Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

S. Faisal Ahmed; John Achermann; Julie Alderson; Naomi S. Crouch; Sue Elford; Ieuan A. Hughes; Nils Krone; Ruth McGowan; Talat Mushtaq; Stuart O'Toole; Leslie Perry; Martina E. Rodie; Mars Skae; Helen E. Turner

Disclosures

Clin Endocrinol. 2021;95(6):818-840. 

In This Article

The Human Chorionic Gonadotrophin Stimulation Test

Stimulation with human chorionic gonadotrophin (hCG) allows the identification of functioning Leydig cells as well as biosynthetic defects in testosterone synthesis (Figure 3). However, it is an invasive test and its results require careful interpretation as outlined in Figure 3 and it should only be performed at a later stage in the diagnostic pathway under the direction of the regional DSD centre.[54] Generally, in routine cases of XY DSD, serum AMH has a high predictive value for a post-hCG testosterone.[80] Most protocols for hCG stimulation in the UK use intramuscular hCG 1000–1500units on three consecutive days[81] and this can be followed by further hCG stimulation with 1500 units on two days a week for the following 2 weeks for a prolonged period of hCG stimulation.[82] The 3 week hCG stimulation test may be more appropriate in those cases where there is a high suspicion that a functioning gonad may not be present such as in bilateral cryptorchidism or where there is a high suspicion of hypogonadotropic hypogonadism where the Leydig cells may require more prolonged stimulation. In young infants and adolescents, 3 days of hCG stimulation may be sufficient and in the very young infant with an intrinsically active gonadal axis, an hCG stimulation test may not be necessary if serial blood samples show raised serum testosterone concentrations. A testosterone response to hCG may be labelled as normal if absolute testosterone concentrations reach a level that is above the upper limit of the normal prepubertal range or rise by more than twice the baseline value.[83] Other androgens that should also be measured include androstenedione and dihydrotestosterone and with the use of LC-MS/MS, the sample volumes have become lower. For these two metabolites, the post-hCG, day 4 sample is more important than the pre-hCG sample on day 1. If a prolonged hCG stimulation test is performed, the day 22 sample that is collected at the end for testosterone measurement should be stored and can be used to measure DHT or androstenedione if a sufficient sample was not available on day 4. There is no evidence that a urine steroid profile or a serum AMH checked after hCG stimulation has any added diagnostic value. There is less experience as well as a lower demand for a corresponding test to assess ovarian tissue or reserve in DSD. Whilst reports of ovarian hormones following stimulation with FSH need further exploration, none of the current tests of ovarian reserve are reliable predictors of reduced ovarian function.[84] In the presence of a poor testosterone response following hCG stimulation, assessment of adrenal function by a standard short synacthen stimulation test should be considered. There is currently insufficient evidence to recommend that everybody with XY DSD should have a ACTH stimulation test but clinicians should be aware of the clear association between some forms of DSD and primary adrenal insufficiency and should consider thorough assessment of adrenal function in those diagnoses where an association has already been described[85] and in those with any clinical suspicion of adrenal insufficiency, especially those with low steroid precursors on USP.

Figure 3.

Interpretation of the results of the hCG stimulation test when investigating XY DSD and pointers for consideration of prolonged hCG stimulation and ACTH stimulation. *A prolonged hCG stimulation test should be considered in those cases where there is a poor testosterone response to a standard hCG stimulation test or where a poor response is anticipated. **A synacthen stimulation test should be considered in those cases who show a poor testosterone response to hCG stimulation or if there is a clinical or biochemical suspicion of adrenal insufficiency. 17α-OH—17α hydroxylase, 17bHSD3—17β-hydroxysteroid dehydrogenase type 3, 3βHSD2 def—3β-hydroxysteroid dehydrogenase II, AIS—androgen insensitivity syndrome, AKR, aldoketoreductase; CAH, congenital adrenal hyperplasia; LCH, Leydig Cell Hypoplasia; P450 OR, P450 oxidoreductase; SCC, side-chain cleavage; def, deficiency

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