Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia.

OBJECTIVE: Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. DESIGN: We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. METHODS: Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. RESULTS: The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L-1 (IQR 8.3) versus 10.5 nmol L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L-1 s-1 (IQR 1.0) to 0.48 ng L-1 s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L-1 s-1 (IQR 0.66) to 0.52 ng L-1 s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L-1 to 139.3 ± 1.8 mmol L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L-1 to 139.3 ± 1.9 mmol L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. CONCLUSION: 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Transcriptional comparison of testicular adrenal rest tumors with fetal and adult tissues.

Background: Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. Objective: This study aims to unravel the identity and etiology of TART. Methods: Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. Results: We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. Conclusion: Our data suggest that TART is induced - most likely via activation of a cAMP/protein kinase A-dependent receptor - from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.

Diurnal salivary androstenedione and 17-hydroxyprogesterone levels in healthy volunteers for monitoring treatment efficacy of patients with congenital adrenal hyperplasia.

OBJECTIVE: Treatment of congenital adrenal hyperplasia (CAH) patients with glucocorticoids is often challenging since there is a delicate balance between over- and undertreatment. Treatment can be monitored noninvasively by measuring salivary androstenedione (A4) and 17-hydroxyprogesterone (17-OHP). Optimal treatment monitoring requires the establishment of reference values in saliva. DESIGN: A descriptive study. PATIENTS: For this study saliva of 255 healthy paediatric and adult volunteers with an age range of 4-75 years old was used. MEASUREMENTS: We developed a sensitive liquid chromatography-tandem mass spectrometry method, assessed salivary A4 and 17-OHP stability, and measured A4 and 17-OHP concentrations in saliva collected in the morning, afternoon, and evening. RESULTS: We quantified A4 and 17-OHP concentrations in the morning, afternoon, and evening and demonstrated that there is a significant rhythm with the highest levels in the morning and decreasing levels over the day. A4 and 17-OHP concentrations display an age-dependent pattern. These steroids remain stable in saliva at ambient temperature for up to 5 days. CONCLUSIONS: Good stability of the steroids in saliva enables saliva collection by the patient at home. Since salivary A4 and 17-OHP display a diurnal rhythm and age-dependent pattern, we established reference values for both children and adults at three time points during the day. These reference values support treatment monitoring of children and adults with CAH.

Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.

Quality of Life in Men With Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p<0.05). Patients treated with dexamethasone or prednisone scored higher on the physical health, psychological health, and social relationships domains, but not on the environmental domain. In conclusion, QoL domain scores appeared to be comparable to healthy reference populations and higher compared to patients with a chronic illness. QoL was not influenced by genotype, but undertreatment and use of dexamethasone or prednisone were associated with higher QoL.

Sexuality in Males With Congenital Adrenal Hyperplasia Resulting From 21-Hydroxylase Deficiency.

PURPOSE: Although sexuality has been reported to be impaired in females with congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency, sexuality in males with CAH so far has remained largely unconsidered. PATIENTS: One of the largest European male cohorts of patients with CAH in which sexuality in male patients with CAH was assessed. METHODS: Sexuality was evaluated in 91 sexually active male patients with CAH using questionnaires investigating sexual orientation, age at sexual initiation, sexual activity, satisfaction with sex life, and sexual problems, such as fears or dislike of sexual activity, lack or excessive sexual desire, difficulties getting aroused or reaching an orgasm, premature ejaculation, and no or incomplete erection. RESULTS: Sexuality in male patients with CAH was similar to European reference populations. If sexuality problems were present, they were less frequently reported by the most severely affected CAH males. Adducing a holistic perspective, sexual problems showed substantial association to psychological problems, such as anxiety and depression. CONCLUSIONS: Sexuality in male patients with CAH in general was unaffected and sexuality problems seemed to be associated in particular with psychological problems. Because sexual health is a key factor of general health, we recommend that sexuality as well as psychological issues explicitly should be addressed in health care of patients with a CAH diagnosis, independent of sex.

