Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature
Abstract
CONTEXT: 3β-hydroxysteroid dehydrogenase deficiency (3βHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3βHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk. OBJECTIVE: To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation. METHODS: Biochemical, genetic and immunohistochemical investigations on human biomaterials. RESULTS: A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes. CONCLUSIONS: The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.
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HSD3B2 deficiency causes DSD in both sexes: genetic females are mildly virilized because some fetal adrenal DHEA is converted to testosterone by HSD3B1; genetic males synthesize some androgens by peripheral conversion of DHEA, but these are insufficient for complete male genital development.
“HSD3B2 deficiency causes DSD in both sexes: genetic females are mildly virilized because some fetal adrenal DHEA is converted to testosterone by HSD3B1; genetic males synthesize some androgens by peripheral conversion of DHEA, but these are insufficient for complete male genital development (59).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [59]
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
Self-citation
- Authors
- Burckhardt, M.-A., Udhane, S. S., Marti, N., Schnyder, I., Tapia, C., Nielsen, J. E., Mullis, P. E., Rajpert-De Meyts, E., & Flück, C. E.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Flück, Christa E
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-11
- Volume
- 173
- Issue
- 5
- Pages
- K1-K12
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2107795317
- Cited by
- 49
- References
- 45
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 1 · 2015: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- 3β-hydroxysteroid dehydrogenase deficiency, HSD3B2, HSD3B1, 46,XY disorders of sex development, testicular histology, Leydig cells, fertility, gonadal malignancy risk, androgen production, breast augmentation, steroid profiling
- MeSH terms
- Adrenal Hyperplasia, Congenital, Humans, Infant, Newborn, Infertility, Male, Male, Mutation, Puberty, Testis
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