Elisabeth Thibaud

Long-Term Outcome of Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Aims: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. Methods: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. Results: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 ± 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). Conclusions: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration

BackgroundPrimary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.MethodsWe directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations.ResultsAmong the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration.ConclusionsThe genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.

Long-Term Followup and Comparison Between Genotype and Phenotype in 29 Cases of Complete Androgen Insensitivity Syndrome

PURPOSE Diagnosis and management of the complete androgen insensitivity syndrome have dramatically changed in the last few decades, with earlier diagnosis and the development of molecular biology. Some phenotypic features such as development of wolffian and mullerian remnants have been suggested to be an index of subtle residual androgen activity. Variations of these features clearly exist among patients and may influence treatment. Our aim was to assess the safety of keeping gonads in place for spontaneous puberty in a cohort of patients with genetically proved complete androgen insensitivity syndrome. In parallel to the risks of virilization at puberty and gonadal tumor some additional features, such as need for vaginal surgery, were investigated. MATERIALS AND METHODS We studied the genotype, phenotype, anatomy of the internal and external genitalia, and clinical outcome of 29 cases of complete androgen insensitivity syndrome, managed by the same team from diagnosis (frequently in early childhood) to adulthood. RESULTS All patients had a complete female phenotype. A total of 19 different mutations (including 7 unreported) were found. Each family presented with a different mutation. No somatic mosaicism was detected. Vas deferens and epididymis were found in all types of mutations (missense, nonsense and frameshift). Of the patients 23 were postpubertal (19 spontaneously). No postpubertal virilization occurred. Only 1 carcinoma in situ was detected (postpubertally). Vaginal surgery was rarely necessary. CONCLUSIONS Our data advocate for keeping the gonads in the complete androgen insensitivity syndrome, at least until completion of spontaneous puberty. The risk of virilization at puberty should be ruled out for each androgen receptor mutation before management decisions and genetic counseling. Vaginal surgery should not be indicated as first line treatment.

Long-Term Surgical Results and Patient Satisfaction With Male Pseudohermaphroditism or True Hermaphroditism: A Cohort of 63 Patients

PURPOSE To improve treatment policy, we retrospectively evaluated the results of early corrective genital surgery in 63 sexually ambiguous patients 14 to 38 years old. MATERIALS AND METHODS We analyzed all records classified under male pseudohermaphroditism and true hermaphroditism. Anatomical and functional results and data on self-reported satisfaction were recorded by the managing physician at the last routine followup visit. RESULTS A total of 38 patients were raised female and 25 were raised male. Basal procedures for external genital reconstruction were initiated shortly after birth, when gender was assigned. Complementary surgical procedures were usually required later. In both sexes there was a significant negative correlation between the number of basal, but not complementary, procedures required and year of birth, due to the adoption of 1-stage procedures in the early 1980s. Most patients with gonadal dysgenesis were raised as females and menstruated under treatment but breast development was abnormal in 30%. Spontaneous puberty was observed in true hermaphrodites raised as either sex. In females with partial androgen insensitivity the main problem was shortness of the vagina. Amenorrhea and infertility often led to transient distress. In males results were poor due to intractable micropenis and minimal virilization. Results were good in 5alpha-reductase deficiency. CONCLUSIONS Results of intersex surgery have clearly improved with time, and apart from a patient with 5alpha-reductase deficiency who underwent a successful sex change, no patient expressed dissatisfaction with sex of rearing. However, in the absence of an in-depth psychological survey, these optimistic conclusions are valid only in the settings of our study.

Pitfalls in the diagnosis and management of obstructive uterovaginal duplication: a series of 32 cases.

OBJECTIVES. Obstructive uterovaginal duplication is rare and frequently misdiagnosed. The aims of this study were to review all the patients managed for this malformation in our institution, evaluate their long-term outcomes, and discuss the embryologic origin of this malformation. METHODS. From 1984 to 2007, we treated 32 patients for obstructive uterovaginal duplication in our institution. We separated them in 2 groups (prepubertal [n = 8] and pubertal [n = 24]) and analyzed their clinical and radiologic presentations and their treatments. Patients >18 years of age (n = 22) were recontacted. RESULTS. For the prepubertal group, the median age at diagnosis was 6 months. Postnatal ultrasound showed an absent ipsilateral kidney in 6 case subjects, although 4 patients had a prenatal diagnosis of ipsilateral multicystic dysplastic kidney. This renal anomaly was associated with a pelvic sonolucent mass in 3 case subjects, allowing us to prenatally suspect the diagnosis. All of the patients were cured by vaginal approach. For the pubertal group, the median delay of diagnosis after menarche was 9 months. Among patients managed in an emergency setting (n = 11), there were 9 misdiagnoses with inappropriate abdominal surgeries, including 3 hysterectomies of the obstructed hemiuterus. Concerning long-term results, 5 patients were attempting to have children, with successful pregnancies for 4 of them. One patient suffered from infertility attributable to contralateral isthmic stenosis after a hysterectomy of the obstructed hemiuterus. CONCLUSIONS. Obstructive uterovaginal duplication is a benign pathology when properly managed. Therefore, management of abdominal pain in peripubertal girls should include systematic abdominal and gynecologic examinations completed by radiologic pelvic and renal evaluation. Surgical treatment should be performed by vaginal approach to avoid infertility. Concerning the origin of the malformation, the high association of prenatal dysplastic kidneys and postnatal absent kidneys suggests anomalies of both wolffian and müllerian duct development, contrasting with the classic definition of this malformation.

