INTRODUCTION — Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90 percent of cases of congenital adrenal hyperplasia [1]. This conversion is mediated by 21-hydroxylase, or in current terminology, P450 21A2, encoded by the CYP21A2 gene. This results in 1) impaired cortisol biosynthesis and adrenal insufficiency, and 2) adrenal hyperandrogenism (figure 1).
Patients with "classic" or the most severe form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) present during the neonatal period and early infancy with adrenal insufficiency with or without salt losing or as toddlers with virilization. Females have genital ambiguity.
The treatment of classic congenital adrenal hyperplasia due to 21OHD in adults will be reviewed here. The genetics, clinical manifestations, and diagnosis of 21OHD and the management of infants and children with 21OHD are discussed elsewhere. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
APPROACH TO MANAGEMENT
Clinical issues — While the issues of adrenal insufficiency and adrenal hyperandrogenism are shared by adults and children with classic 21-hydroxylase deficiency (21OHD), adults have additional health concerns. It is therefore important to plan for the transition from pediatric to adult care and to address issues that arise after puberty. These include sexual dysfunction, hyperandrogenic symptoms (in women), infertility, and long-term complications of the disease and chronic glucocorticoid therapy, such as obesity, short stature, bone loss, and impaired quality of life [2-5]. Patient education and assumption of responsibility for their care is critical for compliance and successful outcomes [6]. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Clinical presentation'.)
The labeling of "salt wasting" versus "simple virilizing" subtypes of disease, which is important for newborns with classic 21OHD, is confusing and irrelevant for adults. The use of these terms often encourages withholding of vital therapies and should be avoided.
Goals of therapy — The two major goals of therapy for classic 21OHD in adults are to:
●Provide adequate glucocorticoid and mineralocorticoid replacement, as with any form of adrenal insufficiency
●Reduce the excessive secretion of both corticotropin-releasing hormone (CRH) and corticotropin (ACTH) and, thus, attenuate the production of adrenal-derived androgens
These goals can be difficult to achieve without overtreatment, with its attendant risk of bone loss, obesity, and other clinical manifestations of Cushing's syndrome. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)
In addition to these general goals for all patients, there are additional treatment goals specific to men and women. (See 'Additional considerations' below.)
Glucocorticoids — Similar to patients with any form of adrenal insufficiency, patients with 21OHD require adequate glucocorticoid and mineralocorticoid replacement. Glucocorticoids also reduce the excess production of adrenal androgens.
Routine daily regimens — Hydrocortisone, a short-acting glucocorticoid, is the treatment of choice in adults as it is the glucocorticoid least likely to cause Cushingoid complications. However, hydrocortisone is less convenient than other synthetic glucocorticoids, and to be effective, it is typically administered in three divided doses totaling 15 to 30 mg (table 1).
Prednisolone and methylprednisolone are longer-acting glucocorticoids that are sometimes effective given once daily on arising or, more commonly, twice a day with a larger dose in the morning to replace the cortisol deficiency (4 to 6 mg) and a small dose at bedtime to attenuate the pre-dawn ACTH rise (1 to 2.5 mg) [7]. Prednisone is a pro-drug that requires hepatic conversion to prednisolone to be active, and the variability in these kinetics makes prednisone a poor choice (table 1).
Dexamethasone, a very potent and long-acting glucocorticoid, effectively suppresses ACTH secretion but almost always causes the development of Cushingoid features with chronic use [8-11]. Bedtime administration of 0.25 to 1 mg is the most effective regimen for ACTH suppression but does not replace the cortisol deficiency well. Liquid forms of prednisolone and dexamethasone are available for precise titration of small doses.
Combination therapy, with typical doses of hydrocortisone to replace the cortisol deficiency during the day and a very small dose of a long-acting glucocorticoid at bedtime (1 to 2 mg prednisolone or methylprednisolone; 0.1 to 0.25 mg dexamethasone), is very effective in keeping ACTH low and minimizes glucocorticoid exposure. We suggest this approach when standard hydrocortisone regimens are ineffective. "Inverse diurnal rhythm" dosing, in which the larger dose is given at bedtime (ie, methylprednisolone 2 mg on arising and 6 mg at bedtime), does not replace the cortisol deficiency well, overtreats during the night, and should be avoided.
