C-17 Hydroxylase Deficiency Medication

Updated: Dec 16, 2014
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Medication

Medication Summary

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, either naturally occurring or synthetic, and are readily absorbed from the gastrointestinal tract. The predominant effects of glucocorticoids include the stimulation of gluconeogenesis, lipolysis, and fat redistribution, as opposed to the predominant activity of mineralocorticoids, which 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 nondihydropyridine (eg, verapamil) and dihydropyridine (eg, nifedipine) calcium channel blockers.

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Glucocorticoids

Class Summary

These agents are used to inhibit ACTH-stimulated bilateral adrenal hyperplasia. They have 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.

Dexamethasone (Decadron, AK-Dex, Alba-Dex)

Synthetic adrenocortical steroid. White, odorless, crystalline powder that is stable in air and practically insoluble in water. Lacks virtually any mineralocorticoid activity.

Hydrocortisone (Hydrocortone, Hydro-Tex, Hydrocort)

Principal hormone secreted by the adrenal cortex. White, odorless, crystalline powder largely insoluble in water. Readily absorbed from the GI tract.

Prednisone (Deltasone, Orasone)

Recommended for use in older patients, because it is longer-acting than hydrocortisone.

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Estrogens

Class Summary

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.

Estradiol-17B (Estrace, Climara, FemPatch, Estraderm, Noven, Vivelle, Vivelle-Dot, Alora)

White, crystalline solid, chemically described as estra-1,3,5(10)-triene-3,17(beta)-diol. Estrogen drug products act by regulating transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences or hormone-response elements, which enhances transcription of adjacent genes and, in turn, leads to the observed effects.

Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat.

Estrogens are intricately involved with other hormones, especially progesterone, in the processes of ovulatory menstrual cycle and pregnancy and affect release of pituitary gonadotrophins. They also contribute to shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in epiphyses of long bones that allow for the pubertal growth spurt and its termination, and pigmentation of nipples and genitals.

Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70-500 mcg of estradiol daily, depending on phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone, especially in its sulfate ester form, is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.

Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption usually is sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed, with a prolonged duration of action such that a single IM injection of estradiol valerate or estradiol cypionate is absorbed over several wk.

Administered estrogens and their esters are handled essentially the same as the endogenous hormones within the body. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect) but also at local target tissue sites.

Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms that are continually interconverted, especially between estrone and estradiol, and between esterified and nonesterified forms. Although naturally occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species.

A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catechol-estrogens, which interact with catecholamine metabolism, especially in the CNS), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

When given PO, naturally occurring estrogens and their esters are extensively metabolized (first-pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency.

In contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency.

Estrogen drug products administered by nonoral routes are not subject to first-pass metabolism but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling. Transdermal estrogen preparations provide systemic estrogen replacement therapy by delivering estradiol, the major estrogenic hormone secreted by the human ovary, through the area of intact skin covered by the system.

Circulating estrogen concentration modulates the pituitary secretion of the gonadotrophins LH and FSH through a negative feedback mechanism, and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.

Therapy with Estrace (estradiol tabs, USP) should be initiated as soon as possible after menopause to prevent postmenopausal bone loss.

Induction of puberty may be individualized and adjusted according to patient's needs.

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Progestogens

Class Summary

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.

Medroxyprogesterone (Cycrin, Provera, Amen)

Administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered medroxyprogesterone acetate inhibits gonadotrophin production, which in turn prevents follicular maturation and ovulation; available data indicate that this does not occur when the usual recommended oral dosage is given as a single daily dose.

Progestational agents have been used beginning with the first trimester of pregnancy in an attempt to prevent habitual abortion. No adequate evidence suggests that such use is effective when such drugs are given during the first 4 mo of pregnancy. Furthermore, in the vast majority of women, the cause of abortion is a defective ovum, which progestational agents could not be expected to influence. In addition, the use of progestational agents, with their uterine-relaxant properties, in patients with fertilized defective ova may cause a delay in spontaneous abortion. Therefore, the use of such drugs during the first 4 mo of pregnancy is not recommended.

Dose is variable depending on progestogen type being used.

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Androgens

Class Summary

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.

Testosterone (Andro-LA, Delatest, Androderm)

Indicated for testosterone replacement therapy in men for conditions associated with a deficiency or absence of endogenous testosterone. These include primary hypogonadism (congenital or acquired); testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchiectomy; Klinefelter syndrome; chemotherapy; or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations accompanied by gonadotrophins (FSH, LH) above the normal range. Other conditions include secondary, ie, hypogonadotropic hypogonadism (congenital or acquired); idiopathic gonadotrophin or luteinizing hormone-releasing hormone (LHRH) deficiency; or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low serum testosterone concentrations without associated elevation in gonadotrophins.

Appropriate adrenal cortical and thyroid hormone replacement therapy may be necessary in patients with multiple pituitary or hypothalamic abnormalities.

Transdermal systems deliver physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate the normal circadian rhythm of healthy young men. The other major replacement method is using IM injections given every 1-2 wk. In Europe particularly and far less so in the US, testosterone also is repleted by SC testosterone pellet implantation that is done every 5-6 mo. Androderm (testosterone transdermal system) delivers testosterone, the primary androgenic hormone.

Testosterone is responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; and alterations in body musculature and fat distribution.

Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, and regression of secondary sexual characteristics.

Androgens promote retention of nitrogen, sodium, potassium, and phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when sufficient intake of calories and protein occurs.

Androgens also are responsible for the growth spurt of adolescence and for the eventual termination of linear growth that is brought about by the fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause disproportionate advancement in bone maturation. Long-term use may result in fusion of the epiphyseal growth centers and termination of the growth process.

Androgens have been reported to stimulate the production of red blood cells by enhancing erythropoietin production. During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary LH secretion. With large doses of exogenous androgens, spermatogenesis also may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) secretion.

Substantial evidence indicating that androgens are effective in accelerating fracture healing or in shortening postsurgical convalescence is lacking.

Dehydroepiandrosterone, prasterone (Aslera, GL701, Vitamist DHEA-M for men)

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 with 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.

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 DHEA-S (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 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 DHEA-S via dehydroepiandrosterone sulfotransferase. 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.

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Antihypertensive agents

Class Summary

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

Spironolactone (Aldactone)

Specific pharmacologic antagonist of aldosterone that acts primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule.

Eplerenone (Inspra)

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.

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Antihypertensives: Potassium-sparing diuretics

Class Summary

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

Amiloride (Midamor)

Antikaliuretic diuretic agent. A pyrazine-carbonyl-guanidine that is chemically unrelated to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. In some clinical studies, its activity increased effects of thiazide diuretics.

Amiloride is not an aldosterone antagonist, and its effects are observed even in the absence of aldosterone.

Exerts potassium-sparing effect through inhibition of sodium reabsorption at distal convoluted tubule, cortical collecting tubule, and collecting duct. This decreases the net negative potential of the tubular lumen and reduces potassium and hydrogen secretion and their subsequent excretion.

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Antihypertensives: Dihydropyridine calcium channel blockers

Class Summary

This and other calcium channel blockers (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 congenital adrenal hyperplasia, such as occurs in 17-hydroxylase deficiency and 11-beta-hydroxylase deficiency.

Nifedipine (Adalat, Procardia)

Calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that selectively inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle without changing serum calcium concentrations. The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation by direct effects and resulting reduction in peripheral vascular resistance.

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