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Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults

Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults
Literature review current through: Jan 2024.
This topic last updated: Sep 12, 2023.

INTRODUCTION — More than 90 percent of cases of congenital adrenal hyperplasia (CAH) result from impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol [1]. This conversion is mediated by 21-hydroxylase, or in current terminology, P450 21A2, which is encoded by the CYP21A2 gene. Inadequate 21-hydroxylase activity results in both adrenal insufficiency due to impaired cortisol biosynthesis and adrenal hyperandrogenism (figure 1).

Patients with "classic" or the more severe form of CAH due to 21-hydroxylase deficiency (21OHD) present during the neonatal period and early infancy with adrenal insufficiency or as toddlers with virilization. Females have atypical genitalia.

The treatment of adults with classic CAH due to 21OHD will be reviewed here. The genetics, clinical manifestations, and diagnosis of classic 21OHD and the management of classic 21OHD in infants and children are discussed elsewhere. The diagnosis and treatment of nonclassic 21OHD in adults are also discussed separately.

(See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

(See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

TRANSITION FROM PEDIATRIC TO ADULT CARE

Establishing care — For individuals with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), the transition from pediatric to adult care should be carefully planned to help prepare patients for issues that arise postpuberty. In both children and adults with classic 21OHD, management of adrenal insufficiency and adrenal hyperandrogenism are central goals of treatment. However, adults have additional health concerns including sexual function and fertility [2]. Adults with classic 21OHD also face potential long-term complications of both the disease itself and chronic glucocorticoid therapy, such as obesity, adrenal rest tumors, bone loss, and impaired quality of life [2-5]. Ideally, adults with classic 21OHD should have interdisciplinary care that includes an endocrinologist and a reproductive specialist with expertise in CAH, as well as a urologist (for males) or gynecologist (for females).

When possible, engagement in adult care should begin several years prior to cessation of pediatric care [2]. This overlap enables the gradual introduction of issues and concerns specific to adult care and maintains contact with familiar pediatric providers while relationships with adult providers are established.

Initial evaluation — During the transition to adult care, adrenal hormone treatment regimens should be reassessed. Patient education and safety should be reinforced and remain cornerstones of treatment. Additional assessments reflect the overarching goal of optimizing reproductive health during adulthood.

Glucocorticoid and mineralocorticoid treatment regimens – All adults with classic 21OHD require continued glucocorticoid therapy, and most require continued mineralocorticoid therapy. Therefore, in adults, a distinction between "salt wasting" versus simple virilizing" subtypes of classic 21OHD should be avoided. This distinction is important for newborns with classic 21OHD, but it is irrelevant for adults and often encourages withholding of vital therapies. Nonetheless, adrenal hormone dosing requirements often change with age and cessation of growth.

Glucocorticoid therapy – In adults with classic 21OHD, glucocorticoid therapy is required to treat cortisol deficiency, optimize reproductive function and, in females, minimize hyperandrogenic symptoms. Hydrocortisone therapy can achieve these goals and imparts lower risk of long-term complications than longer-acting glucocorticoids. (See 'Goals of adrenal hormone therapy' below and 'Hydrocortisone (preferred glucocorticoid)' below.)

Mineralocorticoid therapy – In virtually all adults with classic 21OHD, continued fludrocortisone therapy is needed to treat mineralocorticoid deficiency. However, dosing requirements are usually lower than in children or adolescents. (See 'Mineralocorticoid replacement' below.)

Patient counseling – Patient education and engagement in self-care are critical for treatment adherence and safety [6]. Extensive patient counseling is essential to help prepare patients for both acute and long-term management issues. (See 'Patient safety and counseling' below and 'Monitoring for long-term complications' below.)

Evaluation of patient-centered goals and concerns – In adults with classic 21OHD, glucocorticoid therapy is tailored in part to achieve individualized patient goals. We ask all patients about their long-term goals for reproductive health and fertility. We ask females about their goals for management of hyperandrogenic symptoms (eg, unwanted androgen-dependent terminal hair growth, acne). (See 'Fertility and reproductive health' below and 'Additional intervention for persistent symptoms' below.)

Genetic counseling – Genetic counseling should be provided during adolescence and again during the transition to adult care to help inform decisions about fertility [2]. (See 'Genetic counseling for all adults' below and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genetics'.)

Testicular ultrasound (males) – For males, a testicular ultrasound should be performed to evaluate for testicular adrenal rest tumors (TARTs) [2]. Thereafter, the frequency of monitoring depends in part on laboratory and physical examination findings. (See 'Screening for testicular adrenal rest tumors' below.)

Menstrual history and gynecologic examination (females) – For females, a genitourinary examination should be performed (if not performed previously during adolescence), and menstrual history should be assessed. In postpubertal females with classic 21OHD, central goals of management are to optimize menstrual and sexual function. (See 'Females' below.)

CONTINUED ADRENAL HORMONE THERAPY

Goals of adrenal hormone therapy — In adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), the two major goals of adrenal hormone therapy are to:

Provide adequate glucocorticoid and mineralocorticoid replacement, as with any form of adrenal insufficiency.

Attenuate the production of adrenal-derived steroids through partial suppression of both corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion.

Adequate suppression of CRH and ACTH can be difficult to achieve without supraphysiologic glucocorticoid dosing, which confers long-term risks of bone loss, cardiometabolic disease, and other clinical manifestations of iatrogenic Cushing syndrome. Therefore, careful dose titration is needed to find the lowest glucocorticoid dose that achieves both treatment goals. (See 'Monitoring and dose adjustment' below.)

