Fertility in patients with nonclassical congenital adrenal hyperplasia
2019; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2018.11.023
ISSN1556-5653
AutoresMaria I. New, Lucia Ghizzoni, Heino F. L. Meyer‐Bahlburg, Ahmed Khattab, David E. Reichman, Zev Rosenwaks,
Tópico(s)Urologic and reproductive health conditions
ResumoNonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder. Nonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/41239-27332 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/41239-27332 We begin this discussion of nonclassical congenital adrenal hyperplasia (NC-CAH) with a story of a historic family in whom consanguinity may have played a role in their infertility. Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that occurs more frequently in consanguineous families. The great historian Salo Wittmayer Baron, in his study of the Old Testament and the teachings of Jewish history, revealed that an ancient pedigree demonstrated consanguinity (Fig. 1). Sarah, Abraham's wife, was also his niece, the daughter of his dead younger brother, Haran. Sarah was infertile and did not bear Abraham a son until she was 99 years old. One can only speculate whether they may have had nonclassical steroid 21-hydroxylase deficiency, but nonclassical steroid 21-hydroxylase deficiency is well known to be associated with impaired fertility, and consanguinity is frequently observed in families with this deficiency. In 1957, Decourt et al. (1Decourt J. Jayle M.F. Baulieu E. Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production.Ann Endocrinol (Paris). 1957; 18 ([in French]): 416-422PubMed Google Scholar) presented one of the first reports of a mild form of adrenal steroid 21-hydroxylase deficiency. It was not until 1979 that Rosenwaks et al. (2Rosenwaks Z. Lee P.A. Jones G.S. Migeon C.J. Wentz A.C. An attenuated form of congenital virilizing adrenal hyperplasia.J Clin Endocrinol Metab. 1979; 49: 335-339Crossref PubMed Scopus (83) Google Scholar) first described its autosomal recessive pattern of inheritance, which they initially called an attenuated form of congenital virilizing adrenal hyperplasia. Subsequent cases were later confirmed by Birnbaum and Rose (3Birnbaum M.D. Rose L.I. The partial adrenocortical hydroxylase deficiency syndrome in infertile women.Fertil Steril. 1979; 32: 536-541Abstract Full Text PDF PubMed Scopus (22) Google Scholar), who referred to the disorder as partial adrenocortical hydroxylase deficiency syndrome. In contrast to classical CAH, this milder form of CAH is associated with partial retention of 21-hydroxylase enzyme activity: salt wasting is not encountered, anatomic changes are not evident at birth, and biochemical findings are less pronounced. The disorder is characterized in adolescent and adult females by hyperandrogenemia, oligo-ovulation, and infertility (Fig. 2). Affected males, on the other hand, do not generally exhibit symptoms, except in rare cases of testicular adrenal rest tumors, which are associated with classical disease (4Tanaka M. Enatsu N. Chiba K. Fujisawa M. Two cases of reversible male infertility due to congenital adrenal hyperplasia combined with testicular adrenal rest tumor.Reprod Med Biol. 2018; 17: 93-97Google Scholar). In 1986, Dewailly et al. (5Dewailly D. Vantyghem-Haudiquet M.C. Sainsard C. Buvat J. Cappoen J.P. Ardaens K. et al.Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency.J Clin Endocrinol Metab. 1986; 63: 418-423Crossref PubMed Scopus (132) Google Scholar) characterized the various clinical phenotypes and HLA genotypes for the condition. Although varying clinical severities of CAH had always been observed, it was not until 2006 that the seminal work by New (6New M.I. Extensive clinical experience: nonclassical 21-hydroxylase deficiency.J Clin Endocrinol Metab. 2006; 91: 4205-4214Crossref PubMed Scopus (255) Google Scholar) described the specific hormonal and genetic criteria for the diagnosis and gene map for CAH (Figure 3, Figure 4, Figure 5).Figure 3HLA region of chromosome 6p. The active gene is 21B, and the pseudogene is 21A. (Figure 6 from New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endo Metab 2006;91:4205-14.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4The two homologs: CYP21A2 (the active gene) and CYP21A1P (the pseudogene). Mutations associated with nonclassical 21-hydroxylase deficiency (NC21OHD) are indicated with black squares (exons 1, 7, 8, and 10). (Figure 2 adapted from New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endo Metab 2006;91:4205-14.