AUTHOR AND EDITOR INFORMATION

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• Treatment
• Medication
• Follow-up
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

The rare variant of congenital adrenal hyperplasia (CAH) known as 17-hydroxylase deficiency was first described in the 1960s in patients with sexual infantilism and hypertension. It has also been described to present in the setting of male pseudohermaphroditism. Patients with 17-hydroxylase deficiency have alterations in their CYP17 gene that encodes the P450C17 enzyme. This enzyme plays a central role in steroidogenesis (see Image 1). It is essential for the production of cortisol and sex steroids. Thus, patients with 17-hydroxylase deficiency have reduced secretion of cortisol, androgen, and estrogen, with both adrenal and gonadal steroidogenesis impairment. Although patients with 17-hydroxylase deficiency have decreased cortisol production, they do not have signs or symptoms of adrenal insufficiency due to elevations of corticosterone and glucocorticoids.

CAH due to 17-hydroxylase deficiency is associated with hypertension and an excess of deoxycorticosterone (DOC), which is the second most common naturally occurring mineralocorticoid after aldosterone. DOC excess typically is associated with hypertension, hypokalemia, and renin and aldosterone suppression. Among the conditions associated with DOC excess are Cushing syndrome (particularly the ectopic adrenocorticotropic hormone [ACTH] variants and in the setting of adrenocortical carcinomas), adrenal tumors, CAH due to 11-hydroxylase deficiency, and primary cortisol resistance.

Pathophysiology

In the zona fasciculata, the typical end-product of the steroid biosynthetic pathway is cortisol (see Image 1), and cortisol regulates pituitary ACTH production through negative feedback inhibition. Loss of 17-hydroxylase activity in the adrenal gland blocks the synthesis of cortisol and results in an increase in ACTH production.

Aldosterone is the main mineralocorticoid produced by the adrenal zona glomerulosa, and its production is regulated by the renin-angiotensin-system. A 17-hydroxy pathway similar to the active pathway in the zona glomerulosa occurs in the zona fasciculata; however, the final product is corticosterone rather than aldosterone. Corticosterone is hydroxylated and oxidized at the 18 position to produce aldosterone in the glomerulosa, but not in the fasciculata. The adrenal fasciculata production of corticosterone, a weak glucocorticoid, and DOC, a potent mineralocorticoid, is minimal and relatively unimportant in healthy normal individuals, but it is important in patients with 17-hydroxylase deficiency.

Patients with 17-hydroxylase deficiency do not manifest symptoms of adrenal insufficiency because of increased production of corticosterone, a glucocorticoid. Because corticosterone is a weaker glucocorticoid than cortisol, very high levels of corticosterone are necessary before feedback inhibition on pituitary ACTH production occurs. As a result, a new steady state is established, with dramatically elevated levels of steroid intermediates such as progesterone, DOC, and corticosterone.

As the biosynthetic pathway diagram shows (see Image 1), 17-hydroxylase is not required for aldosterone synthesis. However, the elevated DOC levels from the zona fasciculata result in salt retention, volume expansion, hypertension, hypokalemia, and downregulation of the renin-angiotensin axis. This secondarily inhibits aldosterone production, which is typically virtually absent in affected patients.

The persistently elevated ACTH levels continue to drive overproduction of the preceding precursors, especially progesterone, DOC, and corticosterone. In these patients, DOC is principally under the control of ACTH rather than angiotensin, and it is predominantly secreted by the zona fasciculata rather than the glomerulosa. DOC is metabolized in the liver to tetrahydro-DOC, which is then conjugated to glucuronic acid and excreted in the urine. DOC can be further hydroxylated to 19-Nor-DOC, which also is a potent mineralocorticoid. Thus, 19-Nor-DOC levels also are elevated in patients with this syndrome.

In all variants of 17-hydroxylase deficiency, the production of sex steroids is absent, resulting in a compensatory increase in follicle-stimulating hormone and luteinizing hormone, comparable to menopausal levels. In humans, the gene product for 17-alpha hydroxylase (P450C17) is expressed in the adrenal cortex, testis, and ovaries but not the placenta. The adrenals produce glucocorticoids, mineralocorticoids, and C-19 steroids. The gonads, on the other hand, predominantly produce the C-19 steroids and sex hormones. Thus, in patients with 17-hydroxylase deficiency, both adrenal and gonadal steroidogenesis are impaired.