High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles

OBJECTIVES To compare the pubertal development, the hormonal profiles and the prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus (T1DM). METHODS Data were collected from 96 obese adolescent girls and 78 adolescent girls with T1DM at Tanner stage IV or V, whose ages ranged between 11.9 and 17.9 years. RESULTS High prevalence of hirsutism and menstrual disorder was found in the obese adolescent girls (36.5 and 42% respectively) and the adolescent girls with T1DM (21 and 44% respectively). The obese girls were significantly younger at pubarche, thelarche and menarche than the girls with T1DM. Hirsutism in the obese girls and those with T1DM was associated with hyperandrogenaemia and a raised free androgen index (FAI). When the cause of the raised FAI was investigated in both the groups of girls with hirsutism, the raised FAI in the obese girls was due to low serum sex hormone-binding globulin (SHBG) levels. In contrast, the raised FAI of the girls with T1DM and hirsutism was due to hyperandrogenaemia. Menstrual disorders in the T1DM girls were associated also with hyperandrogenaemia unlike obese girls. CONCLUSIONS Hirsutism and menstrual disorders are common in obese adolescent girls and adolescent girls with T1DM. Although hyperandrogenaemia is present in both groups of girls, the androgenic profiles of the two groups differ. The hyperandrogenaemia in the obese girls is primarily due to their decreased serum SHBG levels, whereas the hyperandrogenaemia in the girls with T1DM is due to their increased androgen production.

Idiopathic Premature Ovarian Failure in 63 Young Women

Background: Premature ovarian failure (POF) in adolescents is defined as primary or secondary amenorrhea associated with high follicle-stimulating hormone (FSH) levels. In normal 46,XX patients, its etiology is most often unknown. We have evaluated the clinical, hormonal and ovarian phenotypes in patients with a normal karyotype who were diagnosed with POF before the age of 18. Methods: Sixty-three patients were included in this retrospective study. Results: The mean patient age was 20.4 years. The patients presented with three clinical patterns: lack of pubertal development (n = 23), primary amenorrhea with interrupted puberty (n = 18), and secondary amenorrhea with normal puberty (n = 22). Ten patients had a familial history of POF and 6 presented with hypothyroidism. The FSH, estradiol and inhibin B levels were not statistically different in the three clinical groups. Fifty percent of the patients presented small ovaries (length <2 cm) at ultrasonography. The presence of follicles was found at histology in only 7 of the 27 patients who underwent an ovarian biopsy. Conclusion: 46,XX patients presenting with early POF rarely presented a specific, identifiable disorder. We discuss the clinical management and different diagnosis strategies to improve our current knowledge of this syndrome.

Breast Diseases in Adolescents

Fibroadenomas and breast growth disorders are the most common breast diseases in adolescent women. Assessment of breast disorders in this age group generally involves clinical evaluation through history and physical examination and when is needed ultrasonography. Due to the absence of breast cancer in adolescent women, it is easy to reassure women at the first consultation. Breast growth disorders can lead great psychological and physical embarrassment. Treatment consists of surgical procedures when the cosmetic defect is severe. According to the ANDI classification, small fibroadenomas are normal, clinical fibroadenomas are a mild aberration of the normal processes, and giant or multiple fibroadenomas are placed to the disease end of the spectrum. Fibroadenomas can be treated conservatively provided diagnosis is confident. Giant fibroadenomas are treated by surgical enucleation. Breast abscess is mainly due to the duct ectasia. In adolescence, ectasia has been described as an exaggeration of sinus duct development and can be considered as a variant of normality. Diseases of the adolescent breast are usually benign and their management are simple using medical strategy and more rarely surgical therapy.

Effects of growth reduction therapy using high‐dose 17β‐estradiol in 26 constitutionally tall girls

Objective  The efficacy and safety of height‐limiting therapy with high‐dose 17β‐oestradiol in girls with constitutionally tall stature (CTS) are controversial. We evaluated the effectiveness of high‐dose 17β‐oestradiol in premenarchal girls with CTS treated until their bone age reached 14 years.

Phenotypic Variation of SF1 Gene Mutations

Knockout of the steroidogenic factor 1 (Sf1) gene in 46,XY mice causes complete adrenal failure associated with gonadal dysgenesis, undervirilization, and persistence of mullerian ducts [1]. SF1 (NR5A1, SF1/Ad4BP/FTZF1) is a member of the nuclear receptor superfamily, and it plays a crucial role in the fetal development of the adrenal gland [2] and testes [3]. Sf1 is considered to be the master regulator of the reproductive system because it regulates the expression of a wide array of genes required for testis and adrenal development and hormone synthesis [4].