Stress dosing — 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 glucocorticoid) for emergencies. Patients with 21OHD suffer increased mortality from adrenal crises, even today [12,13]. (See "Treatment of adrenal insufficiency in adults", section on 'Special considerations'.)
Mineralocorticoid replacement — Mineralocorticoid therapy is given as 9-alpha-fludrocortisone acetate, in a dose sufficient to restore normal serum potassium concentrations, standing blood pressure, and plasma renin activity (see "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid replacement'). Excessive dosing can induce hypertension and hypokalemia, as seen in any form of primary mineralocorticoid excess (see 'Monitoring therapy' below). Optimal mineralocorticoid replacement has the added advantage of sometimes permitting the glucocorticoid dose to be reduced [14,15]. The need for mineralocorticoids typically decreases after infancy but remains relatively stable during adulthood [2].
Underdosing can lead to chronic volume depletion that can be clinically inapparent or cause chronic fatigue but also 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 [16].
The usual adult dose of fludrocortisone is 0.1 to 0.2 mg/day, but some patients require more to normalize the clinical and laboratory parameters above [17]. (See "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid replacement'.)
Additional considerations
Men — Men with classic 21OHD require lifelong treatment with glucocorticoids, at a minimum to replace the cortisol deficiency, plus mineralocorticoid as needed in most cases. Many men will self-discontinue all treatment for months to years without apparent consequence, as long as they do not suffer a significant concurrent illness.
This resilience should not be interpreted as escape from cortisol deficiency, which becomes evident when an illness precipitates a major catastrophe. In addition, patients who are undertreated and in chronic poor control develop testicular adrenal rest tumors (TARTs), which are difficult to treat and often cause irreversible consequences. Thus, adherence to therapy is essential in all men with classic 21OHD. (See 'Testicular adrenal rest tumors' below.)
Infertility — Sperm production is often impaired in men with poorly controlled classic 21OHD for two reasons. First, adrenal-derived androgens suppress gonadotropins and subsequent testosterone production from Leydig cells. High adrenal-derived androgen production compensates for attendant hypogonadism and, paradoxically, maintains male secondary sexual characteristics, creating the false impression that testicular function is normal. Second, roughly half of these men develop TARTs. A study from Germany found abnormal semen analysis in 100 percent of 22 men with classic 21OHD [18]. In a larger study from London of 50 men with classic 21OHD, 48 percent had severe oligospermia, and 59 percent of the 17 who desired to be fertile required treatment intensification to improve sperm production [19].
Testicular adrenal rest tumors — Men with classic 21OHD are prone to develop TARTs and/or oligospermia, especially when control is poor. The pathogenesis of TARTs is not known, but TARTs are believed to be derived from ectopic adrenal cortex remnants in the testis or from reprogrammed Leydig stem cells, which differentiate and grow under the influence of chronically elevated ACTH. The mass effect increases the intratesticular pressure, impairs blood flow to the normal testis, and hinders outflow of semen. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Male reproduction'.)
TARTs are firm, irregular masses originating near the rete testes, are typically bilateral, and can be painful when large. Multiple studies have shown that 30 to 50 percent of adolescent and adult males with classic 21OHD develop TART, and ultrasonography is the most sensitive method of detection [8,9,20,21]. Intensified glucocorticoid therapy, but not surgery, might restore fertility.
Intensified glucocorticoid treatment is sometimes, but not always, effective for decreasing the size of TARTs and relieving pain. Case reports have noted either a decrease in size or even disappearance of testicular masses with supraphysiologic doses of dexamethasone or with daytime hydrocortisone plus bedtime dexamethasone [8,9]. The best approach to prevent TARTs is to maintain treatment in adolescent boys and men with adequate replacement glucocorticoids and to avoid long lapses in treatment.