P450C17 performs multiple biochemical transformations. It 17-hydroxylates pregnenolone and progesterone and also is responsible for 17,20-lyase activity. Lin and colleagues described the differential regulation of the 2 principal activities of P450C17. Also, Zhang and associates described the developmentally regulated expression of P450C17. They suggest that P450C17 may play an important role in adrenarche, an event in children that is characterized by a dramatic rise in adrenal dehydroepiandrosterone (DHEA) production.

Patients with 17-hydroxylase deficiency typically have impairments of both 17-alpha-hydroxylase and 17,20-lyase activity. Recently, cases of isolated 17,20-lyase deficiency have been described, and CYP17 gene mutations have been confirmed by molecular genetic studies. Similarly, cases of isolated 17-alpha-hydroxylase deficiency have also been described.

Frequency

United States

The disorder reportedly is very rare. It comprises less than 1% of all patients with CAH. At least 14 cases of isolated 17,20 lyase deficiency have been reported in the presence of normal 17-alpha-hydroxylase activity.

International

A deficiency of 21-hydroxylase is by far the most common variant of CAH (95% of all cases), but the exact prevalence of 17-hydroxylase deficiency is unknown. Most authorities indicate that it is rare and certainly less common than 11-beta-hydroxylase deficiency. More than 120 cases of C-17 hydroxylase deficiency have been reported in the world medical literature. Prevalence may be more common in Brazil where there appears to be a founder effect with more than 80% of the gene mutations identified being due to two specific mutations. In Japan, several cases of 17-alpha hydroxylase deficiency have been reported associated with elevated aldosterone levels. The exact pathophysiologic mechanism for this enigmatic situation is unclear.

Mortality/Morbidity

• The major morbidities and mortality associated with the condition mainly stem from delayed recognition or nonrecognition of hypertension.
• The long-term sequelae of myocardial infarction, cerebrovascular accident, renal failure, heart failure, and peripheral vascular disease may occur if blood pressure is not well controlled.
• The psychologic impact of the hypogonadism and/or ambiguous genitalia associated with the condition may impact the quality of life and social adjustment of patients with this disorder.

Race

• Fewer than 150 well-validated cases have been documented in the medical literature; therefore, making any definitive statement as to relative frequency among the major ethnic groups is difficult.
• Cases from all over the world have been described, but a relatively low rate of both this syndrome and CAH in general appears among blacks from both Africa and the black diaspora.

Sex

• This is an autosomal recessive disease; therefore, males and females are affected equally.
• Of importance to note is that if karyotypes are not checked, more women will be detected because the males with classic 17-hydroxylase deficiency are phenotypic females.

Age

• The most common age at detection is in late adolescence, when the lack of sexual development associated with the syndrome becomes evident. Patients also may present with hypertension and hypokalemia.

CLINICAL

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History

This syndrome typically is first recognized in puberty, with the discovery of hypertension, hypokalemia, and hypogonadism. Patients present as phenotypic females with sexual infantilism and primary amenorrhea. Genetic male (XY) patients typically present with complete male pseudohermaphroditism characterized by female external genitalia, a blind ending vagina but no uterus or fallopian tubes. These patients tend to have intra-abdominal testicles. Less severely affected XY patients may present earlier in life with ambiguous genitalia due to underproduction of androgens. Typically, male patients have been raised as females, and the condition is only identified during puberty when the expected pubertal changes do not occur and then in-depth investigation is carried out. 

• Approximately 90% of patients are hypertensive or hypokalemic at presentation.



• Less commonly, the presentation may include malignant hypertension.



• Severe hypokalemia associated with muscle weakness, abdominal distension, or intestinal obstruction may be a predominant feature.



