Pubertal development and premature ovarian insufficiency in patients with APECED

in European Journal of Endocrinology
View More View Less
  • 1 Children’s Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 2 Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  • 3 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 4 Folkhälsan Research Center, Helsinki, Finland
  • 5 Department of Molecular Medicine and Surgery, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

Correspondence should be addressed to S Laakso; Email: saila.laakso@helsinki.fi
Restricted access

Objective:

To determine the natural course of pubertal development, growth during puberty, and development of POI in females with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I.

Design:

Longitudinal follow-up study.

Methods:

A national cohort of females with APECED aged ≥12 years were followed during 1965–2018. Attainment of adult height was defined when patients’ height increased less than 1 cm per year. Diagnosis of POI was based on delayed puberty or POI symptoms with amenorrhea, and/or FSH ≥40 IU/L.

Results:

Altogether 40 women with APECED were followed up to the average age of 37.3 (range: 14.6–61.9) years; 16 females (40%) were ≥ 40 years. Pubertal development started spontaneously in 34 patients and 29 had spontaneous menarche. POI developed in 28 patients (70%) at the median age of 16.0 years (range: 11.3–36.5), and in 20 of them (71%) before attaining adult height. In 11 cases puberty was induced or completed by hormonal therapy. Patients with POI were significantly shorter at menarche, but adult heights did not differ from non-POI females. Patients with POI had more often primary adrenocortical insufficiency (93% vs 58%, P = 0.017) and ovarian antibodies (81% vs 30%, P=0.003) compared to those with normal ovarian function (n = 12).

Conclusions:

POI developed in the majority of patients with APECED, often before or shortly after menarche. Timely commencement of hormonal replacement therapy is important to ensure optimal pubertal development and growth. The possibility of fertility preservation before development of POI in APECED patients should be further studied.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 153 153 125
Full Text Views 15 15 14
PDF Downloads 11 11 10
  • 1

    Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nature Genetics 1994 8 8387. (https://doi.org/10.1038/ng0994-83)

    • Search Google Scholar
    • Export Citation
  • 2

    Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) in a series of 68 patients. New England Journal of Medicine 1990 322 18291836. (https://doi.org/10.1056/NEJM199006283222601)

    • Search Google Scholar
    • Export Citation
  • 3

    Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A, Perniola R, Pura M, Bøe Wolff AS, Husebye ES & Lilic D et al. Autoantibodies against Type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome Type I. Journal of Clinical Endocrinology and Metabolism 2008 93 43894397. (https://doi.org/10.1210/jc.2008-0935)

    • Search Google Scholar
    • Export Citation
  • 4

    Meager A, Visvalingam K, Peterson P, Möll K, Murumägi A, Krohn K, Eskelin P, Perheentupa J, Husebye E & Kadota Y et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome Type 1. PL o S Medicine 2006 3 e289. (https://doi.org/10.1371/journal.pmed.0030289)

    • Search Google Scholar
    • Export Citation
  • 5

    Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Journal of Clinical Endocrinology and Metabolism 2006 91 28432850. (https://doi.org/10.1210/jc.2005-2611)

    • Search Google Scholar
    • Export Citation
  • 6

    Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertility and Sterility 1990 53 804810. (https://doi.org/10.1016/S0015-0282(16)53513-4)

    • Search Google Scholar
    • Export Citation
  • 7

    Nelson LM. Clinical practice. Primary ovarian insufficiency. New England Journal of Medicine 2009 360 606614. (https://doi.org/10.1056/NEJMcp0808697)

    • Search Google Scholar
    • Export Citation
  • 8

    De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010 376 911921. (https://doi.org/10.1016/S0140-6736(10)60355-8)

  • 9

    Goswami D, Conway GS. Premature ovarian failure. Human Reproduction Update 2005 11 391410. (https://doi.org/10.1093/humupd/dmi012)

  • 10

    Davis SR. Premature ovarian failure. Maturitas 1996 23 18. (https://doi.org/10.1016/0378-5122(95)00966-3)

  • 11

    Yeganeh L, Boyle JA, Wood A, Teede H, Vincent AJ. Menopause guideline appraisal and algorithm development for premature ovarian insufficiency. Maturitas 2019 130 2131. (https://doi.org/10.1016/j.maturitas.2019.09.009)

    • Search Google Scholar
    • Export Citation
  • 12

    Orlova EM, Sozaeva LS, Kareva MA, Oftedal BE, Wolff ASB, Breivik L, Zakharova EY, Ivanova ON, Kämpe O & Dedov II et al. Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome Type 1. Journal of Clinical Endocrinology and Metabolism 2017 102 35463556. (https://doi.org/10.1210/jc.2017-00139)

