Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review.

A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.

Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile.

Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.

Virilization of a young girl caused by concomitant ectopic and intra-adrenal adenomas of the adrenal cortex.

BACKGROUND: Adenomas of the adrenal gland are rare causes of virilization in childhood. CASE REPORT: A girl aged 2 years and 4 months presented with pubarche, distinct clitoral hypertrophy, tall stature, and increased height velocity. Plasma testosterone and dehydroepiandrosterone were elevated. Androgens remained unchanged after adrenocorticotropic hormone, and dexamethasone administrations. Ultrasound examination and magnetic resonance imaging indicated an extra-adrenal mass adjacent to the left adrenal gland, which was removed by endoscopic surgery. However, plasma androgens remained elevated and (131)I-iodomethyl-norcholesterol scintigraphy revealed tracer enhancement in the right adrenal gland, which was consecutively removed. Virilization regressed after extirpation of the adenomas and height velocity normalized. RESULTS: Histology revealed a circumscribed adenoma in the right adrenal gland and an epithelial mass with adrenal cortical cells in the left-sided ectopic tumor. In the ectopic tumor, melanocortin 2 receptor expression was augmented threefold compared to the control, indicating adrenal origin. CONCLUSIONS: In this young girl, virilization is due to concomitant ectopic and intra-adrenal adenomas of the adrenal cortex. By melanocortin 2 receptor expression, it was confirmed that the ectopic adenoma derived from the adrenal cortex. Specific scintigraphy, if available, assists in allocating the source of androgen hypersecretion.

Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS).

CONTEXT: Sexual dimorphism suggests a role for androgens in body fat distribution. Women with polycystic ovary syndrome (PCOS), a mainly androgen excess disorder, often present with abdominal obesity and visceral adiposity. OBJECTIVE: We hypothesized that women with PCOS have a masculinized body fat distribution favoring the deposition of fat in visceral and organ-specific adipose tissue depots. DESIGN: This was a case-control study. SETTING: The study was conducted at an academic hospital. PARTICIPANTS: Women with PCOS (n = 55), women without androgen excess (n = 25), and men (n = 26) presenting with similar body mass index participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Ultrasound measurements of adipose tissue depots including sc (minimum and maximum), preperitoneal, ip, mesenteric, epicardial, and perirenal fat thickness were obtained and total body fat mass was estimated using a body fat monitor. RESULTS: Men and patients with PCOS had increased amounts of total body fat compared with control women. Men had increased thickness of intraabdominal adipose tissue depots compared with the control women, with the women with PCOS showing intermediate values that were also higher than those of control women in the case of ip and mesenteric fat thickness and was close to reaching statistical significance in the case of epicardial fat thickness. Women with PCOS also showed increased minimum sc fat thickness compared with the control women. Obesity increased the thickness of all of the adipose tissue depots in the 3 groups of subjects. CONCLUSIONS: Women with PCOS have higher global adiposity and increased amounts of visceral adipose tissue compared with control women, especially in the ip and mesenteric depots.

Prostate gland development and adrenal tumor in a female with congenital adrenal hyperplasia: a case report and review from radiology perspective.

We describe a case of a female with simple virilizing congenital adrenal hyperplasia (CAH) reared as a male diagnosed at the late age of 64. Computed Tomography (CT) demonstrated a large adrenal mass, bilateral diffuse adrenal enlargement, female pelvic organs as well as a clearly visualized prostate gland. This is to the best of our knowledge the first case of such a sizable prostate gland in a female CAH patient documented on CT. We review the literature regarding aspects where radiologists may encounter CAH and the finding of presence of a prostate gland in female CAH patients.

Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study.

