in fish is sufficient to develop a risk management strategy for estrogenically active effluents that discharge to the aquatic environment.

Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature.

UNLABELLED: We describe the clinical presentation, biochemical features, diagnostic criteria, clinical course and differential diagnosis in three cases of feminizing adreno-cortical carcinoma (FACC) with a review of the literature. PATIENTS: From 1970 throughout December 2003 among a series of 801 adrenalectomies, three had been performed for FACC. RESULTS: Age at presentation was 74, 63 and 23 years. Estradiol hypersecretion was observed in 3/3 patients, 17 OH progesterone was elevated in 2/3 patients and both of them had a diminution of testosterone, delta 4 androstenedione was elevated in 1/3 patients. Imaging studies suggested malignancy in 3/3 patients by the presence of necrosis, heterogeneity, calcifications, size of the tumor and compression of adjacent organs. All patients were stage III at presentation and had a Weiss score >or=6. Size and weight of the tumors were 30, 20, 15cm and 3750, 480 and 275g respectively. All 3 patients received mitotane and cortisone post-operatively and at follow up (7, 3 and 2 years) all 3 died of the disease. CONCLUSIONS: Feminizing adreno-cortical carcinomas in adults are exceedingly rare (1-2% of adreno-cortical carcinomas). Tumors are huge and even after surgery for cure their prognosis is worse than for other varieties of adreno-cortical carcinomas either secreting or non secreting. Early diagnosis and treatment may improve overall prognosis.