AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

The condition 5-alpha-reductase type 2 deficiency (5-ARD) is an autosomal recessive sex-limited condition resulting in the inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT). Because DHT is required for the normal masculinization of the external genitalia in utero, genetic males with 5-ARD are born with ambiguous genitalia (ie, male pseudohermaphroditism).

The described clinical abnormalities range from infertility with normal male genital anatomy to underdeveloped male with hypospadias to predominantly female external genitalia, most often with mild clitoromegaly. The uterus and fallopian tubes are absent because of the normal secretion of the müllerian-inhibiting factor. Testes are intact, as are wolffian structures (epididymis, vas deferens, seminal vesicles). Male internal ducts are present but terminate either in a blind pseudovaginal pouch or on the perineum. A hypoplastic prostate may be present, regardless of degree of undervirilization of the external genitalia.

Pathophysiology

A deficiency of the type 2 isozyme 5-alpha-reductase, which transforms testosterone to DHT, is the root cause of this disorder. The conversion involves hydroxylation at the 5 carbon position of the A ring of the steroid molecule. This steric change flattens the configuration of DHT, allowing it to fit into the androgen receptor in a way testosterone cannot. Thus, DHT, the most potent androgen, is bound selectively to the androgen receptors in genital skin and fibroblasts, making its action necessary for the development of normal male genital anatomy in the fetus. As with most single enzyme disorders, 5-ARD is autosomal recessive and sex limited, since it only affects genetic males.

Two genes coding for 5-alpha-reductase have been identified, each for a slightly different isoenzyme. The gene for 5-alpha-reductase type 1 has been determined to be on chromosome 5. Its product is expressed only in nongenital skin and liver at low levels from the time the individual is aged 3 years to puberty, at which time enzyme expression is measurable in sebaceous glands and scalp. Linkage analysis has demonstrated that the type 1 enzyme is unrelated to the clinical syndrome of 5-ARD. The other isoenzyme, 5-alpha reductase type 2, determined on chromosome 2, correlates with clinical symptoms. It is expressed in high levels in the prostate and other androgen-sensitive tissues. Interestingly, partial virilization of males with 5-ARD occurs at puberty and may be attributable to the rise in type 1 enzyme activity at that time.

More than 20 different mutations of this gene have been reported in people with clinical and biochemical evidence of the enzyme deficiency. The clinical picture caused by most mutations is quite variable, even within the same family.

Frequency

United States

The carrier frequency and number of individuals with this disorder are not established.

International

Although overall frequencies for various countries are not established, increased frequency is reported in the Dominican Republic, some highland tribes in New Guinea, and in Turkey. The high frequency in these areas represents the effect of consanguinity in specific kindreds.

Mortality/Morbidity

• This enzyme deficiency is not life threatening; however, if intra-abdominal testes are retained, an increased risk of gonadoblastoma exists.
• Secondary issues include a risk of osteoporosis (see Bone mineralization) if hormone replacement therapy is not initiated in the patient with a gonadectomy and psychological morbidity due to gender or sexual identity issues (see Psychological support).

Sex

• Clinical 5-ARD is limited to genetic males.
• While the enzyme deficiency can be documented in heterozygous females, no clinical or developmental need for DHT is documented in women.

Age

• Most individuals with 5-ARD are identified in the neonatal period because of ambiguous genitalia. However, some of these children are misdiagnosed as having partial or complete androgen insensitivity syndrome (AIS), which can produce almost identical phenotypes. As noted above, some patients with 5-ARD virilize partially at puberty.
• Adult males presenting for infertility with anatomically normal genitalia have been diagnosed with 5-ARD. These incidents represent mutations with very mild effects on residual enzyme activity.