Glucocorticoid therapy for all patients — In adults with classic 21OHD, limited data are available to guide selection of a specific glucocorticoid regimen. The approach to management detailed below is guided primarily by clinical experience and largely consistent with the Endocrine Society guidelines [2].

Selection of regimen — For adults with classic 21OHD, we suggest the short-acting glucocorticoid hydrocortisone. Among options for glucocorticoid treatment, hydrocortisone is the least likely to cause cushingoid complications. However, it is less convenient than other synthetic glucocorticoids as it is typically administered in multiple daily doses. (See 'Transition to adult dosing' below.)

Adolescents with classic 21OHD may use longer-acting glucocorticoid regimens to promote treatment adherence. When such individuals establish adult care, we encourage transition to hydrocortisone therapy.

If an individual anticipates substantial difficulty adhering to three times daily hydrocortisone, or if adherence proves difficult after a trial of hydrocortisone therapy, we substitute a longer-acting glucocorticoid, typically prednisolone or methylprednisolone. Where available, modified-release hydrocortisone is a reasonable alternative. (See 'Longer-acting glucocorticoids for adherence challenges' below and 'Modified-release hydrocortisone (limited availability)' below.)

In adults with severe 21OHD who do not achieve adequate adrenal androgen suppression on hydrocortisone alone, we add a small dose of a longer-acting glucocorticoid at bedtime to suppress overnight ACTH secretion. (See 'Combined regimens for persistent hyperandrogenism' below.)

Hydrocortisone (preferred glucocorticoid)

Transition to adult dosing — For adults with classic 21OHD, a typical regimen is hydrocortisone 15 to 30 mg daily administered in three divided doses (table 1). The largest dose is taken in the morning upon waking, and progressively smaller doses are taken late morning/midday and late afternoon/early evening (eg, 15, 5, and 2.5 mg). The total daily dose depends on both the patient's body size and severity of 21OHD. Individuals with larger body size generally require higher hydrocortisone doses for sufficient cortisol replacement, and those with more severe 21OHD require higher doses for adequate adrenal androgen suppression.

In contrast to other types of adrenal insufficiency, adequate treatment of classic 21OHD usually requires three rather than two daily doses of hydrocortisone. The third dose helps to limit the overnight rise in ACTH secretion that promotes adrenal androgen production. Hydrocortisone administration three times daily usually provides sufficient suppression of adrenal steroids without imparting clinical manifestations of glucocorticoid excess.

Monitoring and dose adjustment — During the transition to adult care or titration of hydrocortisone therapy, adults with classic 21OHD should be evaluated every three to four months through both clinical and laboratory assessments. Adults who are on stable hydrocortisone regimens should be seen at least once annually.

The goal of dose titration is to achieve the lowest hydrocortisone dose that provides both adequate cortisol replacement and sufficient suppression of adrenal steroid production.

Clinical assessment – Clinical assessments include measurement of body weight, blood pressure, and heart rate. Patients should be queried about sleep quality, changes in body weight and appetite, energy, cognition and concentration, daytime somnolence, and nausea. Signs and symptoms that suggest undertreatment include weight loss, weakness, hypotension, and fatigue. Signs and symptoms of overtreatment include body weight gain, impaired sleep, increased blood pressure, and edema. Signs of chronic overtreatment include dermal atrophy, bruising, proximal muscle weakness, purple striae, and other manifestations of Cushing syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

In addition, females should be assessed for signs of androgen excess (eg, acne, hirsutism, oily skin, sweating) at each visit.

In males, testicular atrophy on examination suggests chronic gonadotropin suppression from adrenal-derived androgens and thus indicates glucocorticoid undertreatment. Testicular examinations are performed primarily to evaluate for testicular adrenal rest tumors (TARTs). (See 'Screening for testicular adrenal rest tumors' below.)

Laboratory assessment – Blood draws for laboratory testing are best performed consistently at the same time of day (ideally in the morning) due to circadian variation in these levels. Routine laboratory measurements should include serum concentrations of the following [7]:

Androstenedione (generally considered the most relevant biomarker)

Testosterone

Sex-hormone binding globulin (SHBG; used to calculate free and bioavailable testosterone)

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH; routinely in males and in females with oligo- or amenorrhea)

Serum 17-hydroxyprogesterone also may be useful for detecting glucocorticoid overtreatment, but routine measurement is not essential for treatment monitoring in adults. Given the limitations of current therapy and the adverse consequences of supraphysiologic glucocorticoid dosing, target laboratory values for titrating glucocorticoid therapy cannot be uniformly established for adults with 21OHD. In undertreated males and all females with classic 21OHD, the most abundant circulating androgen is not testosterone but rather 11-ketotestosterone, which is only measured in certain reference and research laboratories [8]. The following guidance is based on clinical experience and consensus guidelines [2].

Males – In males, glucocorticoid therapy should be titrated to maintain testicular function, which generally requires the serum androstenedione level at or near the upper limit of the normal range. In contrast, normalization of 17-hydroxyprogesterone indicates glucocorticoid overtreatment. Gonadotropin (FSH and LH) levels should be maintained in the normal range; suppressed gonadotropins and/or an androstenedione/testosterone ratio >1 indicate inadequate suppression of adrenal androgen production. Such findings should prompt both consideration of glucocorticoid therapy intensification and additional evaluation for TARTs with testicular examination and/or ultrasound. (See 'Screening for testicular adrenal rest tumors' below.)

