Hans-Peter Schwarz

The quality of life in adult female patients with congenital adrenal hyperplasia: A comprehensive study of the impact of genital malformations and chronic disease on female patients life

Female patients with congenital adrenal hyperplasia have been frequently studied in order to determine the impact of prenatal androgen exposure on various aspects of psychological, psychosocial and psychosexual development. There is no published study to evaluate the impact of the genital malformation, genital operations and chronic medication on the quality of life in adult females with congenital adrenal hyperplasia. We performed a quality-of-life evaluation in adult female patients with congenital adrenal hyperplasia due to a 21-hydroxylation defect. The patients were asked to fill out questionnaires covering the four domains of health-related quality of life, namely physical state, psychological well-being, social relationships and functional capacity as well as questionnaires covering the areas of psychosexual identification and psychosocial integration. In addition a semistructured interview was performed covering medical history as well as physical, emotional, social and psychosexual development. The results were evaluated using a computerized statistical program for social sciences. Forty-five patients agreed to participate (44 could be interviewed) and their medical data did not differ from the 20 patients (medical data were available from 16 patients) who refused to participate. Median age at diagnosis was below 1 year in 54.8 of the participating patients; range was from 0 to 30 years. Of the participants, 48.6%, 34.2% and 17.2% suffered from the simple-virilizing-, salt-wasting-, and late-onset-form of congenital adrenal hyperplasia, respectively. The mean adult height was 157.8 cm, and mean weight was 56.8 kg. In 35.7% the degree of genital virilization was classified as Prader stage 3 or 4.(ABSTRACT TRUNCATED AT 250 WORDS)

High Prevalence of Reduced Fecundity in Men with Congenital Adrenal Hyperplasia

CONTEXT Testicular adrenal rest tumors (TARTs) are regarded to contribute to the high prevalence of subfertility in males with congenital adrenal hyperplasia (CAH). OBJECTIVES Our objectives were to evaluate reduced fecundity and its possible causes in well-controlled adult males with CAH, and to investigate diagnostic tools for improved treatment monitoring with respect to fertility outcomes. DESIGN In a cross-sectional study at the Department of Endocrinology at the University Hospital München, Germany, 22 adult male CAH patients (15 salt wasting and seven simple virilizing, age 19-48 yr) were clinically assessed according to their hormonal control. We performed testicular ultrasound (22 of 22), magnetic resonance imaging (18 of 22), and a semen analysis (19 of 22) in the participants. RESULTS All patients had a pathological semen analysis. TART prevalence was 10 of 22 (eight salt wasting, two simple virilizing). Poor therapy control was present in five patients, and all five had TARTs. Of the other 17 well-controlled patients with normal or suppressed adrenal androgens and 17-hydroxyprogesterone levels, five presented with TARTs. There was a significant correlation between sperm concentration and functional testicular volume (r = 0.70; P = 0.002), TART volume (r = -0.70; P = 0.036), as well as inhibin B levels (r = 0.75; P < 0.0001), respectively. In several men, hormonal control parameters suggested hypogonadism, with glucocorticoid overtreatment as a relevant factor for poor semen quality. CONCLUSIONS Poor semen parameters are common in male CAH patients. TARTs, most likely reflecting undertreatment, as well as inhibin B are important indicators of fecundity. On the other hand, long-term glucocorticoid overtreatment also seems to contribute to low semen quality.