• In classic 17-hydroxylase deficiency, patients with both XX and XY karyotypes are phenotypic females. Both present with lack of secondary sexual development.
• • The testes of 46,XY patients do not produce testosterone in utero, resulting in absence of masculinization of the external genitalia. However, normal production of müllerian inhibitory substance occurs, resulting in müllerian duct regression. Thus, these patients have a blind vagina, absence of müllerian structures (fallopian tubes, uterus, and upper one third of vagina), and female external genitalia.
  
  
  
  • Patients with 46,XY karyotype and incomplete deficiency may present with ambiguous genitalia. Occasionally, these patients may be misdiagnosed with androgen insensitivity or other defects in androgen production.
     
• Because this syndrome is autosomal-recessive linked, a screening history of potentially affected pedigrees needs to exclude the possibility of consanguinity, closed communities with significant inbreeding, and the possibility of a founder effect.



• Partial 17-hydroxylase deficiency (nonclassic variant) has been described in a few families in the setting of consanguinity.
• • The clinical phenotype is less severe, and XY patients may present with microphallus, perineoscrotal hypospadias, scrotal testicles, and mild hypertension.
  
  
  
  • XX patients typically are infertile and have hypertension, irregular menses or primary amenorrhea, and hypoplastic breasts.
  
  
  
  • The hypogonadism associated with the condition is associated with bone age retardation and osteoporosis.
  
  
  
  • Patients fail to have a distinct adrenarche or pubarche.

Physical

In the classic variants, both 46,XY and 46,XX patients present as phenotypic females.

• Both XX and XY patients
• • Hypertension is common.

  • Secondary sexual characteristics, including axillary and pubic hair, are absent.

  • Breasts and genitalia are infantile.

  • Patients may be tall, with eunuchoid proportions due to lack of sex steroids and thus delayed fusion of epiphysis.

• Patients who are 46,XX: Internal female genitalia are normal but underdeveloped.
• Patients who are 46,XY
• • External genitalia are female, but they do not have the corresponding internal müllerian structures (eg, uterus, fallopian tubes, and ovaries are absent).

  • In utero, these patients do not have significant testosterone production, but the production of müllerian inhibitory factor from the testicles is normal, which prevents the development of female internal structures.

  • Patients may have inguinally located testicles that may present as inguinal hernias.

Causes

• The human CYP17 gene codes for the 508 amino acid enzyme, with a molecular weight of approximately 57,000.
  
  
  • The enzyme has both 17,20-lyase and 17-alpha-hydroxylase activities.
  
  
  
  • The gene consists of 8 exons.
     
• Most of the described clinical cases are associated with small base substitutions or insertions on the gene located in the 10q24-25 band that result in premature peptide termination. Single or multiple codon deletions as well as large deletions, nonsense mutations, and missense mutations have also been described. About 40 different mutations of the gene have been described so far. No strong genotype phenotype correlation exists in this condition.



• As with other variants of CAH, it is an autosomal recessive disease.



• Most mutations are random and spontaneous.
  
  
  • Clusters of patients with the same mutation have been identified in Holland, Brazil, and Japan, suggesting a founder effect.
  
  
  
  • Mutations that retain partial enzymatic activity also have been described.
  
  
  
  • A very rare variant of combined CYP21A2 and CYP17 deficiency has been described and appears to be due to mutations in the gene for P450 oxidoreductase rather than either the CVP17 or CYP21A2 genes.

DIFFERENTIALS

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Other Problems to be Considered

5-alpha reductase deficiency
3-beta hydroxylase steroid dehydrogenase deficiency
Androgen resistance syndromes
Lipoid CAH
Pure and/or mixed gonadal dysgenesis
Hypertension due to 11-beta hydroxylase deficiency
Hypertension due to primary hyperaldosteronism
Hypertension due to glucocorticoid remediable aldosteronism
Hypothalamic pituitary amenorrhea
Primary ovarian failure
Premature ovarian failure
Testicular feminization syndrome
Delayed puberty
Hypogonadotrophic hypogonadism
Ambiguous genitalia

WORKUP

Section 5 of 11  

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Lab Studies

• Diagnosis may be established by measuring precursor-to-product ratios during an ACTH stimulation test.



