5-Alpha-Reductase Deficiency Treatment & Management

Updated: Dec 08, 2021
  • Author: Anna H Isfort, MD; Chief Editor: Robert P Hoffman, MD  more...
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Medical Care

Caring for patients with 46,XY DSD requires parental and, when appropriate, patient, education regarding the specific developmental abnormalities found on the physical examination of the patient, contrasted with normal sexual development. This education should include an open and frank discussion of what is known, and not known, about long-term effects of gender assignment, including gender identity, gender role, and sexual satisfaction. These discussions need to begin as soon as the patient is discovered to have ambiguous genitalia, and is ideally performed by a multidisciplinary team that includes representation from pediatric endocrinology, pediatric urology or surgery, genetics, and mental health.

Although everyone agrees that an expeditious and thorough assessment in regard to the diagnosis is critical, decisions with lifelong impact, such as surgical intervention should not be rushed. Families must be afforded time to digest the information, adjust to the implications of the diagnosis, and be provided open and ready access to members of the treatment team as they work through the decision process.

Full disclosure of the diagnosis, prognosis (gender identity outcome as well as potential for fertility and sexual function), rationale with risks and benefits for proposed procedures, alternative treatments, and local clinical experience must be shared under the standard of informed consent.

Gender assignment

Multiple factors must be considered in recommending gender assignment for children born with ambiguous genitalia. These include diagnosis, genital appearance, surgical options for both cosmetic and functional outcome, potential for fertility, potential need for lifelong hormone replacement therapy, and the particular social, religious, and cultural context of the family.

The ultimate medical goal of treatment is to restore external genitalia as close to a nonambiguous appearance as possible while retaining full sensation, the ability for sexual satisfaction (to include penetrative intercourse), and ideally, fertility. In conditions where androgen response or synthesis leads to a DSD, such as partial androgen insensitivity syndrome (PAIS), 17-beta-hydroxysteroid dehydrogenase deficiency, and 5-alpha-reductase deficiency (5-ARD), attaining all of these goals is unlikely. Conveying this to the parents and/or patient while being empathetic to their anxiety is essential.

Affording the child the best opportunity for a healthy long-term psychosocial development is the foundation for recommendations of gender assignment. In select cultures with high prevalence of 5-alpha-reductase deficiency, such as the Dominican Republic and Papua New-Guinea, gender role change is an accepted part of culture. Unfortunately, for most other cultures, a third gender is not accepted, suggesting that a decision for gender assignment should occur before the patient is able to make an individual choice. Although gender assignment in the newborn period may not be ideal, this well-intended, and perhaps justifiable approach is undertaken due to social as well as developmental concerns because children typically develop a sense of gender identity by age 3 years.

Proponents of early surgery for female gender assignment suggest that early gonadectomy increases the likelihood of gender satisfaction and stability and that surgical outcome is improved due to increased tissue plasticity. Opponents point out the increased likelihood of repeat surgical intervention, the irreversible nature of the procedure made at a time when patient consent is not attainable, and the high incidence of gender dysphoria and sexual dissatisfaction.

The most important message from the surgical literature is that the timing of the surgery appears to be of lesser importance than ensuring that the surgery be performed by a surgeon with extensive experience in caring for patients with DSD. [14]

Medical care

Medical care is dictated by gender assignment and surgical intervention

Hormone replacement therapy should be considered in patients raised in the male gender and is required in patients raised in the female gender that have undergone gonadectomy

In patients with 5-alpha-reductase deficiency who are raised as male, testosterone or dihydrotestosterone (DHT) therapy may increase penile length. Two doses of testosterone ester (125 mg per dose), given 3 weeks apart has been used in prepubertal children to increase penile length, and should be considered prior to hypospadias repair. [25] Higher dose therapy (250-500 mg 1-2 times per week given for 6-36 mo) has been used in pubertal or postpubertal patients. [25, 26, 13]

If testosterone is used in a prepubertal patient for a prolonged course of therapy, parents should be counseled over the potential to decrease final adult height secondary to androgen associated skeletal advancement

In patients with 5-alpha-reductase deficiency who are raised female, estrogen replacement therapy should be initiated at a bone age of 12 years or once an increase in gonadotropins is observed. The dose is tailored to reach adult replacement levels over a 3-4 year range. Progesterone or cycling of estrogen therapy is not required due to the absence of a uterus.

Decreased bone mineral density may be a complication for female patients who are not initiated or not maintained on appropriate estrogen replacement therapy but does not appear to be a problem for male patients with intact gonads. [27]


Surgical Care

Female gender assignment

In patients with near complete enzyme dysfunction, infants have pseudovaginal perineoscrotal hypospadias, severely bifid scrotum, small phallic structure (microphallus or clitoromegaly, description designated based on gender assignment), and urogenital sinus (blind vaginal pouch). [13]

Feminizing genitoplasty is a broad term to describe potential surgical interventions, and may include gonadectomy (removal of the testes), restructuring of the labioscrotal folds into labia, and reduction or recession of the phallus to provide a more clitoral appearance. Recent advances in surgical techniques have focused on procedures that spare the clitoral enervation; however, no long-term studies have assessed the success of these procedures.

Specific surgeries include gonadectomy, clitoroplasty with preservation of the clitoral glans and sensory input, separation of the urethra from the vagina, and construction (eg. Y-V vaginoplasty, colovaginoplasty).

