Eleonora Dati

Hormonal Management of Complete Androgen Insensitivity Syndrome from Adolescence Onward

Complete androgen insensitivity syndrome (CAIS) represents a main disorder of sex development. Women with CAIS may have their gonads removed before, during or after adolescence, thus requiring hormonal replacement therapy to induce puberty and/or maintain secondary sexual characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Usually estrogens are used for this purpose, but formulations and doses should be better defined in multicentric prospective studies. Some women started testostosterone as hormonal replacement therapy, but this practice remains anecdotal. Bone health remains a crucial aspect in the management of persons with CAIS, but few sound data are available to guide clinical practice.

Disorders of sex development: Hormonal management in adolescence

Hormonal treatment represents the principal aspect of clinical management of people with disorders of sex development (DSD) from adolescence onwards. In fact, individuals with DSD may require sex steroid replacement to induce secondary sex characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Testosterone is the main hormone for treatment in males and estrogens in females. The optimal regimens for sex steroid substitutive therapy in subjects with DSD should be better defined in multi-center prospective studies. Bone health remains a crucial aspect in the management of these persons, but few sound data are available to guide clinical practice.

Quality of Life and Psychological Adjustment of Women Living with 46,XY Differences of Sex Development

BACKGROUND Progressive care improvement for differences of sex development (DSD), regarding diagnosis communication, psychological, medical and surgical management has been claimed. AIM OF THE STUDY To assess clinical management, quality of life (QoL) and the general psychosocial adjustment of individuals with 46,XY DSD. Some differences related to age at diagnosis are investigated. DESIGN Cross-sectional study using standardized questionnaires. POPULATION Forty-three Caucasian females with 46,XY DSD (self declared diagnoses: complete androgen insensitivity syndrome, n = 34; complete gonadal dysgenesis, n = 1; 5α-reductase deficiency, n = 4; Leydig cell hypoplasia, n = 1; unknown diagnosis, n = 3; age years: 31.5 ± 9.6 [range 18-57 years]). SETTING University Hospitals. METHODS Subjects were required to fill in questionnaires (ABCL, WHOQOL, dedicated 17-item questionnaire). Academic and socioeconomic data were compared with those of the Italian population. QoL and psychological data were compared with those of a comparison group (46,XX healthy females: n = 43; age, years: 34.5 ± 9.7, range 22-51 years). RESULTS Present sample of women living with 46,XY DSD were well adapted and were higher achievers than controls, both in educational and professional life. They showed good QoL, but they appeared less satisfied in psychological and social areas. They had borderline mean scores and statistically higher scores than the comparison group for depression, anxiety, internalizing and externalizing problems. Younger persons living with a 46,XY DSD showed better psychosocial adjustment than older ones. Younger women showed lower age at diagnosis communication. Psychological support was more often proposed at the time of diagnosis communication to younger individuals, and they undertook it more frequently than older ones. CONCLUSIONS Italian people living with 46,XY DSD were well adapted and successful; they reported a good QoL but showed higher degree of psychological distress than the comparison group. Lower psychological distress in younger women could indicate some positive effects of changes in management.

Body composition and metabolic profile in women with complete androgen insensitivity syndrome.

Clinical and experimental data suggest that androgen receptor (AR) signaling plays a role on body composition, glucose homeostasis and lipid metabolism. The effect of AR disruption on such parameters was not extensively investigated in human people. A group of young to middle-age adult women with complete androgen insensitivity syndrome (CAIS, n = 18, age 32.2 ± 9.3 years; women with testes removed n = 14) was investigated for body mass index (BMI), body composition (dual energy X-ray absorptiometry), serum glucose levels, insulin sensitivity (HOMA-IR) and lipid profile. Mean BMI (24.2 ± 7.4 kg/m2) was not significantly increased (T-score 1.0 ± 2.5, p = NS vs Italian female reference values), but prevalence of obesity was higher in women with CAIS than that reported in age-related Italian females (16.7% vs 3.6%, respectively). The majority of obese individuals with CAIS was in the subgroup with intact testes (3/4). DXA assessment (n = 15) demonstrated values of total free fat mass similar to that of 46,XX female controls. Increased body fat was found in CAIS women in comparison with both female and male controls. Abnormal values of cholesterol (total and LDL) and HOMA-IR were present in a large subset of patients. Our data suggest that in women with CAIS disruption of AR signaling may increase body fat and affect some metabolic parameters. Assessment of body composition, metabolic profile and, likely, cardiovascular risk seems to be advisable with ageing in these individuals.