Females – In females not pursuing fertility, glucocorticoid therapy should be titrated to achieve normalized menstrual function and individualized goals for suppression of hyperandrogenic symptoms (eg, unwanted androgen-dependent terminal hair growth or acne). These goals are usually achieved with androgen (androstenedione, testosterone) levels at or near the upper limit of the normal range. Testosterone and androstenedione should not be suppressed below the normal range, as this indicates overt glucocorticoid overtreatment. A normalized 17-hydroxyprogesterone level similarly indicates glucocorticoid overtreatment.

In females pursuing fertility, treatment goals differ and are reviewed below. (See 'Fertility' below.)

Dose adjustment – We adjust the hydrocortisone dose in 2.5 to 5 mg increments as needed based on evidence of over- or undertreatment. If signs or symptoms of cortisol deficiency are evident throughout the day, we preferentially increase the morning dose. If additional suppression of adrenal androgens is needed, we empirically increase the doses throughout the day; increasing more than one dose is often necessary for sufficient adrenal steroid suppression.

Increased evening doses of hydrocortisone may be limited by impaired sleep. If impaired sleep or other evidence of glucocorticoid excess develops, or if adequate adrenal androgen suppression cannot be achieved on a total daily hydrocortisone dose ≤30 to 35 mg, combination therapy may be helpful. (See 'Combined regimens for persistent hyperandrogenism' below.)

In females with persistent signs of hyperandrogenism despite normalized serum androgen levels, we pursue alternative treatment strategies. (See 'Additional intervention for persistent symptoms' below.)

Alternative regimens

Combined regimens for persistent hyperandrogenism — In adults in whom adequate adrenal steroid suppression cannot be achieved with standard hydrocortisone regimens, we suggest combination therapy [9]. Combination therapy entails typical cortisol replacement doses of hydrocortisone (eg, 10 to 25 mg daily) during the day and a very small dose of a longer-acting glucocorticoid at bedtime (eg, 1 to 2 mg prednisolone or methylprednisolone) (table 2). The lowest dose of the longer-acting glucocorticoid that achieves adequate adrenal steroid suppression should be used. Combination therapy is very effective for suppressing ACTH and minimizes total glucocorticoid exposure.

Combined regimens may be particularly helpful in the following settings:

In females pursuing pregnancy who need additional suppression of serum progesterone. (See 'Fertility' below.)

In males in whom reducing TART size is a goal of care. (See 'Screening for testicular adrenal rest tumors' below.)

Longer-acting glucocorticoids for adherence challenges

Prednisolone and methylprednisolone (preferred longer-acting agents) – For individuals with classic 21OHD who have difficulty adhering to three daily doses of hydrocortisone, we prefer prednisolone or methylprednisolone (table 1). These longer-acting glucocorticoids are typically administered twice a day with a larger dose in the morning to replace the cortisol deficiency (eg, 3 to 5 mg) and a small dose at bedtime to attenuate the pre-dawn ACTH rise (eg, 1 to 2.5 mg) [10]. We avoid "inverse diurnal rhythm" dosing, in which the larger dose is given at bedtime (eg, methylprednisolone 2 mg upon waking and 5 mg at bedtime); such regimens do not replace the cortisol deficiency well and overtreat during the night.

PrednisonePrednisone is a pro-drug that requires hepatic conversion to prednisolone to be biologically active, and interindividual variability in these kinetics makes prednisone a poor choice.

Dexamethasone – In adults with classic 21OHD, dexamethasone is not preferred. Dexamethasone, a very potent and long-acting glucocorticoid, effectively suppresses ACTH secretion but almost always causes the development of cushingoid features with chronic use [11-14]. Further, bedtime administration of 0.25 to 1 mg does not replace the cortisol deficiency well, although this is the most effective regimen for ACTH suppression. Dexamethasone therapy should be of limited duration and reserved for specific treatment goals (eg, TART shrinkage). (See 'Screening for testicular adrenal rest tumors' below.)

Modified-release hydrocortisone (limited availability) — Modified-released hydrocortisone is authorized for use in adolescents and adults with CAH in regions including the United Kingdom and Europe. In individuals with inadequate adrenal androgen suppression on immediate-release hydrocortisone, modified-release hydrocortisone is a reasonable alternative. The total daily dose is 15 to 25 mg, administered in two divided doses. The first dose is taken upon waking, and the second dose is taken at night immediately prior to sleep. The bedtime dose should be approximately 65 to 75 percent of the total daily dose, with the remainder taken in the morning.

Patient safety and counseling — For all adults with classic 21OHD, ensuring patient safety is a cornerstone of treatment. At each visit, we counsel patients about the importance of adherence to therapy and the potentially life-threatening risks of cortisol deficiency. We ask about any challenges to adherence and any interim periods of nonadherence. We also provide ongoing counseling about circumstances that require glucocorticoid dose adjustments or emergency treatment with injectable glucocorticoid. We ask patients about interim use of stress-dose or emergency injectable glucocorticoid therapy. Key components of patient education are described in detail elsewhere. (See "Treatment of adrenal insufficiency in adults", section on 'Patient education'.)

Cortisol deficiency can be life-threatening, and adrenal crisis remains a leading cause of mortality in individuals with classic 21OHD. A study from Sweden of 588 adults with classic 21OHD found approximately a two- to fourfold increase in mortality compared with population norms [15]. The major causes of death were adrenal crisis (42 percent), cardiovascular disease (32 percent), cancer (16 percent), and suicide (10 percent). Mortality was highest among males and patients with the most severe disease.

