Case Reports in Obstetrics and Gynecology

Case Reports in Obstetrics and Gynecology / 2014 / Article

Comment on “Complete Androgen Insensitivity Syndrome: Optimizing Diagnosis and Management”

  • Antonio Balsamo | Federico Baronio | ... | Santiago Vallasciani |
  •  Article ID 285715 |
  •  Published 12 May 2014

Response to: Comment on “Complete Androgen Insensitivity Syndrome: Optimizing Diagnosis and Management”

  • Antonio Simone Laganà | Alfonsa Pizzo |
  •  Article ID 808270 |
  •  Published 11 Dec 2014
  • | View Article

Letter to the Editor | Open Access

Volume 2014 |Article ID 285715 | https://doi.org/10.1155/2014/285715

Antonio Balsamo, Federico Baronio, Marta Berra, Silvano Bertelloni, Franco D’Alberton, Giacinto Marrocco, Santiago Vallasciani, "Comment on “Complete Androgen Insensitivity Syndrome: Optimizing Diagnosis and Management”", Case Reports in Obstetrics and Gynecology, vol. 2014, Article ID 285715, 3 pages, 2014. https://doi.org/10.1155/2014/285715

Comment on “Complete Androgen Insensitivity Syndrome: Optimizing Diagnosis and Management”

Academic Editor: Dan Hellberg
Received15 Apr 2014
Accepted27 Apr 2014
Published12 May 2014

We read with interest the paper of Pizzo et al. [1], confirming that adolescence is a key period for the diagnosis of 46,XY disorders of sex development (DSD) [2].

However, in our opinion, some points should be better addressed. Among these, we have the following.(1)The authors stated that the reported girl showed “normal intellectual function,” but this information had little relevance because mental function is not impaired in females with 46,XY DSD, reaching adolescence without any clinical suspicions. Indeed, this statement might be stigmatizing for these persons.(2)The statement that this adolescent was affected by hypergonadotropic hypogonadism (HH) is correct, according to the high LH and FSH values shown in Table 1 [1]. Very low levels of both 17β-estradiol and testosterone were also shown [1]. This endocrine pattern is not typical of late adolescent and young adult females with complete androgen insensitivity syndrome (CAIS) and intact testes. On the contrary, these persons show high/normal levels of both 17β-estradiol (for a person with a 46,XY karyotype) and testosterone [35]. In addition, adolescent/young adult women with CAIS did not show HH: LH is in high normal range or slightly elevated (due to the androgen resistance at central level), but FSH is in normal range (due to unaffected inhibin secretion from Sertoli cells) [35]. In addition, SHBG was reported within adult male range by Pizzo et al. [1], suggesting a normal sensitivity to the low levels of androgens in this girl [6]. Indeed, SHBG is within normal female range in women with CAIS, due to peripheral androgen resistance [5]. All these findings show poor agreement with the affirmed diagnosis of CAIS [1].(3)The clinical phenotype of the reported girl did not match with the phenotype of adolescents with CAIS; in fact, the latter shows normal breast development related to the relatively high normal estrogen levels and unopposed androgen action [3, 4, 7] and does not show hypotrophic breasts [1].(4)It is quite surprising that hormonal replacement therapy was started before any diagnosis was established.(5)Histological findings do not completely agree with the diagnosis of CAIS, in particular the absence of Leydig cells, which are abundant in adolescent females with CAIS and sometimes formed aggregates up to 2 mm in diameter [8, 9].(6)46,XY karyotype, female phenotype, and absence of mullerian derivatives may be present in several 46,XY DSD; they should be excluded before diagnosis of CAIS by optimal clinical, endocrine, and genetic investigations [10]. For example, the testosterone/Δ4-androstenedione ratio in the adolescent reported by Pizzo et al. [1] is very low (0.13; normal values >0.8 [11]). Thus, diagnoses of 17β-hydroxysteroid-dehydrogenase deficiency type 3 or 46,XY gonadal dysgenesis [11, 12] must be considered in the diagnostic process.(7)Risk of gonadal cancer largely varies among 46,XY DSD. For example, in CAIS is very low at least during the first two decades of life [1315]. Thus, delayed gonadal removal can be recommended to permit both full sexual development [15] and better bone health [16]. If diagnosis of CAIS is certain, surgery can be postponed—at least until the legal age at which the propositus can participate in decision making [1, 15, 1719].(8)We are concerned and in complete disagreement with the decision to perform gonadectomy without full disclosure and assent of the adolescent [1719].

In conclusion, some findings are poorly consistent with a diagnosis of CAIS, which should be confirmed by molecular analysis of androgen receptor gene [2, 7]. In our experience, more than 25% of the females referred to our departments with clinical/endocrine diagnosis of CAIS did not have this diagnosis confirmed by genetic analysis [20].

Clinical approach should be changed according to the new guidelines for management of persons with 46,XY DSD and directly involving the girl in the decision process [2, 18, 21]. We also stress that multidisciplinary team evaluation in tertiary centers with documented experience in this field must be guaranteed to each person with 46,XY DSD for optimal holistic management [21], especially before performing irreversible surgical procedures.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

We thank the Italian Network on Disorders of Sex Development (It-DSD) for scientific support. The constructive opinions of Italian and English Androgen Insensitivity Support Groups are also acknowledged.

