Imaging features, clinical characteristics and neonatal outcomes of pregnancy luteoma: A case series and literature review.

INTRODUCTION: This study aimed to investigate the imaging features, clinical characteristics and neonatal outcomes of pregnancy luteoma. MATERIAL AND METHODS: We retrospectively analyzed patients with pregnancy luteoma admitted to the First Affiliated Hospital of Sun Yat-sen University between January 2003 and December 2022. We recorded their imaging features, clinical characteristics and neonatal outcomes. Additionally, we reviewed relevant studies in the field. RESULTS: In total, 127 cases were identified, including eight from our hospital and 119 from the literature. Most patients (93/127, 73.23%) were of reproductive age, 20-40 years old, and 66% were parous. Maternal hirsutism or virilization (such as deepening voice, acne, facial hair growth and clitoromegaly) was observed in 29.92% (38/127), whereas 59.06% of patients (75/127) were asymptomatic. Abdominal pain was reported in 13 patients due to compression, torsion or combined ectopic pregnancy. The pregnancy luteomas, primarily discovered during the third trimester (79/106, 74.53%), varied in size ranging from 10 mm to 20 cm in diameter. Seventy-five cases were incidentally detected during cesarean section or postpartum tubal ligation, and 39 were identified through imaging or physical examination during pregnancy. Approximately 26.61% of patients had bilateral lesions. The majority of pregnancy luteomas were solid and well-defined (94/107, 87.85%), with 43.06% (31/72) displaying multiple solid and well-circumscribed nodules. Elevated serum androgen levels (reaching values between 1.24 and 1529 times greater than normal values for term gestation) were observed in patients with hirsutism or virilization, with a larger lesion diameter (P < 0.001) and a higher prevalence of bilateral lesions (P < 0.001). Among the female infants born to masculinized mothers, 68.18% (15/22) were virilized. Information of imaging features was complete in 22 cases. Ultrasonography revealed well-demarcated hypoechoic solid masses with rich blood supply in 12 of 19 cases (63.16%). Nine patients underwent magnetic resonance imaging (MRI) or computed tomography (CT), and six exhibited solid masses, including three with multi-nodular solid masses. CONCLUSIONS: Pregnancy luteomas mainly manifest as well-defined, hypoechoic and hypervascular solid masses. MRI and CT are superior to ultrasonography in displaying the imaging features of multiple nodules. Maternal masculinization and solid masses with multiple nodules on imaging may help diagnose this rare disease.

Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.

AIM: Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. METHODS: Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. RESULTS: Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. CONCLUSION: This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.

Outcomes of one-stage feminizing genitoplasty in children with congenital adrenal hyperplasia and severe virilization.

PURPOSE: To present our surgical experience and outcomes in congenital adrenal hyperplasia (CAH) patients with severe virilization using a combined technique of total urogenital mobilization (TUM) and a modified pull-through vaginoplasty to perform a safe and effective one-stage feminizing genital reconstruction for these children. METHODS: Fourteen CAH patients with severe virilization, defined by a Prader IV and V rating of the external genitalia, underwent TUM followed by a limited vaginal pull-through procedure from June 2016 to December 2020. Postoperative anatomical and cosmetic outcomes, and urinary continence, were evaluated. RESULTS: Out of the 14 cases in this study, 8 were classified as prader IV and 6 as Prader V. The median age at surgery was 11 months (range 6-36 months), and the mean urethral length was 1.4 cm (range 1.2-1.8 cm). The median follow-up period was 4 years. Our cosmetic outcomes were good in 11 (78.5%), satisfactory in 2, and poor in one case. All patients achieved age-appropriate toilet training without urinary incontinence. CONCLUSION: Adopting our surgical approach of TUM with modified pull-through vaginoplasty has simplified feminizing surgical reconstruction in CAH cases with severe genital atypia and a very high vaginal confluence with short urethral length, yielding adequate introitus with good anatomical and cosmetic appearance and adequate urinary continence outcomes.

Androgen Excess and Deficiency: Analytical and Diagnostic Approaches.

BACKGROUND: Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways. CONTENT: The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens. SUMMARY: During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.

Evaluation of aggression level in adolescent girls with classical congenital adrenal hyperplasia.