Testicular Adrenal Rest Tumors: Current Insights on Prevalence, Characteristics, Origin, and Treatment.

This review provides the reader with current insights on testicular adrenal rest tumors (TARTs), a complication in male patients with congenital adrenal hyperplasia (CAH). In recent studies, an overall TART prevalence of 40% (range, 14% to 89%) in classic patients with CAH is found. Reported differences are mainly caused by the method of detection and the selected patient population. Biochemically, histologically, and molecularly, TARTs exhibit particular adrenal characteristics and were therefore thought to originate from aberrant adrenal cells. More recently, TARTs have been found to also exhibit testicular characteristics. This has led to the hypothesis of pluripotent cells as the origin of TARTs. High concentrations of ACTH could cause hyperplasia of these pluripotent cells, as TARTs appear to be associated with poor hormonal control with concomitant elevated ACTH. Unfortunately, as yet there are no methods to prevent the development of TARTs, nor are there guidelines to treat patients with TARTs. Intensified glucocorticoid treatment could improve fertility status in some cases, although studies report contradicting results. TARTs can also lead to irreversible testicular damage, and therefore semen cryopreservation could be offered to patients with TARTs. Further research should focus on the etiology and pharmacological treatment to prevent TART development or to treat TARTs and improve the fertility status of patients with TARTs.

Enhanced self-efficacy after a self-management programme in pituitary disease: a randomized controlled trial.

CONTEXT: Patients with pituitary disease report impairments in Quality of Life (QoL) despite optimal biomedical care. Until now, the effects of a self-management intervention (SMI) addressing psychological and social issues for these patients and their partners have not been studied. OBJECTIVE: To examine the effects of a SMI i.e. Patient and Partner Education Programme for Pituitary disease (PPEP-Pituitary). DESIGN AND SUBJECTS: A multicentre randomized controlled trial included 174 patients with pituitary disease, and 63 partners were allocated to either PPEP-Pituitary or a control group. PPEP-Pituitary included eight weekly sessions (90 min). Self-efficacy, bother and needs for support, illness perceptions, coping and QoL were assessed before the intervention (T0), directly after (T1) and after six months (T2). Mood was assessed before and after each session. RESULTS: Patients in PPEP-Pituitary reported improved mood after each session (except for session 1). In partners, mood only improved after the last three sessions. Patients reported higher self-efficacy at T1 (P = 0.016) which persisted up to T2 (P = 0.033), and less bother by mood problems directly after PPEP-Pituitary (P = 0.01), but more bother after six months (P = 0.001), although this increase was not different from baseline (P = 0.346). Partners in PPEP-Pituitary reported more vitality (P = 0.008) which persisted up to T2 (P = 0.034). At T2, partners also reported less anxiety and depressive symptoms (P ≤ 0.014). CONCLUSION: This first study evaluating the effects of a SMI targeting psychosocial issues in patients with pituitary disease and their partners demonstrated promising positive results. Future research should focus on the refinement and implementation of this SMI into clinical practice.

Adrenal Crisis: Still a Deadly Event in the 21st Century.

Adrenal crisis is a life-threatening medical emergency, associated with a high mortality unless it is appropriately recognized and early treatment is rendered. Despite it being a treatable condition for almost 70 years, failure of adequate preventive measures or delayed treatment has often led to unnecessary deaths. Gastrointestinal illness is the most common precipitant for an adrenal crisis. Although most patients are educated about "sick day rules," patients, and physicians too, are often reluctant to increase their glucocorticoid doses or switch to parenteral injections, and thereby fail to avert the rapid deterioration of the patients' condition. Therefore, more can be done to prevent an adrenal crisis, as well as to ensure that adequate acute medical care is instituted after a crisis has occurred. There is generally a paucity of studies on adrenal crisis. Hence, we will review the current literature, while also focusing on the incidence, presentation, treatment, prevention strategies, and latest recommendations in terms of steroid dosing in stress situations.

