Adolescence Emerges as Decisive Window for Fertility Care in Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia, or CAH, has long been understood as a disorder of hormones and metabolism, but a new comprehensive review published in Frontiers in Adolescent Medicine makes a compelling case that its most underappreciated consequences unfold in a place few clinicians look: the reproductive lives of teenagers. The review, led by Lea Tschaidse, Matthias K. Auer, Hanna F. Nowotny and Nicole Reisch of LMU University Hospital in Munich, argues that adolescence is not simply a transitional phase for young people with CAH but a decisive window in which fertility, sexuality and long-term reproductive health can either be safeguarded or quietly compromised. Drawing on decades of epidemiological and endocrine research, the authors lay out a detailed map of how the disease interferes with reproduction in both sexes and what clinicians can do about it before parenthood is ever on the horizon.

CAH is a group of autosomal recessive disorders caused by defects in the enzymes that manufacture cortisol in the adrenal glands. In roughly 90 percent of cases, the culprit is a mutation in the gene encoding 21-hydroxylase. When cortisol production falls short, the pituitary gland responds by pumping out adrenocorticotropic hormone, or ACTH, which chronically stimulates the adrenals and drives them to overproduce androgens. The severity of the resulting disease depends on how much residual enzyme activity remains. The classic salt-wasting form typically announces itself in the newborn period, the simple virilizing form preserves partial cortisol production, and the milder non-classic form often goes undetected until adolescence or adulthood, sometimes only surfacing during an infertility work-up. Diagnosis hinges on measuring 17-hydroxyprogesterone, the steroid precursor that accumulates when 21-hydroxylase is deficient, with newborn screening now enabling early detection of classic disease.

For girls and women with classic CAH, the endocrine obstacles to reproduction are formidable. Adrenal androgen excess disrupts follicular maturation and ovulation, while elevated 17-hydroxyprogesterone acts much like a contraceptive progestin: it binds the progesterone receptor or is converted to progesterone itself, thickening cervical mucus, impairing endometrial development and suppressing ovulation. Elevated androgens and progesterone can also disturb the pulsatile secretion of luteinizing hormone, further scrambling menstrual cycles. The clinical data are sobering. In a Swedish population-based cohort of 272 women with CAH, only 25.4 percent had at least one child, and affected women had fewer children and were older at the birth of their first child than controls. Menstrual disturbances occur in more than 30 percent of women with classic CAH who are not using hormonal contraception, and more severe genotypes are consistently associated with poorer reproductive outcomes.

Yet the picture is far from hopeless, and the review emphasizes that biology is only part of the story. Adequate glucocorticoid replacement can restore hormonal balance, and in well-controlled patients fecundity can approach that of the general population. In a multicenter study of 72 adult women with different CAH phenotypes, time to pregnancy was often prolonged, with a median ranging from 8 to 24 months, and about a quarter of the women required fertility-enhancing medication or assisted reproductive techniques. Despite that, live birth numbers per woman and miscarriage rates were broadly comparable to the general population. Intriguingly, lower birth rates in women with classic CAH may partly reflect a reduced desire for parenthood rather than absolute infertility: only 23.6 percent of women with classic disease in one study expressed a wish for pregnancy, compared with nearly half of women with non-classic CAH, a gap that points squarely at psychosocial influences.

Those psychosocial influences run deep. Psychosexual development in girls with classic CAH is shaped by prenatal androgen exposure, chronic endocrine imbalance, genital reconstructive surgery and body image concerns, factors that accumulate from early childhood onward. Females with CAH report higher rates of sexual dysfunction than controls, including vaginal stenosis, reduced lubrication, diminished genital sensitivity and painful intercourse, and in one cohort more than one-third of women with CAH had never engaged in vaginal intercourse at all. Repeated surgical procedures in childhood and adolescence carry significant psychological burden, and women with null mutations report lower sexual satisfaction and more surgical complications. Gender identity presents additional complexity: reviews suggest roughly 94.8 percent of 46,XX individuals raised as girls maintain a female gender identity, with about 4 to 5 percent experiencing gender identity difficulties, rates that rise substantially in those raised as males. Factors associated with later gender dysphoria include marked virilization, delayed diagnosis and poor hormonal control, underscoring the need for repeated, developmentally appropriate psychological assessment.

Non-classic CAH tells a subtler story in girls. Because the enzyme defect is milder, most affected girls have normal external genitalia and become symptomatic only in late childhood or adolescence, when hyperandrogenic features emerge. Premature pubarche is often the first sign, with one study finding that 92 percent of girls under ten presented this way. During adolescence, hirsutism, acne, alopecia and menstrual disturbances become prominent: in a cohort of 220 adolescents, 56 percent had irregular menses and 9 percent had primary amenorrhea. The phenotype closely resembles polycystic ovary syndrome, including polycystic ovarian morphology. Fertility is generally less affected than in classic disease and most women conceive spontaneously, but reduced fertility is still reported in 10 to 30 percent of women of reproductive age, primarily through anovulation. The stakes of early diagnosis are vivid: live birth rates were 86 percent in women diagnosed before conception versus 69 percent in those diagnosed only after pregnancy, and miscarriage rates fell from about 25 percent before diagnosis to roughly 10 percent after treatment began.

