Turner Syndrome Minipuberty Study

NCT04189406 | Unknown

• 1 other identifier: 2019-5955
• Study Type: observational
• Target: 30
• Locations: 5 countries
• Sites: 13

Brief Summary

Rationale: Due to accelerated germ cell loss, infertility is a major problem in girls with Turner syndrome (TS). Therefore, cryopreservation of ovarian tissue or oocytes before exhaustion of the ovarian reserve may preserve fertility in patients with TS. However, in the majority of females with TS , the ovarian reserve is exhausted before the age of menarche. Early markers indicating and predicting the ovarian reserve are necessary. During mid-childhood the hypothalamic-pituitary-gonadal (HPG) axis is quiescent and gonadotropins are usually unmeasurable. Nonetheless, this axis is active during infancy. Therefore, gonadotropins are measurable with peak values at 3 months of age and with lower (but still measurable) values at 9 months of age, in a period called the minipuberty. The aim of this study is to find markers of ovarian capacity, during the minipuberty, in order to predict ovarian reserve in the future. Objective: The hormonal range of LH, FSH, AMH, inhibin B, testosterone and estradiol in girls with TS during the minipuberty and the relation of the hormone serum levels with the karyotype. Study design: A prospective, cohort study with a duration of 3 years. Study population: Girls with a pre- or perinatal diagnosis TS who are born in a medical centre in the Netherlands during the duration of the study Main study parameters/endpoints: Serum levels of FSH, LH, AMH, inhibin B, testosterone and estradiol at the age of 3 and 9 months.

Conditions

Turner Syndrome; Infertility, Female; Premature Ovarian Failure; Gonadal Dysgenesis; Premature Menopause; Sex Chromosome Disorders; Ovarian Diseases

Keywords

Minipuberty; Turner Syndrome; Infertility; Premature Ovarian Failure

Outcome Measures

Primary Outcomes (6)

• Defining the LH range in blood during minipuberty in girls with TS at 3 months of age and at 9 months of age

  LH (luteinizing hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.

  1 year after venapuncture

• Defining the FSH range during minipuberty in girls with TS at 3 months of age and at 9 months of age

  FSH (follicle stimulating hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.

  1 year after venapuncture

• Defining the AMH range during minipuberty in girls with TS at 3 months of age and at 9 months of age

  AMH (Anti-Müllerian hormone) will be collected with a venapuncture and analysed on the Access of Beckman Coulter.

  1 year after venapuncture

• Defining the estradiol range during minipuberty in girls with TS at 3 months of age and at 9 months of age

  estradiol will be collected with a venapuncture and analysed with the LCMSMS analysis method.

  1 year after venapuncture

• Defining the testosterone range during minipuberty in girls with TS at 3 months of age and at 9 months of age

  testosterone will be collected with a venapuncture and analysed with the LCMSMS analysis method.

  1 year

• Defining the inhibin B range during minipuberty in girls with TS at 3 months of age and at 9 months of age

  inhibin B will be collected with a venapuncture and analysed with the GEN II ELISEA of Beckman Coulter.

  1 year after venapuncture

Secondary Outcomes (6)

• Patient's karyotype vs LH

  1 year after venapuncture

• Patient's karyotype vs FSH

  1 year after venapuncture

• Patient's karyotype vs AMH

  1 year after venapuncture

• Patient's karyotype vs estradiol

  1 year after venapuncture

• Patient's karyotype vs testosterone

  1 year after venapuncture

Study Arms (1)

Girls with Turner syndrome

Girls with a pre- or perinatal diagnosis TS who are born in a medical centre in the Netherlands during the duration of the study. The subjects will have an extra venapuncture of 3.5 mL blood at 3 and 9 months.

Other: Venapunction

Interventions

Venapunction OTHER

A blood sample of 3.5 mL (0.2 mL serum for FSH and LH, 0.15 mL serum for E2, 0.15 mL serum for T, 0.15 mL serum for AMH and 0.25 mL serum for Inhibin B) will be collected of all girls with TS at 3 months and 9 months of age. For the girls with TS, this will be collected with an extra venapuncture during a regular outpatient visit within the usual care.

Girls with Turner syndrome

Eligibility Criteria

• Age: 1 Month - 3 Months
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

We include girls with the diagnosis TS before the age of 3 months based on full or partial absence of one X-chromosome or a mosaic pattern. We will recruit the girls with TS from all medical centres in the Netherlands. The control group consists of girls who have blood collected at 3 months and at 9 months of age for another indication. Participants in the control group will be recruited in the Radboudumc in Nijmegen.

You may qualify if:

• In order to be eligible to participate in the TS group of this study, a subject must meet all of the following criteria:
• A diagnosis of TS before the age of three months;
• Girls with a diagnosis of classic TS or other variants (i.e. 45,X, 45,X/46XiXq, 45,X/46,XY, 45,X/46,XX, 45,X/47,XXX, 45,X/46,X,r(X), 46,XiXq, other);
• Whose parents have agreed to participate in the study through a signed written informed consent form.
• In order to be eligible to participate in the control group of this study, a subject must meet all of the following criteria:
• No diagnosis of TS or any other diagnosis that might affect the HPG axis;
• Girls that will have a blood collection within their usual care at 3 months and at 9 months of age.
• Whose parents have agreed to participate in the study through a signed informed consent form.

