Gonadal function in adult male patients with congenital adrenal hyperplasia

in European Journal of Endocrinology
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  • 1 Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
  • | 2 Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
  • | 3 Klinik für Pädiatrie m.S. Endokrinologie und Diabetologie, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
  • | 4 Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
  • | 5 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  • | 6 Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK
  • | 7 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
  • | 8 Department of Women’s and Children’s Health, Division of Pediatric Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  • | 9 Department of Radiation Oncology, Radiotherapy & OncoImmunology laboratory, RIMLS, Radboud University Medical Center, Nijmegen, the Netherlands
  • | 10 Centre of Reproductive Medicine and Andrology, Clinical Andrology, University Hospital Münster, Münster, Germany
  • | 11 Endocrinologie Pédiatrique, Centre de Référence des Maladies Rares du Développement Sexuel, Hôpital Bicêtre, Université Paris-Sud, Le Kremlin-Bicêtre, France
  • | 12 Department of Pediatric Urology, Radboud University Medical Center, Nijmegen, the Netherlands
  • | 13 Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands
  • | 14 Medizinische Klinik IV, Klinikum der Universität München, München, Germany
  • | 15 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Context

Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH.

Objective

To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort.

Design

Cross-sectional clinical outcome study, including retrospective data from medical records.

Methods

Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes.

Results

At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9–57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1–732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients.

Conclusions

Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Abstract

Context

Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH.

Objective

To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort.

Design

Cross-sectional clinical outcome study, including retrospective data from medical records.

Methods

Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes.

Results

At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9–57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1–732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients.

Conclusions

Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Introduction

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder resulting in impaired adrenocortical steroid synthesis by several enzyme deficiencies. The most common form (>95%) is 21-hydroxylase deficiency (21OHD) with an incidence of 1:15 000, leading to glucocorticoid and often also mineralocorticoid deficiency in combination with androgen excess (1, 2).

Reported fertility and fecundity in men with CAH on routine steroid replacement therapy range from normal to severely impaired. Fertility can be compromised due to primary (hypergonadotropic) hypogonadism or central (hypogonadotropic) hypogonadism (3, 4, 5, 6, 7, 8, 9, 10, 11). In addition, reduced fertility and fecundity rates in CAH can be caused by psychosexual factors (4). Central or secondary hypogonadism is defined as decreased testosterone concentrations in combination with either low or low-normal LH or FSH concentrations. In men with CAH, secondary hypogonadism is most likely caused by the suppressive effect of elevated adrenal androgens (that are aromatized to estrogens) on the hypothalamic-pituitary-gonadal (HPG) axis (6). Differentiation between gonadal and adrenal testosterone is difficult, complicating the diagnosis of hypogonadism in men with CAH. One of the commonest complications in men with CAH is the presence of testicular adrenal rest tumor (TART)s, which can cause disturbances of gonadal function, including mechanical obstruction of the seminiferous tubules. The reported prevalence of TARTs ranges between 12.5% and 94% in the populations studied (4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22).

Until now, the data on fertility outcome in men with CAH are scarce (3, 4, 5, 6, 7, 8, 9, 10, 11) and often derived from studies with patients from a single center or country. Our aim was to study gonadal function in a large European multicenter cohort of male patients with CAH by evaluating hormone concentrations, semen parameters and TART frequency.

Subjects and methods

Subjects

dsd-LIFE is a cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). Fourteen study centers in 6 European countries (France (n = 4), Germany (n = 4), United Kingdom (n = 1), Poland (n = 2), Sweden (n = 1) and the Netherlands (n = 2)) included former and current patients as participants from February 2014 to September 2015. In addition to DSD participants, 121 male participants with CAH (46XY karyotype) aged 16–68 years were recruited as they may face similar clinical challenges as DSD patients, including sex hormone imbalances and fertility problems, although male patients with CAH do not fit into the classification of DSD. Written informed consent was obtained from all participants and/or their parents, with assent of minors. Ethical approvals were obtained as appropriate for each country. The theoretical and methodological framework of the dsd-LIFE study have been published in detail (23). Patients were investigated in their local treatment center. Cross-sectional data were obtained for serum hormone concentrations, semen parameters and testicular imaging. The genotype of patients with 21OHD was classified into genotype groups null, A, B, and C (24). General patient characteristics and clinical parameters included: country of inclusion, age, age at diagnosis, CAH genotype and phenotype, socioeconomic status and obesity, as well as height, weight and BMI throughout the years (at diagnosis, 9 months old, 6 years old, Tanner stage 2, 16 years old and current age). Patients’ educational levels were established according to the EU classification. We combined the standardized ES-ISCED (international standard classification of education) scale to low (ES-ISCED I = less than lower secondary and ES-ISCED II = lower secondary); medium (ES-ISCED IIIb = lower tier upper secondary; ES-ISCED IIIA = upper tier upper secondary; ES-ISCED IV = advanced vocational, sub-degree) and high (ES-ISCED V1 = lower tertiary education, BA level; ES-ISCED V2 = higher tertiary education, ≥MA level). Data were collected during medical examination at study inclusion (cross-sectional) and retrieved from medical records (retrospective data).

Hormonal analysis

Blood samples were taken during day time, but mostly in the morning, before intake of the glucocorticoid medication (23). Total testosterone, SHBG, LH, FSH, inhibin B, AMH, androstenedione, 17-hydroxyprogesterone (17OHP) concentrations and renin/plasma renin activity were measured in the local hospital laboratory and compared to local references. Values are reported in SI or international units and reported as ‘below reference range’, ‘within reference range’, ‘above reference range up to twice the upper limit’ and ‘more than twice the upper limit of the reference range’. To increase the number of patients per category, we combined the latter 2 categories into the category ‘above reference range’.

The serum androstenedione/testosterone ratio (AD/TS) was calculated and divided into normal (<0.5; interpreted as testosterone mainly of testicular origin), ≥0.5 and <1 (significant fraction of testosterone is of adrenal origin) and ≥1 (testosterone mainly of adrenal origin) as suggested by others (25).

Semen analysis

Semen analysis was performed by the local hospital laboratory and interpreted in accordance with the 2010 World Health Organization criteria (26), including sperm concentration (lower reference limit (LRL): 15 × 106/mL), motility (LRL: 40%), morphology (LRL: 4%), vitality (LRL: 58%) and volume (LRL: 1.5 mL).