OBJECTIVE: In patients with classical congenital adrenal hyperplasia (CAH), virilization affects the brain and external genitalia due to antenatal androgen exposure. There are few studies on how the effects of androgens on brain virilization are reflected in behavior. However, there is no study focused on the adolescence period. The aim of this study was to evaluate the level of aggression in adolescent girls with classical CAH (due to 21 hydroxylase and 11ß hydroxylase deficiency) and to investigate the disease-related factors that may affect aggression. DESIGN: Twenty female and 20 male patients aged 13-20 years, diagnosed with classical CAH, with 21 hydroxylase deficiency and 11ß hydroxylase deficiency, and 20 healthy girls and 20 boys from the same age group were included. The Buss-Perry Aggression Scale (BPAS), which consists of four subgroups measuring physical aggression, verbal aggression, hostility, and angry behaviors, was used. RESULTS: The ages of the male and female patients with CAH were 16.30 ± 2.65 and 16.60 ± 2.41 years, respectively. Total aggression scale scores were 73.3 ± 14.6 in adolescent girls with CAH, 74.1 ± 11.2 in healthy girls, 71.5 ± 14.8 in boys with CAH, and 75.3 ± 14.5 in healthy boys (p > .05). There was no difference between the subscale scores of patients and healthy adolescents. Aggression scores in adolescents with CAH increased significantly with age. CONCLUSIONS: In this study, we found no difference between the aggression scores of adolescents with classical CAH compared to their healthy peers. The total aggression score and subscale were similar in unaffected female adolescents.

Tendencies Toward Supernormality/Subnormality in Generating Attractive and Unattractive Female and Male Avatars: Gender Differences.

In the present study, we investigated the differences in the experience of attractiveness and unattractiveness of human bodies. A total of 101 participants (55 females) were asked to create the most attractive and the most unattractive female and male figures using a computer animation. They performed this task by adjusting the size of six body parts: shoulders, breasts/chest, waist, hips, buttocks, and legs. Analyses indicated that attractive body parts were distributed normally with the peak shifted to moderately supernormal sizes, while unattractive body parts had mostly U-shaped or skewed distributions with extremes in super-supernormal and/or subnormal sizes. Generally, both male and female attractive bodies had prominent "sporty" look: supernormally wide shoulders and long legs. Gender differences showed that men prefer more supernomal masculine and feminine sizes, while women show an ambivalence toward both groups of traits. Principal components analysis revealed gender differences on the multitrait level: males focus on prominent masculine and feminine traits, while women focus on traits that make both male and female bodies more elongated and slender. Gender differences were in line with specific male and female positions in the partner selection process, while a certain tendency toward masculinization of the female body required the inclusion of social factors, such as the influence of the culture of a sporty and fit look.

Clinical characteristics, AR gene variants, and functional domains in 64 patients with androgen insensitivity syndrome.

BACKGROUND: Androgen insensitivity syndrome (AIS) is caused by abnormal androgen receptor (AR) genes that show variable genotypes and phenotypes. However, the correlation between genotype and phenotype is unclear. METHODS: We retrospectively evaluated 64 patients with AIS at Shanghai Children's Hospital from 2015 to 2022. We analysed the clinical data of the patients, including hormone levels, AR gene variants, and functional domains. RESULTS: Variants occurred in the 3 major functional domains in 56 patients, including 23 patients with complete androgen insensitivity syndrome (CAIS) and 33 with partial androgen insensitivity syndrome (PAIS). The incidence of nonscrotal fusion (P = 0.019) and proximal urethral opening (P = 0.0002) in the ligand-binding domain (LBD) group was higher than that in the non-LBD group. The phallus length in the LBD group was significantly shorter than that in the non-LBD group (P = 0.009). The external masculinization score (EMS) in the LBD group was significantly lower than that in the non-LBD group (P = 0.013). The levels of inhibin-B (INHB; P = 0.0007), basal luteinizing hormone (LH; P = 0.033), LH peak (P = 0.002), and testosterone (T) after human chorionic gonadotropin (HCG) stimulation (P = 0.001) in the LBD group were higher than those in the non-LBD group. There were 53 variants in 64 patients, including 42 reported and 11 novel AR variants, including p.Met247Arg, p.Asp266Glyfs*39, p.Arg362Serfs*140, p.Ala385Val, p.Glu541Asp, p.Pro613Leu, p.Pro695Leu, p.Asn757Asp, c.1616 + 1dup, c.1886-1G > A and exon 5-7 deletion. CONCLUSIONS: The EMS of patients with AIS in the LBD group was significantly lower than that in the non-LBD group. The phallus length was shorter, and the incidences of proximal urethral opening and nonscrotal fusion were higher, suggesting that the phenotypes in the LBD group were more severe. The levels of INHB, basal LH, peak LH, and T after HCG stimulation in the LBD group were higher than those in the non-LBD group, suggesting that androgen resistance in the LBD group was more severe. We identified 53 variants in 64 patients: 42 reported and 11 novel AR variants. These findings provide new and deeper insight into AIS diagnosis and genetic assessment of AIS.