Endocrine disorders in septo-optic dysplasia (De Morsier syndrome) — evaluation and follow up of 18 patients

Septo-optic dysplasia (SOD) is characterized by hypoplasia of the optic nerve, various types of forebrain defects and hormonal deficiencies. We have studied the clinical and endocrinological characteristics of 18 such patients retrospectively to: (1) better define the endocrine abnormalities in children with SOD; and (2) to find approaches for the interdisciplinary long-term care of children with SOD. The children were seen at the Childrens Hospital of the University of Munich from 1976 to 1992 (8 boys, 10 girls; age at initial presentation: 1 day–13 years of age, mean 1.9 years). Unilateral hypoplasia of the optic nerve was found in 7 cases, bilateral hypoplasia in 11. Sonographic, CCT or MRI yielded the following results: 4 of the patients had a cavum septum pellucidum, 3 patients had hypoplasia of the cerebellum, 1 aplasia of the corpus callosum and 1 aplasia of the fornix. An empty sella with or without an ectopic pituitary was seen in 4 cases. Height standard deviation score (SDS) at time of diagnosis was −4.0 to +0.4, mean −2.92. Endocrine deficiencies were present in all 11 patients who had undergone endocrinological investigations. Seven patients suffered from isolated growth hormone (GH) deficiency or multiple hypopituitarism. One had diabetes insipidus centralis, 2 had hypogonadotropic hypogonadism, 1 had hypothyroidism and 2 adrenal insufficiency. Hypothalamic testing was performed only in a subset of patients: in 5 of 11 children tested a thyrotropin releasing hormone (TRH test), in two out of nine a gonadotropin releasing hormone (GnRH) test, and in three out of six GH releasing hormone (GHRH) test yielded abnormal results. High prolactin levels were measured in two out of five patients.ConclusionSOD is characterized by optic nerve hypoplasia and a variety of endocrine deficiencies. In addition, forebrain malformations are present in most SOD patients. Hormonal disorders are present in some SOD patients which may be of hypothalamic origin and need to be investigated systematically.

Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency

OBJECTIVE To study adrenal crisis (AC) in patients with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (21-OHD). AC was defined as an acute state of health impairment requiring i.v. glucocorticoid administration and hospital admission. DESIGN AND METHODS In a cross-sectional study with detailed retrospective assessment, AC was studied following two approaches: i) questionnaire based: 122 adult 21-OHD patients (50 men, 72 women, median age 35 years, range 18-69 years) completed a disease-specific questionnaire; and ii) patient chart based: charts of 67 21-OHD patients (32 males, 35 females, median age 31 years, range 20-66 years) were analyzed from diagnosis to last follow-up with regard to frequency and causes of AC since diagnosis. RESULTS Evaluation of questionnaires revealed 257 ACs in 4456 patient years (py; frequency 5.8 crises/100 py), while patient charts documented 106 ACs in 2181 py (4.9 crises/100 py). The chart-based evaluation showed that gastrointestinal infections (29%) and salt-wasting crisis (18%) were the main causes of AC. In 14%, the cause remained uncertain. There was no difference in the overall frequency of AC in males and females. AC mostly occurred during childhood, with more than 70% of AC in the first 10 years of life and one-third of AC in the first year of life. Still, 20% of cases of AC were observed in adults (>18 years). CONCLUSION Our data demonstrate a significant risk of AC in patients with 21-OHD over lifetime. Specific age-adapted and repeated crisis prevention training may help to reduce morbidity due to AC in 21-OHD.

Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus – data from a German/Austrian multicentre survey

Objective:  Type 1 diabetes mellitus (T1DM) is associated with other autoimmune diseases such as celiac disease (CD) and Hashimoto thyroiditis. The aim of this study was to evaluate the screening frequency for CD and thyroid antibodies in a multicentre survey.

Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function

Depot gonadotropin releasing hormone (GnRH) agonist (GnRHa) therapy is the treatment of choice for patients with central precocious puberty (CPP). It is still unclear whether long-term exposure to GnRHa is associated with impaired reproductive function in adulthood. The present study was performed on 46 women, former CPP patients, 12.5+/-3.7 years after the discontinuation of treatment with depot GnRHa. In a structured interview, we assessed general health status, clinical signs possibly associated with hyperandrogenism, menstrual cycle, gynaecological diseases and reproductive function. It appears that long-term treatment with depot GnRHa is safe and does not impair reproductive function. The risk of former CPP patients to develop hirsutism and/or polycystic ovary syndrome does not seem to be increased compared to the normal population but this issue needs to be addressed in further long-term follow-up studies.

