Skip to main content
SpringerLink
Log in

Clinical analysis of 78 patients with nonclassical 21-hydroxylase deficiency

  • Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Retrospectively analyze the clinical characteristics of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) as well as the relationship between the gene mutations and endocrine hormones. In addition, the relationship between different basal 17-hydroxyprogesterone (17OHP) levels and patients’ glucolipid metabolism, hormone levels, pregnancy, and treatment outcomes were examined.

Methods

Clinical data of 78 females with NC21OHD from January 2012 to July 2022 in the Department of Endocrinology and Metabolism of the Third Affiliated Hospital of Guangzhou Medical University were retrospectively analyzed. Diagnosis was based on the 17OHP level combined with clinical manifestations, imaging, and other endocrine hormones and the cytochrome P450 c21, steroid 21-hydroxylase (CYP21A2) gene.

Results

The age at diagnosis of the 78 patients was 29.1 ± 4.2 years; 83.3% (65/78) of the patients had menstrual abnormalities, 70 patients were of childbearing age, and 97.1% (68/70) had a history of infertility with a median time of infertility of 3.6 years. Moreover, 71.8% (56/78) of the patients had polycystic ovaries, 26.9% (21/78) had hyperandrogenemia manifestations on physical examination, 66.7% (52/78) had adrenal hyperplasia, 32.1% (25/78) had combined dyslipidemia, and 41.0% (32/78) had combined insulin resistance. Pathogenic mutations were detected in 78.2% (61/78) of the patients with both CYP21A2 alleles; 14.1% (11/78) of the patients had only one allele and 7.7% (6/78) had no pathogenic mutations. The levels of total testosterone (TT), progesterone (P) (0 min, 30 min), and 17-OHP (0 min, 30 min, 60 min) in the adrenocorticotropic hormone (ACTH) stimulation test varied between the groups. Furthermore, patients with NC21OHD were divided into 17OHP < 2 ng/ml, 2 ng/ml < 17OHP < 10 ng/ml, and 17OHP ≥ 10 ng/ml groups according to their different basal 17OHP levels. The 17OHP ≥ 10 ng/ml group had significantly higher TT, FT4, basal and post-stimulation progesterone, and 17OHP, net value added of 17-hydroxyprogesterone (△17OHP), net value added of 17-hydroxyprogesterone/net value added of cortisol ratio (△17OHP/△F), the incidence of adrenal hyperplasia, and number of gene mutations compared to those of the 17OHP < 2 ng/ml group (P < 0.05). NC21OHD infertile patients who received low-dose glucocorticoids showed a significant increase in pregnancy and live birth rates, and a significant decrease in miscarriage rate (all P < 0.05).

Conclusion

Comprehensive analysis is important as NCCAH diagnoses may be false positive or false negative based on clinical characteristics, hormone levels, and gene detection. Females with NC21OHD showed varying degrees of fertility decline; thus, low doses of glucocorticoid treatment for infertile females with NC21OHD can improve fertility and fertility outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability statement

We confirmed that the data supporting the findings of this study were available within the manuscript.

References

  1. Parsa AA (2016) New MI. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. J Steroid Biochem Mol Biol 165:2–11. https://doi.org/10.1016/j.jsbmb.2016.06.015

    Article  CAS  PubMed  Google Scholar 

  2. Speiser PW, White PC (2003) Congenital adrenal hyperplasia. N Engl J Med 349(8):776–788. https://doi.org/10.1056/NEJMra021561

    Article  CAS  PubMed  Google Scholar 

  3. Guarnotta V, Niceta M, Bono M, Marchese S et al (2020) Clinical and hormonal characteristics in heterozygote carriers of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol 198:105554. https://doi.org/10.1016/j.jsbmb.2019.105554

    Article  PubMed  Google Scholar 

  4. Falhammar H, Nordenström A (2015) Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine 50(1):1–19. https://doi.org/10.1007/s12020-015-0656-0

    Article  CAS  Google Scholar 

  5. Turcu AF, Auchus RJ (2015) Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 44(2):275–296. https://doi.org/10.1016/j.ecl.2015.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  6. Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Azziz R (2017) Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update 23(5):1–20. https://doi.org/10.1093/humupd/dmx014