    • Search Google Scholar
    • Export Citation
  • 13

    Bruserud Ø, Oftedal BE, Landegren N, Erichsen MM, Bratland E, Lima K, Jørgensen AP, Myhre AG, Svartberg J & Fougner KJ et al. A longitudinal follow-up of autoimmune polyendocrine syndrome Type 1. Journal of Clinical Endocrinology and Metabolism 2016 101 29752983. (https://doi.org/10.1210/jc.2016-1821)

    • Search Google Scholar
    • Export Citation
  • 14

    Ferre EMN, Rose SR, Rosenzweig SD, Burbelo PD, Romito KR, Niemela JE, Rosen LB, Break TJ, Gu W & Hunsberger S et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight 2016 1 e88782. (https://doi.org/10.1172/jci.insight.88782)

    • Search Google Scholar
    • Export Citation
  • 15

    Dragin N, Bismuth J, Cizeron-Clairac G, Biferi MG, Berthault C, Serraf A, Nottin R, Klatzmann D, Cumano A & Barkats M et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. Journal of Clinical Investigation 2016 126 15251537. (https://doi.org/10.1172/JCI81894)

    • Search Google Scholar
    • Export Citation
  • 16

    Laakso S, Borchers J, Toiviainen-Salo S, Pekkinen M, Mäkitie O. Severe phenotype of APECED (APS1) increases risk for structural bone alterations. Frontiers in E ndocrinology 2020 11 109. (https://doi.org/10.3389/fendo.2020.00109)

    • Search Google Scholar
    • Export Citation
  • 17

    Tanner JM. Growth at A dolescence: With A G eneral C onsideration of the E ffects of H ereditary and E nvironmental F actors upon G rowth and M aturation from B irth to M aturity, 2nd ed. Oxford: Blackwell Publishing, 1962.

    • Search Google Scholar
    • Export Citation
  • 18

    Saari A, Sankilampi U, Hannila ML, Kiviniemi V, Kesseli K, Dunkel L. New Finnish growth references for children and adolescents aged 0 to 20 years: length/height-for-age, weight-for-length/height, and body mass index-for-age. Annals of Medicine 2011 43 235248. (https://doi.org/10.3109/07853890.2010.515603)

    • Search Google Scholar
    • Export Citation
  • 19

    Kantero R, Widholm O. The age of menarche in Finnish girls in 1969. Acta Obstetricia et Gynecologica Scandinavica 1971 50 718. (https://doi.org/10.3109/00016347109155076)

    • Search Google Scholar
    • Export Citation
  • 20

    Pennell LM, Galligan CL, Fish EN. Sex affects immunity. Journal of Autoimmunity 2012 38 J282J291. (https://doi.org/10.1016/j.jaut.2011.11.013)

    • Search Google Scholar
    • Export Citation
  • 21

    Warren BD, Ahn SH, McGinnis LK, Grzesiak G, Su RW, Fazleabas AT, Christenson LK, Petroff BK, Petroff MG. Autoimmune regulator is required in female mice for optimal embryonic development and implantation. Biology of Reproduction 2019 100 14921504. (https://doi.org/10.1093/biolre/ioz023)

    • Search Google Scholar
    • Export Citation
  • 22

    Moreira-Filho CA, Bando SY, Bertonha FB, Ferreira LR, Vinhas CdF, Oliveira LHB, Zerbini MCN, Furlanetto G, Chaccur P, Carneiro-Sampaio M. Minipuberty and sexual dimorphism in the infant human thymus. Scientific Reports 2018 8 13169. (https://doi.org/10.1038/s41598-018-31583-3)

    • Search Google Scholar
    • Export Citation
  • 23

    Borchers J, Pukkala E, Mäkitie O, Laakso S. Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections. Journal of Clinical Endocrinology and Metabolism 2020 105 e2207–e2213. (https://doi.org/10.1210/clinem/dgaa140)

    • Search Google Scholar
    • Export Citation
  • 24

    Ahonen P, Miettinen A, Perheentupa J. Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. Journal of Clinical Endocrinology and Metabolism 1987 64 494500. (https://doi.org/10.1210/jcem-64-3-494)

    • Search Google Scholar
    • Export Citation
  • 25

    Söderbergh A, Myhre AG, Ekwall O, Gebre-Medhin G, Hedstrand H, Landgren E, Miettinen A, Eskelin P, Halonen M & Tuomi T et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome Type I. Journal of Clinical Endocrinology and Metabolism 2004 89 557562. (https://doi.org/10.1210/jc.2003-030279)

    • Search Google Scholar
    • Export Citation