Advice on the Management of Ambiguous Genitalia to a Young Endocrinologist From Experienced Clinicians

Jean D. Wilson, M.D.; Marco A. Rivarola, M.D.; Berenice B. Mendonca, M.D., Ph.D.; Garry L. Warne, A.M., M.B.B.S., F.R.A.C.P.; Nathalie Josso, M.D., Ph.D.; Stenvert L.S. Drop, M.D., Ph.D.; Melvin M. Grumbach, M.D.

Disclosures

Semin Reprod Med. 2012;30(5):339-350. 

In This Article

Berenice B. Mendonca, M.D., Ph.D.

The birth of a newborn with ambiguous genitalia brings the family and physicians great turmoil and concern, and this situation must be considered a medical emergency. When we are called to see a newborn with DSD, the first step is to interview the parents. It is important to ask them the following questions:

  1. What they know about the child's problem? At this moment, what you tell the parents is very important because the first information will be remembered by the parents all their lives.

  2. Was baby's sex defined by the ultrasound or prenatal sex determination? The majority of the parents know the sex of the newborn and usually prepare the baby's clothing and decorate the room in advance to receive a boy or a girl.

  3. Which sex do the parents desire? In some cultures, such as Asian and Muslim, the male sex is very desired for the first child.

  4. Which sex do the parents feel the newborn is? Each parent couple has their own impression of the sex of their baby and sometimes the mother and father have different impressions and desires and we have to take this in consideration in assigning the sex of rearing.

The physician's role is to show serenity and assurance; explain to the parents the principles of sex development; compare genital ambiguity to other congenital malformations; explain that the karyotype does not define gender identity; advise parents on how to explain the disorder to their family and friends; and clarify that genital ambiguity is not linked to homosexuality.

Diagnosis

A detailed clinical history is very important to determine if there is consanguinity and presence of similar cases in the family, the ethnicity, problems such as use of hormones during pregnancy, and birth weight, because there is a higher incidence of hypospadias in small-for-gestational-age babies. On physical examination dysmorphic appearance, size of the phallus, position of the urethra, number of perineal orifices, scrotum hyperpigmentation, and the presence of gonads should be evaluated.

Laboratory evaluation consists of imaging evaluation (pelvic ultrasound, retrograde genitourinary image, or intraoperative cystoscopy, which we prefer) and cytogenetic analysis by karyotype or through assessment of the SRY gene by polymerase chain reaction or fluorescence in situ hybridization.

Baseline serum levels of sodium, potassium, and cholesterol and of luteinizing hormone, follicle-stimulating hormone, anti-Müllerian hormone, adrenocorticotropin, 17-OH-progesterone, 17-OH-pregnenolone, dehydroepiandrosterone sulfate, androstenedione, cortisol 11-deoxycortisol, aldosterone, renin, testosterone, and dihydrotestosterone should be obtained.

Stimulation tests with human chorionic gonadotropin and/or adrenocorticotropic hormone and determination of urinary steroids followed by molecular analysis of candidate genes are other tools useful to clarify the diagnosis in these patients. Most of the 46,XX DSD patients have the etiology of their disease defined, whereas most of the patients with dysgenetic or undetermined 46,XY DSD remain without a known cause of their disorder.

Surgical Treatment

The aim of the surgical treatment is to allow development of adequate external genitalia and to remove internal structures that are inappropriate for the social sex. Patients must undergo surgical treatment preferably before 2 years of age, which is the time when the child becomes aware of his or her genitals and social sex. Only skilled surgeons with specific training in the surgery of DSD should perform these procedures. Inadequate treatment results in irreversible damage for the patient.[7]

Feminizing genitoplasty should provide an adequate vaginal opening into the perineum, create a normal-looking vaginal introitus, separate urethral from the vaginal orifice, and remove phallic erectile tissue preserving glandular enervation and blood supply. In our experience, the single-stage feminizing genitoplasty consisting of clitoroplasty with the preservation of dorsal nerves and vessels and ventral mucosa, vulvoplasty and Y-V perineal flap, followed by vaginal dilation with acrylic molds allows good cosmetic and functional results.[8] Failure to interpose an adequate flap will result in persistent introital stenosis, requiring later surgical revision. Frank's method to increase vaginal size is very useful. Vaginal dilation with acrylic molds in patients with introitus stenosis is a good treatment choice when these patients wish to start sexual intercourse.[9]

In the male social sex patients, surgery is generally performed in two steps and consists of orthophaloplasty, scrotoplasty with resection of vaginal pouch, proximal and distal urethroplasty, and orchidopexy. In our experience, the most frequent complication was urethral fistula (30%) and urethral stenosis (25%) that can occur several years after surgery. Laparoscopy is the ideal method to remove dysgenetic gonads, which present a potential for malignancy, and the gonads and ductal structures that are contrary to the assigned gender.[10] In addition to being a minimally invasive surgery, one of the main advantages of this method is the lack of scars.

Hormone Treatment

In patients with female social sex, the treatment must simulate normal puberty; this is done by administering low doses of estrogen (one-sixth to one-quarter of the adult dose) between the ages of 11 and 12 years to avoid excessive bone maturation and short stature in adulthood. Doses can be adjusted according to the response (breast Tanner stage and bone age), with the aim of gradually completing feminization over a 2 to 3 year period. In tall 46,XY females, adult estrogen dosage is recommended at the beginning of treatment to avoid high final stature.

In patients with male social sex, testosterone replacement is started at age 12 years, simulating normal puberty according to the child's psychological development and height. Intramuscular depot injections of testosterone esters are commonly used; another option is oral testosterone undecanoate or transdermal preparations. The initial dose of depot injections of testosterone esters is 25 to 50 mg/mo administered intramuscularly. The maintenance dose in an adult patient is 200 to 250 mg every 2 weeks or 1000 mg each 3 months. In male patients with androgen insensitivity, higher doses of testosterone esters (250 to 500 mg twice a week) are used to increase penile length and male secondary characteristics. Maximum penis enlargement is obtained after 6 months of high doses and after that, the normal dosage is re-instituted. The use of topical dihydrotestosterone gel is also useful to increase penile length in 5αR2 deficiency, with the advantage of not causing gynecomastia and promoting faster increase of penis size as it is 50 times more active than testosterone.[11]

In our cohort, all but two patients with undetermined 46,XY DSD presented a final penile length corresponding to less than −2 SDs. Even though patients complained about penile length, there was no statistically significant difference in final penile length between satisfied and unsatisfied groups.[7] Most of our patients report satisfactory sexual performance as long as they have a penile length of at least 6 cm.

Last advice to young clinicians regarding the approach of DSD patients based in my own experience of more than 450 patients. Keep it simple. The following needs, do's, and don'ts can help in the management of patients with ambiguous genitalia:

  • Needs: A trained multidisciplinary team and resources for the laboratory diagnosis.

  • Do's: show serenity and assurance; advise the family regarding the child's diagnosis and development, and finally, respect the parents' wish regarding sex assignment even when it is not in accordance with physician's opinion.

  • Don'ts: Never assign the social sex of child with ambiguous genitalia by yourself; be certain as one can about the social sex even if it takes some time.

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