• The 17-deoxysteroids, progesterone, corticosterone, and DOC rise 5- to 10-times normal following ACTH stimulation. The aldosterone levels in most cases are low due to the renin suppression induced by the elevated levels of DOC and other precursor mineralocorticoids.



• Elevated progesterone, corticosterone, and DOC levels in the setting of a virtual absence of 17-hydroxyprogesterone, estrogens, and androgens are characteristic of the syndrome.



• Corticosterone typically is 50- to 100-fold higher than the reference range.



• Most patients have DOC levels greater than 100 ng/dL (normal 2-20 ng/dL).



• The majority of patients (80-90%) present with hypokalemic metabolic alkalosis.



• Patients will have elevated 18-hydroxycorticosterone and 18-hydroxyDOC.



• Follicle-stimulating hormone and luteinizing hormone levels are markedly elevated, while ACTH levels are marginally elevated.



• Patients with isolated 17,20-lyase deficiency may have normal 17-hydroxyprogesterone, cortisol, and 11-deoxycortisol levels with low levels of androgens and estrogens, testosterone, androstenedione, DHEA, DHEA-S, and estradiol. These findings are exaggerated with ACTH and human chorionic gonadotropin (HCG) stimulation. They also may have normal DOC levels.



• Biochemical testing may detect heterozygosity in family members of patients with 17-hydroxylase deficiency.
  
  
  • Corticosterone, 18-hydroxycorticosterone, and the 18-hydroxycorticosterone-to-aldosterone ratio are elevated following ACTH stimulation.
  
  
  
  • Heterozygotes may have exaggerated responses to ACTH stimulation.
  
  
  
  • Ratio of urinary metabolites of corticosterone to those of cortisol is low.
     
• Molecular genetics is highly sensitive but currently is only available in research laboratory settings.

Imaging Studies

• The diagnosis of this condition is not made by radiologic findings. However, being aware of potential radiologic findings that may have been obtained in the course of a workup for hypogonadism or ambiguous genitalia is worthwhile.
• • Abdominal CT scan or MRI may reveal bilateral thickening of the limbs of the adrenal.

  • Occasionally, particularly in adult patients, the adrenals may have a multinodular appearance.

  • NP-59 Iodo cholesterol scans are not performed routinely or necessary. Findings are consistent with the adrenocortical hyperplasia associated with CAH, ie, bilateral radioisotope uptake.

• Pelvic ultrasound reveals lack of müllerian structures in 46,XY patients and normal but underdeveloped müllerian structures in 46,XX patients. The gonads may be intra-abdominal or in the inguinal canal in 46,XY patients.

Other Tests

• In patients presenting with primary amenorrhea and sexual infantilism, karyotyping to determine the genetic sex of the patient is important. Even in genetic XY patients who have been hitherto raised as females, recognition of the genetic sex is critical as the undescended testicles in these patients invariably need to be removed surgically given their potential for malignant degeneration over time (associated increased risk for development of intratubular germ cell tumors estimated to be 40-100 times more common in the setting of cryptorchidism).

Histologic Findings

A description of the histologic findings in these patients is as sparse as the total number reported cases.

Typically, the adrenal glands are hyperplastic, enlarged, and show diffuse nodular hyperplasia, diffuse cortical hyperplasia, or adenomatous hyperplasia. The adrenal cortex is the area involved in the hyperplasia, predominantly the zona fasciculata and reticularis. The zona glomerulosa reportedly is normal histologically. The component cells involved in the hyperplasia typically are clear cells, with sporadic myelolipomatous tissue noted in several cases. A few cases have been reported where the hyperplasia is associated with coexisting adenomas.

In one case, pituitary gland examination showed evidence of enlargement found to be secondary to ACTH basophil cell hyperplasia.

The ovarian pathologic findings are variable. Multiple ovarian cysts have been described in adult patients, and the ovaries ultimately have a polycystic appearance (probably the result of chronic gonadotrophin stimulation). The ovaries typically show fibrous stromal cells without hyperplasia, few ova, and few follicles. However, most of the follicles are atretic with a few small graafian follicles.