Body Mass Index and Body Composition in Adolescents Treated with Gonadotropin-Releasing Hormone Analogue Triptorelin Depot for Central Precocious Puberty: Data at Near Final Height

Background/Aim: In children with central precocious puberty (CPP), gonadotropin-releasing hormone (GnRH) analogue treatment has been associated with an increase in body mass index (BMI). We evaluated BMI and body composition in adolescents treated with GnRH analogue at their near final height to assess the long-term effects of therapy on these parameters. Patients and Methods: We studied 20 patients (14.8 ± 1.6 years; 17 females) previously treated with triptorelin depot for CPP (3.75 mg/28 days) from 8.1 ± 0.8 to 11.5 ± 0.8 years. 23 healthy adolescents with normal onset of puberty (14.7 ± 2.1 years, 19 females) were the controls. BMI and body composition (dual-energy x-ray absorptiometry) were assessed. Results: Patients reached their near adult height (–0.5 ± 1.1 standard deviation score (SDS)); the girls were menstruating and the majority (15/17) had regular cycles, the boys showed normal testicular function. BMI was unchanged from the start of GnRH analogue therapy (0.4 ± 1.0 SDS) to near adult height (0.2 ± 1.0 SDS, p = NS vs. 0). Total fat mass (TFM) was significantly increased (16,144 ± 8,065 g; controls 10,712.1 ± 4,120.4 g, p < 0.02); glucose homeostasis and lipid profile corresponded to reference ranges. Conclusions: GnRH analogue therapy did not show long-term detrimental effects on BMI, but it may increase TFM, suggesting that body composition should be monitored till adulthood.

Characteristic features of reproductive hormone profiles in late adolescent and adult females with complete androgen insensitivity syndrome.

Little is known about gonadotropins and sex steroid levels in postpubertal women with complete androgen insensitivity syndrome (CAIS). In order to define reproductive hormone profiles in women with CAIS and intact gonads, 42 postpubertal females with proven CAIS (age range 14-50 years) with testes in situ were examined. Reproductive hormone values [testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH)] were assessed by commercially available immunoassays. In women with CAIS, LH levels (median 18.5 IU/l, range 5.5-51.1 IU/l) were elevated above the usual adult reference ranges, whereas FSH values (3.5 IU/l, 0.4-16.3 IU/l) were not. Basal T (20 nmol/l, 6-52 nmol/l) and E2 values (113 pmol/l; 18-257 pmol/l) were found in the usual adult male reference ranges; SHBG levels (53 nmol/l, 15-180 nmol/l) were in the adult female reference range. Calculated free androgen indices (Tx10³/SHBG: 380, 114-863) and aromatization indices (E2/T: 0.052, 0.020-0.196) did not differ from the reference ranges for adult men given in the literature (Tx10³/SHBG: 315-936; E2/T: 0.03-0.07). Reproductive hormone profiles in women with CAIS do not follow the usual male/female pattern, suggesting a specific postpubertal hormone milieu. Albeit calculation of CAIS-specific reference ranges requires larger series and standardization of laboratory methods, these results may be a prerequisite for the identification of pathologic hormone patterns in women with CAIS and gonads in situ. The present data will also be useful to monitor hormone replacement therapy in individuals with removed gonads.

