Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

all neonates presenting with atypical genitalia

1st line – multidisciplinary approach

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INITIAL
|
all neonates presenting with atypical genitalia
1st line – 

multidisciplinary approach

Initial management is a social and clinical emergency.

The child should be referred to as "baby," not boy or girl.

Members of the local team have key roles in coordinating the initial assessment and investigations, managing the clinical emergency, and supporting parents.

The multidisciplinary team should include an endocrinologist, a neonatologist, a urological surgeon, a radiologist, a clinical psychologist, and a specialist nurse.[7]

The core MDT should have links with a wider team, including specialists from genetics, biochemistry, relevant adult medical specialties, such as gynecology and endocrinology, social services, and if possible a clinical ethics forum.[7]  

Ongoing communication and support for the family is crucial, as well as communication with the primary care physician.[7][18][29]

ACUTE

46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)

1st line – multidisciplinary consultation + probable female sex assignment

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ACUTE
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)
1st line – 

multidisciplinary consultation + probable female sex assignment

Sex assignment should be undertaken by a specialist differences of sex development multidisciplinary team.

Patients are typically assigned a female sex, as fertility is preserved.

Plus – glucocorticoid replacement

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ACUTE
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)
Plus – 

glucocorticoid replacement

Treatment recommended for ALL patients in selected patient group

Glucocorticoids are required to replace cortisol. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong. Hydrocortisone is preferred to other glucocorticoids because of their greater potential for adverse effects. See Congenital adrenal hyperplasia

Primary options

hydrocortisone: 10-15 mg/square meter of body surface area/day orally given in 3-4 divided doses

Consider – surgical correction

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ACUTE
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

Some centers consider delaying or avoiding surgical intervention and individualizing the decision to intervene. The option of no surgery and psychology support should be considered.

Consider – mineralocorticoid replacement

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ACUTE
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)
Consider – 

mineralocorticoid replacement

Treatment recommended for SOME patients in selected patient group

If there is salt wasting, fludrocortisone is required to replace aldosterone. It usually takes at least 4 days after birth for serum electrolytes to become abnormal and if untreated, adrenal crisis may ensue in the second week of life. Electrolytes should be carefully monitored during this period. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong. Over-treatment must be avoided.

Additional salt supplementation is usually required in the first 1-2 years of life. See Congenital adrenal hyperplasia

Primary options

fludrocortisone: 0.1 to 0.3 mg orally once daily

46,XY

1st line – sex assignment after multidisciplinary consultation

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ACUTE
|
46,XY
|
with testosterone biosynthetic defects
1st line – 

sex assignment after multidisciplinary consultation

Guiding principles for sex assignment:[1][2]​​[19][30][31]

Sex assignment should be undertaken by a specialist differences of sex development multidisciplinary team.

Encourage the family to delay naming the baby until the evaluation has been completed and sex has been assigned.

Sex assignment is based on the underlying diagnosis if known, appearance of external genitalia, surgical reconstructive options, need for hormonal replacement therapy, potential for future fertility, culture/preferences of the family, exposure of high levels of testosterone on brain development, potential for future sexual function, and gender identity.

Understand and respect the needs, background, culture, and expectations of the parents. Psychological support should be provided for the family, particularly where there has been a delay in sex assignment.

Consider – glucocorticoid replacement if adrenal insufficiency

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ACUTE
|
46,XY
|
with testosterone biosynthetic defects
Consider – 

glucocorticoid replacement if adrenal insufficiency

Treatment recommended for SOME patients in selected patient group

Patients with defects that are common to the adrenal gland and the testes (i.e., defects early in the steroid biosynthetic pathway) may also have deficiencies of glucocorticoid deficiency. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong. Hydrocortisone is preferred to other glucocorticoids because of their greater potential for adverse effects.

Primary options

hydrocortisone: 10-15 mg/square meter of body surface area/day orally given in 3-4 divided doses

Consider – mineralocorticoid replacement if adrenal insufficiency

Back
ACUTE
|
46,XY
|
with testosterone biosynthetic defects
Consider – 

mineralocorticoid replacement if adrenal insufficiency

Treatment recommended for SOME patients in selected patient group

If there is salt wasting in addition to glucocorticoid deficiency, fludrocortisone is required to replace aldosterone. It may take up to 4 days after birth to become apparent and electrolytes should be carefully monitored. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong.