Stress dosing and emergency precautions — As with any form of adrenal insufficiency, patients with classic 21OHD should be provided with sick-day rules for stress dosing, medical alert identification, and injectable hydrocortisone hemisuccinate (or other injectable glucocorticoid) for emergencies (table 3). At each visit, we verify that patients always wear or carry a medical alert identifier and have an unexpired emergency glucocorticoid injection kit.

Glucocorticoid dose adjustment during acute stress – An increase in glucocorticoid dose is critical during acute physiologic stress including illness or surgery. Increased glucocorticoid doses are usually not needed during routine psychological stress or exercise [2]. A detailed approach to stress-dose glucocorticoid therapy is discussed separately. (See "Treatment of adrenal insufficiency in adults", section on 'Circumstances requiring glucocorticoid dose adjustment'.)

Emergency glucocorticoid injection – Every patient should have injectable glucocorticoid (eg, 100 mg vials of hydrocortisone), along with syringes for injection. Patients should keep emergency injection kits in a readily accessible place known to all members of the household. Injectable hydrocortisone should be administered immediately in case of significant physical injury (eg, fracture), inability to retain oral medications due to nausea and vomiting, symptoms of incipient adrenal crisis, or if the patient has reduced consciousness or is found unconscious. A detailed approach to the provision and use of emergency glucocorticoid therapy is reviewed separately. (See "Treatment of adrenal insufficiency in adults", section on 'Emergency precautions'.)

Treatment adherence — For individuals with classic 21OHD, lifelong adherence to adrenal hormone therapy is essential for safety. For females, avoidance of hyperandrogenic symptoms can motivate adherence to therapy. In contrast, some males may self-discontinue all treatment for months to years without apparent consequence, as long as they do not suffer a significant intercurrent illness. However, this apparent resilience does not indicate remission of cortisol deficiency, and illness or trauma can still precipitate life-threatening adrenal crisis. In addition, males who are undertreated can develop TARTs, which are difficult to treat and can cause pain and irreversible infertility. (See 'Screening for testicular adrenal rest tumors' below.)

Additional intervention for persistent symptoms — In many adults with classic 21OHD, adequate suppression of adrenal androgen production can be achieved without excessive glucocorticoid exposure. Nonetheless, some females may require additional intervention to manage signs of hyperandrogenism, in part because these signs reflect not only circulating androgen concentrations but also tissue-specific regulation of androgen production and signaling. In some adults with severe disease, high glucocorticoid doses are required to suppress adrenal androgen production and lead to chronic, intractable symptoms of excessive glucocorticoid exposure.

Androgen excess (females) – In females with 21OHD, additional intervention may be necessary to manage hyperandrogenic symptoms (eg, hirsutism, acne) or to regulate menstrual function. In such cases, combined oral contraceptives can be used in conjunction with glucocorticoid therapy. Combined oral contraceptives both regulate menstrual function and mediate antiandrogenic effects by raising SHBG. In females with hirsutism, mechanical or topical hair removal methods also can be used. However, we avoid spironolactone for antiandrogen treatment, as it antagonizes the effect of fludrocortisone and can cause volume depletion. Fludrocortisone treatment for mineralocorticoid replacement therapy is discussed below, and the management of hirsutism in premenopausal females is reviewed in detail separately. (See 'Mineralocorticoid replacement' below and "Management of hirsutism in premenopausal women", section on 'Management'.)

Progressive signs and symptoms due to glucocorticoid excess – For adults with classic 21OHD and significant health deterioration due to chronic, supraphysiologic glucocorticoid treatment, enrollment in a clinical trial may provide access to better tolerated treatment regimens.

Although a few cases have been reported of unilateral or bilateral adrenalectomy for severe 21OHD [16-18], we avoid this intervention. The major benefit of adrenalectomy is the immediate elimination of adrenal androgen and progesterone secretion, which allows treatment with lower glucocorticoid doses. However, the reduction in adrenal androgen production may be only temporary with unilateral adrenalectomy. Bilateral adrenalectomy heightens the dependency on glucocorticoid and mineralocorticoid replacement therapy and therefore increases risk of adrenal crisis. Further, adrenalectomy does not always prevent subsequent development of adrenal rest tumors, even in females [19].

Mineralocorticoid replacement — Although mineralocorticoid replacement needs usually decrease in adulthood, most adults with classic 21OHD require continued mineralocorticoid therapy with fludrocortisone [2]. The reduced dose requirement reflects the increases in both dietary sodium intake and mineralocorticoid signaling that occur with progression from infancy to adulthood [2].

Transition to adult fludrocortisone dose — In individuals transitioning from pediatric to adult care, the initial adult fludrocortisone dose is determined by the patient's current dose and assessment of blood pressure, serum potassium concentration, and plasma renin activity (PRA). We adjust the pediatric dose as needed based on these assessments, detailed below. (See 'Monitoring and dose adjustment' below.)

In adults with classic 21OHD, a typical fludrocortisone dose is 0.05 to 0.2 mg daily [20]. This may be taken once daily or in two divided doses. The dose depends on the severity of mineralocorticoid deficiency and concurrent glucocorticoid therapy. Hydrocortisone has greater mineralocorticoid activity than other options for glucocorticoid therapy, so adults on hydrocortisone typically require lower fludrocortisone doses (eg, 0.05 to 0.1 mg daily).

