C-17 Hydroxylase Deficiency 

Updated: Feb 01, 2018
Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

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.[1, 2]  Patients with 17-hydroxylase deficiency have alterations in their CYP17 gene, which encodes the P450C17 enzyme.[3, 4, 5, 6]  This enzyme plays a central role in steroidogenesis. See the image below. Steroidogenesis 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 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.

See the image below.

Generic adrenocortical steroidogenesis pathway. Generic adrenocortical steroidogenesis pathway.

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.[7, 8]

Pathophysiology

In the zona fasciculata, the typical end-product of the steroid biosynthetic pathway is cortisol, as shown in the image below, which 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. See the image below.

Generic adrenocortical steroidogenesis pathway. Generic adrenocortical steroidogenesis pathway.

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. In the glomerulosa, but not in the fasciculata, corticosterone is hydroxylated and oxidized at the 18 position to produce aldosterone. The adrenal fasciculata's 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 above shows, 17-hydroxylase is not required for aldosterone synthesis.[9] However, the elevated DOC levels from the zona fasciculata result in salt retention, volume expansion, hypertension, hypokalemia, and down-regulation of the renin-angiotensin axis. This secondarily inhibits aldosterone production, which typically is virtually absent in affected patients.

The persistently elevated ACTH levels continue to drive overproduction of the preceding precursors, especially progesterone, DOC, and corticosterone.[10] 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 by the glomerulosa. DOC is metabolized in the liver to tetrahydrodeoxycorticosterone, which is then conjugated to glucuronic acid and excreted in the urine. DOC can be further hydroxylated to 19-nordeoxycorticosterone, which also is a potent mineralocorticoid. Thus, 19-Nor-deoxycorticosterone 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 levels of follicle-stimulating hormone and luteinizing hormone comparable to that in menopause. In humans, the gene product for 17-alpha hydroxylase (P450C17) is expressed in the adrenal cortex, testes, and ovaries but not in 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, 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.[11] Also, Zhang and associates described the developmentally regulated expression of P450C17.[12] They suggested 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 17-alpha-hydroxylase and 17,20-lyase activity. However, cases of isolated 17,20-lyase deficiency have been described, with CYP17 gene mutations for such cases having been confirmed by molecular genetic studies.[13] Cases of isolated 17-alpha-hydroxylase deficiency have also been described.

Epidemiology

Frequency

United States

The occurrence of 17-hydroxylase deficiency reportedly is very rare. It is responsible for less than 1% of all cases of congenital adrenal hyperplasia. 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 is 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 2 specific mutations.[14] In Japan, several cases of 17-alpha hydroxylase deficiency associated with elevated aldosterone levels have been reported. The exact pathophysiologic mechanism for this enigmatic situation is unclear.

Mortality/Morbidity

Mortality and major morbidities associated with 17-hydroxylase deficiency stem mainly 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 17-hydroxylase deficiency.

Race

Fewer than 150 well-validated cases of 17-hydroxylase deficiency have been documented in the medical literature; therefore, making any definitive statement as to the relative frequency of this condition among the major ethnic groups is difficult.

Cases from all over the world have been described, but a relatively low rate of this syndrome and of congenital adrenal hyperplasia in general appears among blacks from Africa and from the black diaspora.

Sex

Because 17-hydroxylase deficiency is an autosomal recessive disease, males and females are affected equally.

It is important to note is that if karyotypes are not checked, the disease will be detected more often in females than in males, because males with classic 17-hydroxylase deficiency are phenotypic females.

Age

The most common stage of life at which 17-hydroxylase deficiency is detected is late adolescence, when the lack of sexual development associated with the syndrome becomes evident. Patients also may present with hypertension and hypokalemia.[15]

 

Presentation

History

Typically, 17-hydroxylase deficiency is first recognized in puberty, with the discovery of hypertension, hypokalemia, and hypogonadism. Patients present as phenotypic females, with sexual infantilism and primary amenorrhea. Patients with the condition who are genetic males (XY) typically present with complete male pseudohermaphroditism; they are characterized by external female genitalia, with a blind-ending vagina, but no uterus or fallopian tubes, present. These patients tend to have intra-abdominal testes. 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, with the condition being identified only during puberty, when the expected pubertal changes have not occurred (and have therefore led to an in-depth investigation).

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

  • Less commonly, the presentation may include malignant hypertension.[15]

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

  • In classic 17-hydroxylase deficiency, patients with XX or 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, 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.[16]

    • The clinical phenotype is less severe, and XY patients may present with microphallus, perineoscrotal hypospadias, scrotal testes, 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, 46,XY and 46,XX patients present as phenotypic females.

  • XX and XY patients

    • Hypertension is common.[15]

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

    • Breasts and genitalia are infantile.