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Spectrum of disease severity correlated with CYP21A2 mutations. (Figure 3a.8 from New MI. Chapter 3A. In: New MI, Yuen TT, Parsa A, Lekarev O, eds. Genetic steroid disorders. New York: Elsevier, 2014.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) In this context, it is worthwhile to describe the discovery by New of the first nonclassical case of CAH. New was taking care of a young man who had classical simple virilizing CAH and was definitively genotyped to have simple virilizing CAH. Then because New was interested in seeing which mutations came from which parent, she genotyped the parents. When she received the hormone results from the father, she was surprised to find that he was hormonally affected. His genetics revealed that he was a compound heterozygote, having a severe and a mild mutation (Ex7/Ex4, Ex6). He passed his severe mutation to his son, who then received a second severe mutation from his mother, thus resulting in the classical simple virilizing CAH. The father then suggested that his own sister may also have this nonclassical form of CAH because she did not have menstrual periods and struggled with infertility. On genotyping his sister, she was indeed found to be a compound heterozygote like her brother, the very first patient diagnosed with nonclassical 21-hydroxylase deficiency. NC-CAH is one of the most common autosomal recessive disorders, and the most common genetic steroid disorder. Estimating the exact prevalence of NC-CAH is challenging, however, given that newborn screening does not reveal an elevated 17-OH progesterone (17-OHP), and genital ambiguity is not observed in either male or female newborns. The prevalence of this disorder in early childhood has thus likely been grossly underestimated. Typically, the disorder manifests later in life but can sometimes be evident in childhood, presenting as premature pubarche, acne, and accelerated bone age. Moreover, diagnosis in adults is often obscured by the overlapping of symptoms with polycystic ovary syndrome (PCOS). Indeed, the prevalence of NC-CAH has been estimated in certain populations to be as high as 1 in 27 (7New M.I. Abraham M. Gonzalez B. Dumic M. Razzaghy-Azar M. Chitayat D. et al.Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing 21-hydroxylase deficiency.Proc Natl Academy Science. 2013; 110: 2611-2616Crossref PubMed Scopus (220) Google Scholar). The genotypes of nonclassical 21-hydroxylase deficiency are ethnic specific, with the highest prevalence observed in Ashkenazi Jews (Fig. 6, Table 1).Table 1Ethnic-specific genotype frequencies (%) of nonclassical 21-hydroxylase deficiency (NC21OHD) probands.Ethnic groupnExon 7/Exon 7Exon 7/Intron 2Deletion/Exon 7OtherAshkenazi Jews14050181814African Americans4250075Hispanics3324272128Italian Americans4817191549Non-Jewish Caucasians921716760Total31731181536Table 1 from New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endo Metab 2006;91:4205-14. Open table in a new tab Table 1 from New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endo Metab 2006;91:4205-14. Diagnosis of NC-CAH is frequently made by reproductive endocrinologists, as infertility is a frequent presenting symptom; in 13% of NC-CAH cases, infertility is the symptom precipitating evaluation and diagnosis (8Trakakis E. Loghis C. Kassanos D. Congenital adrenal hyperplasia because of 21-hydroxylase deficiency: a genetic disorder of interest to obstetricians and gynecologists.Obstet Gynecol Surv. 2009; 64: 177-189Crossref PubMed Scopus (28) Google Scholar). In women for whom the diagnosis is suspected, a morning 17-OHP level can be assessed in the follicular phase (care should be taken to avoid assessment in the luteal phase, during which levels may be transiently elevated due to progesterone production). All patients presenting with a PCOS-like phenotype should be screened before a diagnosis of PCOS is made, given the significant phenotypic overlap of these two conditions. A morning follicular phase 17-OHP level of >200 ng/dL strongly suggests the diagnosis, which can then be confirmed via a high-dose corticotropin stimulation test, with measurement of 17-OHP levels at baseline and 60 minutes after adrenocorticotropic hormone administration (9Azziz R. Hincapie L.A. Knochenhauer E.S. Dewailly D. Fox L. Boots L.R. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study.Fertil Steril. 