CLINICAL

Section 3 of 10  

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

History

• Diagnosis of 5-ARD usually is made in the newborn period when the infant presents with ambiguous genitalia. No risk factors or clinical markers in pregnancy are known. Genital ambiguity rarely is diagnosed prenatally when an infant who is demonstrated by amniocentesis or chorionic villus sampling to be karyotypically XY fails to have a demonstrable penis on ultrasonography.
• Some infants are misdiagnosed as having partial or complete AIS. Diagnosis then is suggested when the child begins to virilize rather than feminize in early puberty.

Physical

• Neonatal presentation
• • Phenotypic findings in a newborn are limited to the genitalia. A spectrum of findings exist ranging from minimal undervirilization presenting with normal male anatomy, except for isolated micropenis or hypospadias, to severe undervirilization presenting as normal female external genitalia with mild clitoral enlargement as the only physical finding.
  • Most commonly, the external genitalia exhibit labial appearance to the labioscrotal folds with some mild rugation or pigmentation present in some patients.
  • The phallus is indeterminate in size. Its length falls between 1.0 cm (ie, usual maximum for a clitoris) and 2.0 cm (ie, lower limit of normal for a penis).
  • The urethra may empty anywhere from the tip of the phallus to the perineum, with the latter observed more often.
  • The testes are usually in the inguinal canals bilaterally; however, in some individuals with 5-ARD, the testes can be found in the labioscrotal folds or retained in the abdomen.
  • A pseudovaginal blind-ending introitus usually is present with a normal hymen.
  • Since the uterus is absent, a rectal examination is negative for a cervical mass.
  • The rest of the examination is within normal limits.
• Presentation of males at puberty
• • Clear signs of virilization predominate at this age.
  • The escutcheon is male in distribution.
  • The phallus exhibits definite enlargement.
  • The shoulders are relatively broad and the hips are narrow.
  • Muscularity and body hair may increase.
  • No breast development is generally present.
  • A prominent Adam's apple may start to develop.
  • Facial hair develops.
  • The child's voice may begin to deepen.
  • The mucosa of the vaginal introitus remains atrophic in appearance (remaining red) rather than the thickened pink of estrogen-stimulated mucosa.
• Presentation of females
  • Females homozygous for 5-ARD have very subtle manifestations, such as delayed menarche and minimal body hair.
  • Fertility is normal in females.

Causes

• The cause of 5-ARD is the deficiency of the type 2 isozyme of 5-alpha-reductase. As with most single enzyme disorders, 5-ARD is an autosomal recessive trait and sex limited, since the clinical syndrome only affects genetic males.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

XO/XY mosaicism (mixed gonadal dysgenesis)
XY gonadal dysgenesis (Swyer syndrome)
Leydig cell hypoplasia
Maternal ingestion of progestins and estrogens
True hermaphroditism

WORKUP

Section 5 of 10  

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

Lab Studies

• Testosterone-to-dihydrotestosterone level
• • The hallmark of 5-ARD is an elevated ratio in serum of the testosterone-to-DHT ratio (T/DHT).
  • Usually, the testosterone level is normal to modestly elevated, while the DHT level is low to undetectable.
  • These levels can be measured at birth during the testosterone surge that occurs when an infant is aged 1-3 months or after human chorionic gonadotropin (hCG) stimulation.
  • In the older child, hCG stimulation is required for adequate levels of testosterone to demonstrate lack of conversion to DHT.
  • Although in healthy prepubertal children the baseline T/DHT ratio is 1:2, following hCG stimulation the ratio generally falls between 8:1 and 14:1. At puberty, random samples again can be used.
• Mutation analysis of the 5-alpha-reductase type 2 gene
• • Located at band 2p23, mutation analysis of the 5-alpha-reductase type 2 gene is a theoretical diagnostic tool.
  • Currently, it is primarily a research tool and not commercially available.
• Urinary ratios of various metabolites: Although sometimes used, they are not readily available commercially.

Imaging Studies

• Ultrasonography
• • Although not diagnostic for 5-ARD, ultrasonography of the pelvis is useful.
  • Ultrasonography can verify the location of the testes and the absence of the uterus, which may be present in other conditions of the differential diagnosis.
• Vaginogram
• A vaginogram (ie, dye introduced into the vagina via small catheter or feeding tube) is a useful tool to assess vaginal length.
• This study can verify that no fistulous connections are present between the urinary tract and vagina.