Central Precocious Puberty: Treatment with Triptorelin 11.25 mg

Background. Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). Aim. To assess the efficacy of triptorelin 11.25 mg in children with CPP. Patients. 17 patients (16 females) with CPP (7.9 ± 0.9 years) were treated with triptorelin 11.25 mg/90 days. Methods. Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7 ± 16.5 IU/L at baseline to 0.9 ± 0.5 IU/L at M3 (P < 0.0001); they did not significantly changed at M6 and M12. Conclusions. Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Diagnosis of 17β-hydroxysteroid dehydrogenase deficiency

17β-hydroxysteroid dehydrogenase deficiency is a rare autosomal recessive inherited disorder of sex development, affecting only 46,XY individuals. It is due to mutations in the HSD17B3 gene, encoding the 17β-hydroxysteroid-dehydrogenase type 3 enzyme. Mutated enzymes lead to absent or reduced ability to convert Δ4-androstenedione to testosterone in the testis. Affected 46,XY individuals present with testes located in the inguinal canal and underdeveloped or hypoplastic Wolffian structures, but female or ambiguous external genitalia. Such individuals are usually raised as females, but show spontaneous virilization at puberty. Correct diagnosis is mandatory to optimize treatment and follow-up. The clinical and laboratory approach, as well as the follow-up of subjects with 17β-hydroxysteroid-dehydrogenase deficiency, are detailed in this review, and the genetic mutations characterized to date are summarized.

IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene

BACKGROUNDShort stature represents one of the main features of children with Noonan syndrome. The reason for impaired growth remains largely unknown.OBJECTIVETo assess GH and IGF1 secretion in children with Noonan syndrome. Patients: 12 prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene [7 males, 6 females; median age, years: 8.6 (range 5.1–13.4)] were studied; 12 prepubertal children with short stature (SS) [7 males, 5 females; median age, years: 8.1 (range 4.8–13.1)] served as the control group. Measurements: GH secretion after arginine stimulation test; IGF1 generation test by measurement of IGF1 levels before and after recombinant GH (rGH) administration (0.05 mg/kg/day for 4 days).RESULTSBaseline and stimulated peak values of GH were not significantly different between the two groups. At +120 minutes, GH levels remained significantly higher (p = 0.0121) in comparison with baseline values in children with Noonan syndrome. Baseline IGFI levels in patients and in SS controls were not significantly different, in contrast to values after the rGH generation test [205 ng/mL (interquartiles 138.2–252.5 ng/mL) and 284.5 ng/mL (inter-quartiles 172–476 ng/mL), respectively; p = 0.0248]. IGF1 values were significantly related to height (baseline: r = 773, p = 0.0320; peak: r = 0.591, p = 0.0428) in children with Noonan syndrome.CONCLUSIONSBlunted increase of IGF1 after the rGH generation test was present in children with Noonan syndrome due to mutations in the PTPN11 gene in comparison with SS children. This finding may be due to partial GH resistance in the former likely related to altered Ras-MAPK signaling pathway.

45,X Maleness: Clinical and Cytogenetic Features in Two Patients

45,X maleness is a very rare disorder. We report on 2 new 45,X males aged 9 10/12 and 39 years, respectively. The boy presented for developmental delay, while the man was referred to us because of infertility. Both patients showed short stature (boy –2.29 SDS, man –4.05 SDS) and an unbalanced translocation of Yp, including SRY, onto the long arm of chromosome 10 and short arm of chromosome 14, respectively. The growth pattern of the 2 patients and literature data suggest the presence of a specific growth gene in the pericentrometric region of Yq. In addition, developmental delay in some 45,X males may be related to specific deletion of telomeric autosome regions, but involvement of gene(s) on the Y chromosome may play a role as well. Albeit in the boy inhibin B levels were in the normal range for age, azoospermia was demonstrated in the adult, supporting that infertility is a feature of adult 45,X men with AZFa–c deletion.