Symptoms Of Virilization Research Articles

Clinical Course of Patients with Nonclassical 21-hydroxylase Deficiency (21-OHD) Diagnosed in Infancy and Childhood

We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilization and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.

Virilization caused by an ectopic adrenal tumor located behind the iliopsoas muscle

Virilization due to androgen-secreting neoplasms in women is a result of androgen overproduction from benign or malignant tumors that are found in the ovaries or rarely in the adrenal glands. Virilizing tumors that arise from ectopic adrenal tissue are extremely rare. We describe a very rare case of an ectopic androgen-producing adrenal tumor. Case report study. Endocrinology outpatient department of university-affiliated teaching hospital. A 45-year-old woman with symptoms of virilization of abrupt onset and rapid progression, with high serum androgen hormone levels and normal glucocorticoid secretion. Basal hormonal levels, stimulation and suppression tests, imaging techniques, and selective venous sampling. Localization and surgical removal of the source of androgen production. An ectopic mass was detected behind the left iliopsoas muscle. The patient was operated on and an oblong-shaped lesion, weighing 6 g, was removed. Histologically, the tissue was identified to be of adrenal origin. Postoperatively the androgen levels decreased to normal levels. This case illustrates difficulties in detecting and localizing the rare contingence of an ectopic adrenocortical androgen-secreting tumor.

Hirsutismo: diagnóstico diferencial

Hirsutism is one of the manifestations of the hyperandrogenic syndromes. A practical approach consists of dividing the hyperandrogenic syndromes into virilizing and non-virilizing, in accordance to the presence or absence of virilization symptoms. A case of a patient with hirsutism and a high basal and post-ACTH stimulation concentration of 17-OHP is presented. The absence of virilization and of clinical history discarded as etiology the virilizing neoplasias and hyperthecose of the ovary. Among the causes of non-virilizing syndromes, the presence of the menstrual disturbance and hyperandrogenemia discarded idiopathic hirsutism. In accordance to the Consensus of Rotterdam, the diagnosis of polycystic ovary syndrome was considered. For to exclude the non classic form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the patient was submitted to a short ACTH-(1-24) stimulation test. The 17-OHP concentrations after stimuli were 14 ng/dL, being that, in the dependence of the limit of considered cut-off, it would be compatible with this illness. Although the promoter region had not been studied, we can consider that this diagnosis was excluded through the sequencing of CYP21A2 gene, since mutation on the promoter region is a rare event.

Tumor ovárico virilizante mixto de células de Sertoli-Leydig/granulosa (ginandroblastoma) en adolescente de 15 años

Sertoli-Leydig cell tumors constitute less than 5% of ovarian tumors. We report the case of a 15-year-old girl with virilization, amenorrhea, and abdominal pain, who was diagnosed with a left annexal tumor. Laboratory investigations revealed isolated testosterone elevation. Because the tumor was unilateral, the capsule was intact, and the patient wished to preserve her fertility, left salpingooophorectomy was performed. Histopathological examination revealed a mixed Sertoli-Leydig/juvenile granulosa cell tumor with a cartilaginous heterologous component, which could be considered a gynandroblastoma. Symptoms of virilization progressively improved.

Virilization due to ovarian androgen hypersecretion in a patient with ectopic adrenocorticotrophic hormone secretion caused by a carcinoid tumour: Case Report

A 52-year-old woman presented with symptoms of virilization, which had been ongoing for 5 months. At the age of 34 years, she had a large abdominal carcinoid tumour removed. Twelve years later, she presented with Cushing's syndrome due to ectopic adrenocorticotrophic hormone (ACTH) production by carcinoid metastases localized in the right parametrium, fornix posterior and right diaphragm. Debulking laparotomy was performed followed by remission of hypercortisolism. Relapse of hypercortisolism followed 3 years later, and a second debulking laparotomy was performed including resection of the right ovary. In the following year, relapses of hypercortisolism were observed until bilateral adrenalectomy was performed. Laboratory evaluation revealed elevated serum levels of testosterone (23.0 nmol/l), androstenedione and 17-hydroxyprogesterone, and a serum estradiol (E2) level in the premenopausal range. The computerized tomography (CT) of the abdomen showed a large pelvic mass on the left side of the uterus without a recognizable left ovary. Treatment with a GnRH agonist (goserelin, 3.6 mg s.c., monthly) was initiated, resulting in normalization of the androgen levels. One year later, obstruction of the right ureter occurred due to progression of the pelvic metastases, thus a third debulking laparotomy with resection of the pelvic metastases including the left ovary was performed. The microscopic examination of the removed pelvic mass showed malignant carcinoid tissue with focal remnants of atrophic ovarian tissue. Two years after surgery, serum androgen levels are undetectable. We hypothesize that the high levels of ACTH at the site of the left ovary have induced androgen hypersecretion by steroid-producing cells in the ovary of our patient.