1999; 72: 915-925Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). A corresponding 17-OHP nomogram has been published that allows the clinician to subsequently categorize the patient's diagnosis according to the elicited hormone data (Fig. 7) (10New M.I. Lekarev O. Parsa A. Yuen T.T. O'Malley B.W. Hammer G.D. Genetic steroid disorders. Elsevier, Amsterdam2014Google Scholar). For patients in whom the diagnosis of NC-CAH is made based on dynamic hormone testing, sequencing of the 21-hydroxylase gene can determine the mutation present and help to clarify the risks to a potential fetus of an NC-CAH affected individual based on the known severity of the mutation (Fig. 8). Male partners of affected female patients should similarly have sequencing of the 21-hydroxylase gene performed so as to determine the risk to offspring. Dynamic hormone testing of the male partner is less useful in this scenario. The projected probability for an NC-CAH mother to have a female infant affected with classical CAH is 1 in 720 (11Speiser P.W. Knochenhauer E.S. Dewailly D. Fruzzetti F. Marcondes J.A. Azziz R. A multicenter study of women with nonclassical congenital adrenal hyperplasia: relationship between genotype and phenotype.Mol Genet Metab. 2000; 71: 527-534Crossref PubMed Scopus (76) Google Scholar, 12Deneux C. Tardy V. Dib A. Mornet E. Billaud L. Charron D. et al.Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.J Clin Endocrinol Metab. 2001; 86: 207-213Crossref PubMed Scopus (0) Google Scholar). Such couples are thus at a significantly higher risk of having an infant with classical CAH than the general population (∼1:16,000-1:20,000 live births) (13White P.C. Neonatal screening for congenital adrenal hyperplasia.Nat Rev Endocrinol. 2009; 5: 490-498Crossref PubMed Scopus (159) Google Scholar). Moreover, these patients should be counseled that there is a roughly 1 in 32 chance of conceiving a fetus with the same disorder (14Reichman D.E. White P.C. New M.I. Rosenwaks Z. Fertility in patients with congenital adrenal hyperplasia.Fertil Steril. 2014; 101: 301-309Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). These statistics may be underestimated, however, given the propensity toward intermarriage within certain populations in which carrier frequencies are enriched. In a specific study examining the offspring of women with NC-CAH, 4 out of 162 live-born infants (2.5%) were diagnosed with classical disease (15Moran C. Azziz R. Weintrob N. Witchel S.F. Rohmer V. Dewailly D. et al.Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia.J Clin Endocrinol Metab. 2006; 91: 3451-3456Crossref PubMed Scopus (118) Google Scholar). In fetuses that are determined to be at risk, cell-free fetal DNA testing can now aid in noninvasive prenatal diagnosis (16New M.I. Tong Y.K. Yuen T. Jiang P. Pina C. Chan K.C. et al.Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma.J Clin Endocrinol Metab. 2014; 99: E1022-E1030Crossref PubMed Scopus (183) Google Scholar). Such early noninvasive diagnosis can aid in ruling out females at risk for ambiguous genitalia, thus obviating the use of experimental treatment with dexamethasone to suppress fetal androgen production. The pathophysiology of NC-CAH, in terms of the exact mechanisms by which elevated androgen production impairs ovulation, remains complex and somewhat poorly understood (17Azziz R. Slayden S.M. The 21-hydroxylase-deficient adrenal hyperplasias: more than ACTH oversecretion.J Soc Gynecol Investig. 1996; 3: 297-302Crossref PubMed Scopus (17) Google Scholar). While it was initially presumed that hyperandrogenemia leads to excess estrogen via peripheral aromatization, subsequent lines of inquiry have focused on the direct effects of elevated androgens on the gonadotropin-releasing hormone (GnRH) pulse generator itself (18Ravichandran K.G. Boddupalli S.S. Hasermann C.A. Peterson J.A. Deisenhofer J. Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450's.Science. 1993; 261: 731-736Crossref PubMed Scopus (907) Google Scholar). Treatment with steroids in CAH patients leads to normalization of luteinizing hormone (LH) levels and LH responsiveness to GnRH pulses, underscoring this mechanism (19Geley S. Kapelari K. Johrer K. Peter M. Glatzl J. Vierhapper H. et al.CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.J Clin Endocrinol Metab. 