Surgical removal provides good long-term control of TART growth and pain, but as demonstrated in a series from Rotterdam of eight patients with TART [22], testicular testosterone production and sperm production rarely, if ever, occurs postoperatively. The presence of TART and elevated follicle-stimulating hormone (FSH) are poor prognostic factors for fertility in men with 21OHD [19].
We suggest testicular ultrasound screening beginning in adolescence to detect TARTs, including one at the time of transition to adult care. We perform a physical exam and/or ultrasound monitoring for TART at least annually.
An elevated FSH indicates a poor prognosis for recovery of fertility in men with TARTs. A normal semen analysis is the best evidence of good disease control without overtreatment, and sperm banking may be considered in young men who express a desire to preserve their fertility. Testicular atrophy on exam (without TART development) is suggestive of poor disease control and chronic gonadotropin suppression from adrenal-derived androgens.
Women
Menstrual function and hyperandrogenism — Beyond adrenal replacement for adrenal insufficiency, the goal of treating women with 21OHD is to lower the adrenal-derived androgens and progesterone sufficiently to meet the patient's needs, including cosmetic effects of high androgens (hirsutism, acne), menstrual irregularities, and fertility.
For a woman who is not attempting to have children, monthly menses and control of unwanted androgen-dependent terminal hair growth or acne is good clinical evidence of adequate therapy. Other treatments, such as oral contraceptive pills to raise sex hormone-binding globulin (SHBG) and to regulate menses and mechanical or topical hair removal methods similar to polycystic ovary syndrome (PCOS) therapy, can be combined with glucocorticoids. However, we do not suggest spironolactone, an antiandrogen commonly used for women with hirsutism, as it antagonizes the effect of fludrocortisone and can cause volume depletion.
Fertility — Fertility rates in women with classic 21OHD are markedly reduced [23-25]. 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
●Psychological factors
●Ovarian hyperandrogenism secondary to chronic anovulation
●Ovarian adrenal rest tumors
The majority of women with 21OHD never attempt to conceive. Only 25 percent of women with classic 21OHD and 10 percent of the most severely affected ("salt-wasting") women ever attempt to conceive [26]. For these women who receive proper treatment and have regular intercourse, pregnancy rates exceed 90 percent.
More stringent control is necessary at least for several months before attempting pregnancy. The key parameter is follicular-phase serum progesterone concentrations, and glucocorticoid therapy is titrated to achieve values <0.6 ng/mL (2 nmol/L). Prior to attempting pregnancy, women with classic 21OHD should have gynecological consultation, ideally with a surgeon who can provide initial or repair previous genital reconstruction surgery. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction'.)
Adrenal rests — Besides TARTs, adrenal rests may develop elsewhere in the retroperitoneum, including the ovaries and surrounding structures. Ovarian adrenal rest tumors appear to be uncommon in women with classic 21OHD, with none found in a systematic evaluation of 13 women [27] and only scattered cases reported in the literature [28-30]. The etiology appears related to sustained elevations in ACTH as a result of poor compliance, as in men with TART. It is not known if glucocorticoid or mineralocorticoid therapy reduces adrenal rest development and/or size.
The sensitivity of ultrasound and magnetic resonance imaging (MRI) for detecting small ovarian rest tumors is not known, and other androgen-producing tumors of the ovary often are not found with conventional imaging studies. Thus, the true prevalence may be higher, as most tumors have been identified during surgery or at autopsy. Rest tumors occur primarily in the ovarian tissue and, less often, in the paraovarian/adnexal area. Imaging with 18-fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) has been used to identify rest tissue in three women [28-30] (including one with Nelson syndrome); in one case, tumors were only visible after concurrent administration of cosyntropin [29].
Pregnancy — During pregnancy, women should not receive glucocorticoids that cross the placenta, such as dexamethasone, for routine replacement therapy. Instead, hydrocortisone or prednisolone should be used in combination with fludrocortisone [2]. Once pregnancy is achieved, replacement therapy is continued until term.
During the third trimester, the dose of glucocorticoid needed to achieve adequate adrenal replacement might need to be increased up to 50 percent in some women. Other than electrolytes, laboratory data are of limited utility during pregnancy for women with classic 21OHD, and dose adjustments are largely guided on clinical grounds, as in women with other forms of adrenal insufficiency.