For males with classic CAH, the reproductive threats are different but equally serious. Hypogonadotropic hypogonadism, in which adrenal-derived steroids suppress the hypothalamic-pituitary-gonadal axis through negative feedback, is observed in 20 to 52 percent of men with 21-hydroxylase deficiency, and impaired semen quality or reduced sperm concentrations have been described in up to two-thirds of affected individuals. Multiple steroids contribute to this suppression, including testosterone acting through the androgen receptor, androstenedione after aromatization to estradiol, and 17-hydroxyprogesterone and progesterone through the progesterone receptor. Recently, 11-oxygenated adrenal androgens such as 11-ketotestosterone have emerged as potent contributors whose androgenic activity rivals that of classical androgens, potentially explaining why some men with low circulating testosterone show few obvious symptoms of deficiency. Because adrenal and testicular testosterone are biologically indistinguishable, clinicians can use the androstenedione-to-testosterone ratio, with values of 0.5 or higher suggesting significant adrenal contribution, to identify the source of hormonal disruption.

The most distinctive threat to male fertility, however, is the testicular adrenal rest tumor, or TART, a benign lesion that histologically resembles adrenocortical tissue and typically originates in the rete testis. Prevalence is estimated at 30 to 50 percent in adolescent boys and adult men with classic CAH, with bilateral occurrence in about 80 percent of cases. Tumors smaller than two centimeters cannot be detected by palpation, making scrotal ultrasound the diagnostic modality of choice, while magnetic resonance imaging offers no meaningful advantage. Current evidence suggests TARTs may arise not from embryonic adrenal rests, as long assumed, but from pluripotent steroidogenic cells, possibly fetal Leydig cell precursors, whose proliferation is driven by chronic ACTH excess and, during puberty, possibly by luteinizing hormone. Larger tumors can mechanically obstruct seminiferous tubules, damage Sertoli cells and germ cells, and produce azoospermia, and because they retain adrenal-like enzymatic machinery they can locally manufacture androgens, including 11-oxygenated varieties, that may further impair spermatogenesis through paracrine effects. Encouragingly, biochemical hypogonadism appears to be a stronger determinant of impaired spermatogenesis than tumor bulk alone, and intensifying glucocorticoid therapy to suppress ACTH can shrink tumors and sometimes restore fertility, an approach that works best in younger patients before fibrosis sets in.

The review’s practical recommendations follow from these findings. Boys with classic CAH should begin annual scrotal ultrasound screening for TARTs around age eight, and sperm cryopreservation should be offered when tumors are detected even if paternity is not yet desired. Preliminary evidence suggests a modified-release hydrocortisone formulation can improve sperm quality and gonadal function without increasing overall glucocorticoid exposure, while testis-sparing surgery has not been shown to improve fertility and should be reserved for pain. For women planning pregnancy, endocrine optimization is the cornerstone: hydrocortisone is preferred for its short half-life, adequate mineralocorticoid replacement may improve fertility even without overt salt wasting, and dexamethasone should be avoided during pregnancy because it crosses the placenta. Genetic counseling should be offered to all patients, beginning in adolescence, since classic 21OHD occurs in roughly 1 in 10,000 to 15,000 newborns and the carrier frequency is estimated at about 1 in 55 in the general population. Prenatal dexamethasone treatment, which must begin before gestational week eight to prevent virilization of affected female fetuses, remains controversial and is limited to specialized centers and research settings given unnecessary fetal exposure and uncertain long-term effects. Above all, the authors insist, structured transition care, beginning in early adolescence and tailored to readiness rather than age, with counseling on sexuality, fertility, contraception, inheritance and pregnancy planning delivered by multidisciplinary teams, is the single most powerful tool for converting these reproductive risks into manageable, and often reversible, challenges.

Subject of Research: Reproductive and fertility challenges in adolescents with congenital adrenal hyperplasia

Article Title: Reproductive and fertility challenges in adolescents with congenital adrenal hyperplasia

Article References: Reproductive and fertility challenges in adolescents with congenital adrenal hyperplasia. (n.d.). https://doi.org/10.3389/fradm.2026.1878713

Image Credits: AI Generated

DOI: 10.3389/fradm.2026.1878713

Keywords: congenital adrenal hyperplasia, fertility, adolescence, 21-hydroxylase deficiency, testicular adrenal rest tumors, hyperandrogenism, psychosexual development, genetic counseling, transition care, endocrinology, pregnancy, reproductive medicine