Histologic Findings

The testes exhibit Leydig cell hyperplasia and decreased spermatogenesis. However, testicular biopsy is not part of the routine evaluation.

TREATMENT

Section 6 of 10  

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

Medical Care

• Gender assignment
  • The major issue for individuals with 5-ARD is gender assignment. Almost all children with 5-ARD are assigned a female gender at birth.
  • In the United States, surgical feminizing genitoplasty is performed during infancy; however, more recently, this procedure has been called into question.
  • In many cultures in which early surgery is not performed, some individuals with 5-ARD adopt male gender identity and a male gender role at puberty.
  • Now individuals in the United States, including some postsurgery, are coming forward to identify themselves as male as they grow up and are switching gender roles to accommodate their new identities.
  • However, most of these individuals continue living in the female role and gender identity.
  • Thus, at the current time, assigning most infants with 5-ARD an initial female gender appears to be appropriate.
• Treatment
• • No medical treatment per se required in infancy and childhood
  • Male gender identity and hormone replacement therapy
    • Some evidence suggests that DHT therapy administered prior to puberty may increase penile size. DHT therapy is ineffective once puberty starts, probably because it merely suppresses and replaces the endogenous production of testosterone, maintaining a normal total serum level.
    • Most males virilize adequately for normal sexual function without replacement. The unaffected less active 5-ARD type 1 enzyme may provide adequate activity for this; or, even with the lower level of receptor binding, the large amount of testosterone produced at puberty may suffice for this masculinization.
  • Female gender identity and hormone replacement therapy
    • After gonadectomy, which should be performed prior to puberty and usually is performed in the newborn period, start hormone replacement therapy at an appropriate age.
    • Many endocrinologists use an arbitrary bone age of approximately 13 years; starting therapy too early causes premature epiphyseal fusion.
    • Other endocrinologists start measuring luteinizing hormone (LH) and follicle-stimulating hormone (FSH) when the individual is aged approximately 10 years and begin therapy when the gonadotropins begin to rise.
    • Either ethinyl estradiol or conjugated estrogens can be used initially.
    • Progesterone usually is not added in the absence of a uterus.
• Psychosocial support
  • Providing appropriate psychosocial support for the child and family is important. Questions about gender and sexuality are extremely anxiety provoking and emotionally upsetting. Ensuring that the family feels informed and involved in the entire decision-making process is important. After all, they are the ones who manage the issues on a day-to-day basis. Providing accurate and complete information to the child with 5-ARD so that an appropriate sense of self can develop is essential.
  • Psychosocial support can begin with a genetic counselor who can explain the etiology, genetics, and recurrence risks of 5-ARD.
  • A child psychiatrist or pediatric psychologist with experience working with intersex also should be involved. Their role includes emotional support of the family, helping the family formulate questions, and facilitating communication between the family and medical team. As the child gets older, the mental health professional can help provide age-appropriate information to the child about the condition and its treatment, assuage fears and childhood misconceptions, and help the individual with 5-ARD work with issues of gender role and identity.
  • A second source of psychosocial help for the child and family is referral to a support group. While currently no group exists specifically for individuals with 5-ARD, the AIS support group can serve this purpose. It has branches in several countries and maintains an active web site (see Androgen Insensitivity Syndrome Support Group). Members have made the group available to individuals with several conditions besides AIS that result in female phenotypes in XY individuals.
• Bone mineralization
  • Over the long term, a question about adequacy of bone mineralization is present.
  • While no studies are published on adults with 5-ARD, individuals with a similar condition (ie, AIS) have been reported to decrease bone mineralization by dual photon studies and clinical osteoporosis despite hormone replacement therapy.
  • Monitor bone mineralization in all individuals with 5-ARD until sufficient data specific to this condition emerge.

