Gynecologic clinical examination of the child and adolescent.

Pediatric gynecological examination is very simple, but usually unrecognized by physicians without a specific experience in pediatric gynecology. It is always necessary and most of the time sufficient in children and adolescents consulting for gynecological complaints, endocrine problems, or sexual abuse. However, accurate evidence-based data on its normality is poor in the literature, because of bias represented by the inclusion of abused patients in these studies. Our aim was to describe the preparation to a full gynecological examination, the adequate positions, and the sequence and technique required for a well-accepted and nontraumatic clinical examination. Normal findings are described depending on the age of the patient (child, newborn, adolescent), and are based on evidence from the literature. Indications for vaginoscopy and bacterial sampling are discussed according to the age of the patient. The most important factors in the achievement of a full gynecological examination and a trusting patient-physician relationship are a good anatomical and physiological knowledge of the genital system in children, and the learning of nonaggressive examination technical skills associated with good communication skills. Clinical examination is always necessary and most of the time is sufficient together with the medical history to diagnose and treat the child's gynecological problems. Evidence-based data on normal genital findings is poor in the literature, because many studies include abused children or present bias in the methods of recruitment and assessment of normal girls [1].

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

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.

Norethisterone-induced hepatic adenomas can cause life-threatening bleeding in girls with inherited platelet disorders.

OBJECTIVE: To describe four cases of hepatic adenoma in adolescents and women with severe inherited bleeding disorders treated with norethisterone. DESIGN: Case reports. SETTING: Necker-Enfants Malades University Hospital, Paris, Department of Pediatric Endocrinology, Gynecology and Diabetes. PATIENT(S): Two adolescents and two young women with inherited platelet disorders, treated with high-dose norethisterone (10 to 20 mg/day) to induce amenorrhea. INTERVENTION(S): Immediate cessation of norethisterone. MAIN OUTCOME MEASURE(S): Spontaneous regression of hepatic adenoma. RESULT(S): In four patients with inherited platelet disorders, hepatic adenoma developed at 14, 18, 22, and 24 years of age, respectively, during continuous norethisterone therapy started at 1.5, 2.5, 10.0, and 13.0 years of age, respectively. Life-threatening bleeding occurred in two patients. Immediate norethisterone discontinuation was followed by complete or nearly complete tumor regression within a few months. CONCLUSION(S): Our four cases strongly support a causal link between norethisterone treatment and hepatic adenoma. Continuous high-dose (10 to 20 mg/day) continuous norethisterone to treat menorrhagia in adolescents and young women with bleeding disorders is inadvisable. If other nortestosterone derivatives are needed, the patient should be closely monitored for the development of hepatic adenoma.

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

BACKGROUND: Primary 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: The 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.

Neonatal bilateral ovarian sex cord stromal tumors.

A child was referred for evaluation after prenatal diagnosis with macrosomia, clitoromegaly, labial hypertrophy, and a left ovarian cyst. The karyotype was 46,XX. The postnatal pelvic ultrasound was normal. High levels of anti-mullerian hormone and testosterone led to a hCG stimulation test, which was followed by isosexual precocious puberty and the appearance of a bilateral ovarian enlargement with a left tumoral mass. A left ovarian tumorectomy revealed a fibrothecoma. Six weeks later, a tumoral relapse occurred and completion of oophorectomy revealed a juvenile granulosa cell tumor (JGCT). Whereas hormonal levels decreased after surgery, a new rise associated with an enlargement of the right ovary led to the diagnosis of right JGCT. A right oophorectomy was proposed to the parents, who declined further surgery. After 2 months, the hormonal levels normalized. This case illustrates the confusing overlap between developmental and neoplastic biology in neonates.

Complete androgen insensitivity syndrome: diagnosis and management.

Complete androgen insensitivity syndrome (CAIS) is an X-linked genetic disorder affecting 46,XY individuals, characterized by the loss of function of the androgen receptor gene resulting in complete peripheral androgen resistance. Patients have a nonambiguous female phenotype with normal female external genitalia. Gonads are undescended testes (either intra-abdominal or inguinal), there is no uterus and the length of the vagina is usually very short. Gender identity is always female. This review focuses on the importance of accurate diagnosis of CAIS versus partial androgen insensitivity syndrome and other disorders of sex development by genotyping the androgen receptor, and raises issues of the optimal management of these patients. In the era of the Consensus Statement on Management of Intersex Disorders, we provide new insights into CAIS screening, surgical management of the gonads (balancing between hormonal production and malignancy risk) and of vaginal adequacy, and the ethics concerned with the disclosure to patients and their families.

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.

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.

Rokitansky syndrome: clinical experience and results of sigmoid vaginoplasty in 23 young girls.