Monitoring and dose adjustment — During the transition to adult care or titration of fludrocortisone therapy, adults with classic 21OHD should be evaluated every three to four months through both clinical and laboratory assessments, and then at least once annually. Optimal mineralocorticoid replacement may enable reduction of the glucocorticoid dose [21,22].

Clinical assessment – Clinical assessments include measurement of seated and upright blood pressure and symptom monitoring. Signs and symptoms of fludrocortisone undertreatment include salt craving, lightheadedness, chronic fatigue, postural hypotension, and nausea, whereas elevated blood pressure and dependent edema can be evidence of overtreatment.

Laboratory assessment – Laboratory assessments include measurement of serum potassium and PRA. The goals of fludrocortisone treatment are to normalize the serum potassium level and achieve a PRA in the normal reference range. However, if PRA remains elevated in adults who are asymptomatic with a normal potassium level, the fludrocortisone dose should not be further increased; in this setting, an increased dose can lead to hypokalemia.

Laboratory assessment is essential and should be performed even in asymptomatic individuals. Undertreatment can lead to chronic volume depletion that may be clinically silent and evident only on laboratory testing. Irrespective of whether it causes symptoms, undertreatment results in persistent overproduction of renin and angiotensin II. Angiotensin II can stimulate early steps in the steroidogenic pathway, leading to higher adrenal androgen synthesis [23].

Dose adjustment – We adjust the fludrocortisone dose as needed in 0.05 to 0.1 mg increments based on evidence of under- or overtreatment. In adults, once a therapeutic replacement dose is established, the fludrocortisone dose generally remains stable for years. However, further dose adjustments may be needed in the setting of increased salt losses (eg, exposure to warm climates, vigorous exercise) or the development of primary hypertension. These adjustments are reviewed in detail elsewhere. (See "Treatment of adrenal insufficiency in adults", section on 'Dose adjustments for increased salt losses or primary hypertension'.)

FERTILITY AND REPRODUCTIVE HEALTH

Genetic counseling for all adults — All individuals with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) should receive genetic counseling during adolescence and at the transition to adult care. Genetic counseling should be provided to both individuals with CAH and their partners during preconception planning. Patients should understand the autosomal recessive inheritance of CAH, the difference between affected and carrier status, and the carrier frequency in the general population. Based on the incidence of classic 21OHD and an estimated carrier frequency of 2 percent of the population, an individual with classic 21OHD has an approximately 1:120 probability of having a child with classic 21OHD [2]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genetics'.)

Females — For females with classic 21OHD, monthly menses and satisfactory sexual function are goals of care, irrespective of the individual's plans for immediate or long-term fertility. Achievement of these goals requires both optimized glucocorticoid therapy and functional anatomy.

Normalize menstrual function — Glucocorticoid under- and overtreatment both can cause menstrual irregularity. If adequate adrenal steroid suppression cannot be achieved without excessive glucocorticoid exposure, combined oral contraceptives might help to regulate menstrual function. Adrenal-derived progesterone, rather than androgens, is the major cause of menstrual irregularity and infertility in females with classic 21OHD.

Achieve functional anatomy — Females with classic 21OHD who plan to be sexually active with males typically require reconstructive gynecologic surgery as adolescents or adults. Various vaginoplasty procedures, with or without nerve-sparing clitoroplasty [1,24], may be performed either as an initial procedure or revision of a procedure performed earlier. Females may have a delay in establishing sexual relationships, and sexual function may not be optimal, regardless of previous reconstructive surgery [25]. These issues may require counseling and possibly treatment, including additional surgery and/or a vaginal dilation program. Regular dilation and adequate lubrication are important to reduce the risk of restenosis and dyspareunia.

In one report of 16 adult females with 21OHD, 15 had undergone reconstructive genital surgery, with 8 of 16 requiring second procedures; most females (12 of 15) who had undergone surgery were considered to have an adequate vaginal introitus for sexual activity [24].

Fertility

Prior to attempted conception – Prior to attempting pregnancy, females with classic 21OHD should have gynecologic consultation, ideally with a surgeon who can provide initial genital reconstruction surgery or modification of previous surgery if needed. This evaluation also facilitates diagnosis of other conditions that can impair fertility independent of 21OHD (eg, tubular obstruction, endometriosis). (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction'.)

Once functional anatomy is achieved, glucocorticoid therapy is intensified to achieve greater suppression of adrenal steroid production. The goal of therapy is to achieve a follicular-phase progesterone concentration <0.6 ng/mL (2 nmol/L). This intensified treatment is generally necessary for at least several months to achieve conception and often requires combination therapy with both immediate-release hydrocortisone and a longer-acting glucocorticoid administered at bedtime [9]. (See 'Combined regimens for persistent hyperandrogenism' above.)

If impaired fertility is evident (eg, inability to conceive after 6 to 12 months), despite regular menses and follicular-phase progesterone at goal, referral to a reproductive or fertility specialist should be offered [26].

Outcomes – In females with classic 21OHD, fertility rate is reduced [27-29]. Initial studies found that only 25 percent of females with classic 21OHD and 10 percent of those with severe disease ever attempted to conceive [9]. In contrast, a 2021 study from Sweden found that 40 to 42 percent of females with either nonclassic or "simple virilizing" classic 21OHD had borne children, similar to the general population (45 percent); however, <10 percent of females with severe "salt wasting" classic disease had biological children [30]. Furthermore, in individuals who receive proper treatment and have regular intercourse, pregnancy rates exceed 90 percent. Thus, females with classic 21OHD have normal fertility potential, and the low desire to pursue parenthood appears restricted to those with the most severe disease.