Imaging of testes

At the study visit, 68 patients (56.2%) underwent testicular ultrasound. The presence of TART at the age of 16 years was also reported retrospectively (in 30/68 patients with cross-sectional TART data). In addition, retrospective data were available for 12 participants based on ultrasound findings or MRI (n = 11) and on histological findings (n = 1).

Paternity

Data about paternity and relationships were collected from the dsd-LIFE questionnaires (23).

Medication and estimation of metabolic control in the past

Patients used different formulations of glucocorticoids, including hydrocortisone, prednisone, prednisolone and dexamethasone. Furthermore, we converted all glucocorticoid preparations to hydrocortisone equivalents, using the following factors for the glucocorticoid equivalent dose: 1 (hydrocortisone), 4 (prednisone or prednisolone), 30 (dexamethasone) and 15 (fludrocortisone) (27). We also calculated mineralocorticoid equivalent dose using the following factors: 1 (hydrocortisone), 0.8 (prednisone or prednisolone), 0 (dexamethasone) and 200 (fludrocortisone) (27). In addition to the serum 17OHP concentrations presented in the section hormonal analysis, we also assessed metabolic control by a subjective rating, of the local examining physician at 5 different time points: at diagnosis, at the age of 9 months, at Tanner stage 2, at age 16 years and at study inclusion, using the following scores: ‘poor’, ‘moderate’, ‘good’, ‘excellent’ or ‘unknown’.

Statistical analysis

SPSS Statistics 22 (SPSS) was used for all analyses. Descriptive analyses were performed for all variables. Depending on normality, mean and 95% confidence intervals (95% CI) or median and interquartile ranges (IQR) were calculated. We compared patients with values below or above reference range to patients with normal values (within the reference range). Odds ratios (OR) with 95% CI were calculated if at least 3 cases were present in both subgroups. If any cell count in the contingency table was zero, OR and 95% CI were calculated manually by using a continuity correction (+0.5 in each cell).

Missing data were evaluated for each variable and the total number of participants in a particular analysis was reported exactly. Analysis of the variables was performed only if the number of participants was ≥25% of the total cohort of male patients with CAH.

Three patients were excluded from part of the analyses as they received testosterone substitution, which directly affects testosterone and gonadotropin concentrations. Two of these patients had data on TART available; these are described in the ‘Results’ section. Furthermore, we excluded 22 patients with missing genotype information and 2 patients with 11β-hydroxylase deficiency from all comparative analyses.

Results

General characteristics of the male CAH cohort

A total of 121 male patients were included in the CAH cohort in the dsd-LIFE study. General characteristics are shown in Table 1. The median age of the study population was 28 years (IQR: 18.5–37.5, range 16–68). Mean height was 170.7 (95% CI: 169.3–172.0) cm and median BMI was 25.6 (IQR: 22.0–29.2) kg/m2 (data available for 119 patients). Nearly all patients had 21OHD (119/121), and 97 were confirmed by molecular genetic analysis. The remaining 2 patients had 11β-hydroxylase deficiency. Among the 97 patients with genetically confirmed 21OHD, 24.7% were classified as genotype null, 38.1% as genotype A, 34.0% as genotype B and 3.1% as genotype C. Glucocorticoids were used by 116 (95.9%) patients, most commonly hydrocortisone, followed by prednisone or prednisolone and dexamethasone. Fludrocortisone was used by 86 patients (71.1%). The patients’ education was intermediate or high in 54.5% and 22.3%, respectively. Furthermore, 54.6% of the patients were in a relationship at the time of study.

Table 1

General characteristic of 121 male patients with congenital adrenal hyperplasia. Continuous variables are displayed as median (IQR) or mean (95% CI), depending on normality of the data. Categorical variables are displayed as number of patients and percentage. Patients with 21-hydroxylase deficiency were classified according to severity of the disease. Genotype was classified in genotype group null (0) to group C (24)

ParameternCohort results
Age, years (median (IQR))12128 (18.5–37.5)
Severity of disease121
 Genotype
  21OHD group 024 (19.8%)
  21OHD group A37 (30.6%)
  21OHD group B33 (27.3%)
  21OHD group C3 (2.5%)
  No mutation analysis done22 (18.2%)
  CYP11B1 mutation2 (1.7%)
Medication121
 Hydrocortisone*67 (55.4%)
 Prednisone, Prednisolone or hydrocortisone & prednisolone^32 (26.4%)
 Dexamethasone or hydrocortisone & dexamethasone#17 (14.0%)
 No medication3 (2.5%)
 Fludrocortisone alone2 (1.7%)
 Fludrocortisone + glucocorticoid84 (69.4%)
Testosterone substitution1213 (2.5%)
Height, cm (mean (95% CI)119170.7 (169.3–172.0)
BMI, kg/m2 (median (IQR))11925.6 (22.0–29.2)
Education112
 Low15 (13.4%)
 Intermediate61 (54.5%)
 High25 (22.3%)
 Other, n/a11 (9.8%)
Partnership situation 108
 In current relationship
 Yes59 (54.6%)
 No49 (45.4%)

*Hydrocortisone retard was used by 2 patients, ^A combination of prednisolone and hydrocortisone was used by 1 patient, 17 patients were on prednisolone, 13 on prednisone, and 1 on prednisone retard, #Dexamethasone was used combined with hydrocortisone in 9 patients, while 8 patients were on dexamethasone; Fludrocortisone given in addition to any of the glucocorticoid combinations listed.

21OHD, 21-hydroxylase deficiency; 95% CI, 95% confidence interval; IQR, interquartile range; n, number of patients.

We analyzed all variables mentioned in the ‘Methods’ section, but we only present in detail the data that differed between the analyzed groups (no overlap in the confidence intervals). In the following sections, we will present data regarding hormone concentrations, semen analysis and TART.

Hormone concentrations

Univariate descriptive analyses of hormone concentrations were performed. The proportion of patients with normal, decreased or increased serum testosterone, LH, FSH, inhibin B, AMH and SHBG concentrations is illustrated in Fig. 1A. Hormone concentrations were below the reference range in 19/97 (19.6%: testosterone), 8/43 (18.6%: inhibin B), 12/90 (13.3%: LH), 9/90 (10.0%: FSH) and 1/69 (1.4%: SHBG) of the participants. SHBG concentrations were above the reference range in 14.5% (10/69).