Total Adrenal Volume But Not Testicular Adrenal Rest Tumor Volume Is Associated with Hormonal Control in Patients with 21-Hydroxylase Deficiency

CONTEXT Patients with 21-hydroxylase deficiency (21-OHD) have been shown to develop adrenal adenomas and, in males, testicular adrenal rest tumors (TARTs) at a high percentage. OBJECTIVE The aim of this study was to evaluate the interrelation of adrenal masses and TARTs as well as factors stimulating tumor growth of orthotopic and ectopic adrenal tissue in 21-OHD. DESIGN In a cross-sectional study, 26 adult male patients with classic 21-OHD (15 salt wasting, 11 simple virilizing; age range, 18-48 yr) were clinically assessed according to their hormonal control. Magnetic resonance imaging of the adrenals (26 of 26) and of the testes (18 of 26) was performed. Adrenal size and morphology was compared to 26 age-matched controls. RESULTS Combined adrenal volume of 21-OHD patients was significantly higher (median, 9.3 ml; range, 3.2-124.5 ml) in comparison to controls (median, 7.4 ml; range, 5.5-10.8 ml; P = 0.005). Morphologically, adrenals were classified as normal without nodules in 27% of 21-OHD patients compared to 69% of controls. None of the controls, but 42% of 21-OHD patients had an overall adrenal volume higher than 11 ml. Ten of 18 patients had TARTs with a median volume of 3.3 ml (range, 0.4-21.6 ml). Total adrenal volume and tumor size but not TART volume correlated positively with current parameters of hormonal control (androstenedione, morning 17-OHP in serum, pregnanetriol in 24-h urine; P < 0.001 for each). Baseline ACTH was independent of adrenal and TART volume. There was no correlation of total adrenal or adrenal tumor size with TART volume. CONCLUSION These data provide indirect evidence that different factors regulate the growth of orthotopic adrenal tissue and ectopic adrenal remnants in TARTs.

Auxological and endocrinological evaluation of children with hydrocephalus and/or meningomyelocele.

Abstract Short stature and precocious puberty are frequently found in children with hydrocephalus and/or meningomyelocele (MMC). However, aetiology and pathophysiology have not been well characterized. In this study, 108 patients aged between 3 and 17.8 years were evaluated. Growth was documented on the basis of arm span measurements. Short arm span was found in 47 (43.5%) children with hydrocephalus and/or MMC. Mean arm span was −2.0 standard deviation score (SDS) (−6.4 to +0.8) in 43 girls and −1.4 SDS (−5.6 to +1.3) in 65 boys. When growth deficiency (more than −2.0 SDS) was diagnosed by arm span measurement (24 F, 23 M) or when early sexual maturation was found (6 F, 9 M), endocrine evaluation followed. Levels of serum insulin-like growth factor and insulin-like growth factor binding protein-3 were low in 22 of 62 (33.8%) patients. In 9 of 62 (14.5%) patients, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were found to be increased. Growth hormone (GH) deficiency was diagnosed by means of two different stimulation tests (clonidine and arginine) in 7 of 62 (11.3%) patients. In another 3 of 62 (4.8%) children, 12 h night time GH sampling showed low maximum peak levels and decreased area under the curve values, suggesting neurosecretory GH dysfunction.Precocious puberty or early onset of puberty associated with elevated luteinising hormone and follicle stimulating hormone concentrations after stimulation with luteinising hormone releasing hormone was found in 13 of 108 (12.0%) patients (age 7–9 years). Free thyroxine was abnormally low in 2 of 62 (3.2%) patients. Cortisol was within the normal range in all 62 (100%) tested patients. Conclusions Short arm span in children with hydrocephalus and/or MMC is frequently accompanied by GH deficiency or neurosecretory GH dysfunction. Early onset of puberty is another frequent finding. Both hormonal disorders may be the consequence of damage to the hypothalamus or the pituitary gland caused by increased intracerebral pressure or increased mass of cerebrospinal fluid.