PURPOSE: The Mayer-Rokitansky-Kuster-Hauser syndrome (Rokitansky syndrome) is a frequently misdiagnosed congenital anomaly of the female genital tract. Of several surgical treatments sigmoid vaginoplasty is among the few that provide a functional self-lubricating neovagina. We evaluated the results of sigmoid neovagina in girls affected by the Rokitansky syndrome. MATERIALS AND METHODS: We followed 26 patients with the Rokitansky syndrome between 1990 and 2005. Diagnosis was based on clinical examination, normal ovarian hormones and pelvic ultrasound or magnetic resonance imaging. Associated anomalies were detailed. Vaginoplasty was performed in 23 patients. Functional results and complications were assessed. RESULTS: Renal anomalies were found in 11 patients (42%) and skeletal anomalies in 6 (23%). Six girls (23%) had a family history of the Rokitansky syndrome and/or renal agenesis. Vaginoplasty was performed at a mean age of 16 years (range 10.3 to 18.8). Median postoperative followup was 3.4 years. Postoperative complications included lower extremity compartment syndrome (1 patient), pelvic hematoma (1), mucosal prolapse (2), cystitis (2) and introital stenosis (1). Of the 23 patients undergoing surgery 9 (39%) had an active sex life postoperatively. CONCLUSIONS: Sigmoid vaginoplasty is a valuable procedure in girls with the Rokitansky syndrome. We recommend reconstruction during adolescence because the local conditions are excellent and it allows adaptation of the anatomy to physical development.

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.

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.

Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor?

CONTEXT: Conflicting data have been reported regarding the presence of a constitutive activation of Galphas in ovarian granulosa cell tumors (OGCTs). Although the precise role of this mutation in the transformation of ovarian cells into malignant cells remains debatable, it has been demonstrated in other tissues that the rate of cell proliferation and invasiveness can be influenced by the gsp oncogene. OBJECTIVE: The objective of this study was to determine whether activating mutations of Galphas or Galphai are present in juvenile OGCTs and, if so, whether these mutations are significant prognostic factors. DESIGN AND SETTING: This was a multicentric nationwide study. PATIENTS AND METHODS: Thirty children with juvenile OGCT were included from the malignant germinal tumor protocol of the French Society for Childhood Cancer. Genetic studies of the tumoral DNA used nested PCR, laser microdissection, and direct sequencing. RESULTS: Galphas-activating mutations in hot spot position 201 were found in nine patients (30%). Laser microdissection confirmed that mutations R201C and R201H were exclusively localized in the tumoral granulosa cells and were absent in the ovarian stroma. Patients with a hyperactivated Galphas exhibited a significantly more advanced tumor (P < 0.05) because seven of them (77.7%) were staged as Ic or had had a recurrence. Galphai did not exhibit any mutation. CONCLUSIONS: Activating mutations of Galphas are present in 30% of juvenile OGCTs. The gsp oncogene, which is known to be implicated in cell proliferation and tumoral invasiveness, can be considered as a new prognostic factor of these tumors.

Endocrine consequences of premature pubarche in post-pubertal Caucasian girls.

BACKGROUND: It has been postulated that intrauterine undernutrition may predispose to serious endocrine consequences, including precocious pubarche (PP), functional ovarian hyperandrogenism and insulin resistance syndrome. OBJECTIVE: The aim of this study was to determine whether a history of PP was associated with the development of hyperandrogenism and/or metabolic consequences and to evaluate the effect of birth weight on this association. PATIENTS: The study population comprised 27 Caucasian girls with a history of PP and 25 healthy girls of similar age (17.4 +/- 1.3 vs. 17.7 +/- 0.9 years). RESULTS: Gynecological age, irregular menses and oral contraceptive use were similar in the two groups. PP girls showed an increased Ferriman-Gallway Score [median (range) 8 (4-17) vs. 6 (2-10), P = 0.02] and tended to have more previous history of acne. No statistical differences were found between the groups for mean testosterone (1.7 +/- 0.7 vs. 1.4 +/- 0.7 nmol/l, P = 0.49) and dehydroepiandrosterone sulphate concentrations (7.2 +/- 3.7 vs. 5.8 +/- 2.0 micromol/l, P = 0.15), but mean Delta4-androstenedione concentrations (7.3 +/- 2.4 vs. 4.9 +/- 2.1 nmol/l, P = 0.007) and free androgen index (8.5 +/- 9.7 vs. 3.6 +/- 3.9 IU, P = 0.003) were significantly increased in the PP group. All girls showed normal glucose tolerance with an oral glucose tolerance test. Derived insulin resistance parameters were not statistically different between the two groups and fasting lipids were comparable in both groups. There was no significant effect of birth weight on androgen levels in the PP girls. Moreover, none of the PP girls demonstrated the above-described association. CONCLUSIONS: Precocious pubarche could be the first sign of future functional ovarian hyperandrogenism but a link between this condition and intrauterine undernutrition or insulin resistance could not be demonstrated in this study.