Surgical Care

• Feminizing genitoplasty
• • In the United States and many other industrialized countries, feminizing genitoplasty traditionally has been performed on infants with 5-ARD.
  • This surgery includes removal of the testes, restructuring of the labioscrotal folds into clear labia, and reduction or recession of the phallus to provide a more clitoral appearance.
  • More recently, this practice is being called into question for 2 reasons.
    • As in less developed countries, if gonadectomy is not performed, some of these children virilize at puberty and adopt a male gender identity and role. Even after gonadectomy, some children assigned a female gender may wish to assume a male gender role, although in the absence of gonadal steroids spontaneous physical virilization does not occur. No process is able to determine which children will identify as male; it does not correlate with degree of prenatal virilization or genetic mutation. Families with multiple children with 5-ARD have been reported; while all were raised as females in childhood, some transitioned to male in adolescence, and others retained female gender identity and role. Surgically feminizing the infant with 5-ARD makes male reconstruction even more difficult if needed later.
    • The issue of diminished sexual sensation and function in the clitoris of surgically altered children is being raised by a vocal group of former patients. They claim that their surgery left them with diminished-to-painful sexual response. While current surgical techniques are more sophisticated in sparing the neurovascular bundle, no long-term follow-up data address the issue.
• Vaginoplasty
• • Vaginoplasty is required at some point for most patients who remain female.
  • Several techniques, including various types of skin flap procedures as well as bowel loop transpositions, are available.
  • The decision as to which technique is most appropriate generally is determined by the anatomy of the individual vaginal remnants.
  • Occasionally, serial dilatation is enough to provide adequate vaginal enlargement.
  • As some of these procedures require recurrent dilation to maintain patency and others can cause mucoid discharge, many surgeons recommend delaying the surgery until the individual is an adolescent or young adult.

Consultations

• Geneticist
• • The geneticist is responsible for verifying the karyotype and discussing with the family the autosomal dominant sex-limited nature of 5-ARD, which includes the recurrence risk of 1:8 for each subsequent pregnancy (50% of XY fetuses) and the potential for prenatal diagnosis.
  • Since most families have no other members with 5-ARD and many also have a feeling of guilt at the birth of a child with the disorder, emphasizing to the family that nothing was missed or could have been done differently during the pregnancy to alter its outcome is important.
• Pediatric endocrinologist
  • The pediatric endocrinologist is responsible for verifying the biochemical nature of the defect, as well as excluding other parts of the differential (eg, congenital adrenal hyperplasia).
  • Pubertal hormone replacement usually is instituted under the supervision of a pediatric endocrinologist when the child attains the appropriate age.
  • Many pediatric endocrine offices offer a multidisciplinary team approach, which may assist the family as the child matures.
• Child psychiatrist or pediatric psychologist
  • The child psychiatrist or pediatric psychologist should be involved from the beginning.
  • These mental health professionals can help the family work with psychological issues (eg, any feelings of guilt or blame) that accompany the birth of a child with 5-ARD and help facilitate communication between the family and the medical consultants.
  • As the child grows, the psychiatrist or psychologist can help the family formulate open, accurate, and age-appropriate responses to the child's condition.
  • In some individuals with 5-ARD, help in establishing whether gender transition is appropriate may be necessary.
  • Pediatric psychology services sometimes are integrated into a multidisciplinary endocrine team.
• Pediatric surgeon or pediatric urologist
• • The pediatric surgeon or pediatric urologist assesses the potential for surgical reconstruction as either male or female. This assessment may affect the initial assignment of the gender of rearing. Because of a relatively small phallus, most infants with 5-ARD initially are reared as females.
  • Surgical planning should begin at birth but needs to account for the possibility of a child assuming a male gender at puberty.
  • As well as genital issues, the surgeon assessment encompasses the possibility of anatomic urinary tract abnormalities.