References

  1. A. Pizzo, A. S. Laganà, I. Borrielli, and N. Dugo, “Complete androgen insensitivity syndrome: a rare case of disorder of sex development,” Case Reports in Obstetrics and Gynecology, vol. 2013, Article ID 232696, 3 pages, 2013. View at: Publisher Site | Google Scholar
  2. I. A. Hughes, C. Houk, S. F. Ahmed, and P. A. Lee, “Consensus statement on management of intersex disorders,” Archives of Disease in Childhood, vol. 91, no. 7, pp. 554–563, 2006. View at: Publisher Site | Google Scholar
  3. K. F. S. Melo, B. B. Mendonca, A. E. C. Billerbeck et al., “Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 7, pp. 3241–3250, 2003. View at: Publisher Site | Google Scholar
  4. L. Audi, M. Fernández-Cancio, A. Carrascosa et al., “Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 4, pp. 1876–1888, 2010. View at: Publisher Site | Google Scholar
  5. U. Doehnert, S. Bertelloni, A. Richter-Unruh, R. Werner, and O. Hiort, “Hormone profiles in adolescents and adults with complete androgen insensitivity syndrome,” in Proceedings of the 3rd International Symposium on Disorders of Sex Development, Lübech, Denmark, May 2011. View at: Google Scholar
  6. G. Sinnecker and S. Köhler, “Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test,” Journal of Clinical Endocrinology and Metabolism, vol. 68, no. 6, pp. 1195–1200, 1989. View at: Google Scholar
  7. I. A. Hughes, J. D. Davies, T. I. Bunch, V. Pasterski, K. Mastroyannopoulou, and J. MacDougall, “Androgen insensitivity syndrome,” The Lancet, vol. 380, no. 9851, pp. 1419–1428, 2012. View at: Publisher Site | Google Scholar
  8. S. E. Hannema, I. S. Scott, E. Rajpert-de Meyts, N. E. Skakkebæk, N. Coleman, and I. A. Hughes, “Testicular development in the complete androgen insensitivity syndrome,” Journal of Pathology, vol. 208, no. 4, pp. 518–527, 2006. View at: Publisher Site | Google Scholar
  9. J. Kaprova-Pleskacova, H. Stoop, H. Brüggenwirth et al., “Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology,” Modern Pathology, vol. 2013, article 193, 2013. View at: Publisher Site | Google Scholar
  10. S. F. Ahmed, J. C. Achermann, W. Arlt et al., “UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development,” Clinical Endocrinology, vol. 75, no. 1, pp. 12–26, 2011. View at: Publisher Site | Google Scholar
  11. A. L. M. Boehmer, A. O. Brinkmann, L. A. Sandkuijl et al., “17β-Hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 12, pp. 4713–4721, 1999. View at: Google Scholar
  12. S. Faisal Ahmed, A. Iqbal, and I. A. Hughes, “The testosterone: androstenedione ratio in male undermasculinization,” Clinical Endocrinology, vol. 53, no. 6, pp. 697–702, 2000. View at: Publisher Site | Google Scholar
  13. J. Pleskacova, R. Hersmus, J. W. Oosterhuis et al., “Tumor risk in disorders of sex development,” Sexual Development, vol. 4, no. 4-5, pp. 259–269, 2010. View at: Publisher Site | Google Scholar
  14. R. Deans, S. M. Creighton, L.-M. Liao, and G. S. Conway, “Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence,” Clinical Endocrinology, vol. 76, no. 6, pp. 894–898, 2012. View at: Publisher Site | Google Scholar
  15. L. Wünsch, P. M. Holterhus, L. Wessel, and O. Hiort, “Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis,” BJU International, vol. 110, pp. E958–E965, 2012. View at: Publisher Site | Google Scholar
  16. S. Bertelloni, G. I. Baroncelli, and S. Mora, “Bone health in disorders of sex differentiation,” Sexual Development, vol. 4, no. 4-5, pp. 270–284, 2010. View at: Publisher Site | Google Scholar
  17. F. D'Alberton, “Disclosing disorders of sex development and opening the doors,” Sexual Development, vol. 4, no. 4-5, pp. 304–309, 2010. View at: Publisher Site | Google Scholar
  18. C. Wiesemann, “Ethical guidelines for the clinical management of intersex,” Sexual Development, vol. 4, no. 4-5, pp. 300–303, 2010. View at: Publisher Site | Google Scholar
  19. M. L. Cull and M. Simmonds, “Importance of support groups for intersex (disorders of sex development) patients, families and the medical profession,” Sexual Development, vol. 4, no. 4-5, pp. 310–312, 2010. View at: Publisher Site | Google Scholar
  20. S. Bertelloni, E. Dati, F. Baldinotti et al., “NR5A1 gene mutations: clinical, endocrine and genetic features in two girls with 46, XY disorder of sex development,” Hormone Research in Paediatrics, vol. 81, no. 2, pp. 104–108, 2014. View at: Publisher Site | Google Scholar
  21. C. E. Brain, S. M. Creighton, I. Mushtaq et al., “Holistic management of DSD,” Best Practice & Research: Clinical Endocrinology & Metabolism, vol. 24, no. 2, pp. 335–354, 2010. View at: Publisher Site | Google Scholar

Copyright © 2014 Antonio Balsamo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

1048 Views | 479 Downloads | 2 Citations
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.