Tumor de células de Leydig de ovario: una causa infrecuente de virilización en la mujer posmenopáusica

Leydig cell tumor of the ovary is a very rare neoplasm that usually occurs in postmenopausal women. We report the case of a 72-year-old woman with symptoms of virilization. Hormonal evaluation showed marked elevation of serum testosterone (12038 pg/ml) and no evidence of increased production of other sexual hormones. Ultrasound examination revealed a 10-mm tumor within the left ovary. Subsequently, total hysterectomy with bilateral oophorectomy was performed. Histopathological examination showed a Leydig cell tumor within the left ovary. Postoperative plasma testosterone levels returned to normal and the patient showed slow regression of clinical symptoms.

Evaluating the accuracy of Malformations Surveillance Program in detecting virilization due to congenital adrenal hyperplasia

Malformations surveillance programs of newborn infants have been developed as a method for identifying serious and relatively common birth defects. The virilization of newborn infants with the classic 21-hydroxylase form of congenital adrenal hyperplasia must be identified early if the associated metabolic crisis in the perinatal period is to be prevented. We compared the detection of virilization associated with 21-hydroxylase congenital adrenal hyperplasia in infants by three methods: an 'active' malformations surveillance of medical records at a large urban hospital; routine medical care by examining physicians; and newborn biochemical screening of blood samples. The experience at a large maternity center in Boston, since 1972, showed that pediatricians often recognized affected females (6/6), but not males (0/2); the state newborn screening program, begun in 1990, identified correctly all affected males and females. The Active Malformations Surveillance Program was the least effective screening method, identifying four of six affected females and neither of the affected males. The low rate of detecting affected females by the Surveillance Program was attributed to a failure to sensitize the research assistants to the importance of physicians' notations regarding the signs and symptoms of virilization. The failure of examining physicians, and thereby, the malformations surveillance program, to detect virilized newborn males was due to the lack of consistent associated physical features. These comparisons between these three methods of detection can be used to design and improve malformations surveillance programs.

Bilateral asynchronous adrenocortical adenoma in a girl with beckwith-wiedemann syndrome.

We report a case of asynchronous occurrence of bilateral adrenocortical adenoma in a 13-yr-old girl with Beckwith-Wiedemann syndrome. A right virilizing adrenal adenoma was surgically removed at age 6, following clinical manifestation of virilization such as acne, voice change, clitoris hypertrophy and overgrowth. Histopathological examination of the resected specimen revealed an adrenocortical adenoma predominantly composed of eosinophilic tumor cells expressing all the steroidogenic enzymes. High serum levels of DHEA-S (6,380 ng/ml) and testosterone (547 ng/dl) were noted prior to the operation. Postoperative course was unremarkable. Menstruation started at age 11, with a regular interval. At the age of 13 yr old, a high serum level of DHEA-S (8,250 ng/ml) was detected. In contrast to the episode of virilization at age 6, however, the serum testosterone level was not so high (122 ng/dl), and no clinical symptoms of virilization were apparent. Abdominal ultrasonography demonstrated the presence of a left adrenocortical adenoma. Pathological examination of the resected specimen revealed a circumscribed and well encapsulated tumor with essentially the same histological features as the tumor previously removed, except that the tumor cells showed a more prominent morphological similarity to the fetal adrenal cortex and did not express 3β HSD. The absence of virilization at the second episode was due to the relatively low serum level of testosterone compared with that of DHEA-S.