    Article  CAS  Google Scholar 

  7. Livadas D, Dastamani S et al (2015) The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol 82(4):543–549. https://doi.org/10.1111/cen.12543

    Article  CAS  Google Scholar 

  8. Li R, Mai T, Zheng S, Zhang Y (2022) Effect of metformin and exenatide on pregnancy rate and pregnancy outcomes in overweight or obese infertility PCOS women: long-term follow-up of an RCT. Arch Gynecol Obstet 306(5):1711–1721. https://doi.org/10.1007/s00404-022-06700-3

    Article  CAS  PubMed  Google Scholar 

  9. Amato MC, Guarnotta V, Forti D, Donatelli M et al (2013) Metabolically healthy polycystic ovary syndrome (MH-PCOS) and metabolically unhealthy polycystic ovary syndrome (MU-PCOS): a comparative analysis of four simple methods useful for metabolic assessment. Hum Reprod 28(7):1919–1928. https://doi.org/10.1093/humrep/det105

    Article  CAS  PubMed  Google Scholar 

  10. Papadakis G, Kandaraki EA, Tseniklidi E, Papalou O et al (2019) Polycystic ovary syndrome and NC-CAH: distinct Characteristics and common findings. A Systematic Review. Front Endocrinol 19(10):388. https://doi.org/10.3389/fendo.2019.00388

    Article  Google Scholar 

  11. Nordenstrom A, Falhammar H (2019) MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency. Eur J Endocrinol 180(3):R127–R145. https://doi.org/10.1530/EJE-18-0712

    Article  PubMed  Google Scholar 

  12. Speiser PW, Wiebke A, Auchus RJ, Baskin LS et al (2018) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 103(11):4043–4088. https://doi.org/10.1210/jc.2018-01865

    Article  PubMed  PubMed Central  Google Scholar 

  13. Maud B, Christine B-C, Marie-Béatrice G-P, Véronique T et al (2009) Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 94(5):1570–1578. https://doi.org/10.1210/jc.2008-1582

    Article  CAS  Google Scholar 

  14. Moran C, Azziz R, Carmina E, Dewailly D et al (2000) 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 183(6):1468–1474. https://doi.org/10.1067/mob.2000.108020

    Article  CAS  PubMed  Google Scholar 

  15. Eyal O, Ayalon-Dangur I, Segev-Becker A, Schachter-Davidov A, Weintrob N (2017) Pregnancy in women with nonclassic congenital adrenal hyperplasia: time to conceive and outcome. Clin Endocrinol (Oxf) 87(5):552–556. https://doi.org/10.1111/cen.13429

    Article  CAS  PubMed  Google Scholar 

  16. Cengiz H, Demirci T, Varim C, Cetin S (2021) Establishing a new screening 17 hydroxyprogesterone cut-off value and evaluation of the reliability of the long intramuscular ACTH stimulation test in the diagnosis of nonclassical congenital adrenal hyperplasia. Eur Rev Med Pharmacol Sci 25(16):5235–5240. https://doi.org/10.26355/eurrev_202108_26537

    Article  CAS  PubMed  Google Scholar 

  17. Sahmay S, Tuten A, Gurleyen H, Oncul M, Erel CT (2014) Diagnosis of late-onset congenital adrenal hyperplasia in clinical practice: current evaluation. Minerva Endocrinol 39(3):215–22

    CAS  PubMed  Google Scholar 

  18. Escobar-Morreale HF, Sanchón R, San Millán JL (2008) A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 93(2):527–533. https://doi.org/10.1210/jc.2007-2053

    Article  CAS  PubMed  Google Scholar 

  19. Kusec V, Dumic M et al (2017) Molecular genetic analysis in 93 patients and 193 family membeis with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia. J Steroid Biochem Mol Biol 165(Pt A):51–56. https://doi.org/10.1016/j.jsbmb.2016.03.035

    Article  CAS  PubMed  Google Scholar 

  20. Moran C, Azziz R, Weintrob N, Witchel SF et al (2006) Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin Endocrinol Metab 91(9):3451–3456. https://doi.org/10.1210/jc.2006-0062