Primary options

fludrocortisone: 0.1 to 0.3 mg orally once daily

Consider – surgical correction

Back
ACUTE
|
46,XY
|
with testosterone biosynthetic defects
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

Hypospadias or chordee may require surgical correction.

1st line – sex assignment after multidisciplinary consultation

Back
ACUTE
|
46,XY
|
with 5 alpha-reductase deficiency
1st line – 

sex assignment after multidisciplinary consultation

Guiding principles for sex assignment:[1][2]​​[19][30][31]

Sex assignment should be undertaken by a specialist differences of sex development multidisciplinary team.

Encourage the family to delay naming the baby until the evaluation has been completed and sex has been assigned.

Sex assignment is based on the underlying diagnosis if known, appearance of external genitalia, surgical reconstructive options, need for hormonal replacement therapy, potential for future fertility, culture/preferences of the family, exposure of high levels of testosterone on brain development, potential for future sexual function, and gender identity.

Understand and respect the needs, background, culture, and expectations of the parents. Psychological support should be provided for the family, particularly where there has been a delay in sex assignment.

Consider – topical dihydrotestosterone (DHT)

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ACUTE
|
46,XY
|
with 5 alpha-reductase deficiency
Consider – 

topical dihydrotestosterone (DHT)

Treatment recommended for SOME patients in selected patient group

For the infant who is sex assigned male, topical DHT cream can be applied to the external genitalia to improve virilization. This product may need to be compounded by a pharmacist.

Consider – surgical correction

Back
ACUTE
|
46,XY
|
with 5 alpha-reductase deficiency
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

Hypospadias or chordee may require surgical correction.

1st line – sex assignment at birth after multidisciplinary consultation

Back
ACUTE
|
46,XY
|
with partial androgen insensitivity
1st line – 

sex assignment at birth after multidisciplinary consultation

Most are raised male. Female sex assignment may be considered in those with severe under masculinization as further virilization will not occur at puberty. In these cases the gonads may be removed to avoid any possibility of further virilization. Removal of gonads will mean the individual will be infertile, so the decision for female sex assignment needs to be considered carefully.

Guiding principles for sex assignment:[1][2]​​[19][30][31]

Sex assignment should be undertaken by a specialist differences of sex development multidisciplinary team.

Encourage the family to delay naming the baby until the evaluation has been completed and sex has been assigned.

Sex assignment is based on the underlying diagnosis if known, appearance of external genitalia, surgical reconstructive options, need for hormonal replacement therapy, potential for future fertility, culture/preferences of the family, exposure of high levels of testosterone on brain development, potential for future sexual function, and gender identity.

Understand and respect the needs, background, culture, and expectations of the parents. Psychological support should be provided for the family, particularly where there has been a delay in sex assignment.

Consider – surgical correction

Back
ACUTE
|
46,XY
|
with partial androgen insensitivity
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

In those assigned male, hypospadias or chordee, if present, may require surgical correction.

In those assigned female, surgical separation of the urethral and vaginal openings may be required.

1st line – sex assignment at birth after multidisciplinary consultation

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ACUTE
|
46,XY
|
with gonadal dysgenesis
1st line – 

sex assignment at birth after multidisciplinary consultation

In partial gonadal dysgenesis, sex assignment may be based on the likelihood of fertility.

Patients with complete gonadal dysgenesis will be infertile.

However, in those with a uterus it may be possible to carry a pregnancy by the use of egg donation.

Guiding principles for sex assignment:[1][2]​​[19][30][31]

Sex assignment should be undertaken by a specialist differences of sex development multidisciplinary team.

Encourage the family to delay naming the baby until the evaluation has been completed and sex has been assigned.

Sex assignment is based on the underlying diagnosis if known, appearance of external genitalia, surgical reconstructive options, need for hormonal replacement therapy, potential for future fertility, culture/preferences of the family, exposure of high levels of testosterone on brain development, potential for future sexual function, and gender identity.

Understand and respect the needs, background, culture, and expectations of the parents. Psychological support should be provided for the family, particularly where there has been a delay in sex assignment.