Cesarean section is almost always required at delivery due to vaginal inadequacy, and one extra dose (25 to 50 mg) of hydrocortisone prior to surgery is appropriate. Full-term pregnancies and delivery of healthy female infants with normal external genitalia can be achieved [31], with subsequent normal growth and development in girls as well as boys [32]. Even if androgen production cannot be suppressed to normal, placental aromatase activity protects the fetal genitalia and, presumably, the brain from masculinization [31].
Prenatal diagnosis and treatment — 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".)
Monitoring therapy
Glucocorticoid treatment — Standards have not been established for monitoring glucocorticoid therapy in adults. The most abundant circulating androgen in poorly controlled men and in all women with classic 21OHD is not testosterone but rather 11-ketotestosterone, which is not measured currently in clinical laboratories [33]. Some of the same principles apply as in treating adolescents [11,34]:
●History and physical exam should assess symptoms and signs of Cushing's syndrome, such as poor sleep, cognitive impairment, dermal atrophy, bruising, proximal muscle weakness, and purple striae. Men should undergo testicular examination at least annually. Women should be assessed for signs of androgen excess. Height and weight should be monitored regularly due to the increased risk of bone loss and obesity.
●Laboratory assessment in men includes monitoring serum concentrations of androstenedione, testosterone, SHBG, and gonadotropins; all should be in the normal range. Low gonadotropins and androstenedione/testosterone ratio >1 should prompt additional testicular evaluation.
●Laboratory assessment in women monitoring serum concentrations of androstenedione, testosterone, SHBG, and, in those attempting to conceive, follicular-phase progesterone. The goal is individualized to achieve patient goals, but testosterone and androstenedione should not be suppressed below the normal range with glucocorticoids; in contrast, follicular-phase progesterone should be maintained <0.6 ng/mL specifically for women attempting to become pregnant [35].
●Imaging studies: For men, a baseline testicular ultrasound should be obtained on transitioning to adulthood and periodically thereafter, depending on laboratory and physical exam data. Bone mineral density (BMD) should be measured periodically to assess bone health for both men and women. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Mineralocorticoid treatment — The aim of mineralocorticoid replacement is to normalize serum potassium concentration, standing blood pressure, and plasma renin activity, in that order (see "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid replacement'). Elevated blood pressure and dependent edema can be evidence of overtreatment. The dose of fludrocortisone acetate generally remains stable for years, but patients may benefit from dose titration when alternating between temperate and hot, humid climates. In addition, hydrocortisone provides some mineralocorticoid activity, so these clinical and laboratory parameters should be monitored after significant changes in glucocorticoid regimens.
Psychological and genetic counseling — Parents should be offered counseling as soon as the diagnosis is established. Children should eventually be informed of their condition by both their clinicians and parents, repeating the information in a manner appropriate for their age. Anticipatory counseling of parents about a possible tendency toward male gender role behavior of affected girls, and sensitive counseling and reassurance of adolescent girls should be provided. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Sexual behavior'.)
Data on long-term psychological outcomes are limited. One study reported an increase in psychiatric disorders in these patients as adults [36], and a larger Swedish series of 253 men with classic 21OHD found an increased prevalence of psychiatric disorders including suicides, which varied with genotype and appeared to decline following the introduction of newborn screening [37]. In contrast, in a study of 18 women with 21OHD, social adjustment and self-esteem scores were normal, with no obvious increase in mood disorders [38].
The Endocrine Society's Clinical Practice Guideline recommends that genetic counseling be provided to adolescents [2]. Patients should understand the autosomal recessive inheritance, the difference between affected and carrier status, and the carrier frequency in the general population. Those with nonclassic 21OHD should understand the difference between classic and nonclassic disease and the high (70 percent) probability that they are compound heterozygous carriers for classic 21OHD.