Salivary morning androstenedione and 17α-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia.

BACKGROUND: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17α-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring. METHODS: We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21-hydroxylase deficiency. RESULTS: A-dione and 17OHP levels and its ratio 17OHP/A-dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46-4.41) during prepuberty; 2.36 nmol/L (0.63-8.89) for boys and 1.99 nmol/L (0.32-6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11-15 mg/m2/day. A-dione levels above the upper reference limit (URL), suggesting undertreatment, coincided with 17OHP levels ≥10 times URL. The percentage of A-dione levels above URL was 16% at ages 4-8 years, but increased to 31% for girls at 16 years and 46% for boys at 17 years. CONCLUSIONS: Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4-6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys.

A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis.

OBJECTIVE: To assess self-management in patients receiving glucocorticoid replacement therapy for primary or secondary adrenal failure before and 6 months after a glucocorticoid education group meeting. METHODS: All patients with primary or secondary adrenal insufficiency, treated at the Department of Medicine, Division of Endocrinology, were invited by their endocrinologist to participate in a 3-h glucocorticoid education group meeting, consisting of a lecture about the disease and glucocorticoid doses adjustments in case of stress, followed by an instruction on how to inject hydrocortisone i.m. Finally, all participants could practise the i.m. injection and discuss their experience with (imminent) adrenal crises with other patients and the health care providers. Two weeks before the meeting and 6 months after the meeting, patients were asked to fill out a questionnaire about how they would act in six different conditions (e.g. febrile illness or vomiting). RESULTS: Of the 405 patients who were invited, 246 patients (61%) participated. At baseline the response by the participants on the questionnaire was 100% (n=246) and at follow-up 74% (n=183). At follow-up, significantly more participants (P≤0.005) gave the correct answers to how to act in different situations (e.g. self-administration of a glucocorticoid injection and phone contact in case of vomiting/diarrhoea without fever). Moreover, the use of self-management tools, such as having a 'medicine passport (travel document with information about disease and medication) (P=0.007) or SOS medallion (P=0.0007)', increased. CONCLUSION: A glucocorticoid education group meeting for patients with adrenal failure seems helpful to improve self-management and proper use of stress-related glucocorticoid dose adjustment.

High level of distress in long-term survivors of thyroid carcinoma: results of rapid screening using the distress thermometer.

CONTEXT: Cancer patients are at increased risk for distress. The Distress Thermometer (DT) and problem list (PL) are short-tools validated and recommended for distress screening in cancer patients. OBJECTIVE: To investigate the level of distress and problems experienced by survivors of differentiated non-medullary thyroid carcinoma (DTC), using the DT and PL and whether this correlates with clinical and demographical variables. PARTICIPANTS, DESIGN AND SETTING: All 205 DTC patients, under follow-up at the outpatient clinic of our university hospital, were asked to fill in the DT and PL, hospital anxiety and depression scale (HADS), illness cognition questionnaire (ICQ) and an ad hoc questionnaire. Receiver Operator Characteristic analysis (ROC) was used to establish the optimal DT cut-off score according to HADS. Correlations of questionnaires scores with data on diagnosis, treatment and follow-up collected from medical records were analyzed. RESULTS: Of the 159 respondents, 145 agreed to participate [118 in remission, median follow-up 7.2 years (range 3 months-41 years)]. Of these, 34.3% rated their distress score ≥5, indicating clinically relevant distress according to ROC analysis. Patients reported physical (86%) over emotional problems (76%) as sources of distress. DT scores correlated with HADS scores and ICQ subscales. No significant correlations were found between DT scores and clinical or demographical characteristics except for employment status. CONCLUSION: Prevalence of distress is high among patients with DTC even after long-term remission and cannot be predicted by clinical and demographical characteristics. DT and PL are useful screening instruments for distress in DTC patients and could easily be incorporated into daily practice.