Figure 1
Figure 1

Hormone concentrations (A) and semen quality (B) in male patients with congenital adrenal hyperplasia. Stacked bars represent percentage of patients within a category. Numbers in the bars represent the specific number of patients within a category, while the total number of patients included in this analysis is stated underneath the x-axis. (A) Hormone concentrations of each patient were measured in the local hospital and compared to the hospitals standard reference ranges. (B) Semen analysis was performed and scored according to World Health Organization 2010 criteria (26): sperm concentration, motility, morphology, and vitality, and semen volume were assessed.AMH, anti-Müllerian hormone; INHB, inhibin B; N, number of patients; T, testosterone.

Citation: European Journal of Endocrinology 178, 3; 10.1530/EJE-17-0862

Table 2 compares testosterone and gonadotropin concentrations in all patients with data on T, LH and FSH available. Seven patients (50%) with decreased testosterone concentrations had decreased gonadotropins, while 6 (42.9%) had normal LH and FSH concentrations and 1 (7.1%) patient had gonadotropin concentrations above reference range. Normal testosterone concentrations were found in 55/69 (79.7%) patients, 44 (80.0%) of whom had normal gonadotropin concentrations, whereas 7 (12.7%) had increased and 4 (7.3%) had decreased concentrations. Decreased testosterone concentrations were clearly associated with decreased LH and/or decreased FSH concentrations (OR: 12.8, 95% CI: 2.9–57.3).

Table 2

Testosterone concentrations, androstenedione/testosterone ratios and gonadotropin concentrations in 83 male patients with congenital adrenal hyperplasia. Testosterone, gonadotropin concentrations and androstenedione/testosterone (AD/T) ratio are presented to identify patients with hypogonadism and with prevalent adrenal-derived hyperandrogenism. The number and percentage of patients in each category are given. Odds ratios with 95% confidence intervals were calculated (testosterone concentrations vs decreased or normal gonadotropins and testosterone concentrations vs increased or normal gonadotropins).

Decreased LH and/or decreased FSH, n (%)Normal LH and normal FSH, n (%)Increased LH and/or increased FSH, n (%)Decreased gonadotropins, OR (95% CI)
Decreased TS7 (50.0%)6 (42.9%)1 (7.1%)12.8 (2.9–57.3)
Normal TS4 (7.3%)44 (80.0%)7 (12.7%)
AD/T >1*10 (45.5%)11 (50.0%)1 (4.5%)39.3 (2.1–732.4)
Normal AD/TS021 (77.8%)6 (22.2%)

*An AD/TS ratio >1 suggests that the testosterone is mainly of adrenal origin.

AD/TS, androstenedione/testosterone ratio; TS, testosterone.

A serum AD/TS ratio was calculated in 49 patients, 22 of whom (44.9%) had an AD/TS ratio ≥1. Ten patients (45.5%) with an AD/TS ≥1 had decreased gonadotropins, while 11 (50.0%) patients had normal gonadotropins and only 1 (4.5%) patient had increased gonadotropins. Normal AD/TS ratios were found in 27/49 (55.1%) patients, 21 of whom had normal gonadotropin concentrations (77.8%), 5 had increased concentrations, but none had decreased gonadotropin concentrations. An AD/TS ratio ≥1 was strongly associated with decreased LH and/or decreased FSH concentrations (OR: 39.3, 95% CI: 2.1–732.4).

Semen analysis

Semen analysis was performed in approximately one-third of the patients (Fig. 1B). Normal values for all known (at least 3 out of 5) semen parameters (normozoospermia) were seen in 11/39 patients in whom semen analysis was performed. Sperm concentration, motility and volume were below the normal ranges in 38.5% (15/39), 35.1% (13/37) and 25.6% (10/39) of the patients, respectively, while morphology and vitality were both impaired in 14.3% (4/28 and 2/14) of the patients. Five of 8 patients (62.5%) with decreased testosterone and gonadotropin concentrations underwent semen analysis, with 4 (80.0%) of them showing abnormal semen parameters (Table 3). In only 2/10 patients with decreased testosterone, but normal gonadotropin concentrations, semen analysis was performed and both had decreased sperm concentrations (7.0 and 10.0 × 106/mL). No statistically significant associations were found.

Table 3

Semen parameters of 5 male patients with CAH and decreased testosterone and gonadotropin concentrations.

Sperm concentration LRL: 15 × 106/mLSperm motility LRL: 40%Sperm morphology LRL: 4%Sperm vitality LRL: 58%Sperm volume LRL: 1.5 mL
p115 × 106/mL35%2%n.d.Normal
p2Normal2%n.d.58%1.1 mL
p37 × 106/mLNormalNormaln.d.Normal
p4Normal35%Normaln.d.1.4 mL
p5NormalNormalNormaln.d.Normal

Eight patients had decreased testosterone and gonadotropin concentrations, of which 5 provided semen samples. Semen analysis was performed and scored according to World Health Organization 2010 criteria (26): sperm concentration, motility, morphology and vitality, and semen volume were assessed.

LRL, lower reference limit; n.d., not determined.

Testicular adrenal rest tumors

TARTs were visualized by ultrasound or MRI at cross-sectional investigation in 28/68 patients. For 1 patient, the diagnosis was based on retrospective histology data. Furthermore, retrospective imaging data were available for 11 men: TARTs were present in 10 of these individuals. In the total population screened, TARTs were present in 39/80 patients (48.8%) of which 34 were bilateral TARTs (87.2%). Documented retrospective TARTs at age 16 years were reported in 16/30 patients (53.3%), all of which were bilateral. In only 2/16 patients (12.5%) with TART reported to be present at age 16 years, TART was no longer observed during the cross-sectional investigation: one patient was misdiagnosed with TART as it appeared to be a varicocele, and in the other patient, TART (size 2 mm) disappeared after treatment with prednisone. This patient was still considered as a patient with TART in all analyses.