Factors that contribute to impaired fertility include:

Increased adrenal-derived progesterone, which unfavorably changes cervical mucus and endometrial function, similar to progestin-only contraceptives

Anovulation

Vaginal stenosis, from intrauterine virilization and/or sequelae from prior genital reconstructive surgery

Psychologic factors

Ovarian hyperandrogenism secondary to chronic anovulation

Ovarian adrenal rest tumors

No role for screening for adrenal rest tumors — In females with classic 21OHD, we do not screen for adrenal rest tumors. Ovarian adrenal rest tumors appear uncommon in treated females with classic 21OHD, with none found in a systematic evaluation of 13 females [31] and only scattered cases reported in the literature [19,32,33]. The sensitivity of ultrasound and magnetic resonance imaging (MRI) for detecting small ovarian rest tumors is not known, although other androgen-producing tumors of the ovary are difficult to detect with conventional imaging studies. Thus, the true prevalence of ovarian rest tumors may be higher because most of these tumors are identified during surgery or at autopsy. Imaging with 18-fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) has been used to identify rest tissue in three females (including one with Nelson syndrome) [19,32,33]; in one case, tumors were only visible after concurrent administration of cosyntropin [19].

As in males with testicular adrenal rest tumors, the etiology of rest tumors in females appears related to sustained elevations in ACTH due to glucocorticoid undertreatment or nonadherence. However, in females, whether glucocorticoid therapy reduces adrenal rest development and/or size is unknown. In females, adrenal rests may develop in the retroperitoneum, including the ovaries and surrounding structures. They occur primarily in the ovarian tissue and, less often, in the paraovarian/adnexal area.

Males

Screening for testicular adrenal rest tumors — Adult males with classic 21OHD are at risk for testicular adrenal rest tumors (TARTs). The pathogenesis of TARTs is not known, but they are believed to derive either from ectopic adrenal cortex remnants in the testis or from reprogrammed Leydig stem cells, which differentiate and grow under the influence of chronically elevated corticotropin (ACTH). The mass effect of TARTs increases the intratesticular pressure, impairs blood flow to the normal testis, and hinders outflow of semen. Thus, TARTs can cause infertility through multiple mechanisms. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Male reproduction'.)

Screening – In males with classic 21OHD, testicular ultrasound screening should begin in adolescence to detect TARTs, including once at the time of transition to adult care. Thereafter, we perform a physical examination and/or ultrasound monitoring for TARTs at least annually, with additional evaluation performed whenever a period of glucocorticoid undertreatment is detected through laboratory monitoring. (See 'Monitoring and dose adjustment' above.)

On physical examination, TARTs are firm, irregular masses originating near the rete testes. They are typically bilateral and can be painful when large. However, masses may be small and not palpable on physical examination. Ultrasonography is the most sensitive method of detection [11,12,34,35].

Multiple studies have shown that 30 to 50 percent of adolescent and adult males with classic 21OHD develop TARTs [36].

Management – The best approach to prevent TARTs is to provide adequate glucocorticoid therapy and to avoid long lapses in treatment. Intensified glucocorticoid treatment is sometimes, but not always, effective for decreasing the size of TARTs, relieving pain, and restoring fertility. Case reports have noted either a decrease in size or even disappearance of testicular masses with a course of supraphysiologic doses of dexamethasone or with daytime hydrocortisone plus bedtime dexamethasone [11,12]. TART shrinkage typically requires several months of treatment intensification, but side effects from these dexamethasone-containing regimens limits the duration of use.

Surgical removal provides good long-term control of TART growth and pain, but as demonstrated in a series of eight patients with TART [37], surgery is unlikely to restore testicular testosterone and sperm production.

In the presence of TART(s), an elevated follicle-stimulating hormone (FSH) level indicates testicular injury and is a poor prognostic factor for fertility [38]. (See 'Fertility' below.)

Fertility — In males with classic 21OHD, a normal semen analysis is the best evidence of good disease control without overtreatment, and sperm banking is an option for young males who want to preserve their fertility. In males, both elevated and suppressed FSH levels can indicate impaired fertility. In males with TARTs, an elevated FSH level suggests testicular injury. A suppressed FSH (and LH) level reflects inadequate glucocorticoid treatment and leads to impaired spermatogenesis. In some males with gonadotropin suppression, glucocorticoid treatment intensification can restore sperm production.

Males with classic 21OHD are prone to develop oligospermia and infertility, particularly in the setting of chronic glucocorticoid undertreatment. Undertreatment leads to impaired sperm production for two reasons. First, adrenal-derived androgens suppress gonadotropins, leading to reduced testosterone production from Leydig cells. High adrenal-derived androgens compensate for hypogonadism and maintain male secondary sexual characteristics, creating the false impression that testicular function is normal. Second, roughly one-half of these males develop TARTs. (See 'Screening for testicular adrenal rest tumors' above.)

A study from Germany found abnormal semen analysis in 100 percent of 22 males with classic 21OHD [39]. In a larger study from London of 50 males with classic 21OHD, 48 percent had severe oligospermia, and 59 percent of those who desired fertility required treatment intensification to improve sperm production [38].

