Gonadal function in adult male patients with congenital adrenal hyperplasia

Engels, Manon; Gehrmann, Katharina; Falhammar, Henrik; Webb, Emma; Nordenström, Anna; Sweep, Fred C.G.J.; Span, P.N.; Herwaarden, Antonius E. van; Rohayem, Julia; Richter-Unruh, A; Bouvattier, Claire; Köhler, Birgit; Kortmann, Barbara; Arlt, Wiebke; Roeleveld, Nel; Reisch, Nicole; Stikkelbroeck, Nike M. M. L.; Grinten, Hedi L Claahsen–van der; _, _; Cohen-Kettenis, Peggy; Vries, Annelou de; Wiesemann, Claudia; Słowikowska-Hilczer, Jolanta; Perrière, Aude Brac de la; Sultan, Charles; Paris, Florentin; Thyen, Ute; Pienkowski, Catherine; Szarras‐Czapnik, Maria

doi:10.1530/eje-17-0862

Cited by 59 publications

(50 citation statements)

References 38 publications

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“…Fertility in males with CAH has been reported to be severely impaired (89,113,114,115,116,117), mainly due to hyper-or hypogonadotrophic hypogonadism. Testicular adrenal rest tumours (TARTs) were present in up to 86-94% of all adolescents and adults with CAH (114,118).…”

Section: Menmentioning

confidence: 99%

“…In spite of all this, almost nothing was known about male fertility in NCAH (18) until recently (116). TARTs had only been described in occasional males with NCAH (114,117); hence, it was assumed that the fertility would be less affected in males with NCAH. This was recently confirmed in the largest study investigating fertility outcomes including 221 males with CAH and 22 024 matched controls (116).…”

Section: Menmentioning

confidence: 99%

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MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

Nordenström

Falhammar

2019

European Journal of Endocrinology

110

124

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Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.

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Section: Menmentioning

confidence: 99%

Section: Menmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

Nordenström

Falhammar

2019

European Journal of Endocrinology

110

124

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“…However, factors other than poor hormonal control have been implicated in the development of TART; these include testicular 'misplacement' of adrenal cells during development, with prenatal exposure to increased ACTH levels, and the presence of pluripotent cells which can differentiate into adrenocortical cells after ACTH stimulation (34,35).…”

Section: Discussionmentioning

confidence: 99%

Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis

Kallali

Gray²,

Mehdi

et al. 2020

European Journal of Endocrinology

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Objective CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array. Family study The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative. In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15–20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART). Conclusion This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART.

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“…In patients with CAH and during period of suboptimal [16] (P22H, p.Pro221His) Female Premature pubarche Moisan [16] (G294V, p.Gly294Val) Male Hypospadias Moisan [16] SW Salt wasting treatment, high levels of ACTH and angiotensin II can stimulate adrenal-like cells causing development of testicular adrenal rest tumors (TARTs) and rarely ovarian adrenal rest tumors [75,87]. The prevalence of TARTs varies between 34 and 94% according to different reports in males with CAH due to 21OHD [82,85,88,89]. TARTs have been reported in some patients with 3βHSD2D [15,63,75], but it is difficult to estimate the prevalence.…”

Section: Testicular Adrenal Rest Tumorsmentioning

confidence: 99%

Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency

2019

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Purpose 3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare variant of congenital adrenal hyperplasia (CAH) causing less than 0.5% of all CAH. The aim was to review the literature. Methods PubMed was searched for relevant articles. Results 3βHSD2D is caused by HSD3B2 gene mutations and characterized by impaired steroid synthesis in the gonads and the adrenal glands and subsequent increased dehydroepiandrosterone (DHEA) concentrations. The main hormonal changes observed in patients with 3βHSD2D are elevated ratios of the Δ5-steroids over Δ4-steroids but molecular genetic testing is recommended to confirm the diagnosis. Several deleterious mutations in the HSD3B2 gene have been associated with saltwasting (SW) crisis in the neonatal period, while missense mutations have been associated with a non-SW phenotype. Boys may have ambiguous genitalia, whereas girls present with mild or no virilization at birth. The existence of non-classic 3βHSD2D is controversial. In an acute SW crisis, the treatment includes prompt rehydration, correction of hypoglycemia, and parenteral hydrocortisone. Similar to other forms of CAH, glucocorticoid and mineralocorticoid replacement is needed for long-term management. In addition, sex hormone replacement therapy may be required if normal progress through puberty is failing. Little is known regarding possible negative long-term consequences of 3βHSD2D and its treatments, e.g., fertility, final height, osteoporosis and fractures, adrenal and testicular tumor risk, and mortality. Conclusion Knowledge is mainly based on case reports but many long-term outcomes could be presumed to be similar to other types of CAH, mainly 21-hydroxylase deficiency, although in 3βHSD2D it seems to be more difficult to suppress the androgens.

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Gonadal function in adult male patients with congenital adrenal hyperplasia

Cited by 59 publications

References 38 publications

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis

Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency

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