Case Report of Male Pseudohermaphroditism (Androgen Insensitivity Syndrome): Congenital Disorder of Sexual Differentiation.

INTRODUCTION: A broad spectrum of anomalies of sexual differentiation may exist at birth, which can be unreported until adolescence. A 17-year-old patent with female phenotype came with complaints of primary amenorrhea. On imaging (ultrasound and MRI) uterus and bilateral ovaries were absent. Small blind-ending vaginal pouch was noted along with features suggesting bilateral cryptorchidism. No definite male external genitalia/scrotal sac was seen except for subtle rudimentary bulbo-cavernous muscles. Karyotyping confirmed 46 XY consistent with Male Pseudohermaphroditism. MATERIALS: Male pseudohermaphroditism refers to a condition that affects 46, XY individuals with differentiated testes who exhibit varying degrees of feminization. In these cases there is a spectrum of external genitalia; some individuals are completely phenotypically female. Androgen insensitivity syndrome (AIS), also known as the testicular feminization syndrome, results from end-organ resistance to androgens, particularly testosterone. As the appearance of the external genitalia often is not distinctive enough to make a specific diagnosis, this must be accomplished by clinical findings along with a combination of imaging, cytogenetic and biochemical studies. Ultrasound and MRI studies are extremely useful to diagnose such conditions at the earliest as these patients have an increased incidence of malignancy in the undescended testes. The treatment is influenced by genital tissue responsiveness to androgens and reconstructive surgical procedures. There is a need for counselling regarding pubertal development, sexual performance and fertility. RESULT: A 17year old patent came with complaints of primary amenorrhea. On examination patient has normal external female genitalia, with developed breast. On laboratory correlation, it shows high testosterone level: 881 ng/dL and Normal progesterone level: 0.182 ng/mL. On karyotyping, it shows 46XY karyotype. On USG: Uterus is not well appreciated. There is iso-echogenic oval shaped soft tissue seen in bilateral inguinal regions with vascularity within-likely to be gonads. On MRI: Absence of uterus and bilateral ovaries are confirmed with evidence of symmetrical oval-shaped soft tissue lesions identified within bilateral inguinal canals - consistent with bilateral cryptorchidism. Male pseudohermaphroditism refers to a condition that affects 46, XY individuals with differentiated testes who exhibit varying degrees of feminization. CONCLUSION: In cases of male pseudohermaphroditism, there is a spectrum of external genitalia; some individuals are completely phenotypically female, whereas others appear to be normal males with varying spermatogenesis and/or pubertal virilization. As the appearance of the external genitalia often is not distinctive enough to make a specific diagnosis, this must be accomplished by clinical findings along with a combination of cytogenetic, biochemical, and radiologic studies. Sonographic and radiographic studies are often used initially to evaluate such conditions. Male pseudohermaphrodites all possess testes yet exhibit incomplete virilization of the genital ducts and/or external genitalia. The findings depend on the underlying defect. Complete androgen insensitivity (testicular feminization) is an X-linked recessive disorder in which the absence of cytoplasmic testosterone receptors prevents specific gene activation and subsequent differentiation of the external genitalia. In this disorder, the external genitalia are completely feminized, while in the other forms of male pseudohermaphroditism various degrees of virilization occur. The absence of internal female genital tract structures reflects the synthesis of active Mullerian regression factor by the testes, which may be maldescended. Multiplanar MR images will confirm the absence of a uterus and demonstrate intraabdominal or inguinal testes. Integrated imaging in the form of ultrasound, genitography and MRI is important in demonstrating the anatomy, classification, possible effects or congenital malformations in other organs, warning patients of any risk of neoplasia and guiding the clinician to plan other investigations, hormonal replacement or reconstruction surgery if required. References Tanaka YO, Mesaki N, Kurosaki Y, et al. Testicular feminization: role of MRI in diagnosing this rare male pseudohermaphroditism. J Comput Assist Tomogr 1998;22(6):884-888. Nakhal RS, Hall-Craggs M, Freeman A, et al. Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268(1):153-160.