    Article  CAS  PubMed  Google Scholar 

  21. Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Golmard JL et al (2010) Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 95(3):1182–1190. https://doi.org/10.1210/jc.2009-1383

    Article  CAS  PubMed  Google Scholar 

  22. Dauber A, Kellogg M, Majzoub JA (2010) Monitoring of Therapy in Congenital Adrenal Hyperplasia. Clin Chem 56(8):1245–1251. https://doi.org/10.1373/clinchem.2010.146035

    Article  CAS  PubMed  Google Scholar 

  23. Speiser PW, Azziz R, Baskin LS, Ghizzoni L et al (2010) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 95(9):4133–4160. https://doi.org/10.1210/jc.2009-2631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moran C, Azziz R (2003) 21-hydroxylase-deficient nonclassic adrenal hyperplasia: the great pretender. Semin Reprod Med 21(3):295–300. https://doi.org/10.1055/s-2003-43307

    Article  CAS  PubMed  Google Scholar 

  25. Hanedan N, Ersoy B, Hanedan C, Ozyurt BC, Taneli F (2022) Effect of the presence of polycystic ovary syndrome-related features on anti-Mullerian hormone and androstenedione levels in adolescents with or without menstrual irregularity. Arch Gynecol Obstet 306(2):523–531. https://doi.org/10.1007/s00404-022-06505-4

    Article  CAS  PubMed  Google Scholar 

  26. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI (1985) High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37(4):650–667 (PMID: 9556656)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wilson RC, Nimkarn S, Dumic M, Obeid J, Azar MR, Najmabadi H, Saffari F, New MI (2007) Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Mol Genet Metab 90(4):414–421. https://doi.org/10.1016/j.ymgme.2006.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Witchel SF (2012) Nonclassic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 19(3):151–158. https://doi.org/10.1097/MED.0b013e3283534db2

    Article  CAS  PubMed  Google Scholar 

  29. Trakakis E, Loghis C, Kassanos D (2009) Congenital adrenal hyperplasia because of 21-hydroxylase deficiency. a genetic disorder of interest to obstetricians and gynecologists. Obstet Gynecol Surv 64(3):177–189. https://doi.org/10.1097/OGX.0b013e318193301b

    Article  PubMed  Google Scholar 

  30. Nordenström A, Falhammar H (2019) Management of endocrine disease: diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency. Eur J Endocrinol 180(3):R127–R145. https://doi.org/10.1530/EJE-18-0712

    Article  PubMed  Google Scholar 

  31. Moran C, Potter HD, Reyna R, Boots LR, Azziz R (1999) Prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess. Am J Obstet Gynecol 181(3):596–600. https://doi.org/10.1016/s0002-9378(99)70498-9

    Article  CAS  PubMed  Google Scholar 

  32. Pall M, Azziz R, Beires J, Pignatelli D (2009) The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 94(2):684–689. https://doi.org/10.1016/j.fertnstert.2009.06.025

    Article  CAS  PubMed  Google Scholar 

  33. Coeli-Lacchini FB, Turatti W, Elias PC, Elias LL et al (2013) A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Gene 526(2):239–45. https://doi.org/10.1016/j.gene.2013.03.082

    Article  CAS  PubMed  Google Scholar 

  34. Mohamed S, El-Kholy S, Al-Juryyan N, Al-Nemri AM, Abu-Amero KK (2015) A CYP21A2 gene mutation in patients with congenital adrenal hyperplasia Molecular genetics report from Saudi Arabia. Saudi Med J 36(1):113–6. https://doi.org/10.15537/smj.2015.1.9697

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wedell A (2011) Molecular genetics of 21-hydroxylase deficiency. Endocr Dev 20:80–87. https://doi.org/10.1159/000321223

    Article  CAS  PubMed  Google Scholar 

  36. Krone N, Rose IT, Willis DS, Hodson J et al (2013) Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom congenital adrenal hyperplasia adult study executive (CaHASE) cohort. J Clin Endocrinol Metab 98(2):E346–E354. https://doi.org/10.1210/jc.2012-3343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. New MI, Abraham M, Gonzalez B, Dumic M et al (2013) Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci USA 110(7):2611–6. https://doi.org/10.1073/pnas.1300057110