Diffusion tensor imaging (DTI) can sensitively detect white matter sex differences and the effects of pharmacological treatments. Before cross-sex hormone treatment, the white matter microstructure of several brain bundles in female-to-male transsexuals (FtMs) differs from those in females but not from that in males. The purpose of this study was to investigate whether cross-sex hormone treatment (androgenization) affects the brain white matter microstructure. Using a Siemens 3 T Trio Tim Magneton, DTI was performed twice, before and during cross-sex hormonal treatment with testosterone in 15 FtMs scanned. Fractional anisotropy (FA) was analyzed on white matter of the whole brain, and the latter was spatially analyzed using Tract-Based Spatial Statistics. Before each scan the subjects were assessed for serum testosterone, sex hormone binding globulin level (SHBG), and their free testosterone index. After at least seven months of cross-gender hormonal treatment, FA values increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) in FtMs compared to their pre-treatment values. Hierarchical regression analyses showed that the increments in the FA values in the SLF and CST are predicted by the free testosterone index before hormonal treatment. All these observations suggest that testosterone treatment changes white matter microstructure in FtMs.

Hyperandrogenic states in pregnancy.

Hyperandrogenic states in pregnancy are almost always the result of a condition that arises during pregnancy. The onset of virilization symptoms is often very fast. The mother is protected against hyperandrogenism by a high level of SHBG, by placental aromatase and a high level of progesterone. The fetus is protected from the mother's hyperandrogenism partly by the placental aromatase, that transforms the androgens into estrogens, and partly by SHGB. Nevertheless there is a significant risk of virilization of the female fetus if the mother's hyperandrogenic state is serious. The most frequent cause of hyperandrogenic states during pregnancy are pregnancy luteoma and hyperreactio luteinalis. Hormonal production is evident in a third of all luteomas, which corresponds to virilization in 25-35 % of mothers with luteoma. The female fetus is afflicted with virilization with two thirds of virilized mothers. Hyperreactio luteinalis is created in connection with a high level of hCG, e.g. during multi-fetus pregnancies. This condition most frequently arises in the third trimester, virilization of the mother occurs in a third of cases. Virilization of the fetus has not yet been described. The most serious cause of hyperandrogenism is represented by ovarian tumors, which are fortunately rare.

Adrenal gland scintigraphy.

There is no question that high-resolution imaging techniques have revolutionized the approach to diagnostic imaging. Computed tomography (CT) and magnetic resonance imaging provide exquisite images of the adrenal glands and offer the best initial imaging approach in the evaluation of patients with suspected adrenal disease. However, an assessment of anatomy is only a portion of the diagnostic effort, which begins with a biochemical evaluation to establish the presence of adrenal gland dysfunction. With a confirmed biochemical diagnosis in hand, a logical and stepwise diagnostic approach can be tailored to a particular patient. Where scintigraphy fits in the evaluation of diseases of the adrenal cortex and medulla in the context of high-resolution imaging and which radiopharmaceuticals should be deployed has changed substantially during the last 2 decades. Adrenal functional imaging has evolved from classic planar scintigraphy to single-photon emission computed tomography (SPECT) and positron emission tomography (PET) using tracers that, by targeting specific metabolic or synthetic processes within the gland, have depicted adrenal pathophysiology. New PET/CT and SPECT/CT technologies integrate anatomic and functional information and redefine the radiotracer principle in the larger context of high resolution anatomic imaging.

Magnetic resonance imaging of adrenocortical adenomas in childhood: correlation with computed tomography and ultrasound.

There are few descriptions of the magnetic resonance (MR) appearance of hyperfunctioning adrenocortical tumours, particularly those occurring in childhood. We studied five patients, two girls and three boys, aged 6-14.3 years, presenting with clinical syndromes of adrenocortical hyperfunction. The diagnoses were Cushing's syndrome (n = 2), virilisation (n = 2), and Conn's syndrome (n = 1). Biochemical features suggested an adrenal lesion in each case. MR and ultrasound were performed in all five cases, with CT in four. Each patient had a functional adrenal tumour secreting either cortisol, androgens or aldosterone alone, or a combination of cortisol, androgens and oestradiol. The histological diagnosis was adenoma in four cases and tumour of indeterminate nature in one case. MR clearly showed the tumours (diameter 1.0-7.5 cm), all the lesions being of high signal intensity relative to liver on T2-weighted sequences. CT revealed an adrenal mass in each of the four patients scanned, three of which enhanced after intravenous contrast medium injection. The multiplanar imaging of MR allowed better distinction from adjacent structures and also demonstrated an unenlarged contralateral adrenal gland. In the patient with a 1-cm Conn's adenoma the lesion was more easily seen on MR than CT. Ultrasound showed the four larger tumours but was unable to visualise the contralateral adrenal or the Conn's adenoma. In conclusion, the MR appearances of four adrenocortical adenomas and one indeterminate tumour in children are described. MR has been found to be at least equal to CT in the detection of these tumours, with some possible advantages. Both techniques are superior to ultrasound.