    • Patients may be tall, with eunuchoid proportions due to a 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

    • The external genitalia are female, but they do not have the corresponding internal müllerian structures (eg, uterus, fallopian tubes, ovaries).

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

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

Causes

The human CYP17 gene codes for the 508 amino acid enzyme, which has a molecular weight of approximately 57,000.

  • The enzyme has 17,20-lyase and 17-alpha-hydroxylase activities.[13]

  • The gene consists of 8 exons.

Most of the described clinical cases of 17-hydroxylase deficiency are associated with small base substitutions or insertions, resulting in premature peptide termination, on the gene located in the 10q24-25 band. Single or multiple codon deletions, as well as large deletions, nonsense mutations, and missense mutations, have also been described.[17] Overall, about 40 different mutations of the gene have been described so far. No strong genotype-phenotype correlation exists in 17-hydroxylase deficiency.

As with other variants of congenital adrenal hyperplasia, 17-hydroxylase deficiency 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 featuring combined CYP21A2 and CYP17 deficiency has been described; it appears to result from mutations in the gene for P450 oxidoreductase rather than from mutations in either the CYP17 or CYP21A2 genes.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

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

  • The 17-deoxy steroids, as well as progesterone, corticosterone, and DOC, rise to 5-10 times their normal levels 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 levels being 2-20 ng/dL).

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

  • Patients have elevated levels of 18-hydroxycorticosterone and 18-hydroxydeoxycorticosterone.

  • 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 sulfate (DHEA-S), and estradiol. These findings are exaggerated with ACTH and human chorionic gonadotrophin stimulation. Patients also may have normal DOC levels.

  • Biochemical testing may detect heterozygosity in family members of patients with 17-hydroxylase deficiency.

    • Corticosterone and 18-hydroxycorticosterone levels, as well as the 18-hydroxycorticosterone – to – aldosterone ratio, are elevated following ACTH stimulation.

    • Heterozygotes may have exaggerated responses to ACTH stimulation.[18]

    • The ratio of urinary metabolites of corticosterone to those of cortisol is low.

Molecular genetics is highly sensitive but currently is available only 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.[19]

  • Abdominal computed tomography (CT) scanning or magnetic resonance imaging (MRI) may reveal bilateral thickening of the limbs of the adrenal.

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

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

Pelvic ultrasonography reveals a lack of m ü llerian structures in 46,XY patients and demonstrates normal, but underdeveloped, m ü llerian 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, because the undescended testes in these patients invariably need to be removed surgically, given their potential for malignant degeneration over time. The associated increased risk for the development of intratubular germ cell tumors is estimated to be 40-100 times more common in the setting of cryptorchidism.

Histologic Findings

A description of the histologic findings in patients with 17-hydroxylase deficiency 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, predominantly the zona fasciculata and the reticularis, is the area involved in the hyperplasia. 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 in which 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 as a 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 testes usually are small, with atrophic seminiferous tubules and little evidence of spermatogenesis. Associated secondary Leydig cell hyperplasia also is present. The testes 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

Medical Care

As with other variants of congenital adrenal hyperplasia (CAH), appropriate glucocorticoid replacement is the cornerstone of therapy.[20, 21]

  • 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 be sustained if it has not been 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 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 the 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; if that time has passed, the replacement therapy is initiated at the time of diagnosis.

  • 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 instead effect a sex identity change and treat such patients with androgen replacement and extensive genital reconstructive surgery should not be entered into lightly. The treatment should be used only if the patient and parents/guardians decide on this 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, these patients often require extensive reconstructive surgery of the external genitalia, 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.[22]

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 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, have suggested that DHEA supplementation in females who have adrenal insufficiency significantly improves overall well-being and sexual function.[23, 24]

Surgical Care

Affected 46,XY patients require gonadectomy to prevent malignant degeneration of their gonads.

  • Because of the significant neoplastic risk of undescended dysplastic testes (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 testes 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 17-hydroxylase deficiency require a multidisciplinary approach to issues of sexual orientation, sexual identity, body image, and psychosocial support.[25]

  • Consultation with a psychiatrist and/or psychologist often is very useful in helping to 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, patients may have difficulty comprehending the complexity of their condition.

  • 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 gonadotrophin-releasing hormone analogs and who subsequently had a successful pregnancy using in-vitro fertilization techniques.

 

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.

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.

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.

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.

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.

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.

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.

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.

 

Follow-up

Complications

Complications related to hypergonadotropic hypogonadism are as follows:

  • Osteoporosis

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

  • Dyslipidemia

Complications 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 eMedicineHealth's Women's Health Center. Also, see eMedicineHealth's patient education article Amenorrhea.