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

Prevalence of ovarian adrenal rest tumours and polycystic ovaries in females with congenital adrenal hyperplasia: results of ultrasonography and MR imaging.

The aim of the investigation was to assess the prevalence of ovarian adrenal rest tumours and polycystic ovaries in female patients with congenital adrenal hyperplasia (CAH). Thirteen female CAH patients (median age 19.8 years, range 14.8-23.5 years) underwent transvaginal (n=6) or transabdominal (n=7) ultrasonography by a gynaecologist and MR imaging (n=13) of the ovaries (pre and post contrast-enhanced T1- and T2-weighted images). Ovarian adrenal rest tumours were defined as small hypoechoic and multifocal nodules on ultrasound and isointense lesions on T1- and hypointense on T2-weighted MR images (derived from characteristics of testicular adrenal rest tumours). Polycystic ovaries were defined as the presence of > or = 10 follicles arranged peripherally around or scattered throughout increased stroma. No ovarian adrenal rest tumours were found either on ultrasound, or by MR imaging. Polycystic ovaries were found in 2 of the 13 patients (15.4%), both with ultrasound and MR. No ovarian adrenal rest tumours were detected in these female CAH patients, which suggests that ovarian adrenal rest tumours in CAH females are rare. The prevalence of polycystic ovaries corresponded to that in the general population. From these results, we would suggest that routine ovarian imaging in CAH females is not indicated. However, when ovarian dysfunction is present, ovarian imaging is advised, first by ultrasonography, to detect ovarian adrenal rest tumours or polycystic ovaries.

Asymptomatic testicular adrenal rest tumours in adolescent and adult males with congenital adrenal hyperplasia: basal and follow-up investigation after 2.6 years.

AIM: To study the course of asymptomatic testicular adrenal rest tumours in patients with congenital adrenal hyperplasia (CAH) and the association between tumour changes and glucocorticoid therapy adjustments. PATIENTS AND METHODS: Fifteen male patients with CAH (21-hydroxylase deficiency), in whom asymptomatic testicular adrenal rest tumours had been found at a baseline investigation, underwent scrotal ultrasonography and venous blood sampling (for LH, FSH and testosterone) on average 2.6 years later. The level of hormonal control was assessed by measurement of androstenedione in three diurnal saliva samples. Data on changes in glucocorticoid therapy since baseline were obtained from the patients' records. RESULTS: Tumour decrease, defined as > or =30% decrease in the sum of the longest diameter(s) of the lesion(s), was found in six patients; tumour increase, defined as > or =20% increase, in six and stable tumours in three patients. All three patients with overtreatment showed tumour decrease and of the six patients with undertreatment only one showed tumour decrease. Tumour increase was not only observed in undertreated patients but also in patients with adequate treatment. Changing the night dose of hydrocortisone into dexamethasone, to obtain prolonged ACTH suppression, had resulted in better adrenal suppression in only one patient. CONCLUSIONS: Tumour decrease could be achieved by aiming at adrenal oversuppression, but the required high glucocorticoid doses may induce side effects. In asymptomatic tumours in young male patients with CAH, a practical guideline could be to optimise adrenal suppression to a maximal tolerable glucocorticoid dose and to offer analysis and cryopreservation of semen as soon as the patient can be motivated.

The long term outcome of feminizing genital surgery for congenital adrenal hyperplasia: anatomical, functional and cosmetic outcomes, psychosexual development, and satisfaction in adult female patients.