Pregnancy

Glucocorticoid and mineralocorticoid therapy – Females with classic 21OHD require continued glucocorticoid and mineralocorticoid therapy throughout pregnancy. Hydrocortisone and/or prednisolone should be used in combination with fludrocortisone [2]. Pregnant females should not receive glucocorticoids that cross the placenta (eg, dexamethasone). During the first and second trimesters, the preconception glucocorticoid regimen is typically continued if it is well tolerated. If concerning glucocorticoid-related side effects occur, the dose can be moderated, primarily by reducing or eliminating the bedtime dose. During the third trimester, an increase in the glucocorticoid dose (eg, 30 to 50 percent) may be needed.

The fludrocortisone dose does not usually require adjustment during pregnancy, but clinical and laboratory monitoring are needed. The management of adrenal hormone therapy in pregnant individuals with adrenal insufficiency is reviewed in detail elsewhere. (See "Treatment of adrenal insufficiency in adults", section on 'Pregnancy and labor'.)

Delivery – Cesarean section is almost always required at delivery due to vaginal inadequacy. At the onset of labor or immediately prior to surgery (if Cesarean section is scheduled), glucocorticoid therapy should be intensified as for surgical stress. Glucocorticoid therapy during labor and delivery in females with adrenal insufficiency is reviewed separately. (See "Treatment of adrenal insufficiency in adults", section on 'Pregnancy and labor'.)

Outcomes – Full-term pregnancies can be achieved with delivery of healthy infants who have normal growth and development [40]. Female infants without classic 21OHD are born with typical external genitalia; even when maternal androgen production is not normalized during pregnancy, placental aromatase activity protects the fetal genitalia and brain from excess androgen exposure [41].

Prenatal diagnosis of 21OHD and prenatal treatment of affected offspring are reviewed separately. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal diagnosis' and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal therapy'.)

MONITORING FOR LONG-TERM COMPLICATIONS — Adults with classic 21-hydroxylase deficiency (21OHD) require ongoing monitoring to assess for potential long-term complications of 21OHD or its treatment. These individuals have increased risk of low bone density, obesity, insulin resistance, and hypertension. They also frequently report reduced quality of life.

In addition to routine clinical and laboratory assessments for adrenal hormone therapy, we monitor the following:

Cardiometabolic risk factors – Body weight and blood pressure should be measured at least annually. Additional cardiometabolic screening (eg, fasting glucose, glycated hemoglobin, lipid panel) should be performed as for the general adult population [2]. All adults should receive counseling about general lifestyle measures to promote cardiometabolic health. General recommendations for diet, exercise, and screening for diabetes and hyperlipidemia in adults are reviewed separately. (See "Healthy diet in adults" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Screening for type 2 diabetes mellitus" and "Screening for lipid disorders in adults".)

Whether CAH confers increased cardiometabolic risk in the absence of glucocorticoid overtreatment remains uncertain [42]. Use of dexamethasone and prednisone in particular have been associated with increased risk of obesity and insulin resistance [43,44]. In a meta-analysis of 20 observational studies, individuals with CAH had higher systolic and diastolic blood pressure, insulin resistance, and carotid intimal thickness than individuals without CAH [45]. In individual studies, chronic glucocorticoid therapy in adults with 21OHD has been associated with increased fat mass and body mass index (BMI), particularly in older patients [46,47]. Among adults with classic 21OHD, 35 to 41 percent have obesity [3,48], which has been primarily attributed to glucocorticoid overreplacement. Insulin resistance was found in 29 percent [3] and 38 percent [48] of adults with classic 21OHD in two studies. One study found that females with classic 21OHD have an increased risk of gestational diabetes mellitus, with a reported prevalence of approximately 20 percent compared with an estimated prevalence of 7 to 10 percent in the general population [46,49]. Hypercholesterolemia was found in 46 percent of adults in one study [3], but no differences in serum lipids were found between adults with and without CAH in a subsequent meta-analysis that included this study [45]. Glucocorticoid-sparing treatments in development may provide cardiometabolic benefit [50].

Mental health and quality of life – At each visit, we query patients about mood, stress, daily function (eg, work performance, energy) and overall quality of life. When possible, treatment teams should be interdisciplinary with inclusion of mental health providers [2]. In adults with 21OHD, avoidance of glucocorticoid overtreatment is critical for optimizing mood, energy, and quality of life.

In individuals with classic 21OHD, data on long-term psychologic outcomes are limited and inconsistent [51-54]. One study reported an increase in psychiatric disorders in adults with classic 21OHD [51]. A Swedish series of 253 males with classic 21OHD found an increased prevalence of psychiatric disorders including suicidality and psychotic disorders [52]. However, increased psychiatric morbidity was not evident in individuals with the most severe genotypes and appeared to decline following the introduction of newborn screening, suggesting that early diagnosis and treatment may confer protective effects [52]. In a study of 18 females with 21OHD, social adjustment and self-esteem scores were normal, with no obvious increase in psychiatric disorders [53]. Another study found that aggression did not differ between female adolescents with and without classic CAH [54].

Quality of life is broadly reduced in adults with 21OHD [3,48]. In a report of 151 adults, decreased quality of life was associated with the use of prednisolone or dexamethasone treatment (versus hydrocortisone) [43].

