Turner Syndrome Minipuberty Study
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The subjects will have twice an extra venapunction for collection of 3.5mL blood during their infancy, which is not stated in the guidelines for TS. There is very little risk for adverse events associated with this blood sample collection, however it is an extra procedure. The outcome parameters will not be helpful for individual study participants, however they are likely to help clinicians and researchers in understanding how the ovarian function operates develops in girls with TS. Furthermore, these markers could be used to estimate the ovarian reserve and the urgency of fertility preservation in young females with TS. This information could help clinicians, patients and their parents in decision making.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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
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.
|
Outcome Measures
Primary Outcome Measures
- Defining the LH range in blood during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year after venapuncture]
LH (luteinizing hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.
- Defining the FSH range during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year after venapuncture]
FSH (follicle stimulating hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.
- Defining the AMH range during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year after venapuncture]
AMH (Anti-Müllerian hormone) will be collected with a venapuncture and analysed on the Access of Beckman Coulter.
- Defining the estradiol range during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year after venapuncture]
estradiol will be collected with a venapuncture and analysed with the LCMSMS analysis method.
- Defining the testosterone range during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year]
testosterone will be collected with a venapuncture and analysed with the LCMSMS analysis method.
- Defining the inhibin B range during minipuberty in girls with TS at 3 months of age and at 9 months of age [1 year after venapuncture]
inhibin B will be collected with a venapuncture and analysed with the GEN II ELISEA of Beckman Coulter.
Secondary Outcome Measures
- Patient's karyotype vs LH [1 year after venapuncture]
The association between patient's karyotype and LH level at 3 months of age and 9 months of age
- Patient's karyotype vs FSH [1 year after venapuncture]
The association between patient's karyotype and FSH level at 3 months of age and 9 months of age
- Patient's karyotype vs AMH [1 year after venapuncture]
The association between patient's karyotype and AMH level at 3 months of age and 9 months of age
- Patient's karyotype vs estradiol [1 year after venapuncture]
The association between patient's karyotype and estradiol level at 3 months of age and 9 months of age
- Patient's karyotype vs testosterone [1 year after venapuncture]
The association between patient's karyotype and testosterone level at 3 months of age and 9 months of age
- Patient's karyotype vs inhibin B [1 year after venapuncture]
The association between patient's karyotype and inhibin B level at 3 months of age and 9 months of age
Eligibility Criteria
Criteria
Inclusion Criteria:
In order to be eligible to participate in the TS group of this study, a subject must meet all of the following criteria:
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A diagnosis of TS before the age of three months;
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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);
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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:
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No diagnosis of TS or any other diagnosis that might affect the HPG axis;
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Girls that will have a blood collection within their usual care at 3 months and at 9 months of age.
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Whose parents have agreed to participate in the study through a signed informed consent form.
Exclusion Criteria:
A potential subject who meets any of the following criteria will be excluded from participation in this study:
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Any other diagnosis besides TS that might affect the HPG axis;
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Ovarian surgery in the medical history;
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Critical illness;
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The use of medication affecting the HPG axis (e.g. estrogen suppletion therapy)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Radboud University Medical Center | Nijmegen | Gelderland | Netherlands | 6525GA |
Sponsors and Collaborators
- Radboud University Medical Center
Investigators
- Principal Investigator: Janielle vd Velden, MD, PhD, Paediatric endocrinologist, Radboudumc, Nijmegen
Study Documents (Full-Text)
None provided.More Information
Publications
- Bernard V, Donadille B, Zenaty D, Courtillot C, Salenave S, Brac de la Perrière A, Albarel F, Fèvre A, Kerlan V, Brue T, Delemer B, Borson-Chazot F, Carel JC, Chanson P, Léger 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.
- Borgström B, Hreinsson J, Rasmussen C, Sheikhi M, Fried G, Keros V, Fridström 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. Erratum in: J Clin Endocrinol Metab. 2009 Apr;94(4):1478. Birgit, Borgström [corrected to Borgström, Birgit]; Julius, Hreinsson [corrected to Hreinsson, Julius]; Carsten, Rasmussen [corrected to Rasmussen, Carsten]; Maryam, Sheikhi [corrected to Sheikhi, Maryam]; Gabriel, Fried [corrected to Fried, Gabriel]; Vi.
- Bryman I, Sylvén L, Berntorp K, Innala E, Bergström 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.
- 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.
- 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. Epub 2006 Sep 12.
- 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. Epub 2007 Dec 2.
- 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.
- 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. Review.
- 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.
- 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. Epub 2006 Jul 18.
- 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.
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