Consider – surgical correction

Back
ACUTE
|
46,XY
|
with gonadal dysgenesis
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

In those assigned male, hypospadias or chordee, if present, may require surgical correction.

In those assigned females, surgery may be required, although the timing of this intervention should be individualized and may be deferred until the individual can be involved in the decision. Some centers delay or avoid genital surgery.

45,X/46,XY mixed gonadal dysgenesis

1st line – sex assignment at birth after multidisciplinary consultation

Back
ACUTE
|
45,X/46,XY mixed gonadal dysgenesis
1st line – 

sex assignment at birth after multidisciplinary consultation

Sex assignment can be challenging.

Special consideration should be given to future risk of gonadal malignancy.

Guiding principles for sex assignment:[1][2]​​​[19][30][31]

Encourage the family to delay naming the baby until the evaluation has been completed and sex has been assigned.

Sex assignment is based on the underlying diagnosis if known, appearance of external genitalia, surgical reconstructive options, need for hormonal replacement therapy, potential for future fertility, culture/preferences of the family, exposure of high levels of testosterone on brain development, potential for future sexual function, and gender identity.

Understand and respect the needs, background, culture, and expectations of the parents. Psychological support should be provided for the family, particularly where there has been a delay in sex assignment.

Consider – surgical correction

Back
ACUTE
|
45,X/46,XY mixed gonadal dysgenesis
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

In those assigned male, hypospadias or chordee, if present, may require surgical correction.

In those assigned female, surgery may be required, although the timing of this intervention should be individualized and may be deferred until the individual can be involved in the decision. Some centers delay or avoid genital surgery.

ONGOING

46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (following sex assignment)

1st line – lifelong glucocorticoid replacement

Back
ONGOING
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (following sex assignment)
1st line – 

lifelong glucocorticoid replacement

Glucocorticoids are required to replace cortisol. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong. Hydrocortisone is preferred to other glucocorticoids because of their greater potential for adverse effects.

Primary options

hydrocortisone: children: 10-15 mg/square meter of body surface area/day orally given in 3-4 divided doses; adults: 25-30 mg/day orally given in 2-3 divided doses

Consider – surgical correction at puberty

Back
ONGOING
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (following sex assignment)
Consider – 

surgical correction at puberty

Treatment recommended for SOME patients in selected patient group

Further genitoplasty in adolescence may be necessary.

Consider – lifelong mineralocorticoid replacement

Back
ONGOING
|
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (following sex assignment)
Consider – 

lifelong mineralocorticoid replacement

Treatment recommended for SOME patients in selected patient group

If there is salt wasting, fludrocortisone is required to replace aldosterone. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong.

Primary options

fludrocortisone: children: 0.1 to 0.3 mg orally once daily; adults: 0.1 to 0.2 mg orally once daily

46,XY

1st line – monitoring for spontaneous puberty ± testosterone supplementation

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ONGOING
|
46,XY
|
raised as males
1st line – 

monitoring for spontaneous puberty ± testosterone supplementation

Males with testosterone biosynthetic defects, partial androgen insensitivity, and gonadal dysgenesis may require testosterone supplementation at puberty, particularly if there is poor virilization and/or evidence of gonadal failure.

Patients with 5 alpha-reductase deficiency typically may not need hormonal replacement during puberty. Testosterone levels may be sufficient to permit the development of secondary sexual characteristics despite a lack of the more potent dihydrotestosterone. Individuals tend to develop less facial and body hair than unaffected males.

If additional testosterone is required, consult specialist for guidance on dose.

Consider – lifelong glucocorticoid replacement

Back
ONGOING
|
46,XY
|
raised as males
Consider – 

lifelong glucocorticoid replacement

Treatment recommended for SOME patients in selected patient group

Patients with testosterone biosynthetic defects that are common to the adrenal gland and the testes may have glucocorticoid deficiency. Treatment with glucocorticoids is commenced as soon as the diagnosis is confirmed and is continued lifelong.

Primary options

hydrocortisone: children: 10-15 mg/square meter of body surface area/day orally given in 3-4 divided doses; adults: 25-30 mg/day orally given in 2-3 divided doses

Consider – lifelong mineralocorticoid replacement

Back
ONGOING
|
46,XY
|
raised as males
Consider – 

lifelong mineralocorticoid replacement

Treatment recommended for SOME patients in selected patient group

If there is salt wasting in addition to glucocorticoid deficiency, fludrocortisone is required to replace aldosterone. Treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong.