Approach to androgen excess in women: Clinical and biochemical insights.

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice.

Hyperandrogenism is the main characteristic of polycystic ovary syndrome, which affects placental function and fetal growth, and leads to reproductive and metabolic dysfunction in female offspring. Adiponectin acts on the placenta and may exert endocrine effects on the developing fetus. This study aims to investigate if maternal and/or fetal adiponectin can prevent metabolic and reproductive dysfunction in prenatal androgenized (PNA) female offspring. Adiponectin transgenic (APNtg) and wild-type dams received dihydrotestosterone/vehicle injections between gestational days 16.5-18.5 to induce PNA offspring, which were followed for 4 months. Offspring from APNtg dams were smaller than offspring from wild-type dams, independent of genotype. Insulin sensitivity was higher in wild-type mice from APNtg dams compared to wild-types from wild-type dams, and insulin sensitivity correlated with fat mass and adipocyte size. PNA increased visceral fat% and adipocyte size in wild-type offspring from wild-type dams, while wild-type and APNtg offspring from APNtg dams were protected against this effect. APNtg mice had smaller adipocytes than wild-types and this morphology was associated with an increased expression of genes regulating adipogenesis (Ppard, Pparg, Cebpa, and Cebpb) and metabolism (Chrebp and Lpl). Anogenital distance was increased in all PNA-exposed wild-type offspring, but there was no increase in PNA APNtg offspring, suggesting that adiponectin overexpression protects against this effect. In conclusion, elevated adiponectin levels in utero improve insulin sensitivity, reduce body weight and fat mass gain in the adult offspring and protect against PNA-induced visceral adiposity. In conclusion, these data suggest that PNA offspring benefit from prenatal adiponectin supplementation.

Ovarian steroid cell tumors, not otherwise specified: analysis of nine cases with a literature review.

BACKGROUND: Ovarian steroid cell tumors (SCTs), not otherwise specified (NOS), are rare, with few large studies. The purpose of this study was to analyze the clinical features, prognosis, and treatment choices for these patients of different age groups. METHODS: This was a retrospective study. We identified nine cases of ovarian steroid cell tumor, not otherwise specified, confirmed by post-operative histopathological examination, and analyzed clinical features, surgical procedures, and follow up outcomes. We also reviewed cases reports of ovarian steroid cell tumors, not otherwise specified. RESULTS: A total of nine cases were included. The age range was 9-68 years (mean, 41.89 ± 19.72 years). Clinical features included virilization, amenorrhea, abdominal pain, vaginal bleeding, isosexual precocious puberty, Cushing's syndrome, and abnormal weight gain with elevated testosterone levels. The follow up interval ranged 5-53 months and no recurrence was observed. CONCLUSION: Ovarian steroid cell tumors covered all age groups, with manifestations of androgen excess. Younger patients appeared to have a more favorable prognosis, which provided more opportunities for these patients to pursue treatment options that will preserve reproductive function.

Postmenopausal hyperandrogenism.

Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from the adrenal glands and/or ovaries clinically manifested by the presence of terminal hair in androgen-dependent areas of the body, and other manifestations of hyperandrogenism such as acne and alopecia or the development of virilization. In such circumstances, physicians must exclude the possibility of rare but serious androgen-producing tumors of the adrenal glands or ovaries. Worsening of undiagnosed hyperandrogenic disorders such as polycystic ovary syndrome, congenital adrenal hyperplasia, ovarian hyperthecosis, Cushing syndrome and iatrogenic hyperandrogenism should be considered for differential diagnosis. Elevated serum testosterone not only causes virilizing effects, but also will lead to hypercholesterolemia, insulin resistance, hypertension and cardiac disease. An ovarian androgen-secreting tumor, which is diagnosed in 1-3 of 1000 patients presenting with hirsutism, comprises less than 0.5% of all ovarian tumors. Adrenal tumors, including non-malignant adenomas and malignant carcinomas, are less common than ovarian tumors but cause postmenopausal virilization. Measurement of serum testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate, androstenedione and inhibin B is necessary in postmenopausal women with the complaints and signs of hyperandrogenism. Some tests to discard Cushing syndrome should also be done. After an etiological source of androgen hypersecretion has been suspected, we recommend performing magnetic resonance imaging of the adrenal glands or ovaries. Medical management with gonadotropin-releasing hormone agonist/analogues or antagonists has been reported for women who are either unfit for surgery or in whom the source of elevated testosterone is unidentified.