Bone mineral density measurement by dual x-ray absorptiometry – We perform baseline bone mineral density (BMD) measurement with dual-energy x-ray absorptiometry (DXA) in all patients at age 25 years, the approximate expected age of peak bone accrual [55]. Since lifelong glucocorticoid therapy can impact bone accrual, this baseline measurement is important for interpreting subsequent BMD values. After baseline assessment, we remeasure BMD in adults who have had a prolonged (eg, ≥12 months) exposure to high-dose glucocorticoid treatment (>10 mg/day prednisone or equivalent), who develop other risk factors for bone loss, or who experience an atraumatic fracture. In the absence of these triggers for interim measurement, we remeasure BMD according to age- and sex-based guidelines for the general adult population. (See "Screening for osteoporosis in postmenopausal women and men".)

All adults with classic 21OHD should follow lifestyle measures for optimizing bone health, including adequate intake of calcium and vitamin D and routine physical activity. Vitamin D deficiency is common in children and adults with classic 21OHD. Vitamin D deficiency and insufficiency were observed in 19 and 42 percent of children, respectively, and in 28 and 40 percent of adults, respectively, in a large natural history study [48]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'General measures' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

In adults with classic 21OHD who are diagnosed with osteoporosis based on BMD measurement or atraumatic fracture, management is the same as for other populations with glucocorticoid-induced osteoporosis. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Candidates for pharmacologic therapy'.)

In adults with classic 21OHD, BMD is low compared with healthy individuals. In two large series totaling almost 400 adults (the National Institutes of Health (NIH) natural history study [48] and the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) study [3]), 40 percent of patients who underwent bone densitometry had osteopenia, and 5 to 10 percent had osteoporosis. These cohorts generally comprised young adults, and whether long-term risk of fragility fractures is increased is unknown.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Congenital adrenal hyperplasia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Transition to adult care – In individuals with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), the transition from pediatric to adult care should be carefully planned to help prepare patients for issues that arise postpuberty. (See 'Transition from pediatric to adult care' above.)

Adrenal hormone therapy

Goals of therapy – In adults with classic 21OHD, the two major goals of adrenal hormone therapy are to (see 'Goals of adrenal hormone therapy' above):

-Provide adequate glucocorticoid and mineralocorticoid replacement

-Attenuate the production of adrenal-derived steroids through partial suppression of both corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion

Glucocorticoid therapy – For adults with classic 21OHD, we suggest the short-acting glucocorticoid hydrocortisone instead of other glucocorticoids (Grade 2C). Hydrocortisone is the least likely to cause cushingoid complications. It is typically administered in three divided doses totaling 15 to 30 mg daily (table 1 and table 2). (See 'Hydrocortisone (preferred glucocorticoid)' above.)

-MonitoringHydrocortisone therapy is monitored through both clinical and laboratory assessments. The hydrocortisone dose should be titrated to achieve the lowest dose that provides both adequate cortisol replacement and sufficient suppression of adrenal steroid production. (See 'Monitoring and dose adjustment' above.)

-Combined regimens – In adults in whom adequate adrenal steroid suppression cannot be achieved with standard hydrocortisone regimens, we suggest combination therapy (Grade 2C). Combination therapy entails typical cortisol replacement doses of hydrocortisone (eg, 10 to 25 mg daily) during the day and a very small dose of a longer-acting glucocorticoid at bedtime (eg, 1 to 2 mg prednisolone or methylprednisolone). This strategy suppresses ACTH and minimizes total glucocorticoid exposure. (See 'Alternative regimens' above.)

Combined regimens may be particularly helpful in females pursuing pregnancy who need additional suppression of serum progesterone and in males in whom reducing testicular adrenal rest tumor (TART) size is a goal of care.

-Patient safety – Adults with classic 21OHD should be provided with sick-day rules for glucocorticoid stress dosing, a medical alert identifier, and injectable hydrocortisone (or other injectable glucocorticoid) for emergency use (table 3). (See 'Patient safety and counseling' above and "Treatment of adrenal insufficiency in adults", section on 'Patient education and safety'.)

Mineralocorticoid therapy – Most adults with classic 21OHD require continued mineralocorticoid replacement with fludrocortisone, typically 0.05 to 0.2 mg daily. The dose depends on the severity of mineralocorticoid deficiency and concurrent glucocorticoid therapy. The aim of fludrocortisone treatment is to normalize serum potassium concentration, standing blood pressure, and plasma renin activity (PRA). (See 'Mineralocorticoid replacement' above.)

Fertility and reproductive health

TARTs – In males with 21OHD, ultrasound screening for TARTs should begin during adolescence, including once at the time of transition to adult care. We perform a physical examination and/or ultrasound monitoring for TART at least annually. Intensified glucocorticoid treatment is sometimes, but not always, effective for decreasing the size of TARTs, relieving pain, and restoring fertility. (See 'Screening for testicular adrenal rest tumors' above.)

Reproductive health – For females with classic 21OHD, monthly menses and optimized sexual function are goals of care, which require optimized glucocorticoid therapy and functional anatomy tailored to individualized goals, respectively. (See 'Females' above.)

Fertility – In males, a normal semen analysis is the best evidence of good disease control without overtreatment, and sperm banking is an option for young males who want to preserve their fertility. (See 'Fertility' above.)

In females attempting pregnancy, glucocorticoid therapy should be titrated to achieve a follicular-phase progesterone <0.6 ng/mL (2 nmol/L). (See 'Fertility' above.)

Monitoring for complications – Adults with classic 21OHD require ongoing monitoring to assess for potential long-term complications of 21OHD and/or chronic glucocorticoid treatment. (See 'Monitoring for long-term complications' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

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