The testicles usually are small with atrophic seminiferous tubules and little evidence of spermatogenesis. Associated secondary Leydig cell hyperplasia also is present. The testicles often are ectopically located. As is true for ectopic testes and in patients with other forms of steroid biosynthetic defects, patients with 17-hydroxylase deficiency require gonadectomy to prevent malignant degeneration of their intra-abdominal testes.

TREATMENT

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Medical Care

• As with other variants of CAH, appropriate glucocorticoid replacement is the cornerstone of therapy.
  
  
  • With adequate repletion, natriuresis and normalization of serum renin and potassium occur, and aldosterone levels gradually increase towards normal.
  
  
  
  • Appropriate glucocorticoid replacement normalizes blood pressure. However, hypertension may become sustained if not treated for many years.
  
  
  
  • Hydrocortisone is the ideal glucocorticoid in childhood. The typical hydrocortisone replacement dose is 10-20 mg/m²/d.
  
  
  
  • Dexamethasone may be used in adults. The dexamethasone doses typically are 0.3-0.5 mg/d.
  
  
  
  • Natriuresis and diuresis may occur, resulting in an acute hypovolemic crisis soon after therapy is begun because of a suppressed renin-angiotensin-aldosterone system. This risk is greater in patients with higher initial blood pressure elevations.
  
  
  
  • The timing of recovery of the renin-angiotensin-aldosterone system following effective glucocorticoid repletion is variable and can take months to years.
     
• Among those patients who remain slightly hypertensive even with adequate glucocorticoid replacement, first-line therapy includes the use of a mineralocorticoid antagonist, spironolactone, or eplerenone. Calcium channel blockers are added if hypertension persists.



• Moderation of dietary sodium intake is recommended.



• Hormone replacement regimens are best begun early in adolescence to achieve their greatest potential. They allow development of female secondary sexual characteristics and stimulate the normal increase in bone mass that occurs with puberty.
  
  
  • Estrogen replacement is initiated at the time of expected puberty or at the time of diagnosis if that time has passed.
  
  
  
  • Patients who are 46,XX require combined estrogen/progestin cyclic or combined therapy to prevent endometrial hyperplasia from unopposed estrogen.
  
  
  
  • Patients who are 46,XY lack müllerian structures and are often treated with estrogen alone if they first come to medical attention during the age of puberty and had hitherto been raised as girls. The decision to rather effect a sex identity change and treat such patients with androgen replacement and extensive genital reconstructive surgery should not be entered into lightly and only if the patient and parents/guardians decide on that option after being fully educated regarding the implications, ramifications, and possible consequences of such a decision.
  
  
  
  • To stimulate penile development, testosterone replacement may be given to mildly affected 46,XY patients born with ambiguous genitalia. In addition, they often require extensive external genitalia reconstructive surgery as well as a gonadectomy. The decision to rear these patients as males is complex.
     
• Unlike in the 11-beta hydroxylase or 21-hydroxylase deficiency variants of CAH, which are associated with virilization, prenatal dexamethasone has no role in this setting.



• Goals of treatment
  
  
  • Glucocorticoid replacement with avoidance of glucocorticoid excess (iatrogenic Cushing syndrome)
  
  
  
  • Reduction in mineralocorticoid secretion
  
  
  
  • Normalization of blood pressure
  
  
  
  • Adequacy of glucocorticoid repletion
    
    
    • This is determined by both clinical and biochemical characteristics.
    
    
    
    • Among the clinical indices used most commonly are the child's height and weight velocity and normalization of blood pressure.
       
  • Normalization of plasma potassium concentrations and restoring plasma renin activity to a measurable range
  
  
  
  • Reduction of serum levels of deoxycorticosterone and corticosterone
    
    
    • Normalization of these levels may require overtreatment with glucocorticoids.
    
    
    
    • This should not be a major goal.
       
  • Replacement of sex steroids
  
  
  
  • Preservation of bone mass and prevention of osteoporosis
    
    
    • While adequate hormone replacement may achieve this, calcium and vitamin D supplementation may be needed.
    
    
    
    • Prophylactic or therapeutic bisphosphonate use also may be needed.
       