Diagnostic accuracy and pitfalls of [iodine-131]6-beta-iodomethyl-19-norcholesterol (NP-59) imaging.

NP-59 concentrates in steroid hormone synthesizing tissues, enabling scintigraphic localization and characterization of endocrine dysfunction in the adrenal cortex and ovary. Studying 108 consecutive cases from 1982 to 1985 and using clinical, biochemical, radiographic, and pathologic data, we performed a rigorous assessment of the accuracy and pitfalls of NP-59 scintigraphy. The evaluation was divided into categories of abnormal hormone secretion: Cushing's syndrome, primary aldosteronism, and hyperandrogenism. Additional categories included euadrenal tumors (without detectable hormone dysfunction) and sites of residual adrenal cortical tissue. The accuracy of NP-59 scintigraphy ranged from 71% in primary aldosteronism and 75% in euadrenal tumors, to 100% for Cushing's syndrome and hyperandrogenism. However, more than in most nuclear medicine studies, NP-59 imaging requires well-defined indications to be met for it to be efficacious, including the fulfillment of clear clinical, biochemical, and radiographic criteria. The high reproducibility of NP-59 scintigraphic interpretation was demonstrated when 40 random cases underwent interinstitutional exchange and through interobserver evaluation at the University of Michigan. Responses of 85/126 medical centers to questionnaires revealed the high level of NP-59 safety.

131I-iodocholesterol (NP-59) scintigraphy in adrenocortical diseases.

The diagnostic usefulness of adrenal imaging with 131I-iodocholesterol (NP-59) is now well established. In order to correlate histopathology with the adrenal scan the authors examine and report their experience in 37 patients with surgically proven adrenal lesions or pituitary adenomas. This series included 24 patients with Cushing's syndrome: 14 caused by benign adrenal adenoma and 10 due to bilateral pituitary-ACTH-dependent adrenocortical hyperplasia. Ten patients with primary aldosteronism were submitted to surgery which confirmed the presence of aldosterone-producing adrenal adenomas. Two women with hyperandrogenism (due to virilizing ovarian tumors) had normal adrenals but the ovarian stromal luteoma markedly concentrated the iodocholesterol while the arrhenoblastoma did not. A patient with adrenal hematoma is also included in this report. The overall histopathological correlation with the radiocholesterol scintiscan yields an accuracy in our series of 97% (36/37). The false-negative adrenal scan (also missed by other non-invasive techniques) occurred in a patient with an aldosterone-producing adrenal adenoma measuring 1.0 X 1.5 cm.

Pneumopelvigraphy in childhood.

Pelvic pneumography was performed in 150 children, including those with precocious puberty, suspected pelvic masses, abdominal pain, virilization, ambiguous genitalia, gonadal dysgenesis, Stein-Leventhal syndrome, amenorrhea, and contralateral inguinal hernia detection. Pneumography proved safe, accurate, and easy to perform. However, advances in sonography have limited the use of pneumography primarily to the investigation of infant intersex problems and confirmation of idiopathic precocious puberty in the infant or very young girl.

Virilizing adrenocortical adenoma studied by selective adrenal venography.

A 15-year-old girl with primary amenorrhea, hirsutism, and enlargement of the clitoris was found to have an increased titer of the urinary neutral 17-ketosteroids which failed to decrease after the administration of dexamethasone and an adrenal tumor was demonstrable on venography. Analysis of the adrenal venous effluent revealed gradients on the side of the tumor for testosterone, androstenedione, estradiol, and dehydroepiandrosterone sulfate. Following removal of the tumor, the hirsutism improved markedly, the menses returned, and sexual maturation progressed.