Weight in adolescents with type 1 diabetes mellitus during continuous subcutaneous insulin infusion (CSII) therapy

Continuous subcutaneous insulin infusion (CSII) has become increasingly popular as a form of intensified insulin therapy in adolescents with type 1 diabetes mellitus (DM). One reported drawback was increased weight gain in adolescents after initiation of insulin pump therapy. In a prospective, longitudinal, non-randomized and case controlled study, we followed 12 adolescents (mean age 13.6 yr, 8 males, 4 females) from 6 months before the start of CSII to 12 months on CSII. These 12 adolescents with DM on CSII were matched for age, gender, HbA1c, duration of DM, and body mass index (BMI) with 12 adolescents who continued on multiple injection therapy (MIT). In addition, six of the 12 adolescents on CSII intended to control their weight by means of the insulin pump. These six vs six adolescents within the CSII group were further analyzed for weight development and eating habits. Clinical indications for CSII were dawn phenomenon, night-time hypoglycemia and patient request for more flexibility in DM management. All patients had been in satisfactory metabolic control on MIT. After 12 months of CSII, the daily insulin requirement remained significantly lower than 18 months before (0.79 +/- 0.11 vs 1.02 +/- 27 U/kg/d, p = 0.034) and number of daily meals was lower (4.1 +/- 0.9 vs 6.5 +/- 0.7, p = 0.006). Mean initial HbA1c was 7.4% in the MIT and CSII patients, and remained comparable between these two groups. BMI was not different between the CSII and MIT group over the entire study period. However, those adolescents on CSII who intended to control their weight by means of the insulin pump were able to achieve relative weight loss during the,first 6 months on CSII. Two patients of the CSII group had one severe hypoglycemic episode with loss of consciousness. In conclusion, CSII does not lead to weight gain by itself, but allows sufficient weight control without a negative effect on metabolic control. The general threat of weight gain in patients who switch to insulin pump therapy must be pointed out, and the role of eating habits and caloric content of food should play a central role in insulin pump educational programs.

Steroid 17α-Hydroxylase Deficiency: Functional Characterization of Four Mutations (A174E, V178D, R440C, L465P) in the CYP17A1 Gene

CONTEXT Steroid 17alpha-hydroxylase (CYP17A1, alias P450c17) deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. The CYP17A1 enzyme catalyzes two distinct reactions, 17alpha-hydroxylase and 17,20-lyase activities. OBJECTIVE The aim of the study was to analyze the structural and functional consequences of three novel (A174E, V178D, and L465P) and one previously reported (R440C) CYP17A1 mutation found in three patients clinically and biochemically presenting with 17OHD. PATIENTS AND METHODS Two patients suffering from 46,XY disordered sex development presented at ages 5.5 and 8.8 yr, respectively, with tall stature and hypertension. Mutation analysis revealed compound heterozygous CYP17A1 mutations (A174E/K388X; V178D/R440C). The third patient (46,XX) presented with primary amenorrhea and hypertension at age 15 yr. She was homozygous for the novel L465P mutation. Functional studies employing a yeast microsomal expression system compared wild-type and mutant CYP17A1 both with regard to 17alpha-hydroxylase and 17,20-lyase activity. Mutants were examined in a computational three-dimensional model of the CYP17A1 protein. RESULTS The activity assays showed that all three mutants retain only 0-7% of both 17alpha-hydroxylase and 17,20-lyase activity relative to CYP17A1 wild-type activity, corresponding to the in vivo situation. Enzyme kinetic studies proved the impairment of both reactions, respectively. Computer-based three-dimensional model analysis of CYP17A1 using CYP2B4 as template showed that three of the mutations had no direct effect on the active center, whereas one affects the heme coordination. CONCLUSION The functional studies revealed that the described missense mutations result in severe 17OHD. Our data are important to predict the phenotypic expressions and provide important information for patient management and genetic counseling.