1996; 81: 2896-2901Crossref PubMed Scopus (108) Google Scholar). On the other hand, direct treatment of PCOS patients with androgens fails to alter basal LH secretion, although high-dose androgens slightly reduced follicle-stimulating hormone concentration in women with PCOS (20Dunaif A. Do androgens directly regulate gonadotropin secretion in the polycystic ovary syndrome?.J Clin Endocrinol Metab. 1986; 63: 215-221Crossref PubMed Scopus (78) Google Scholar). Thus, the exact mechanism by which elevated androgens affect the hypothalamus and pituitary remains somewhat obscure. The elevated androgens encountered in NC-CAH also exhibit complex effects on the ovary itself. Elevated adrenal androgens have been demonstrated to inhibit granulosa cell aromatase activity in vitro, but direct administration of androgens leads to thickening of the ovarian capsule, an overall increase in the size of the ovary, and an expansion in the number of preantral follicles (21Jia X.C. Kessel B. Welsh Jr., T.H. Hsueh A.J. Androgen inhibition of follicle-stimulating hormone-stimulated luteinizing hormone receptor formation in cultured rat granulosa cells.Endocrinology. 1985; 117: 13-22Crossref PubMed Scopus (42) Google Scholar, 22Vendola K.A. Zhou J. Adesanya O.O. Weil S.J. Bondy C.A. Androgens stimulate early stages of follicular growth in the primate ovary.J Clin Invest. 1998; 101: 2622-2629Crossref PubMed Scopus (552) Google Scholar). Given the colocalization of androgen receptor and follicle-stimulating hormone receptor mRNA in granulosa cells, it is not surprising that androgens are complex modulators of ovarian steroidogenesis with varying effects modulated by the extent and duration of androgen exposure (23Weil S. Vendola K. Zhou J. Bondy C.A. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development.J Clin Endocrinol Metab. 1999; 84: 2951-2956Crossref PubMed Scopus (454) Google Scholar). Although patients affected with classical disease routinely require treatment with exogenous steroids, many individuals with NC-CAH will conceive with little or no intervention. Patients with classical disease routinely have significant anovulation and progesterone elevation in the follicular phase, as opposed to NC-CAH patients in whom oligo-ovulation is more common and progesterone elevation in the follicular phase is rarely encountered. In a longitudinal study of 95 patients with NC-CAH, 57.2% conceived without specific hormone treatments (24Bidet M. Bellanne-Chantelot C. Galand-Portier M.B. Golmard J.L. Tardy V. Morel Y. et al.Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.J Clin Endocrinol Metab. 2010; 95: 1182-1190Crossref PubMed Scopus (143) Google Scholar). This subset of patients had particularly mild phenotypes; patients exhibiting more pronounced hyperandrogenic symptoms are more likely to require treatment with glucocorticoids, but this intervention alone is typically sufficient to elicit ovulation. This type of successful treatment with low-dose glucocorticoids was first reported by Rosenwaks et al. in 1979 (2Rosenwaks Z. Lee P.A. Jones G.S. Migeon C.J. Wentz A.C. An attenuated form of congenital virilizing adrenal hyperplasia.J Clin Endocrinol Metab. 1979; 49: 335-339Crossref PubMed Scopus (83) Google Scholar). In a later study of 20 affected patients undergoing treatment for infertility, only 1 required additional treatment beyond glucocorticoids (25Feldman S. Billaud L. Thalabard J.C. Raux-Demay M.C. Mowszowicz I. Kuttenn F. et al.Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency.J Clin Endocrinol Metab. 1992; 74: 635-639Crossref PubMed Scopus (0) Google Scholar). Glucocorticoids can also be used for acne and hirsutism, albeit requiring much longer duration for symptom resolution (Fig. 9). For patients who are either poor candidates for glucocorticoids or in whom adverse reactions are noted, clomiphene citrate or aromatase inhibitors such as letrozole are often enough to induce ovulation (26Laohaprasitiporn C. Barbieri R.L. Yeh J. Induction of ovulation with the sole use of clomiphene citrate in late-onset 21-hydroxylase deficiency.Gynecol Obstet Invest. 1996; 41: 224-226Crossref PubMed Scopus (15) Google Scholar). For the most refractory patients, oral ovulation induction agents or judiciously dosed injectable gonadotropins can be superimposed on low-dose glucocorticoid treatment, with a careful eye toward avoiding multifollicular recruitment and ensuing multiple gestations. Nonclassical CAH is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having PCOS, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms that are a cornerstone of the disease.
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