Fertility recovery in patients with non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency

Background. Very little research has been devoted to the studying fertility problem in nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. It is difficult to draw definitive conclusions regarding the need for glucocorticoid therapy in NCAH women based on limited data. Therefore, evaluating fertility in patients with NCAH and exploring the possibility of correcting its disturbances seemed to us to be a matter of importance.

Aims — to evaluate the reproductive function of patients with NCAH and explore potential treatments for this disorder.

Materials and methods. The study group included 60 patients with NCAH aged between 18 and 33 years old. NCAH was diagnosed based on early-morning serum 17-hydroxyprogesterone (17-OHP) levels above 30 nmol/l or 17-hydroxyprogesterone levels after ACTH stimulation above 26 nmol/l and/or characterized by molecular analysis of the CYP21A2 gene. Ultrasonography of the uterus and ovaries were performed in the cycle’s follicular phase. Total testosterone, dehydroepiandrosterone sulfate (DHEAS), Androstenedione, 17-OHP and Progesterone was measured.

Results. Overall, the patients complained of menstrual cycle disorders (60%), infertility — (28%), hirsutism — (63%). Prior to being diagnosed with NCAH, Thirty-four women sought care because of infertility or recurrent miscarriages. Seventeen women (50%) had miscarriages; later on, five of them developed secondary infertility. Two patients became pregnant without treatment being already diagnosed and progressed to delivery. Once the diagnosis of NCAH was made, 58 women started receiving glucocorticoid therapy, Thirty nine (67%) women became pregnant while on glucocorticoid therapy. Thus glucocorticoid therapy reduced the miscarriage rate from 50 to 10.3%; р<0.001. There was no difference in the miscarriage rate between patients who received or quit glucocorticoid therapy during pregnancy.

Conclusions. Glucocorticoid therapy is a highly efficacious method of fertility restoration in NCAH patients. Use of glucocorticoids during pregnancy planning significantly reduced the miscarriage rate. No difference in pregnancy outcome between the patients who received glucocorticoid therapy during pregnancy as opposed to those who did not indicates the advisability of treatment discontinuation once pregnancy is determined.

NCAH, pregnancy, miscarriage, glucocorticoids, CYP21A2

1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21(3):245-291. doi: 10.1210/edrv.21.3.0398

2. White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA. 1986;83(14):5111-5115. doi: 10.1073/pnas.83.14.5111

3. Wedell A, Thilen A, Ritzen EM, et al. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab. 1994;78(5):1145-1152. doi: 10.1210/jcem.78.5.8175971

4. Krone N, Braun A, Roscher AA, et al. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab. 2000;85(3):1059-1065. doi: 10.1210/jcem.85.3.6441

5. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010;2010:625105. doi: 10.1155/2010/625105

6. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133-4160. doi: 10.1210/jc.2009-2631

7. New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2006;91(11): 4205-4214. doi: 10.1210/jc.2006-1645

8. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-47. doi: 10.1093/humrep/deh098

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

10. Bidet M, Bellanné-Chantelot C, Galand-Portier M-B, et al. Fertility in women with nonclassical congenital adrenal yperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2010;95(3):1182-1190. doi: 10.1210/jc.2009-1383

11. Feldman S. Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1992;74(3):635-639. doi: 10.1210/jc.74.3.635

12. Чагай Н.Б., Фадеев В.В. Сложности дифференциальной диагностики и терапии неклассической формы врожденной дисфункции коры надпочечников у пациенток репродуктивного возраста. // Проблемы репродукции. — 2009. — № 3. — С. 93-98. [Chagai NB, Fadeyev VV. Slozhnosti differentsial’noi diagnostiki i terapii neklassicheskoi formy vrozhdennoi disfunktsii kory nadpochechnikov u patsientok reproduktivnogo vozrasta. Modern reproductive technologies. 2009;(3):93-98. (In Russ.)].

13. Терещенко И.В. Глюкокортикоидная терапия врожденной дисфункции коры надпочечников неклассической формы у женщин. // Акушерство и гинекология. — 2016. — № 4. — С. 101-106. [Tereshchenko TIV. Glucocorticoid therapy for nonclassic congenital adrenal hyperplasia in women. Akusherstvo i ginekologiia. 2016;(4):101-106. (In Russ.)]. doi: 10.18565/aig.2016.4.101-106

14. Мельниченко Г.А., Трошина Е.А., Молашенко Н.В., и др. Клинические рекомендации Российской Ассоциации эндокринологов по диагностике и лечебно-профилактическим мероприятиям при врожденной дисфункции коры надпочечников у пациентов во взрослом возрасте. //Consilium Medicum. — 2016. — Т.18. — № 4. — С.8-19. [Mel’nichenko GA, Troshina EA, Molashenko NV, et al. Russian Association of Endocrinologists clinical practice guidelinesfor diagnosis, treatment and preventive measures in congenital adrenal hyperplasia due to 21-hydroxylase deficiency patients in adulthood. Consilium Medicum. 2016;18(4):8-19. (In Russ.].

15. Соболева Е.Л. Дифференциальная диагностика и патогенетическая терапия врожденной гиперплазии коры надпочечников и синдрома поликистозных яичников: Дис. … д-ра мед. наук. — Санкт-Петербург. 2011. [Soboleva EL. Differentsial’naya diagnostika i patogeneticheskaya terapiya vrozhdennoi giperplazii kory nadpochechnikov i sindroma polikistoznykh yaichnikov [dissertation]. Saint-Petersburg. 2011. (In Russ.)]. Доступно по http://www.dissercat.com/content/differentsialnaya-diagnostika-i-patogeneticheskaya-terapiya-vrozhdennoi-giperplazii-kory-nad

16. Parajes S, Quinterio C, Dominguez F, Loidi L. A simple and robust quantitative PCR assay to determine CYP21A2 gene dose in the diagnosis of 21-hydroxylase deficiency. Clin Chem. 2007;53(9):1577-1584. doi: 10.1373/clinchem.2007.087361

17. Lee HH, Chao HT, Ng HT, Choo KB. Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. J Med Genet. 1996;33(5):371-375. doi: 10.1136/jmg.33.5.371

18. Barbat B, Bogyo A, Raux-Demay MC, et al. Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency. Hum Mutat. 1995;5(2):126-130. doi: 10.1002/humu.1380050205

19. Avey R, Honour C. Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms. Clin Endocrinol. 1998;48(6):707-711. doi: 10.1046/j.1365-2265.1998.00402.x

20. Stikkelbroeck NM, Hermus AR, Braat DD, Otten BJ. Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstet Gynecol Surv. 2003;58(4):275-284. doi: 10.1097/01.OGX.0000062966.93819.5B

21. Knobil E. The Neuroendocrine Control of the Menstrual Cycle. Recent Prog Horm Res. 1980;53-88. doi: 10.1016/b978-0-12-571136-4.50008-5

22. Jia XC, Kessel B, Welsh THJr, Hsueh AJ. Androgen inhibition of follicle-stimulating hormone-stimulated luteinizing hormone receptor formation in cultured rat granulosa cells. Endocrinology. 1985;117(1):13-22. doi: 10.1210/endo-117-1-13

23. Okon M. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. Fertil Steril. 1998;69(4):682-690. doi: 10.1016/s0015-0282(98)00007-7