Comparison of patients with and without TART

Table 4 shows associations of TART with various variables in the 68 patients with gonadal imaging data (12 patients were excluded due to testosterone substitution, 11β-hydroxylase deficiency or unconfirmed 21-hydroxylase deficiency), comprising 33 patients with and 35 without TARTs. Genotype was associated with the presence of TART: The null genotype group had the highest prevalence of TART (14/18: 77.8%), while the prevalence was 10/27 (37.0%) for genotype group A and 7/21 (33.3%) for genotype group B. The odds of having TART in the null genotype group was 6.0 (1.5–23.1) and 7.0 (1.7–29.4) times higher compared to the genotype groups A and B, respectively. TARTs were also present in both men in the genotype C group and also in 1 CYP11B1-deficient patient (the other CYP11B1 patient did not undergo assessment for TART). The OR of having TART when having a serum androstenedione concentration above the upper limit of normal at the time of the cross-sectional investigation was 3.6 (1.0–12.7). Similar associations were found for serum 17OHP at the cross-sectional investigation, with an OR of 28.0 ( 3.1–252.5) for having TART when 17OHP concentrations were more than twice the upper level of the reference range and an OR of 18.7 (2.2–158.1) when these concentrations were above the reference range compared to concentrations within the reference range.

Table 4

Comparison of genetic and hormonal characteristics between patients with (n=33) and without testicular adrenal rest tumors (n=35). Odds ratios with 95% confidence intervals were calculated for many comparisons, but only odds ratios that clearly or potentially differ from unity are presented. Data are presented as number and percentage for each characteristic.

CharacteristicsWith TARTs (n=33)Without TARTs (n = 35)OR (95%CI)
Genotype*
 Group null14 (77.8%)4 (22.2%)
 Group A10 (37.0%)17 (63.0%)
 Group B7 (33.3%)14 (66.6%)
 Group null – Group A6.0 (1.5–23.1)
 Group null – Group B7.0 (1.7–29.4)
Androstenedione3.6 (1.0–12.7)
 >ref range12 (66.7%)6 (33.3%)
 Within ref range9 (36.0%)16 (64.0%)
17-OHP
 >2× UL ref range16 (66.7%)8 (33.3%)
 > ref range20 (57.1%)15 (42.9%)
 Within ref range1 (6.7%)14 (93.3%)
 >2× UL – within28.0 (3.1–252.5)
 > ref – within18.7 (2.2–158.1)

Odds ratios with 95% confidence intervals were calculated for many comparisons, but only odds ratios that clearly or potentially differ from unity are presented. Data are presented as number and percentage for each characteristic.

*Genotype group C and CYP11B1 category contained only 2 and 1 case(s), respectively and are not included in the analysis.

CI, confidence interval; OR, odds ratio; ref, reference; TART, testicular adrenal rest tumor; UL, upper limit.

Paternity

Data on paternity were available for 113 of the 121 patients, 26 (23.0%) of whom (age range 26–68 years) had fathered a total of 43 children. Three couples had used assisted reproductive techniques (ART) resulting in 4/43 children. One of the men who had used ART had decreased testosterone concentrations, while another had increased FSH, decreased sperm concentration and TART. No information was available about the third patient who had used ART.

Discussion

This unique and relatively large European multicenter study shows that gonadal dysfunction is a common complication in male patients with CAH. Approximately half of the patients were affected by endocrine disturbances of the HPG axis at an adult age and TARTs were present in approximately half of the patients as well.

The difficulty in diagnosing hypogonadism in men with CAH is related to the fact that testosterone measured in serum is a mixture of testosterone of gonadal and adrenal origin (25, 28). Circulating testosterone in male patients with well-controlled CAH is predominantly derived from testicular production, but when there is poor hormonal control, a relevant contribution arises from adrenal steroidogenesis. Until now, no method is able to discriminate between testosterone derived from the testes or the adrenal gland. Therefore, it has been suggested to use the serum AD/TS ratio in male patients with CAH, as this precursor steroid is elevated in serum when serum androgens are predominantly of adrenal origin (25). Our data point toward an association between an AD/TS ratio ≥1 (testosterone mainly of adrenal origin) and decreased LH and/or decreased FSH concentrations, suggesting that adrenal androgens in men with CAH contribute to the suppression of gonadotropins. In approximately half of the patients, either aberrant testosterone or AD/TS ratios, or aberrant gonadotropin concentrations or a combination of both were found. In previous studies, the reported prevalence of endocrine HPG axis disturbances ranged from 20% to 52% (5, 6, 7, 9, 10). However, only 1 other study provided information on testosterone and gonadotropin concentrations in each patient and also indicated hypogonadism in approximately half of the patients (6). We recommend to include the evaluation of the AD/TS ratio in the regular follow-up of male patients with CAH and interpret this ratio in combination with gonadotropin concentrations in order to detect a disturbance of the HPG axis. Our study does not include data on 11-oxygenated androgens, that are generated through conversion of androstenedione and are reported to be elevated in patients with CAH (29, 30). Recent studies indicate that 11-oxygenated androgens are almost entirely derived from the 11beta-hydroxylation of androstenedione in the adrenal, and as they are potent androgens, they can contribute to suppression of the HPG axis (31). However, their exact role in the evaluation of hormonal control and gonadal function in men with CAH has to be established in further studies. Serum AMH and inhibin B are also used as markers for male fertility (32). However, it has been demonstrated that serum AMH concentrations do not correlate with sperm concentration and other male fertility parameters (33). Serum inhibin B, a marker of Sertoli cell function, is known to correlate with spermatogenesis in healthy men (34) and was decreased in 18.6% of our cohort. Semen quality, assessed in one third of the study cohort, was reduced in 40% of the men. Except for the study of Urban and coworkers (3), all other studies on fertility in male patients with CAH showed decreased sperm concentrations ranging from 47.8% to 66% (4, 5, 6, 7, 9, 10). More strikingly, in all studies, only half of the participants participated in semen analysis. Taken together, these data indicate the need for increased awareness on fertility status in patients with CAH and to start performing semen analysis and gonadal function biomarkers assessment from adolescence on, in order to detect disturbances early and allow semen preservation for later fertility purposes.

Data from our cohort indicate, in agreement with previous studies (4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22), that TART is a common complication in males with CAH (with a prevalence of 48.8%) and can have onset as early as in adolescence. In fact, 14 patients with TART at the time of the dsd-LIFE study already had TART at the age of 16 years. TARTs disappeared on treatment with prednisone in only 1 patient, thus indicating that complete regression of TART might only be achieved in a small proportion of the patients. Hence, prevention of the development of TART should be pursued, by optimizing treatment strategies already in childhood. Current standard of care does not include imaging of testes; however, we recommend incorporating testicular ultrasound in routine clinical practice.