• DHEA supplementation may be considered, although this has not been approved by the US Food and Drug Administration (FDA). Several reports, including that by Arlt and colleagues, suggest that DHEA supplementation in females who have adrenal insufficiency significantly improves overall well-being and sexual function.

Surgical Care

• Affected 46,XY patients require gonadectomy to prevent malignant degeneration of their gonads.
• • Because of the significant neoplastic risk of undescended dysplastic testicles (whether intra-abdominal or inguinal), they should be surgically removed as soon as the elective procedure can be safely performed and certainly before age 8-10 years (if detected in childhood).

  • If found in adulthood, the testicles should be removed as soon as possible because the neoplastic potential in this setting is considerable.

• The reconstruction of ambiguous genitalia may be indicated.

Consultations

The hypogonadism, infertility, and, in some cases, sexual ambiguity associated with this condition require a multidisciplinary approach to issues of sexual orientation, sexual identity, body image, and psychosocial support.

• Consultation with a psychiatrist and/or psychologist often is very useful in helping resolve some of the conflicts and crises that these patients face. Most patients are diagnosed at an age at which their gender identity has been firmly established; however, comprehension of the complexity of their condition may be difficult.
• If fertility is desired, referral to a fertility specialist is indicated.
• • Patients invariably require donor egg or donor sperm programs to be used with artificial insemination, in-vitro fertilization, or intracytoplasmic sperm transfer.

  • One case has been reported in the literature of a woman with 17-hydroxylase deficiency who responded to the induction of ovarian follicular growth using gonadotropin-releasing hormone analogs and subsequently had a successful pregnancy using in-vitro fertilization techniques.

MEDICATION

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Similar to other variants of CAH, the central theme of therapy is the administration of glucocorticoids. Glucocorticoid therapy suppresses the ACTH-induced adrenal hyperplasia and the excess of DOC and corticosterone that play a central role in the pathogenesis of the condition.

Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract and whose predominant effect includes stimulation of gluconeogenesis, lipolysis, and fat redistribution, as opposed to the mineralocorticoids whose predominant activity is the regulation of serum osmolality and intravascular volume.

As discussed in C-11 Hydroxylase Deficiency, blood pressure management also is important and involves variable combinations of potassium-sparing diuretics such as amiloride and triamterene, antialdosterone agents such as spironolactone, and both nondihydropyridine (eg, verapamil) and dihydropyridine (eg, nifedipine) calcium channel blockers.

Drug Category: Glucocorticoids

These agents are used to inhibit ACTH-stimulated bilateral adrenal hyperplasia. Have both anti-inflammatory (glucocorticoid) and salt retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Drug Name	Hydrocortisone (Hydrocortone, HydroTex, Hydrocort)
Description	Principal hormone secreted by the adrenal cortex. White, odorless, crystalline powder largely insoluble in water. Readily absorbed from the GI tract.
Adult Dose	Maintenance: 15-30 mg/d PO divided bid/tid Surgery: 100 mg/m2 IV q6h for 24 h
Pediatric Dose	12-25 mg/m2/d PO divided bid/tid
Contraindications	Documented hypersensitivity; use with caution in active viral, fungal, or tubercular skin infections
Interactions	Corticosteroid clearance may decrease with estrogens; glucocorticoids may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Increase dosages before, during, and after stressful situations Carefully observe infants born to mothers who have received substantial doses of corticosteroids (particularly dexamethasone) during pregnancy for signs of hypoadrenalism; corticosteroids appear in breast milk and could suppress growth or interfere with dosing in the infant Following prolonged high-dose therapy, lower doses may result in symptoms of corticosteroid withdrawal syndrome, including fever, myalgias, arthralgia, and malaise (may occur in patients even without evidence of adrenal insufficiency) Enhanced effect occurs in patients with hypothyroidism or cirrhosis Carefully monitor growth and development of pediatric patients on prolonged therapy Potential adverse effects of high doses include sodium or fluid retention, congestive heart failure, potassium loss, hypokalemic alkalosis, hypertension, muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathologic fracture of long bones, tendon rupture, peptic ulcer, impaired wound healing, thin and fragile skin, petechiae and ecchymoses, convulsions, increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment Other adverse reactions may include psychic disturbances (including frank psychosis or euphoria), menstrual irregularities, development of cushingoid state, growth suppression in children, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, trauma, surgery, or illness), decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in patients with diabetes, hirsutism, cataracts, or glaucoma