Genotypic spectrum of 21-hydroxylase deficiency in an endogamous population.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to autosomal recessive 21-hydroxylase deficiency (21-OHD) is caused by defects in the CYP21 (CYP21A2) gene. Several mutations have been identified in the CYP21 (CYP21A2) gene of patients with 21-OHD. We aimed at determining the frequency of these mutations among a group of Egyptian patients and studying the genotype-phenotype correlation. METHODS: Forty-seven patients with CAH due to 21-OHD from 42 different families diagnosed by clinical and hormonal evaluation and classified accordingly into salt wasting (SW) and simple virilizing (SV) phenotypes were enrolled. Their ages ranged between 1.78 and 18.99 years. Molecular analysis of the CYP21 (CYP21A2) gene was performed for the detection of eleven common mutations: P30L, I2 splice (I2 G), Del 8 bp E3 (G110del8nt), I172N, cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306 + T), Q318X, R356W, P453S, R483P by polymerase chain reaction (PCR) and reverse hybridization. RESULTS: Disease-causing mutations were identified in 47 patients, 55.31% of them were compound heterozygous. The most frequent mutations were I2 splice (25.43%), followed by cluster E6 (16.66%) and P30L (15.78%). Two point mutations (P453S, R483P) were not identified in any patient. In the SW patients, genotypes were more compatible with their phenotypes. CONCLUSION: Molecular characterization should be considered along with clinical and biochemical diagnosis of CAH since it could confirm the diagnosis, outline the treatment strategy and morbidity, and ensure proper genetic counseling.

Alternative pathway androgen biosynthesis and human fetal female virilization.

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Parental income inequality and children's digit ratio (2D:4D): a 'Trivers-Willard' effect on prenatal androgenization?

Income inequality is associated positively with disease prevalence and mortality. Digit ratio (2D:4D) - a negative proxy for prenatal testosterone and a positive correlate of prenatal oestrogen - is related to several diseases. This study examined the association of income inequality (operationalized as relative parental income) and children's 2D:4D. Participants self-measured finger lengths (2D=index finger, and 4D=ring finger) in a large online survey conducted in July 2005 (the BBC Internet Study) and reported their parents' income. Children of parents of above-average income had low 2D:4D (high prenatal testosterone, low prenatal oestrogen) while the children of parents of below-average income had high 2D:4D (low prenatal testosterone, high prenatal oestrogen). The effects were significant in the total sample, present among Whites (the largest group in the sample), in the two largest national samples (UK and USA) and were greater for males than females. The findings suggest a Trivers-Willard effect, such that high-income women may prenatally masculinize their sons at the expense of the fitness of their daughters. Women with low income may prenatally feminize their daughters at the fitness expense of their sons. The effect could, in part, explain associations between low income, high 2D:4D (low prenatal testosterone) and some major causes of mortality such as cardiovascular disease.

New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice.

Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the canonical androgen production pathway and is essential for normal masculinisation and testis function. Disruption to androgen production can result in disorders of sexual development (DSD). In the canonical pathway, 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) is viewed as a critical enzyme in the production of testosterone, performing the final conversion required. HSD17B3 deficiency in humans is associated with DSD due to low testosterone concentration during development. Individuals with HSD17B3 mutations have poorly masculinised external genitalia that can appear as ambiguous or female, whilst having internal Wolffian structures and testes. Recent studies in mice deficient in HSD17B3 have made the surprising finding that testosterone production is maintained, male mice are masculinised and remain fertile, suggesting differences between mice and human testosterone production exist. We discuss the phenotypic differences observed and the possible other pathways and enzymes that could be contributing to testosterone production and male development. The identification of alternative testosterone synthesising enzymes could inform the development of novel therapies to endogenously regulate testosterone production in individuals with testosterone deficiency.

Virilizing doses of testosterone decrease circulating insulin levels and differentially regulate insulin signaling in liver and adipose tissue of females.

