Genetic Variants in Idiopathic Premature Ovarian Insufficiency

NCT07587853 | Not Yet Recruiting

• 1 other identifier: POI-WES-2026-01
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Premature ovarian insufficiency is a condition in which ovarian function decreases or is lost before the age of 40 years. In many patients, the underlying cause remains unexplained. This prospective observational case-control study aims to investigate pathogenic and likely pathogenic genetic variants in DNA repair and meiotic genes related to ovarian reserve and folliculogenesis in women with idiopathic premature ovarian insufficiency. The study will include women younger than 40 years with idiopathic premature ovarian insufficiency and age- and ethnicity-matched control participants with normal ovarian function. Clinical and reproductive data will be collected, and a peripheral blood sample will be obtained from each participant for whole exome sequencing. The frequency of pathogenic or likely pathogenic variants will be compared between the case and control groups. No investigational drug, device, or treatment intervention will be administered.

Conditions

Premature Ovarian Insufficiency

Outcome Measures

Primary Outcomes (1)

• Prevalence of Pathogenic or Likely Pathogenic Variants in the Target Gene Set

  Proportion of participants in each group who carry pathogenic or likely pathogenic variants, classified according to ACMG/AMP criteria, in the predefined 57-gene target set related to ovarian reserve, folliculogenesis, DNA repair, and meiosis.

  Through study completion, up to 24 months

Study Arms (2)

Idiopathic Premature Ovarian Insufficiency Group

Women younger than 40 years diagnosed with idiopathic premature ovarian insufficiency, defined by spontaneous amenorrhea or menstrual irregularity lasting at least 4 months and serum FSH level greater than 25 IU/L, with no known chromosomal abnormality, FMR1 premutation, syndromic genetic diagnosis, or iatrogenic cause.

Control Group

Women younger than 40 years with regular menstrual cycles, age-appropriate ovarian reserve findings, no known history of infertility or premature ovarian insufficiency, no previous gonadotoxic treatment, and no history of ovarian surgery. The control group will be selected to be similar to the case group in terms of age and ethnicity.

Eligibility Criteria

• Age: 18 Years - 39 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of women aged 18 to 39 years who are evaluated at the Department of Obstetrics and Gynecology/Reproductive Endocrinology clinics. The case group will include women diagnosed with idiopathic premature ovarian insufficiency, defined by spontaneous amenorrhea or marked menstrual irregularity lasting at least 4 months and elevated serum FSH levels. The control group will include age- and ethnicity-matched women with regular menstrual cycles, normal ovarian reserve findings for age, and no known history of infertility, premature ovarian insufficiency, gonadotoxic treatment, or ovarian surgery.

You may qualify if:

• For the idiopathic premature ovarian insufficiency group:
• Women aged 18 to 39 years.
• Spontaneous amenorrhea or marked menstrual irregularity lasting at least 4 months.
• Serum FSH level greater than 25 IU/L. In cases of diagnostic uncertainty, FSH measurement may be repeated after 4 to 6 weeks.
• Diagnosis of idiopathic premature ovarian insufficiency, with no known chromosomal abnormality, FMR1 premutation, defined syndromic genetic diagnosis, or iatrogenic cause.
• Willingness to participate in the study and ability to provide written informed consent.
• For the control group:
• Women aged 18 to 39 years.
• Regular menstrual cycles.
• Age-appropriate normal ovarian reserve findings, including FSH and AMH values within age-appropriate reference ranges and, when available, appropriate antral follicle count.
• No known history of infertility, premature ovarian insufficiency, or early menopause.
• No history of gonadotoxic treatment or ovarian surgery.
• Willingness to participate in the study and ability to provide written informed consent.

You may not qualify if:

• For both groups:
• Known chromosomal abnormality, such as Turner syndrome or structural X chromosome abnormality.
• FMR1 premutation carrier status.
• Previously defined syndromic genetic diagnosis.
• Active malignancy.
• History of gonadotoxic chemotherapy or pelvic radiotherapy.
• Iatrogenic ovarian damage or iatrogenic premature ovarian insufficiency after ovarian surgery.
• Clear autoimmune, endocrine, or other clinical condition that may explain secondary amenorrhea.
• Refusal to provide informed consent or request to withdraw study data.
• Insufficient DNA sample quality or inability to complete genetic analysis for technical reasons.
• Known history of infertility, premature ovarian insufficiency, or early menopause.
• Ovarian reserve findings below the expected range for age.
• Previous gonadotoxic treatment or ovarian surgery.

Sponsors & Collaborators

• Abdurrahman Hamdi İnan: lead

Study Sites (1)

University of Health Sciences Tepecik Training and Research Hospital, Department of Obstetrics and Gynecology

Bornova, İzmir, 35100, Turkey (Türkiye)

Location

Related Publications (12)

• European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI; Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de Muinck Keizer-Schrama S, Hogervorst E, Janse F, Liao L, Vlaisavljevic V, Zillikens C, Vermeulen N. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016 May;31(5):926-37. doi: 10.1093/humrep/dew027. Epub 2016 Mar 22.

