MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia (CAH)

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. Clinical consequences of gonadal dysfunction include menstrual disturbances in females and hypogonadism and impaired fertility in males and females. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. In females, gonadal dysfunction can result from an overproduction of adrenal androgens including 11-oxygenated C-19 androgens and progestins, and rarely from ovarian adrenal rest tumours. In all patients with CAH, optimal hormonal control is the key for adequate gonadal function. Therefore, regular measurements of adrenal steroids and/or their metabolites should be performed. In addition, markers of the hypothalamus-pituitary-gonadal axis need to be assessed. In females, the regularity of the menstrual cycle should be evaluated. In males, regular evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. When TART is present, counselling on cryopreservation of semen should be offered.

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Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: 6 years of follow-up

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0512 ◽

2019 ◽

Vol 32 (5) ◽

pp. 519-526 ◽

Cited By ~ 1

Author(s):

Gabriela Werneck ◽

Enda M.R. Rodrigues ◽

Rafael M. Mantovani ◽

Jovita S.S. Lane ◽

Ivani N. Silva

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Tumor Progression ◽

Repeated Measures ◽

Laboratory Data ◽

Hormonal Control ◽

Adrenal Hyperplasia ◽

Testicular Adrenal Rest Tumors ◽

Adrenal Rest ◽

Testicular Adrenal Rest

AbstractBackgroundTesticular adrenal rest tumors (TARTs) leading to primary gonadal failure are the main etiology of infertility in congenital adrenal hyperplasia (CAH). We aimed at identifying the evolution of TART and related findings in young CAH patients.MethodsTwelve male patients (3–23 years old) with 21-hydroxilase deficiency (11 with classic salt-wasting form) were included. Testicular ultrasonography (US) was performed in two moments, by a single blinded specialist in pediatric diagnostic imaging. Tumor progression was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical and laboratory data were retrieved from medical records. Serum 17-OH-progesterone (17OHP) and androstenedione concentrations were evaluated during the whole period of follow-up, from the CAH diagnosis. A logistic regression model with repeated measures was developed for the analysis.ResultsThe prevalence of TART was 41.6% (n = 5) in the initial US evaluation and 66.6% (n = 8) after 6 years of follow-up. Tumor progression was detected in 4 of the 5 patients, and 1 presented with a stable tumor. Three patients presented with new tumors in the second evaluation. Most of the patients (n = 11) were pubertal, including a 7-year-old child with TART who presented with central precocious puberty. At regression analysis, it was observed that an inadequate hormonal control led to a 16 times greater chance of a patient to present with TART (OR = 16.08; confidence interval [CI] 95% = 2.38–108.81; p = 0.004).ConclusionsWe found a high prevalence of progressive TART in young pubertal subjects. US testicular screening should help in improving therapeutic optimization in CAH patients to reduce future impairment in fertility.

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Semen quality and testicular adrenal rest tumor development in 46,XY congenital adrenal hyperplasia - the importance of optimal hormonal replacement

Acta Endocrinologica ◽

10.1530/eje-20-1154 ◽

2021 ◽

Author(s):

Julia Rohayem ◽

Lena Maria Bäumer ◽

Michael Zitzmann ◽

Susanne Fricke-Otto ◽

Klaus Mohnike ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Semen Quality ◽

Hormonal Control ◽

Adrenal Hyperplasia ◽

Therapeutic Control ◽

Hydroxy Progesterone ◽

Adrenal Rest ◽

The Impact ◽

Testicular Adrenal Rest

Objective: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumors (TARTs) in young males with congenital adrenal hyperplasia (CAH). Design: Combined cross-sectional and retrospective clinical study. Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as “poor”, “moderate” or “medium”. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. Results: Semen quality was similar in males with CAH and controls (p = 0.066), however patients with “poor” past control and large TARTs, or with “poor” current CAH control, had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was “poor” (1.8 ± 0.9 U/L; “good”: 3.9 ± 2.2 U/L); p = 0.015); luteinizing hormone was decreased if it was “poor” (1.8 ± 0.9 U/L; p = 0.041) or “moderate” (1.9 ± 0.6 U/L; “good”: 3.0 ± 1.3 U/L; p = 0.025). None of the males with “good” past CAH control, 50% of those with “moderate” past control and 80% with “poor” past control had bilateral TARTs. The prevalence of TARTs in males with severe (class null or A) CYP21A2 mutations was 53%, and 25% and 0% in those with milder class B and C mutations, respectively. Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TARTs. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

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Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Acta Endocrinologica ◽

10.1530/eje-07-0201 ◽

2007 ◽

Vol 157 (3) ◽

pp. 339-344 ◽

Cited By ~ 90

Author(s):

Hedi L Claahsen-van der Grinten ◽

Fred C G J Sweep ◽

Johan G Blickman ◽

Ad R M M Hermus ◽

Barto J Otten

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Tumour Size ◽

Inhibin B ◽

Seminiferous Tubules ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gonadal Dysfunction ◽