Naturally conceived twin pregnancy with hyperreactio luteinalis, causing hyperandrogenism and maternal virilization

Naturally conceived twin pregnancy with <i>hyperreactio luteinalis</i>, causing hyperandrogenism and maternal virilization

Features of Antley-Bixler syndrome in an infant born to a mother with pregnancy luteoma.

We report a female newborn with characteristic signs of Antley-Bixler syndrome (ABS) such as midface hypoplasia, radiohumeral synostosis and multiple joint contractures. The newborn also presented ambiguous genitalia, stage Prader V, and congenital adrenal hyperplasia. The mother experienced midterm virilization due to a pregnancy luteoma. Her elevated androgen levels and virilization symptoms normalized post partum without treatment. The newborn had elevated serum testosterone and 17-OH-progesterone levels which remained elevated because of a 21-hydroxylase deficiency. The child's treatment in order of priority was: hydrocortisone substitution, craniofacial/skeletal anomaly management and surgical correction of the external genitalia. Mutations in the genes for fibroblast growth factor (FGF) 8 and receptors FGFR1, FGFR2, and FGFR3 were not detected. A newborn girl with manifestations of the Antley-Bixler syndrome showed severe virilization probably caused by the association of a mild 21-hydroxylase deficiency and maternal hyperandrogenism due to a pregnancy luteoma. Abnormalities of androgen metabolism may be responsible for virilization reported in other cases of the Antley-Bixler syndrome.

Hormonal and genetic analysis of a patient with congenital adrenal hyperplasia

We describe a patient with signs and symptoms of virilization caused by 21-hydroxylase deficiency. The patient, a Hispanic woman, first sought medical attention at age 24, when she presented to a medical clinic with an uncomplicated urinary tract infection. At that time several signs of virilization were noted and she was referred to the endocrinology clinic. Evaluation revealed temporal balding, hyperpigmentation, acne, absent breast development, a muscular habitus, and clitoromegaly. Radiological studies revealed bilaterally enlarged adrenal glands and ovaries. Laboratory evaluation revealed markedly increased concentrations of 17-hydroxyprogesterone, androstenedione, and testosterone. The patient was diagnosed with congenital adrenal hyperplasia (CAH) and received hormone therapy. In her sister, encouraged to undergo testing for this autosomal recessive disorder, HLA testing demonstrated that certain haplotypes in this family were associated with CAH. The case highlights key steps in the laboratory diagnosis and genetics of CAH.

Androgen Suppressive Effect of GnRH Agonist in Ovarian Hyperthecosis and Virilizing Tumours

Summary OBJECTIVE Recent studies have suggested that androgen secretion by ovarian virllizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion. In women with such tumours. DESIGN AND PATIENTS A single 1.m. Injection Of D-Trp-6-GnRH (GnRHa), 3·75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroeplandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non-classical 21-hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice dally for 3 weeks, starting 1 week before GnRHa administration. MEASUREMENT Testosterone, androstenedione (A), DHEAS, 17-hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa. RESULTS In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoll-Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hllus cell tumour and two hyperthecoses in the four post-menopausal patients. After bilateral ovarlectomy and hysterectomy in the post-menopausal woman and after unilateral ovarlectomy in the premenopausal women, androgen levels were normalized. CONCLUSIONS In virllized women, the findings of Increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarlan androgen-secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.

Structure and expression of the CYP21 (P450c21, steroid 21-hydroxylase) gene with respect to its deficiency.

Steroid 21-hydroxylase (P450c21) deficiency is the major cause of a common genetic disease, congenital adrenal hyperplasia, with the symptoms of virilization due to steroid imbalance. We have devised a fast diagnostic method to detect common mutations in the c21B gene by a two-step gene amplification procedure coupled to restriction digestion. This procedure does not require isotopes and is suitable for routine use in a hospital setting. In addition, we have developed a procedure for the production of active P450c21 in E. coli. We tested many different vector and bacterial strain combinations to find out the best condition for P450c21 expression. The bacteria harboring the P450c21 expression plasmid were grown in a rich media supplemented with trace metals, heme biosynthesis precursor delta-levulinic acid, and induced with IPTG at 20 degrees C for 48 h. We found that low growth temperature and long induction time were important for abundant synthesis of P450c21 in E. coli.

Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing tumours.

Recent studies have suggested that androgen secretion by ovarian virilizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion in women with such tumours. A single i.m. injection of D-Trp-6-GnRH (GnRHa), 3.75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroepiandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non-classical 21-hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice daily for 3 weeks, starting 1 week before GnRHa administration. Testosterone, androstenedione (A), DHEAS, 17-hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa. In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoli-Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hilus cell tumour and two hyperthecoses in the four post-menopausal patients. After bilateral ovariectomy and hysterectomy in the post-menopausal woman and after unilateral ovariectomy in the premenopausal women, androgen levels were normalized. In virilized women, the findings of increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarian androgen-secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.

Bilateral Stromal Leydig Cell Tumour of the Ovary: Case Report and Literature Review

The stromal Leydig cell tumour of the ovary is a very rare benign neoplasm which usually occurs in postmenopausal women. Due to a significant production of androgens by the tumour, it is frequently associated with symptoms of virilization. To our knowledge only 7 cases have been reported in the literature, one of them with bilateral manifestation. We report an additional case affecting both ovaries in a 59-year-old nun with long-standing virilism, review the literature, and discuss the histomorphological features for differential diagnosis.

Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 cases.

Juvenile granulosa cell tumor (JGCT) in children accounted for 12% of all ovarian tumors treated in the Institut Gustave-Roussy (IGR) Pediatric Department from 1967 to 1985. The median age of the 15 girls was 8 years 7 months (range, 22 months to 15 years 7 months). Precocious pseudopuberty was present in six of the seven girls under 8 years. Of the other seven girls, one developed virilization symptoms. Surgery was the first treatment in each case. According to the Wollner classification, there were six stage I, one stage II, six stage III (including four ruptured tumors), and one stage IV JGCT cases. One patient was not available for staging. An adjuvant treatment (five chemotherapy and one radiotherapy combined with chemotherapy) was administered to six patients. Eleven girls are alive and free of disease, with a median follow-up of 6 years (range, 2 to 18 years). Four girls relapsed 6 to 17 months after surgery and died. Two of these relapses occurred in bone. The prognosis for JGCT in children is favorable for the lower stages when treated with surgery, but the best treatment for extensive and recurrent disease has yet to be determined.

Autonomous Cortisol Secretion by a Lipoid Cell Tumor of the Ovary

LIPOID cell tumors are rare ovarian neoplasms that often secrete androgens and manifest themselves with symptoms of virilization. For this reason, androgen secretion has been studied in several previous cases.1-6Cushingoid features have also been associated with a few of these patients,1,4,7,8but in only one was cortisol secretion by the tumor adequately documented.9This article describes a young woman with hirsutism and amenorrhea due to a lipoid cell tumor of the ovary and hypercortisolemia. Proof is provided that the ovarian lipoid cell tumor was the source of her hypercortisolism. Report of a Case A 20-year-old nulligravid woman was referred to the UCLA Gynecologic Endocrinology Clinic because of hirsutism and amenorrhea. Menarche occurred at the age of 12 years and was followed by irregular menses. At the age of 15 years, the patient was first seen for evaluation of hirsutism. At that time, her serum testosterone level

Conversion of virilization to feminization in a young girl with adrenal cortical carcinoma.

A 4-year-old girl presented with signs and symptoms of virilization and hypercortisolism. After removal of an adrenal cortical carcinoma and treatment with op'DDD, her clinical picture initially improved. Therapy with the drug was intermittent and varying in dosage since she had bouts of adrenocortical insufficiency requiring replacement therapy with adrenal cortical steroids, and she repeatedly showed signs of drug toxicity. Recurrences of the tumor and mctastases to the lungs and liver were accompanied by rises in 17-ketosteroid output and feminization. The patient, despite surgical removal of the tumor and hemihepatectomy, died 3 years after the onset of the disease. The unique transition of an androgen- and 17-hydroxycorticoid-producing adrenal cortical carcinoma into one that caused feminization may have been due to biochemical changes in the tumor itself, or to extra-adrenal metabolism of adrenal androgens to estrogens under the effect of op'DDD.