SURGERY
Reconstructive surgery — Women with classic 21-hydroxylase deficiency (21OHD) who plan to be sexually active with men typically require reconstructive gynecologic surgery as adolescents or adults, including clitoroplasty and vaginoplasty [1,39], either as an initial procedure or revision of a procedure performed in infancy. In one report of 16 adult women with 21OHD, 15 had undergone reconstructive genital surgery, with 8 of 16 requiring second procedures; 12 of 15 who had undergone surgery were considered to have an adequate vaginal introitus for sexual activity [39]. Regular dilation and adequate lubrication are recommended to reduce the risk of restenosis and dyspareunia. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Management of the infant with atypical genital appearance (difference of sex development)".)
There may be a delay in establishing sexual relationships, and sexual function may not be optimal, regardless of previous reconstructive surgery [40]. These issues may require counseling and possibly treatment, including additional surgery and/or a vaginal dilation program.
Surgical adrenalectomy — There have been some reports of unilateral or bilateral adrenalectomy for severe 21OHD [41-43]. The major benefit of this procedure lies in at least temporarily lowering adrenal androgen and progesterone secretion and, therefore, allowing lower doses of glucocorticoids. Bilateral adrenalectomy, however, heightens the dependency on glucocorticoid and mineralocorticoid replacement therapy, and adrenal rest tumors can occur subsequently, even in women [29].
LONG-TERM OUTCOMES — Additional outcomes for classic 21-hydroxylase deficiency (21OHD) in adults can be due to the disease itself, the treatments, or both. Some outcomes that have been assessed include bone density, height and weight, cardiovascular risk factors, and quality of life.
Pediatric outcomes (growth) are discussed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Growth'.)
Bone density — Bone mineral density (BMD) in adults with classic 21OHD is low when compared with healthy controls. In two large series totaling almost 400 adults, the National Institutes of Health (NIH) natural history study [44] and the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) study [3], 40 percent of patients who had bone densitometry showed osteopenia, and 5 to 10 percent showed osteoporosis. It is not known if the risk of fragility fractures is increased, but these cohorts were generally young adults. BMD should be measured at the age of peak bone mass accrual (approximately 25 years) and periodically, based on baseline values, glucocorticoid therapy, and other risk factors, to assess bone health for both men and women [45].
Vitamin D deficiency was also common in children and adults with classic 21OHD. Vitamin D deficiency and insufficiency was observed in 19 and 42 percent of children, respectively, and in 28 and 40 percent of adults, respectively, in the NIH natural history study [44].
Height and weight — Adults with classic 21OHD are shorter than expected by approximately 1 standard deviation (SD), and 35 to 41 percent are obese [3,44]. Obesity appears to be related to glucocorticoid over-replacement, whereas both glucocorticoid and sex steroid exposure during childhood contribute to short adult stature.
Cardiovascular risk factors — Insulin resistance was found in 29 percent [3] and 38 percent [44] of adults with classic 21OHD in two studies, and 18 percent of patients met criteria for the metabolic syndrome [44]. One study found that women with classic 21OHD have an increased risk (3 of 14, 21 percent) of gestational diabetes mellitus [46]. Hypercholesterolemia was found in 46 percent of adults in the CaHASE study [3].
Chronic glucocorticoid therapy in adults with 21OHD has been associated with not only Cushingoid features but also unfavorable changes in body composition, specifically an increase in fat mass and body mass index (BMI), particularly in older patients [46,47]. Therefore, the smallest possible dose of glucocorticoid should be used to avoid these adverse effects, and new glucocorticoid-sparing treatments are being studied [48].
Quality of life — Quality of life is broadly reduced in adults with 21OHD [3,44]. In a report of 151 adults, decreased quality of life was associated with the use of prednisolone or dexamethasone treatment (versus hydrocortisone) and with markers of obesity and insulin resistance [49]. These associations were found in patients with both classic and nonclassic forms. Another study from the same group found dexamethasone treatment to be associated with greater insulin resistance [50].
Mortality — A study from Sweden of 588 adults with classic 21OHD found approximately a two- to fourfold increase in mortality compared with population norms [13]. The major causes of death were adrenal crisis (42 percent), cardiovascular (32 percent), cancer (16 percent), and suicide (10 percent). Mortality was highest among men and among patients with the most severe ("salt-wasting") disease.