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nguyen HH, Eiden-Plach A, Hannemann F, Malunowicz EM et al (2016) Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene. J Steroid Biochem Mol Biol 155(Pt A):126–134. https://doi.org/10.1016/j.jsbmb.2015.10.011

    Article  CAS  PubMed  Google Scholar 

  39. Baranowski ES, Arlt W, Idkowiak J (2018) Monogenic Disorders of Adrenal Steroidogenesis. Horm Res Paediatr 89(5):292–310. https://doi.org/10.1159/000488034

    Article  CAS  PubMed  Google Scholar 

  40. Lacey JM, Minutti CZ, Magera MJ, Tauscher AL et al (2004) Improved specificity of newborn screening for congenital adrenal hyperplasia by second-tier steroid profiling using tandem mass spectrometry. Clin Chem 50(3):621–625. https://doi.org/10.1373/clinchem.2003.027193

    Article  CAS  PubMed  Google Scholar 

  41. Weintrob N, Israel S, Lazar L, Lilos P, Brautbar C, Phillip M, Pertzelan A (2002) Decreased cortisol secretion in nonclassical 21-hydroxylase deficiency before and during glucocorticoid therapy. J Pediatr Endocrinol Metab 15(7):985–991. https://doi.org/10.1515/jpem.2002.15.7.985

    Article  CAS  PubMed  Google Scholar 

  42. Wallensteen L, Zimmermann M, Thomsen Sandberg M, Gezelius A et al (2016) Sex-Dimorphic effects of prenatal treatment with dexamethasone. J Clin Endocrinol Metab 101(10):3838–3846. https://doi.org/10.1210/jc.2016-1543

    Article  CAS  PubMed  Google Scholar 

  43. Falhammar H, Thorén M (2012) Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine 41(3):355–373. https://doi.org/10.1007/s12020-011-9591-x

    Article  CAS  PubMed  Google Scholar 

  44. Mallmann MR, Gembruch U (2022) Clinical spectrum of female genital malformations in prenatal diagnosis. Arch Gynecol Obstet 306(6):1847–1862. https://doi.org/10.1007/s00404-022-06441-3

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, Frisén L, Thorén M, Nordenskjöld A (2008) Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod 23(7):1607–1613. https://doi.org/10.1093/humrep/den118

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the staff at the Endocrinology and Metabolism Department and the Gynecology & Obstetrics Department, the Third Affiliated Hospital of Guangzhou Medical University for assistance with study execution and data collection. In particular, we are grateful to the participants of this study and to Ying Zhang, the professor of department of endocrinology and metabolism at The Third Affiliated Hospital of Guangzhou Medical University.

Funding

This study was supported by Health Science and Technology Project of Guangzhou Health Commission (grant no. 20221A011091) and Guangzhou science and technology project (grant no. 202102010084).

Author information

Author notes

  1. En Liu, Hengcong Luo are co first authors of this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, People’s Republic of China

    En Liu, Hengcong Luo, Kailv Zhou & Ying Zhang

  2. Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, People’s Republic of China

    En Liu, Hengcong Luo, Kailv Zhou & Ying Zhang

Authors
  1. En Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hengcong Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kailv Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Professor YZ was involved in the conception and design of the study. EL and KZ were involved in collecting the data. YZ, EL, and HL performed the data analysis, interpreted the data, and drafted the manuscript and statistical analysis and interpretation of the data. EL and HL, these authors contributed equally to this work, are co first authors of this work. All authors contributed to the article. All the authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Ying Zhang.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

All the procedures performed in this clinical trial were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The studies involving human participants were reviewed and approved by the Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University (approval number 2022103).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, E., Luo, H., Zhou, K. et al. Clinical analysis of 78 patients with nonclassical 21-hydroxylase deficiency. Arch Gynecol Obstet 308, 871–882 (2023). https://doi.org/10.1007/s00404-023-06946-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-023-06946-5

Keywords

Search

Navigation