Laparoscopic gonadectomy is recommended, if available. Proponents of female gender assignment recommend early gonadectomy to lessen the exposure to androgen, allowing for development of a more stable female gender identity and to avoid the associated virilization that occurs with puberty.

Although some centers advocate for a single-stage procedure, others delay vaginal reconstruction surgery until puberty when the patient is better able to perform required postsurgical care (dilatation).

Complications include the following:

  • Urinary tract complications

  • Decreased clitoral sensation

  • Vaginal and/or introital stenosis

Estrogen replacement therapy is required for the initiation of puberty. This therapy is typically started after the patient has attained a bone age of 12 years or once an increase in gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) is noted.

Postoperative care for vaginoplasty involves the use of vaginal dilatation with molds and for patients that underwent prepubertal vaginoplasty may require repair of introital and/or vaginal stenosis and vaginal lengthening.

Once gonadectomy has been performed, fertility is not possible, even if the patient decides on a gender-role change during adolescence or adulthood. Childbirth is not possible because no müllerian structures are present due to the presence of müllerian inhibiting substance during fetal development.

Male gender assignment

The same clinical description and timing considerations apply as is described for female gender assignment above. [13, 28]

The surgical correction of hypospadias, chordee, and/or cryptorchidism is required in most cases. The technique is determined by severity. Approaches include the following:

  • Urethroplasty (Perineoscrotal hypospadias repair is typically a multistage procedure.)

  • Repair of bifid scrotum

  • Chordee repair

  • Orchiopexy

Complications include the following:

  • Urethral fistula

  • Urethral stenosis

Micropenis is an anticipated clinical feature, defined by stretched penile length of less than 2.5 cm in a term newborn or a length of less than 7 cm in an adult male. [29, 30]

Testosterone or DHT therapy has been reported to increase penile size and virilization. The nonaromatizable nature of DHT decreases the chance for developing iatrogenic gynecomastia. However, neither DHT gel nor a long-acting injectable form of DHT are FDA approved or currently available in the United States.

If testosterone is administered to prepubertal children for a prolonged course of therapy, advancing skeletal age that ultimately results in decreased final height is a risk.

In patients with 5-alpha-reductase deficiency, limited data suggest that high-dose testosterone may increase penile shaft length and circumference, increase erectile potency and ejaculatory volume, increase facial hair and muscularity, and improve a sense of well-being. [26, 25]

Various penile enhancement procedures are available and are directed at increasing penile length or circumference. Unfortunately, limited standardization of procedures and disappointing short-term and long-term patient satisfaction are reported. [30]

Significant complications associated with the surgical procedures include penile deformity, paradoxical shortening, scarring and granuloma formation, and sexual dysfunction. [30] The average increase in penile length for either medical or surgical intervention is 1-2 cm.

Patients with 5-alpha-reductase deficiency who have not undergone feminizing procedures may be fertile; however, most of this subpopulation require in vitro fertilization or other assisted-fertilization techniques. [31, 32] Sperm counts are typically very low, with abnormal spermatogenesis and thick ejaculate.



Pediatric endocrinologist

The pediatric endocrinologist is responsible for coordinating the laboratory and radiologic evaluation, reviewing the results to determine the etiology of the clinical findings from the other potential diagnoses in the differential, to include defects in gonadal development (Denys-Drash syndrome and others), testosterone production (3-beta-hydroxysteroid dehydrogenase, 17-beta-hydroxysteroid dehydrogenase), and testosterone response (partial androgen insensitivity) and for ensuring that parents feel informed and are educated leaders of the decision-making team.

In addition, the pediatric endocrinologist is responsible for instituting and following hormone replacement when clinically indicated. Many pediatric endocrine offices offer a multidisciplinary team approach, which may assist the family as the child matures.

Pediatric surgeon or pediatric urologist

The pediatric surgeon or pediatric urologist assesses the potential for surgical reconstruction as either male or female based on physical examination, laboratory, and radiologic information. This assessment has significant impact on helping the family make a gender assignment choice. No matter the choice, surgery is likely to be part of the treatment plan, and coordination of the timing and staging for the initial and/or subsequent procedures should be a part of the initial discussion. Surgical planning should begin at birth, but time is available to decide on the appropriate procedure based on family comfort, decreased anesthesia risk, and other issues.


The geneticist is responsible for verifying the karyotype and discussing with the family the male-limited autosomal recessive inheritance pattern for the disorder, to include the recurrence risk of 1:8 for each subsequent pregnancy. Due to a higher incidence in consanguinity, the geneticist is best prepared to interview families for this potential and to provide appropriate counseling. In families with no known genetic risk, many parents have a feeling of guilt at the birth of a child with the disorder. In this situation, emphasize to the family that nothing was missed or could have been done differently during the pregnancy to alter the outcome, but that prenatal diagnosis is an option in future pregnancies.

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-alpha-reductase type 2 deficiency and help facilitate communication between the family and the medical consultants.

A child psychiatrist or pediatric psychologist with experience working with disorders of sexual development can provide emotional support for the family, can help the family formulate questions, and can be the counselor for the family and patient for issues regarding gender identity, gender role, gender satisfaction and potential change in gender role. A long-term relationship with such a support system may ensure that information about the diagnosis and treatment is provided in an age-appropriate fashion, hopefully decreasing fears and misconceptions.