BACKGROUND: There are only a few reports analyzing the long term outcome of feminizing surgery in females with congenital adrenal hyperplasia (CAH). Such analysis is crucial to evaluate the treatment and to make necessary adjustments. STUDY OBJECTIVES: To evaluate the adult outcome after feminizing surgery in adult females with salt wasting CAH. DESIGN: Retrospective observational followup investigation. SETTING: Outpatient clinic of a University Medical Center, in 2002. PARTICIPANTS: Eight patients (born 1973-1983) who underwent feminizing surgery in infancy by the same procedure and the same pediatric surgeon in our center, and 19 healthy female controls (for visual analog scales). METHODS: (a) Study of patients' records (n=8); (b) Systematic evaluation of the current situation (n=6): uroflowmetry, a written questionnaire to screen for psychopathology (Youth Adult Self Report, YASR), structured gynecologic examination and a structured psychosexual interview, including scoring on visual analog scales. RESULTS: (a) The first surgery (age 0.1-3.7 yr) consisted of clitoris reduction and vaginoplasty (single-stage) in 7 patients and clitoris reduction only in one patient. The latter patient had vaginoplasty in puberty. In puberty, 6 of the 7 patients with an initial single-stage procedure required re-vaginoplasty. All 6 patients who participated in this systematic evaluation had undergone (re-) vaginoplasty in puberty; (b) 2 of the 6 patients experienced some urinary incontinence, and in one of them, the uroflowmetry result was abnormal. The YASR showed no psychopathology, except for 1 patient with a slightly elevated externalizing score. Gynecologic examination (n=5) revealed vaginal strictures in 3 patients (1 severe, 2 mild). The 2 patients without vaginal strictures had coitus regularly. In the interview, 2 patients called themselves bisexual, the other 4 heterosexual. None of the patients had homosexual contacts. Sexual developmental milestones (romantic interest, falling in love, kissing and petting, coitus) had been reached by all, except for 1 patient who did not have coitus yet. In the patient group, satisfaction with height, body hair, and external genitalia and sexual fantasies and interest, measured with visual analog scales, was not different compared to the control group, except for satisfaction with total body appearance, which was significantly lower in the patients. CONCLUSION: Despite the poor outcome of the initial single-stage surgery in infancy and the inevitable re-operation in puberty, the adult outcome in our study population seems more positive than the findings in the few previous reports, especially with respect to sexual development and activity.

Monitoring of menstrual cycles, ovulation, and adrenal suppression by saliva sampling in female patients with 21-hydroxylase deficiency.

OBJECTIVE: To investigate the correlation between menstrual cycles, ovulation, and adrenal suppression in congenital adrenal hyperplasia. DESIGN: Prospective observational study. SETTING: An academic outpatient clinic. PATIENT(S): Five females with salt-wasting 21-hydroxylase deficiency, aged 15.5 to 22.9 years; one had amenorrhea, one had irregular bleeding, and three had regular bleeding. INTERVENTION(S): Daily morning saliva sampling for 40 to 280 days. MAIN OUTCOME MEASURE(S): Salivary levels of progesterone (P), 17-hydroxyprogesterone (17-OHP), and androstenedione. RESULT(S): In the amenorrheic patient, the elevated P and 17-OHP levels decreased when the glucocorticoid dose was increased, and subsequently menarche occurred. The androstenedione levels were normal. The correlations between P and 17-OHP levels before and after menarche suggest that adrenal progesterone had prevented menarche. The patient with irregular bleeding showed slightly elevated androstenedione levels and increased levels of 17-OHP and P in an irregular pattern, without correlation in time with vaginal bleeding. Three patients with regular cycles showed a biphasic pattern of P levels, indicating ovulation. CONCLUSION(S): These longitudinal data support the hypothesis that menstrual cycling in females with 21-hydroxylase deficiency can be prevented or disturbed by elevated progesterone levels of adrenal origin, in the absence of androgen excess. Increasing glucocorticoid dose could suppress adrenal progesterone production, resulting in menarche.

Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: in early infancy and (pre)puberty.

In patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, adult height is below target height. This may result from growth inhibition by glucocorticoid treatment. Previous studies suggest that glucocorticoids have a dose-dependent negative effect on growth in CAH patients and that this effect is age dependent. This study analyzed the correlation between glucocorticoid dose and growth in these patients. A retrospective study was carried out on growth data from 48 patients with classic salt-wasting 21-hydroxylase deficiency who all had been diagnosed in the first year of life and treated from the moment of diagnosis with glucocorticoids and mineralocorticoids. Analysis of the effect of prescribed glucocorticoid dose on growth was performed in age intervals, by analysis of covariance (ANCOVA). The dependent variables height for age z-score (HAZ), weight for age z-score (WAZ) (both corrected for secular trend), and weight for height z-score (WHZ), at 10 selected ages (1, 2, 4, 6, 8, 10, 12, 14, 16, and 18 yr) were explained by 1) mean daily glucocorticoid dose per body surface in the preceding age interval; 2) HAZ, WAZ, or WHZ value at the beginning of the age interval; 3) HAZ, WAZ, or WHZ value 1 yr before the beginning of the considered age interval; and 4) midparental height (only for HAZ). ANCOVA showed that the daily glucocorticoid dose had significant negative effects on HAZ between the ages of 6 and 12 months and between the age of 8-10 and 12-14 yr (and a trend toward significance between 10-12 yr). The negative glucocorticoid effect on HAZ in the age interval of 12-14 yr was as large as in the interval between 6 and 12 months of age. Weight and weight for height were not significantly influenced by glucocorticoid dose in any of the age intervals. We conclude that in CAH patients in the first year of life and between the ages of 8 and 14 yr, there is a dose-dependent negative effect of glucocorticoids on linear growth. Therefore, the daily glucocorticoid dose in these periods should be sufficient to avoid androgen excess, but as low as possible to allow optimal linear growth and adult height.

CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. The aim of this study was to assess the frequencies of CYP21 mutations and to study genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of the 370 alleles (31.9%). The most frequent point mutations were I2G (28.1%) and I172N (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in seven unrelated alleles (1.9%). This cluster had been reported before in two other Dutch patients and in two patients in a study from New York, but not in other series worldwide. Six novel mutations were found: 995-996insA, 1123delC, G291R, S301Y, Y376X, and R483Q. Genotype-phenotype correlation (in 87 well documented patients) showed that 28 of 29 (97%) patients with two null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All six patients with mutation P30L, V281L, or P453S (homozygous or compound heterozygous) had nonclassic CAH. The frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in The Netherlands show in general high concordance with previous reports from other Western European countries. However, a cluster of four pseudogene-derived point mutations on exons 7 and 8 on a single allele, observed in almost 2% of the unrelated alleles, seems to be particular for the Dutch population and six novel CYP21 gene mutations were found.

Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features.

The purpose of this study was to investigate the prevalence of testicular adrenal rest tumours in patients with congenital adrenal hyperplasia (CAH), and to describe sonographic and MR features of these lesions. Seventeen postpubertal male CAH patients underwent scrotal sonography, with colour Doppler, and in 16 of them pre- and postcontrast enhanced T1- and T2-weighted MR images of the testes were obtained. Ultrasound revealed lesions in 16 of 17 patients (94%), bilateral in 10 patients and unilateral in 6 patients. The lesions were typically located adjacent to the mediastinum testis. The maximal diameter of the lesions varied from 2 to 40 mm. Margins were blurred in 11 of 31 lesions. Seventeen of the 20 lesions smaller than 2 cm in diameter were hypoechoic, whereas all 11 lesions larger than 2 cm showed hyperechoic reflections. On MR all lesions were isointense on T1- and hypointense on T2-weighted images and lesion margins were clearly defined. Enhancement of the lesions after intravenous contrast was seen in 13 of 15 patients. In our series the prevalence of testicular adrenal rest tumours in postpubertal CAH patients is much higher than in other reported studies. The lesions may develop from some small, hypoechoic, and multifocal nodules and coalesce to large hypoechoic lesions with hyperechoic reflections on ultrasound. As our results suggest that ultrasonography and MR show the lesions equally well, ultrasonography should be the method of first choice for detection and follow-up of these lesions, because it is the cheapest and quickest imaging technique. In case of a partial orchiectomy, MR is recommended because it shows lesion margins optimally.