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Any other diagnosis besides TS that might affect the HPG axis;
• Ovarian surgery in the medical history;
• Critical illness;
• The use of medication affecting the HPG axis (e.g. estrogen suppletion therapy)

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (13)

Righospitalet, University of Copenhagen

Copenhagen, Denmark

RECRUITING

Universitätsklinikum der Ruhr-Universität Bochum

Bochum, Germany

RECRUITING

Justus-Liebig Universität Giessen

Giessen, Germany

RECRUITING

Universitätsklinikum Tübingen

Tübingen, Germany

RECRUITING

Radboud University Medical Center

Nijmegen, Gelderland, 6525GA, Netherlands

RECRUITING

Amsterdam University medical center

Amsterdam, Netherlands

RECRUITING

University medical center Groningen

Groningen, Netherlands

RECRUITING

Leiden University medical center

Leiden, Netherlands

RECRUITING

Maastricht University medical center

Maastricht, Netherlands

RECRUITING

Erasmus University medical center

Rotterdam, Netherlands

RECRUITING

University medical Center Utrecht

Utrecht, Netherlands

RECRUITING

Medical university of Silesia

Katowice, Poland

RECRUITING

University hospital of Umea

Umeå, Sweden

RECRUITING

Related Publications (11)

• Bernard V, Donadille B, Zenaty D, Courtillot C, Salenave S, Brac de la Perriere A, Albarel F, Fevre A, Kerlan V, Brue T, Delemer B, Borson-Chazot F, Carel JC, Chanson P, Leger J, Touraine P, Christin-Maitre S; CMERC Center for Rare Disease. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod. 2016 Apr;31(4):782-8. doi: 10.1093/humrep/dew012. Epub 2016 Feb 13.

  PMID: 26874361 BACKGROUND

• Borgstrom B, Hreinsson J, Rasmussen C, Sheikhi M, Fried G, Keros V, Fridstrom M, Hovatta O. Fertility preservation in girls with turner syndrome: prognostic signs of the presence of ovarian follicles. J Clin Endocrinol Metab. 2009 Jan;94(1):74-80. doi: 10.1210/jc.2008-0708. Epub 2008 Oct 28.

  PMID: 18957497 BACKGROUND

• Bryman I, Sylven L, Berntorp K, Innala E, Bergstrom I, Hanson C, Oxholm M, Landin-Wilhelmsen K. Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil Steril. 2011 Jun 30;95(8):2507-10. doi: 10.1016/j.fertnstert.2010.12.039. Epub 2011 Jan 22.

  PMID: 21256486 BACKGROUND

• Burgoyne PS, Baker TG. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J Reprod Fertil. 1985 Nov;75(2):633-45. doi: 10.1530/jrf.0.0750633.

  PMID: 3906118 BACKGROUND

• Fechner PY, Davenport ML, Qualy RL, Ross JL, Gunther DF, Eugster EA, Huseman C, Zagar AJ, Quigley CA; Toddler Turner Study Group. Differences in follicle-stimulating hormone secretion between 45,X monosomy Turner syndrome and 45,X/46,XX mosaicism are evident at an early age. J Clin Endocrinol Metab. 2006 Dec;91(12):4896-902. doi: 10.1210/jc.2006-1157. Epub 2006 Sep 12.

  PMID: 16968797 BACKGROUND

• Huang JY, Tulandi T, Holzer H, Lau NM, Macdonald S, Tan SL, Chian RC. Cryopreservation of ovarian tissue and in vitro matured oocytes in a female with mosaic Turner syndrome: Case Report. Hum Reprod. 2008 Feb;23(2):336-9. doi: 10.1093/humrep/dem307. Epub 2007 Dec 2.

  PMID: 18056118 BACKGROUND

• Johannsen TH, Main KM, Ljubicic ML, Jensen TK, Andersen HR, Andersen MS, Petersen JH, Andersson AM, Juul A. Sex Differences in Reproductive Hormones During Mini-Puberty in Infants With Normal and Disordered Sex Development. J Clin Endocrinol Metab. 2018 Aug 1;103(8):3028-3037. doi: 10.1210/jc.2018-00482.

  PMID: 29917083 BACKGROUND

• Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne). 2018 Jul 23;9:410. doi: 10.3389/fendo.2018.00410. eCollection 2018.

  PMID: 30093882 BACKGROUND

• Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome. J Clin Endocrinol Metab. 1997 Jun;82(6):1810-3. doi: 10.1210/jcem.82.6.3970.

  PMID: 9177387 BACKGROUND

• Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006 Oct;91(10):3897-902. doi: 10.1210/jc.2006-0558. Epub 2006 Jul 18.

  PMID: 16849410 BACKGROUND

• Sutton EJ, McInerney-Leo A, Bondy CA, Gollust SE, King D, Biesecker B. Turner syndrome: four challenges across the lifespan. Am J Med Genet A. 2005 Dec 1;139A(2):57-66. doi: 10.1002/ajmg.a.30911.

  PMID: 16252273 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Analysing LH, FSH, AMH, estradiol, inhibin B and testosterone in plasma

MeSH Terms

Conditions

Turner Syndrome; Infertility, Female; Primary Ovarian Insufficiency; Gonadal Dysgenesis; Menopause, Premature; Sex Chromosome Disorders; Ovarian Diseases; Infertility

Condition Hierarchy (Ancestors)

Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Sex Chromosome Disorders of Sex Development; Male Urogenital Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Genital Diseases, Female; Genital Diseases; Adnexal Diseases

Study Officials

• Janielle vd Velden, MD, PhD

  Paediatric endocrinologist, Radboudumc, Nijmegen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sanne vd Coelen, MD

CONTACT

+31243098078; sanne.vandercoelen@radboudumc.nl

Janielle vd Velden, MD, PhD

CONTACT

+24 3614430; Janielle.vanderVelden@radboudumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2019
• First Posted: December 6, 2019
• Study Start: February 1, 2020
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: November 29, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (7); DK (1); DE (3); PL (1); SE (1)