In contrast to previous studies (4, 9, 10), we observed an association between the CYP21A2 genotype and the presence of TARTs, with the prevalence of this complication being highest in men with the null CYP21A2 genotype. This supports the current perception that TARTs are more frequently observed in patients with a more severe form of CAH, as these patients are exposed to higher concentrations of ACTH, already in utero, which is thought to be a possible causative factor for TART development (6, 7, 15, 22). However, a clinically relevant finding in this study is that TARTs occur even in less severe forms of 21OHD. In fact, in our study, 2 patients in genotype group C (both compound heterozygous for deletion and P30L mutation) had TARTs. In our current dataset, we could not find an association between genotype and semen quality or genotype and hypogonadism.

We found an association between increased 17OHP concentrations at cross-sectional data assessment and the presence of TART. Although a single 17OHP measurement may not be representative of overall metabolic control, these results could be interpreted as a possible indicator of the patient’s metabolic control in the recent past. Therefore, our results seem to be in accordance with literature reporting higher TART prevalence in patients with poor hormonal control compared to patients with adequate hormonal control (5, 7, 13, 35, 36, 37, 38). The association between increased androstenedione concentrations at cross-sectional data assessment and the presence of TARTs adds evidence to this pathophysiologic concept, even if the AD/T ratios were not clearly associated with TART within this subgroup of patients. Primary gonadal dysfunction may be suggested by raised FSH concentrations. In our dataset, 10 patients (11.1%) had elevated FSH concentrations. Seven of these patients had data on the presence of TART and 4 had evidence of TART. King and coworkers found that testicular failure was a consequence of TART in the majority of cases (10). However, our data are limited and do not allow firm conclusions concerning this issue.

Despite this being the first international multicenter study describing gonadal function in male patients with CAH, the study also has some limitations. All centers included in this consortium are tertiary care centers; therefore, it is possible that the patient groups were selected and that the patients included were more severely affected. Furthermore, serum hormone concentrations were not measured centrally, but in various centers, with a range of different assays. Accounting for this fact, only range variables were used in the data analyses. The median BMI in our patient cohort was 25.6 kg/m2 (range: 22.0–29.2), which is slightly overweight. It has been demonstrated that excess of total and abdominal body fat could represent one cause of fertility impairment in men with CAH (25). Serum total testosterone can be decreased in patients with obesity, as a result of the decreased serum concentration of SHBG. In case of increased serum SHBG (induced by hepatitis, hyperthyroidism or a genetic variant), total testosterone may be increased. Ideally, free testosterone should be measured in these cases, but this requires complex equilibrium dialysis (39). Free testosterone can also be calculated from total testosterone, SHBG and albumin concentrations, but it is crucial that the results of such calculations are compared with the normal range of each separate laboratory. Such data were not available. We are aware that assessment of fertility by paternity numbers in our study was incomplete, as many other factors, including female fertility, were not available. Furthermore, participation in the medical examination was not compulsory for study inclusion. This may have led to even more selection, especially concerning the ultrasound examination and semen analysis. It is likely that only the very motivated patients and the more severely affected patients consented to these additional examinations. Due to the resulting low numbers of available data, multivariable logistic regression analyses were not possible.

In summary, impaired gonadal function is common in adult men with CAH. This is indicated by the presence of TART and/or hypogonadotropic or hypergonadotropic hypogonadism. The risk of TART is highest in men with the most severe enzyme deficiencies underlying CAH. Our data suggest that an association with poor previous hormonal control is likely but requires confirmation by prospective studies. Determination of the serum AD/TS ratio, in addition to serum concentrations of testosterone, androstenedione, LH and FSH may help to differentiate between testicular and adrenal androgens in male patients with CAH and to diagnose gonadal dysfunction. Routinely performed semen analysis, measurement of serum inhibin B and testicular ultrasound investigation already in adolescence are recommended to detect upcoming reproductive problems and to allow for fertility preserving measures, such as sperm banking.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this clinical study.

Funding

dsd-LIFE – The work leading to these results received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 305373. The following author received additional funding: NR: Else Kröner-Fresenius Stiftung (Grant 2011-EKMS.21) and the European Community (Marie Curie European Reintegration Grant PERG-GA-2010-268270).

Acknowledgements

The authors are grateful to the participants of dsd-LIFE and to all of the study centers for their enthusiasm and dedication in contacting potential participants and collecting high-quality data. They especially thank the support groups in the different countries for their help. For an overview of all contributors, we refer to our study protocol (23).

Other members of the dsd-LIFE group are: Peggy Cohen-Kettenis and Annelou de Vries, Amsterdam; Claudia Wiesemann, Gottingen; Jolanta Slowikowska-Hilczer, Lodz; Aude Brac de la Perriere, Lyon; Charles Sultan and Francoise Paris, Montpellier; Ute Thyen, Lubeck; Catherine Pienkowski, Toulouse and Maria Szarras-Czapnik, Warsaw.

References

  • 1

    El-Maouche D, Arlt W & Merke DP. Congenital adrenal hyperplasia. Lancet 2017 390 (10108) 21942210. (https://doi.org/10.1016/S0140-6736(17)31431-9)

  • 2

    Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM & Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 41334160. (https://doi.org/10.1210/jc.2009-2631)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Urban MD, Lee PA & Migeon CJ. Adult height and fertility in men with congenital virilizing adrenal hyperplasia. New England Journal of Medicine 1978 299 13921396. (https://doi.org/10.1056/NEJM197812212992505)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Falhammar H, Nystrom HF, Ekstrom U, Granberg S, Wedell A & Thoren M. Fertility ,sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. European Journal of Endocrinology 2012 166 441449. (https://doi.org/10.1530/EJE-11-0828)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Cabrera MS, Vogiatzi MG & New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2001 86 30703078. (https://doi.org/10.1210/jcem.86.7.7668)