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
●The goals of therapy for adults with classic 21-hydroxylase deficiency (21OHD) include providing glucocorticoids in sufficient doses to replace the cortisol deficiency and to mitigate hyperandrogenemia, plus mineralocorticoids to restore blood pressure, serum electrolyte concentrations, and extracellular fluid volume to normal. (See 'Goals of therapy' above.)
●We suggest hydrocortisone, a short-acting glucocorticoid, as the glucocorticoid of choice in adults as it is the least likely to cause Cushingoid complications (Grade 2C). Hydrocortisone is typically administered in three divided doses totaling 15 to 30 mg to be effective (table 1).
Stepped therapy starts with divided doses of hydrocortisone as for children and adds or substitutes prednisolone, methylprednisolone, or dexamethasone as needed. The dose should be minimized to avoid adverse metabolic complications and decreased quality of life and tailored to maximize compliance. (See 'Routine daily regimens' above.)
●In pregnant women, we recommend using a glucocorticoid that is metabolized by the placenta, such as hydrocortisone, to avoid excessive glucocorticoid exposure to the fetus (Grade 1B). (See 'Pregnancy' above.)
●For mineralocorticoid therapy, the usual adult dose of fludrocortisone is 0.1 to 0.2 mg/day, but some patients require more and some might need less, especially when treated with hydrocortisone. (See 'Mineralocorticoid replacement' above.)
●The normalization of adrenal androgen production may be difficult to achieve without overtreatment, with its attendant risk of osteopenia and clinical manifestations of Cushing's syndrome. (See 'Bone density' above and 'Cardiovascular risk factors' above.)
●Men with classic 21OHD are prone to develop testicular adrenal rest tumors (TARTs) and/or oligospermia, especially when control is poor. We suggest testicular ultrasound screening beginning in adolescence to detect TARTs, including one at the time of transition to adult care. We perform a physical exam and/or ultrasound monitoring for TART at least annually. (See 'Testicular adrenal rest tumors' above.)
•An elevated follicle-stimulating hormone (FSH) indicates a poor prognosis for recovery of fertility in men with TARTs. Intensified glucocorticoid therapy, but not surgery, might restore fertility. A normal semen analysis is the best evidence of good disease control without overtreatment, and sperm banking may be considered in young men.
For men with classic 21OHD, we suggest monitoring serum concentrations of androstenedione, testosterone, sex hormone-binding globulin (SHBG), and gonadotropins; all should be in the normal range. Low gonadotropins and androstenedione/testosterone ratio >1 should prompt additional testicular evaluation. (See 'Monitoring therapy' above.)
●In all patients, we suggest monitoring standing blood pressure, plasma renin activity, and serum electrolytes, with the goal of normalizing all values. (See 'Monitoring therapy' above.)
●Women with classic 21OHD experience hirsutism, acne, irregular menses, and infertility if not adequately treated. Sexual dysfunction and vaginal stenosis/restenosis is common. Only 10 to 25 percent of women attempt to achieve pregnancy. Pregnancy rates are normal, however, in properly treated women. (See 'Women' above.)
For women with classic 21OHD, we suggest monitoring serum concentrations of androstenedione, testosterone, SHBG, and, in those attempting to conceive, follicular-phase progesterone. The goal is individualized to achieve patient goals, but testosterone and androstenedione should not be suppressed below the normal range with glucocorticoids; in contrast, follicular-phase progesterone should be maintained <0.6 ng/mL specifically for women attempting to become pregnant. (See 'Monitoring therapy' above.)
●For patients on mineralocorticoid and/or glucocorticoid therapy, we suggest monitoring annually or more often if treatment goals are not met. (See 'Monitoring therapy' above.)
●Adults with classic 21OHD have increased risk of short stature, obesity, insulin resistance, poor quality of life, and increased mortality (primarily due to adrenal crises). (See 'Long-term outcomes' above.)
DISCLOSURE — 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.