MEDICATION

Section 7 of 10  

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

Because of recent data, reconsidering the past policies of raising children with 46,XY with ambiguous genitalia and small phalli as females may be appropriate.

Drug Category: Hormones

Some males with 5-ARD respond with an increase in penile size when 2% DHT cream is applied to the lower abdomen.

Children reared as girls require estrogen replacement therapy in adolescence. Progestins typically are not required in the absence of a uterus.

Drug Name	Estrogens, conjugated (Premarin)
Description	Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.
Pediatric Dose	Initially administer estrogen at the lowest possible dose (ie, currently, 0.3 mg in tab form), not earlier than a bone age of 13 y
Contraindications	Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Interactions	May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy	X - Contraindicated in pregnancy
Precautions	Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding or mastodynia; estrogens may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia

Drug Name	Ethinyl estradiol (Estinyl)
Description	Induces synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.
Pediatric Dose	0.02 mg/d for 3-6 mo; raise to 0.04 mg/d for an additional 3-6 mo
Contraindications	Documented hypersensitivity; thrombophlebitis; undiagnosed vaginal bleeding
Interactions	May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• After the newborn period, further inpatient care is only necessary at the time of genitoplasty.
• No special care or procedures are required beyond those routine for the specific procedure.

Further Outpatient Care

• Outpatient care generally revolves around mental health support until the time of puberty. Even if the family adjusts well, providing ongoing support to answer questions as they arise is important. As previously noted, these answers should be medically accurate and appropriate to the child's level of understanding (see Child psychiatrist or pediatric psychologist).
• The pediatric endocrinologist is a valuable resource for managing the medical component of any issues raised.
• Support group contacts provide advice based on their own experiences as patient or parent (see Androgen Insensitivity Syndrome Support Group).
• At puberty, initiate hormone replacement therapy for children with a female gender identity. For those identifying as male, hormone replacement usually is not required, but endocrine follow-up monitoring of pubertal progress remains appropriate.

Deterrence/Prevention

• Currently, the only methods of prevention are nonconception by carrier parents and selective termination of affected pregnancies detected by mutation analysis. The latter presents significant ethical issues.

Complications

• Osteoporosis is a significant problem in patients with 5-ARD who have undergone gonadectomy. Hormone replacement therapy should prevent this; however, compliance is a particular problem. Many individuals with 5-ARD have significantly negative experiences with the medical care system and are reticent about taking medications and obtaining appropriate medical follow-up care.
• Psychosexual dysfunction may occur in the presence of genital malformation with or without surgical intervention. Seek appropriately timed consultations for patient and family from mental health professionals experienced in working with this type of problem.

Patient Education

• Education is a key part of the care plan for individuals with 5-ARD.
• • Provide patients (and their families) with accurate complete information about the diagnosis including, but not limited to, the chromosomal make-up of the individual, the presence of testes, and the medical and surgical options available.
  • A mental health professional, preferably a child psychiatrist or pediatric psychologist, should be available to the patient and family due to the emotional loading of some of these issues. In addition to emotional support, they can help facilitate communication between the medical team, the patient, and the family.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Although such cases have not yet been successful, intersex activists are pursuing the possibility of suing physicians who perform early genitoplasty on infants with conditions leading to ambiguous genitalia. Cases in which loss of sexual function is demonstrable or in which the adult gender identity conflicts with the surgically created sex appear likely to be filed. The current defenses are 2-fold, as follows:
• • First, the actions were consistent with the standard of practice at the time. This is consistent with cases in which the surgery was performed 5 or more years ago. Surgeries performed at present may be harder to defend, because this area of medical practice has become clearly controversial.
  • The second defense is that the parents gave informed consent. While not yet tested in the United States, the Constitutional Court of Columbia (equivalent to the US Supreme Court) handed down 2 separate rulings in October 1999 that severely limited the authority of parents to give consent for genitoplasty based on its cosmetic elective nature.

REFERENCES

Section 10 of 10

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

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Article Last Updated: Jun 12, 2006