    • Search Google Scholar
    • Export Citation
  • 6

    Stikkelbroeck NM, Otten BJ, Pasic A, Jager GJ, Sweep CG, Noordam K & Hermus AR. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2001 86 57215728. (https://doi.org/10.1210/jcem.86.12.8090)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M & Beuschlein F et al. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2009 94 16651670. (https://doi.org/10.1210/jc.2008-1414)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS & Rees DA et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. Journal of Clinical Endocrinology and Metabolism 2010 95 51105121. (https://doi.org/10.1210/jc.2010-0917)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Bouvattier C, Esterle L, Renoult-Pierre P, de la Perriere AB, Illouz F, Kerlan V, Pascal-Vigneron V, Drui D, Christin-Maitre S & Galland F et al. Clinical outcome, hormonal status, gonadotrope axis, and testicular function in 219 adult men born with classic 21-hydroxylase deficiency. A French National Survey. Journal of Clinical Endocrinology and Metabolism 2015 100 23032313. (https://doi.org/10.1210/jc.2014-4124)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    King TF, Lee MC, Williamson EE & Conway GS. Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clinical Endocrinology 2016 84 830836. (https://doi.org/10.1111/cen.13001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Falhammar H, Frisen L, Norrby C, Almqvist C, Hirschberg AL, Nordenskjold A & Nordenstrom A. Reduced frequency of biological and increased frequency of adopted children in males with 21-hydroxylase deficiency: a Swedish population-based national cohort study. Journal of Clinical Endocrinology and Metabolism 2017 102 41914199. (https://doi.org/10.1210/jc.2017-01139)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Jaaskelainen & Voutilainen R. Long-term outcome of classical 21-hydroxylase deficiency: diagnosis, complications and quality of life. Acta Paediatrica 2000 89 183187. (https://doi.org/10.1111/j.1651-2227.2000.tb01213.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Kamoun M, Mnif MF, Charfi N, Ben Naceur B, Mnif F, Rekik N, Mnif Z, Sfar MH, Sfar MT & Hachicha M et al. Fertility outcome in male and female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Middle East Fertility Society Journal 2014 19 8995. (https://doi.org/10.1016/j.mefs.2013.05.006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Mouritsen A, Jorgensen N, Main KM, Schwartz M & Juul A. Testicular adrenal rest tumours in boys, adolescents and adult men with congenital adrenal hyperplasia may be associated with the CYP21A2 mutation. International Journal of Andrology 2010 33 521527. (https://doi.org/10.1111/j.1365-2605.2009.00967.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Nermoen I, Rorvik J, Holmedal SH, Hykkerud DL, Fougner KJ, Svartberg J, Husebye ES & Lovas K. High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clinical Endocrinology 2011 75 753759. (https://doi.org/10.1111/j.1365-2265.2011.04151.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Delfino M, Elia J, Imbrogno N, Argese N, Mazzilli R, Toscano V & Mazzilli F. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. Journal of Ultrasound in Medicine 2012 31 383388. (https://doi.org/10.7863/jum.2012.31.3.383)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM & Merke DP. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2012 97 44294438. (https://doi.org/10.1210/jc.2012-2102)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Pierre P, Despert F, Tranquart F, Coutant R, Tardy V, Kerlan V, Sonnet E, Baron S, Lorcy Y & Emy P et al. Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients. Annales d’Endocrinologie 2012 73 515522. (https://doi.org/10.1016/j.ando.2012.09.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Reisch N, Rottenkolber M, Greifenstein A, Krone N, Schmidt H, Reincke M, Schwarz HP & Beuschlein F. Testicular adrenal rest tumors develop independently of long-term disease control: a longitudinal analysis of 50 adult men with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2013 98 E1820E1826. (https://doi.org/10.1210/jc.2012-3181)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Dudzinska B, Leubner J, Ventz M & Quinkler M. Sexual well-being in adult male patients with congenital adrenal hyperplasia. International Journal of Endocrinology 2014 2014 469289. (https://doi.org/10.1155/2014/469289)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Bachelot A, Golmard JL, Dulon J, Dahmoune N, Leban M, Bouvattier C, Cabrol S, Leger J, Polak M & Touraine P. Determining clinical and biological indicators for health outcomes in adult patients with childhood onset of congenital adrenal hyperplasia. European Journal of Endocrinology 2015 173 175184. (https://doi.org/10.1530/EJE-14-0978)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Claahsen-van der Grinten HL, Sweep FC, Blickman JG, Hermus AR & Otten BJ. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. European Journal of Endocrinology 2007 157 339344. (https://doi.org/10.1530/EJE-07-0201)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Rohle R, Gehrmann K, Szarras-Czapnik M, Claahsen-van der Grinten H, Pienkowski C, Bouvattier C, Cohen-Kettenis P, Nordenstrom A, Thyen U & Kohler B et al. Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population. BMC Endocrine Disorders 2017 17 52. (https://doi.org/10.1186/s12902-017-0198-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Krone N & Arlt W. Genetics of congenital adrenal hyperplasia. Best Practice and Research: Clinical Endocrinology and Metabolism 2009 23 181192. (https://doi.org/10.1016/j.beem.2008.10.014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Auchus RJ. Management considerations for the adult with congenital adrenal hyperplasia. Molecular and Cellular Endocrinology 2015 408 190197. (https://doi.org/10.1016/j.mce.2015.01.039)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C & Mbizvo MT et al. World health organization reference values for human semen characteristics. Human Reproduction Update 2010 16 231245. (https://doi.org/10.1093/humupd/dmp048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Claahsen-van der Grinten HL, Stikkelbroeck NM, Otten BJ & Hermus AR. Congenital adrenal hyperplasia – pharmacologic interventions from the prenatal phase to adulthood. Pharmacology and Therapeutics 2011 132 114. (https://doi.org/10.1016/j.pharmthera.2011.05.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Rohayem J, Tuttelmann F, Mallidis C, Nieschlag E, Kliesch S & Zitzmann M. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia. European Journal of Endocrinology 2014 170 K11K17. (https://doi.org/10.1530/EJE-13-0449)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Jones CM, Mallappa A, Reisch N, Nikolaou N, Krone N, Hughes BA, O’Neil DM, Whitaker MJ, Tomlinson JW & Storbeck KH et al. Modified-release and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2017 102 17971806. (https://doi.org/10.1210/jc.2016-2855)