Drug Name	Prednisone (Deltasone, Orasone)
Description	Recommended for use in older patients because it is longer-acting than hydrocortisone.
Adult Dose	5-7.5 mg/d PO divided bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Estrogens

For the purpose of hormone replacement and induction of puberty. Treatment of moderate to severe vasomotor symptoms associated with menopause and vulval and vaginal atrophy. Hypoestrogenism due to hypogonadism, castration, primary ovarian failure, prevention of osteoporosis. No adequate evidence supports that estrogens are effective for nervous symptoms or depression that might occur during menopause, and they should not be used to treat these conditions.

Drug Category: Progestogens

Used for secondary amenorrhea; abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology (eg, fibroids or uterine cancer) and as part of combination hormone replacement therapy in premenopausal and postmenopausal XX adult patients.

Drug Category: Androgens

These are used for hormone replacement therapy in male patients with significant hypogonadism and to assist with induction of puberty in patients with absent or delayed onset of puberty.

Drug Name	Dehydroepiandrosterone, prasterone (Aslera, GL701, Vitamist DHEA-M for men)
Description	Use of adrenal androgen replacement therapy is controversial and not FDA-approved. However, the fact that DHEA constitutes a major component of circulating androgens in healthy women suggests some utility for its replacement in women with adrenal insufficiency. Although available over the counter as a "health supplement" and widely popular in the lay public, few well-conducted studies have fully investigated the utility of DHEA. The major potential area of indication that seems to be appearing is in hormone replacement (androgen replacement) for women with adrenal insufficiency. Recent studies by Callies and associates suggest that, although DHEA oral replacement at 50 mg/d is not associated with significant changes in BMI or parameters of body composition in this group of women, it seems to be associated with significant improvement in well being and sexuality. DHEA is a C-19 steroid also known as 5-androsten-3 beta-ol-17-one. DHEA and DHEAS (an active sulfated form of DHEA) are endogenous hormones secreted by the adrenal cortex in humans, other primates, and a few nonprimate species in response to ACTH. DHEA is a steroid precursor of both androgens and estrogens. Endogenous DHEA is thought to be important in several endocrine processes, but current medical use of DHEA is limited to controlled clinical trials. In 1984, the FDA banned the nonprescription (OTC) sale of exogenous DHEA due to concern over hepatotoxicity noted in animal studies. The FDA formally relegated DHEA to a category II OTC ingredient at that time (ie, not generally recognized as safe and effective). However, in 1994, the passage of the US Dietary Supplement Health and Education Act (DSHEA) allowed DHEA to be marketed as a nutritional supplement, which is the means by which it is accessed presently by most people. Endogenous DHEA is synthesized by the conversion of cholesterol via CYP11A1 to pregnenolone, followed by CYP17 conversion to DHEA, and then to DHEAS via dehydroepiandrosterone sulfatransferase. The synthesis of DHEA occurs exclusively in the adrenal cortex in women, while in men, 10-25% of DHEA is synthesized by the testes and roughly 80% of the DHEA comes from the adrenal glands. DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, androstenediol, testosterone, and estradiol by peripheral tissues. The administration of DHEA supplements results in different hormonal concentration changes in males and females; the actions are dependent on the dose, formulation, route of administration, and age of the person receiving the DHEA. DHEA has been administered via IV, SC, percutaneous, vaginal, topical, or PO routes in clinical trials. As a nutritional supplement, DHEA is most commonly administered PO. Many DHEA products available as nutritional supplements contain varied amounts of DHEA and do not appear to be manufactured according to good manufacturing processes. Using HPLC techniques, one study found that only 7 of 16 assayed products contained DHEA within a 10% variation of the labeled content. Some products contained no detectable DHEA.
Adult Dose	50 mg qd/bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; underlying hepatic disease and/or hepatic impairment; bipolar disorder, breast cancer, breastfeeding, children, diabetes mellitus, endometrial cancer, endometrial hyperplasia, erectile dysfunction, G6PD deficiency, hepatocellular cancer, infertility, ovarian cancer, porphyria, pregnancy, prostate cancer, prostatic hypertrophy, soya lecithin hypersensitivity, uterine cancer, vaginal bleeding, vaginal cancer
Interactions	Actions of DHEA on other exogenous hormonal regimens (eg, androgens, estrogens, oral contraceptives, or progestins) are unclear; either additive or antagonistic effects potentially can occur
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Elderly patients treated with androgens may be at increased risk for prostatic hyperplasia; elderly patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of subclinical or clinical prostate cancer prior to initiation of testosterone replacement therapy because testosterone therapy may promote growth of existing subclinical foci of prostate cancer; in men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for agonadal men Edema, with or without congestive heart failure, may be a serious complication of androgen treatment in patients with preexisting cardiac, renal, or hepatic disease (in addition to discontinuation of the drug, diuretic therapy may be required) Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism; physician should instruct patients to report any of the following adverse effects; too frequent or persistent erections of the penis, nausea, vomiting, jaundice, or ankle swelling Virilization of female sexual partners has been reported with male use of a topical testosterone solution; topically applied creams leave as much as 90 mg residual testosterone on the skin; the occlusive backing film on Androderm (testosterone transdermal system) prevents the partner from coming in contact with the active material in the system (transfer of the system to the partner is unlikely); changes in body hair distribution, significant increase in acne, or other signs of virilization of the female partner should be brought to the attention of a physician