Primary options

fludrocortisone: children: 0.1 to 0.3 mg orally once daily; adults: 0.1 to 0.2 mg orally once daily

1st line – bilateral gonadectomy

Back
ONGOING
|
46,XY
|
raised as females
1st line – 

bilateral gonadectomy

In sex assigned females with gonadal dysgenesis or partial androgen insensitivity, gonadectomy may be required to eliminate the risk of malignancy and prevent virilization at puberty.

In sex assigned females with complete androgen insensitivity, gonadectomy may be postponed until after puberty to allow aromatization of endogenous testosterone to estrogen, which will promote breast development.

There is a low risk of malignant change in gonads in complete androgen insensitivity.

Plus – estrogen supplementation at puberty

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ONGOING
|
46,XY
|
raised as females
Plus – 

estrogen supplementation at puberty

Treatment recommended for ALL patients in selected patient group

Estrogen is needed at puberty to allow pubertal development, including secondary sexual characteristics. An exception to this is complete androgen insensitivity. If gonadectomy has been postponed until after puberty, aromatization of endogenous testosterone to estrogen will promote breast development.

Transdermal or oral estradiol can be given, starting with a low dose and increasing every 6 months up to a normal female adult dose, while monitoring the effect on pubertal development. Consult specialist for guidance on dose.

Consider – surgical correction at puberty

Back
ONGOING
|
46,XY
|
raised as females
Consider – 

surgical correction at puberty

Treatment recommended for SOME patients in selected patient group

Further genitoplasty in adolescence may be necessary.

45,X/46,XY mixed gonadal dysgenesis

1st line – monitoring for spontaneous puberty ± testosterone supplementation

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as males
1st line – 

monitoring for spontaneous puberty ± testosterone supplementation

Testosterone replacement may be required at puberty, particularly if there is evidence of gonadal failure.

The dose of testosterone can be increased over 2 years while monitoring testosterone levels and the effect on pubertal development. Once puberty is completed, a testosterone patch or gel may be offered instead of intramuscular injections. Consult specialist for guidance on dose.

Plus – testicular monitoring ± biopsy

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as males
Plus – 

testicular monitoring ± biopsy

Treatment recommended for ALL patients in selected patient group

Risk of gonadal malignancy is highest in mixed gonadal dysgenesis and in those with an intra-abdominal (undescended) testis. Risk of malignancy in a scrotal testis is not clear but may also be increased. The testis should be carefully monitored and a biopsy during puberty may be indicated if there are clinical concerns.

Consider – bilateral gonadectomy

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as males
Consider – 

bilateral gonadectomy

Treatment recommended for SOME patients in selected patient group

The gonads may need to be removed if there is any risk of malignancy on clinical suspicion or biopsy specimens.

1st line – bilateral gonadectomy

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as females
1st line – 

bilateral gonadectomy

Risk of gonadal malignancy is highest in mixed gonadal dysgenesis, where there is Y chromosomal material present and in those with an intra-abdominal (undescended) gonads. Bilateral gonadectomy may be indicated in this situation.

Plus – estrogen supplementation at puberty

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as females
Plus – 

estrogen supplementation at puberty

Treatment recommended for ALL patients in selected patient group

Estrogen is required for development of secondary sexual characteristics at puberty and maintenance of bone mass.

Transdermal or oral estradiol can be given, starting with a low dose and increasing at 6-monthly intervals up to a normal female adult dose. Consult specialist for guidance on dose.

Consider – surgical correction

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as females
Consider – 

surgical correction

Treatment recommended for SOME patients in selected patient group

Further genitoplasty in adolescence may be necessary.

As risk of gonadal malignancy is high, consideration should be given to early bilateral gonadal malignancy.

Consider – cyclic progesterone

Back
ONGOING
|
45,X/46,XY mixed gonadal dysgenesis
|
raised as females
Consider – 

cyclic progesterone

Treatment recommended for SOME patients in selected patient group

Patients with a uterus need treatment with cyclic progesterone once breakthrough bleeding occurs. Consult specialist for guidance on dose.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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