    • Search Google Scholar
    • Export Citation
  • 30

    Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ & Merke DP. 11-oxygenated androgens are biomarkers of adrenal volume and testicular adrenal rest tumors in 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2017 102 27012710. (https://doi.org/10.1210/jc.2016-3989)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Pretorius E, Arlt W & Storbeck KH. A new dawn for androgens: novel lessons from 11-oxygenated C19 steroids. Molecular and Cellular Endocrinology 2017 441 7685. (https://doi.org/10.1016/j.mce.2016.08.014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lahlou N, Bouvattier C, Linglart A, Rodrigue D & Teinturier C. The role of gonadal peptides in clinical investigation. Annales De Biologie Clinique 2009 67 283292. (https://doi.org/10.1684/abc.2009.0329)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kucera R, Ulcova-Gallova Z, Windrichova J, Losan P & Topolcan O. Anti-mullerian hormone in serum and seminal plasma in comparison with other male fertility parameters. Systems Biology in Reproductive Medicine 2016 62 223226. (https://doi.org/10.3109/19396368.2016.1161864)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Andersson AM, Petersen JH, Jorgensen N, Jensen TK & Skakkebaek NE. Serum inhibin B and follicle-stimulating hormone levels as tools in the evaluation of infertile men: significance of adequate reference values from proven fertile men. Journal of Clinical Endocrinology and Metabolism 2004 89 28732879. (https://doi.org/10.1210/jc.2003-032148)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Claahsen-van der Grinten HL, Dehzad F, Kamphuis-van Ulzen K & de Korte CL. Increased prevalence of testicular adrenal rest tumours during adolescence in congenital adrenal hyperplasia. Horm Res Paediatr 2014 82 238244. (https://doi.org/10.1159/000365570)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Aycan Z, Bas VN, Cetinkaya S, Yilmaz Agladioglu S & Tiryaki T. Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clinical Endocrinology 2013 78 667672. (https://doi.org/10.1111/cen.12033)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Bachelot A, Plu-Bureau G, Thibaud E, Laborde K, Pinto G, Samara D, Nihoul-Fekete C, Kuttenn F, Polak M & Touraine P. Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 2007 67 268276. (https://doi.org/10.1159/000098017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Poyrazoglu S, Saka N, Agayev A & Yekeler E. Prevalence of testicular microlithiasis in males with congenital adrenal hyperplasia and its association with testicular adrenal rest tumors. Hormone Research in Paediatrics 2010 73 443448. (https://doi.org/10.1159/000313587)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM & Task Force ES. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 25362559. (https://doi.org/10.1210/jc.2009-2354)

    • Crossref
    • Search Google Scholar
    • Export Citation

 

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    Hormone concentrations (A) and semen quality (B) in male patients with congenital adrenal hyperplasia. Stacked bars represent percentage of patients within a category. Numbers in the bars represent the specific number of patients within a category, while the total number of patients included in this analysis is stated underneath the x-axis. (A) Hormone concentrations of each patient were measured in the local hospital and compared to the hospitals standard reference ranges. (B) Semen analysis was performed and scored according to World Health Organization 2010 criteria (26): sperm concentration, motility, morphology, and vitality, and semen volume were assessed.AMH, anti-Müllerian hormone; INHB, inhibin B; N, number of patients; T, testosterone.

  • 1

    El-Maouche D, Arlt W & Merke DP. Congenital adrenal hyperplasia. Lancet 2017 390 (10108) 21942210. (https://doi.org/10.1016/S0140-6736(17)31431-9)

  • 2

    Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM & Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 41334160. (https://doi.org/10.1210/jc.2009-2631)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Urban MD, Lee PA & Migeon CJ. Adult height and fertility in men with congenital virilizing adrenal hyperplasia. New England Journal of Medicine 1978 299 13921396. (https://doi.org/10.1056/NEJM197812212992505)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Falhammar H, Nystrom HF, Ekstrom U, Granberg S, Wedell A & Thoren M. Fertility ,sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. European Journal of Endocrinology 2012 166 441449. (https://doi.org/10.1530/EJE-11-0828)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Cabrera MS, Vogiatzi MG & New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2001 86 30703078. (https://doi.org/10.1210/jcem.86.7.7668)