Drug Category: Antihypertensive agents

Particularly useful for the treatment of hypertension associated with 17-hydroxylase deficiency and 11-beta-hydroxylase deficiency.

Drug Name	Eplerenone (INSPRA)
Description	Selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing blood pressure and sodium reabsorption.
Adult Dose	50 mg PO qd; may increase dose after 4 wk, not to exceed 100 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hyperkalemia or coadministration with drugs causing increased potassium; type 2 diabetes with microalbuminuria; moderate-to-severe renal insufficiency (ie, CrCl <50 mL/min or serum creatinine >2 mg/dL [males] or >1.8 mg/dL [females])
Interactions	CYP450 3A4 substrate; potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels about 5-fold, less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole) increase serum levels about 2-fold; grapefruit juice increases serum levels about 25%; coadministration with potassium supplements, salt substitutes, or drugs known to increase serum potassium (eg, amiloride, spironolactone, triamterene, ACE inhibitors, angiotensin II inhibitors) increases risk of hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause hyperkalemia, headache, or dizziness; caution with hepatic insufficiency

Drug Category: Antihypertensives: Potassium-sparing diuretics

One DOC to treat hypertension associated with 17-hydroxylase deficiency.

Drug Category: Antihypertensives: Dihydropyridine calcium channel blockers

This and other calcium channel blockers (both dihydropyridine and nondihydropyridine) have particular utility in the management of hypertension related to mineralocorticoid excess. They are among the most efficacious antihypertensives used in hypertension associated with CAH, such as occurs in 17-hydroxylase deficiency and 11-beta-hydroxylase deficiency.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Those related to hypergonadotropic hypogonadism are as follows:
• • Osteoporosis

  • Delayed epiphyseal fusion resulting in eunuchoid habitus and tall adult stature

  • Dyslipidemia

• Those related to chronic hypertension are as follows:
• • Cardiac failure

  • Hypertensive encephalopathy

  • Cerebrovascular accidents

  • Renal failure

  • Acute coronary syndromes

• Iatrogenic Cushing syndrome

Patient Education

• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Amenorrhea.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• This disorder is an uncommon but important consideration in the evaluation of patients with hypogonadism and hypertension.
• It should be particularly considered in female patients with delayed puberty and low renin hypertension.
• Adequate psychosocial support is important following diagnosis.

MULTIMEDIA

Section 10 of 11