Adrenal Rest ◽

21 Hydroxylase Deficiency ◽

Testicular Adrenal Rest

Objective: Testicular adrenal rest tumours (TART) are a well-known complication in adult male patients with congenital adrenal hyperplasia (CAH), with a reported prevalence of up to 94%. In adulthood, the tumours are associated with gonadal dysfunction most probably due to longstanding obstruction of the seminiferous tubules. The aim of our study was to determine the presence of TART and their influence on gonadal function in childhood. Design: Retrospective study. Patients and methods: Scrotal ultrasound was performed in 34 children with CAH due to 21-hydroxylase deficiency who were between 2 and 18 years old. FSH, LH, testosterone and inhibin B concentrations were measured in serum of 27 patients. Results: TART were detected by ultrasound in 8 out of 34 (24%) children. In two of them, bilateral tumours were found. All lesions were located in the rete testis. Seven patients had the salt-wasting type of CAH; one patient had the simple virilising type of CAH. Mean tumour size was 4.1 mm (range 2–8 mm). In none of the patients were the tumours palpable. Two children with TART were between 5 and 10 years old, the other six children were above 10 years old. In all children with TART, LH, FSH, testosterone and inhibin B levels were similar to the patients without TART. Conclusion: TART can be found in CAH children before the age of 10 years. The absence of gonadal dysfunction in our group of children suggests that gonadal dysfunction as frequently reported in adult CAH patients with TART develops after childhood.

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Absence of Testicular Adrenal Rest Tumors in Newborns, Infants, and Toddlers with Classical Congenital Adrenal Hyperplasia

10.1101/19005975 ◽

2019 ◽

Author(s):

Mimi S. Kim ◽

Christina M. Koppin ◽

Pankhuri Mohan ◽

Fariba Goodarzian ◽

Heather M. Ross ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Hormonal Control ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Young Males ◽

Testicular Adrenal Rest Tumors ◽

17 Hydroxyprogesterone ◽

Adrenal Rest ◽

21 Hydroxylase Deficiency ◽

Testicular Adrenal Rest

AbstractINTRODUCTIONTesticular adrenal rest tumors (TART) are a known consequence for males with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. TART are associated with potential infertility in adults. However, little is known about TART in very young males with CAH.OBJECTIVEWe assessed the prevalence of TART in newborn, infant, and toddler males with classical CAH via scrotal ultrasound.METHODSMales with CAH had scrotal ultrasounds during the first 4 years of life, evaluating testes for morphology, blood flow, and presence of TART. Newborn screen 17-hydroxyprogesterone (17-OHP) and serum 17-OHP at the time of ultrasound were recorded. Bone ages were considered very advanced if ≥ 2SD above chronological age.RESULTSThirty-one ultrasounds in 16 males were performed. An initial ultrasound was obtained in four newborns at diagnosis (6.8 ±2.1 days), six infants (2.2 ±0.9 months), and six toddlers (2.4 ±0.9 years). Eleven males had at least one repeat ultrasound. A large proportion (11/16) were in poor hormonal control with an elevated 17-OHP (325 ±298 nmol/L). One infant was in very poor hormonal control (17-OHP 447 nmol/L) at initial ultrasound, and two toddlers had advanced bone ages (+3.2 and +4.5 SD) representing exposure to postnatal androgens. However, no TART were detected in any subjects.CONCLUSIONSTART were not found in males up to 4 years of age with classical CAH despite settings with expected high ACTH drive. Further research into the occurrence of TART in CAH may elucidate factors which contribute to the detection and individual predisposition to TART.

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Abstract #108 Large Testicular Adrenal Rest Tumors in a Patient with Congenital Adrenal Hyperplasia

Endocrine Practice ◽

10.1016/s1530-891x(20)47011-9 ◽

2018 ◽

Vol 24 ◽

pp. 5

Author(s):

Boji Varghese ◽

Cassandra Falk ◽

Nisha Nigil Haroon

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Testicular Adrenal Rest Tumors ◽

Adrenal Rest ◽

Testicular Adrenal Rest

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Molecular Characterization of Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia: Lesions With Both Adrenocortical and Leydig Cell Features

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2036 ◽

2015 ◽

Vol 100 (3) ◽

pp. E524-E530 ◽

Cited By ~ 28

Author(s):

Evelien E. J. W. Smeets ◽

Paul N. Span ◽

Antonius E. van Herwaarden ◽

Ron A. Wevers ◽

Ad R. M. M. Hermus ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Cortex ◽

Leydig Cell ◽

Adrenal Hyperplasia ◽

Cell Markers ◽

Expression Levels ◽

Adrenal Tissue ◽

Testicular Adrenal Rest Tumors ◽

Adrenal Rest ◽

Testicular Adrenal Rest

Context: Testicular adrenal rest tumors (TART) are one of the major long term complications in patients with congenital adrenal hyperplasia. Although several adrenal-like properties have been assigned to these benign lesions, the etiology has not been confirmed yet. Objective: The aim of this study was to describe TART in more detail by analyzing several (steroidogenic) characteristics that may be classified as adrenal cortex or Leydig cell specific. Methods: Gene expression analysis by qPCR was performed for 14 genes in TART tissue (n = 12) and compared with the expression in healthy control fibroblasts (nonsteroidogenic control). In addition, a comparison was made with the expression levels in testis tissue (n = 9) and adrenal tissue (n = 13). Results: Nearly all genes were highly expressed in TART tissue, including all genes that encode the key steroidogenic enzymes. TART expression levels are in the majority almost identical to those found in adrenal tissue. The expression of adrenal cortex specific genes (CYP11B1, CYP11B2, and MC2R) in both TART and adrenal tissue is approximately 1000–10 000 times higher compared to that in testes samples. In addition, the Leydig cell markers INSL3 and HSD17B3 were not only found in testes, but also in TART, both at significantly higher levels than in the adrenal (p < 0.01). Conclusion: Our study shows for the first time that TART have multiple steroidogenic properties, which include not only the expression of adrenal cortex but also of Leydig cell markers. Therefore, the origin of these tumors might be a more totipotent embryonic cell type.

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