Transgender men undergoing hormone therapy are at risk for insulin resistance. However, how virilizing testosterone therapy affects serum insulin and peripheral insulin sensitivity in transgender men is unknown. This study assessed the effect of acute, virilizing testosterone on serum insulin concentrations and insulin signaling in liver, skeletal muscle, and white adipose tissue (WAT) of female pigs as a translational model for transgender men. Females received three doses of intramuscular testosterone cypionate (TEST females; 50 mg/day/pig) or corn oil (control) spaced 6 days apart starting on the day of estrus (D0). Fasting blood was collected on D0, D3, D5, D11, and D13, and females were euthanized on D13. On D13, TEST females had virilizing concentrations of serum testosterone with normal concentrations of serum estradiol. Virilizing serum testosterone concentrations (D13) were associated with decreased serum insulin and C-peptide concentrations. Blood glucose and serum glycerol concentrations were not altered by testosterone. Virilizing concentrations of testosterone downregulated AR and ESR1 in subcutaneous (sc) WAT and upregulated transcript levels of insulin-signaling pathway components in WAT and liver. At the protein level, virilizing testosterone concentrations were associated with increased PI3K 110α in liver and increased insulin receptor (INSR) and phospho(Ser256)-FOXO1 in visceral (v) WAT but decreased phospho(Ser473)-AKT in vWAT and scWAT. These results suggest that acute exposure to virilizing concentrations of testosterone suppresses circulating insulin levels and results in increased abundance of proteins in the insulin-signaling pathway in liver and altered phosphorylation of key proteins in control of insulin sensitivity in WAT.NEW & NOTEWORTHY Acute virilizing doses of testosterone administered to females suppress circulating insulin levels, upregulate components of the insulin-signaling pathway in liver, and suppress insulin signaling in white adipose tissue. These results suggest that insulin resistance in transgender men may be due to suppression of the insulin-signaling pathway and decreased insulin sensitivity in white adipose tissue.

Incidental Finding of Bilateral Ovarian Adrenal Rest Tumor in a Patient With Congenital Adrenal Hyperplasia: A Case Report and Brief Review.

Ovarian adrenal rest tumors (OART) are tumors that develop in females with congenital adrenal hyperplasia (CAH). In contrast to their counterpart in testicles, they are exceptional and few cases have been reported in the literature. In this report, we present clinicopathological findings of a female patient with CAH due to 21-hydroxylase deficiency who was incidentally diagnosed with OART with a review of the literature. The 14-year-old patient, who was raised as a boy, developed a virilizing syndrome with high testosterone levels that were attributed to non adherence to her replacement corticosteroid therapy. She consulted for sex reassignment surgery. Pelvic ultrasound was normal. She underwent hysterectomy and bilateral adnexectomy. No abnormalities were noticed during the operation. Grossly, both ovaries were variegated with well circumscribed and lobulated, brownish-yellow nodules. Histologically, the nodules were composed of nests of large polygonal cells with centrally located nuclei and prominent nucleoli. There was mild atypia and no crystals of Reinke. Thus, the findings of the histopathological examination were consistent with bilateral OART. Histological differential diagnosis of OART can be challenging particularly with leydig cell tumor, stromal luteoma and steroid cell tumors, not otherwise specified. OART must be considered in women with CAH and persistent virilizing symptoms despite negative imaging results.

Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia.

BACKGROUND/PURPOSE: Although it is known that there is generally a good correlation between genotypes and phenotypes, the number of studies reporting discrepancies has recently increased, exclusively between milder genotypes and their phenotypes due to the complex nature of the CYP21A2 gene and methodological pitfalls. This study aimed to assess CYP21A2 genotyping in children with 21-hydroxylase deficiency (21-OHD) and establish their predictive genotype-phenotype correlation features using a large cohort in Southeastern Anatolia's ethnically diverse population. METHODS: The patients were classified into three groups: salt-wasting (SW), simple virilizing (SV) and non-classical (NC). The genotypes were categorized into six groups due to residual enzyme activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. RESULTS: A total of 118 unrelated children with 21-OHD were included in this study (61% SW, 24.5% SV and 14.5% NC). The pathogenic variants were found in 79.5% of 171 mutated alleles (60.2%, 22.2%, and 17.6% in SW, SV and NC, respectively). Patient distribution based on genotype groups was as follows: null-16.1%, A-41.4%, B-6.0%, C-14.4%, E-22%). In2G was the most common pathogenic variant (33.9% of all alleles) and the most common variant in the three phenotype groups (SW-38.8%, SV-22.2% and NC-23.3%). The total genotype-phenotype correlation was 81.5%. The correlations of the null and A groups were 100% and 76.1%, respectively, while it was lower in group B and poor in group C (71.4% and 23.5%, respectively). CONCLUSION: This study revealed that the concordance rates of the severe genotypes with their phenotypes were good, while those of the milder genotypes were poor. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.