    • Search Google Scholar
    • Export Citation
  • 6

    Stikkelbroeck NM, Otten BJ, Pasic A, Jager GJ, Sweep CG, Noordam K & Hermus AR. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2001 86 57215728. (https://doi.org/10.1210/jcem.86.12.8090)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M & Beuschlein F et al. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2009 94 16651670. (https://doi.org/10.1210/jc.2008-1414)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS & Rees DA et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. Journal of Clinical Endocrinology and Metabolism 2010 95 51105121. (https://doi.org/10.1210/jc.2010-0917)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Bouvattier C, Esterle L, Renoult-Pierre P, de la Perriere AB, Illouz F, Kerlan V, Pascal-Vigneron V, Drui D, Christin-Maitre S & Galland F et al. Clinical outcome, hormonal status, gonadotrope axis, and testicular function in 219 adult men born with classic 21-hydroxylase deficiency. A French National Survey. Journal of Clinical Endocrinology and Metabolism 2015 100 23032313. (https://doi.org/10.1210/jc.2014-4124)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    King TF, Lee MC, Williamson EE & Conway GS. Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clinical Endocrinology 2016 84 830836. (https://doi.org/10.1111/cen.13001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Falhammar H, Frisen L, Norrby C, Almqvist C, Hirschberg AL, Nordenskjold A & Nordenstrom A. Reduced frequency of biological and increased frequency of adopted children in males with 21-hydroxylase deficiency: a Swedish population-based national cohort study. Journal of Clinical Endocrinology and Metabolism 2017 102 41914199. (https://doi.org/10.1210/jc.2017-01139)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Jaaskelainen & Voutilainen R. Long-term outcome of classical 21-hydroxylase deficiency: diagnosis, complications and quality of life. Acta Paediatrica 2000 89 183187. (https://doi.org/10.1111/j.1651-2227.2000.tb01213.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Kamoun M, Mnif MF, Charfi N, Ben Naceur B, Mnif F, Rekik N, Mnif Z, Sfar MH, Sfar MT & Hachicha M et al. Fertility outcome in male and female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Middle East Fertility Society Journal 2014 19 8995. (https://doi.org/10.1016/j.mefs.2013.05.006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Mouritsen A, Jorgensen N, Main KM, Schwartz M & Juul A. Testicular adrenal rest tumours in boys, adolescents and adult men with congenital adrenal hyperplasia may be associated with the CYP21A2 mutation. International Journal of Andrology 2010 33 521527. (https://doi.org/10.1111/j.1365-2605.2009.00967.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Nermoen I, Rorvik J, Holmedal SH, Hykkerud DL, Fougner KJ, Svartberg J, Husebye ES & Lovas K. High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clinical Endocrinology 2011 75 753759. (https://doi.org/10.1111/j.1365-2265.2011.04151.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Delfino M, Elia J, Imbrogno N, Argese N, Mazzilli R, Toscano V & Mazzilli F. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. Journal of Ultrasound in Medicine 2012 31 383388. (https://doi.org/10.7863/jum.2012.31.3.383)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM & Merke DP. Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2012 97 44294438. (https://doi.org/10.1210/jc.2012-2102)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Pierre P, Despert F, Tranquart F, Coutant R, Tardy V, Kerlan V, Sonnet E, Baron S, Lorcy Y & Emy P et al. Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients. Annales d’Endocrinologie 2012 73 515522. (https://doi.org/10.1016/j.ando.2012.09.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Reisch N, Rottenkolber M, Greifenstein A, Krone N, Schmidt H, Reincke M, Schwarz HP & Beuschlein F. Testicular adrenal rest tumors develop independently of long-term disease control: a longitudinal analysis of 50 adult men with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2013 98 E1820E1826. (https://doi.org/10.1210/jc.2012-3181)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Dudzinska B, Leubner J, Ventz M & Quinkler M. Sexual well-being in adult male patients with congenital adrenal hyperplasia. International Journal of Endocrinology 2014 2014 469289. (https://doi.org/10.1155/2014/469289)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Bachelot A, Golmard JL, Dulon J, Dahmoune N, Leban M, Bouvattier C, Cabrol S, Leger J, Polak M & Touraine P. Determining clinical and biological indicators for health outcomes in adult patients with childhood onset of congenital adrenal hyperplasia. European Journal of Endocrinology 2015 173 175184. (https://doi.org/10.1530/EJE-14-0978)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Claahsen-van der Grinten HL, Sweep FC, Blickman JG, Hermus AR & Otten BJ. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. European Journal of Endocrinology 2007 157 339344. (https://doi.org/10.1530/EJE-07-0201)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Rohle R, Gehrmann K, Szarras-Czapnik M, Claahsen-van der Grinten H, Pienkowski C, Bouvattier C, Cohen-Kettenis P, Nordenstrom A, Thyen U & Kohler B et al. Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population. BMC Endocrine Disorders 2017 17 52. (https://doi.org/10.1186/s12902-017-0198-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Krone N & Arlt W. Genetics of congenital adrenal hyperplasia. Best Practice and Research: Clinical Endocrinology and Metabolism 2009 23 181192. (https://doi.org/10.1016/j.beem.2008.10.014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Auchus RJ. Management considerations for the adult with congenital adrenal hyperplasia. Molecular and Cellular Endocrinology 2015 408 190197. (https://doi.org/10.1016/j.mce.2015.01.039)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C & Mbizvo MT et al. World health organization reference values for human semen characteristics. Human Reproduction Update 2010 16 231245. (https://doi.org/10.1093/humupd/dmp048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Claahsen-van der Grinten HL, Stikkelbroeck NM, Otten BJ & Hermus AR. Congenital adrenal hyperplasia – pharmacologic interventions from the prenatal phase to adulthood. Pharmacology and Therapeutics 2011 132 114. (https://doi.org/10.1016/j.pharmthera.2011.05.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Rohayem J, Tuttelmann F, Mallidis C, Nieschlag E, Kliesch S & Zitzmann M. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia. European Journal of Endocrinology 2014 170 K11K17. (https://doi.org/10.1530/EJE-13-0449)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Jones CM, Mallappa A, Reisch N, Nikolaou N, Krone N, Hughes BA, O’Neil DM, Whitaker MJ, Tomlinson JW & Storbeck KH et al. Modified-release and conventional glucocorticoids and diurnal androgen excretion in congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism 2017 102 17971806. (https://doi.org/10.1210/jc.2016-2855)

    • Search Google Scholar
    • Export Citation
  • 30

    Turcu AF, Mallappa A, Elman MS, Avila NA, Marko J, Rao H, Tsodikov A, Auchus RJ & Merke DP. 11-oxygenated androgens are biomarkers of adrenal volume and testicular adrenal rest tumors in 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism 2017 102 27012710. (https://doi.org/10.1210/jc.2016-3989)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Pretorius E, Arlt W & Storbeck KH. A new dawn for androgens: novel lessons from 11-oxygenated C19 steroids. Molecular and Cellular Endocrinology 2017 441 7685. (https://doi.org/10.1016/j.mce.2016.08.014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lahlou N, Bouvattier C, Linglart A, Rodrigue D & Teinturier C. The role of gonadal peptides in clinical investigation. Annales De Biologie Clinique 2009 67 283292. (https://doi.org/10.1684/abc.2009.0329)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kucera R, Ulcova-Gallova Z, Windrichova J, Losan P & Topolcan O. Anti-mullerian hormone in serum and seminal plasma in comparison with other male fertility parameters. Systems Biology in Reproductive Medicine 2016 62 223226. (https://doi.org/10.3109/19396368.2016.1161864)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Andersson AM, Petersen JH, Jorgensen N, Jensen TK & Skakkebaek NE. Serum inhibin B and follicle-stimulating hormone levels as tools in the evaluation of infertile men: significance of adequate reference values from proven fertile men. Journal of Clinical Endocrinology and Metabolism 2004 89 28732879. (https://doi.org/10.1210/jc.2003-032148)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Claahsen-van der Grinten HL, Dehzad F, Kamphuis-van Ulzen K & de Korte CL. Increased prevalence of testicular adrenal rest tumours during adolescence in congenital adrenal hyperplasia. Horm Res Paediatr 2014 82 238244. (https://doi.org/10.1159/000365570)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Aycan Z, Bas VN, Cetinkaya S, Yilmaz Agladioglu S & Tiryaki T. Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clinical Endocrinology 2013 78 667672. (https://doi.org/10.1111/cen.12033)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Bachelot A, Plu-Bureau G, Thibaud E, Laborde K, Pinto G, Samara D, Nihoul-Fekete C, Kuttenn F, Polak M & Touraine P. Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 2007 67 268276. (https://doi.org/10.1159/000098017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Poyrazoglu S, Saka N, Agayev A & Yekeler E. Prevalence of testicular microlithiasis in males with congenital adrenal hyperplasia and its association with testicular adrenal rest tumors. Hormone Research in Paediatrics 2010 73 443448. (https://doi.org/10.1159/000313587)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM & Task Force ES. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 25362559. (https://doi.org/10.1210/jc.2009-2354)

    • Crossref
    • Search Google Scholar
    • Export Citation