  PMID: 27008889 BACKGROUND

• Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspectives. Int J Womens Health. 2015 Sep 23;7:799-810. doi: 10.2147/IJWH.S64024. eCollection 2015.

  PMID: 26445561 BACKGROUND

• Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015 Nov-Dec;21(6):787-808. doi: 10.1093/humupd/dmv036. Epub 2015 Aug 4.

  PMID: 26243799 BACKGROUND

• Bouilly J, Beau I, Barraud S, Bernard V, Azibi K, Fagart J, Fevre A, Todeschini AL, Veitia RA, Beldjord C, Delemer B, Dode C, Young J, Binart N. Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency. J Clin Endocrinol Metab. 2016 Dec;101(12):4541-4550. doi: 10.1210/jc.2016-2152. Epub 2016 Sep 7.

  PMID: 27603904 BACKGROUND

• Heddar A, Ogur C, Da Costa S, Braham I, Billaud-Rist L, Findikli N, Beneteau C, Reynaud R, Mahmoud K, Legrand S, Marchand M, Cedrin-Durnerin I, Cantalloube A, Peigne M, Bretault M, Dagher-Hayeck B, Perol S, Droumaguet C, Cavkaytar S, Nicolas-Bonne C, Elloumi H, Khrouf M, Rougier-LeMasle C, Fradin M, Le Boette E, Luigi P, Guerrot AM, Ginglinger E, Zampa A, Fauconnier A, Auger N, Paris F, Brischoux-Boucher E, Cabrol C, Brun A, Guyon L, Berard M, Riviere A, Gruchy N, Odent S, Gilbert-Dussardier B, Isidor B, Piard J, Lambert L, Hamamah S, Guedj AM, Brac de la Perriere A, Fernandez H, Raffin-Sanson ML, Polak M, Letur H, Epelboin S, Plu-Bureau G, Wolczynski S, Hieronimus S, Aittomaki K, Catteau-Jonard S, Misrahi M. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine. EBioMedicine. 2022 Oct;84:104246. doi: 10.1016/j.ebiom.2022.104246. Epub 2022 Sep 10.

  PMID: 36099812 BACKGROUND

• Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013 Feb 13;5(172):172ra21. doi: 10.1126/scitranslmed.3004925.

  PMID: 23408054 BACKGROUND

• Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, Garcia-Tunon I, Fellous M, Pendas AM, Veitia RA, Vilain E. Mutant cohesin in premature ovarian failure. N Engl J Med. 2014 Mar 6;370(10):943-949. doi: 10.1056/NEJMoa1309635.

  PMID: 24597867 BACKGROUND

• de Vries L, Behar DM, Smirin-Yosef P, Lagovsky I, Tzur S, Basel-Vanagaite L. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J Clin Endocrinol Metab. 2014 Oct;99(10):E2129-32. doi: 10.1210/jc.2014-1268. Epub 2014 Jul 25.

  PMID: 25062452 BACKGROUND

• Zangen D, Kaufman Y, Zeligson S, Perlberg S, Fridman H, Kanaan M, Abdulhadi-Atwan M, Abu Libdeh A, Gussow A, Kisslov I, Carmel L, Renbaum P, Levy-Lahad E. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet. 2011 Oct 7;89(4):572-9. doi: 10.1016/j.ajhg.2011.09.006. Epub 2011 Sep 29.

  PMID: 21963259 BACKGROUND

• Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, Elvin JA, Bronson RT, Crum CP, McKeon F. p63 protects the female germ line during meiotic arrest. Nature. 2006 Nov 30;444(7119):624-8. doi: 10.1038/nature05337. Epub 2006 Nov 22.

  PMID: 17122775 BACKGROUND

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

  PMID: 25741868 BACKGROUND

• Lee S, Abecasis GR, Boehnke M, Lin X. Rare-variant association analysis: study designs and statistical tests. Am J Hum Genet. 2014 Jul 3;95(1):5-23. doi: 10.1016/j.ajhg.2014.06.009.

  PMID: 24995866 BACKGROUND

MeSH Terms

Conditions

Primary Ovarian Insufficiency

Condition Hierarchy (Ancestors)

Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Central Study Contacts

Çağlasu Sancaktar, MD

CONTACT

+90 507 258 3948; caglasukeles@gmail.com

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Department of Obstetrics and Gynecology

Study Record Dates

• First Submitted: April 29, 2026
• First Posted: May 14, 2026
• Study Start: June 10, 2026
• Primary Completion (Estimated): June 10, 2028
• Study Completion (Estimated): June 10, 2028
• Last Updated: May 19, 2026

Record last verified: 2026-05

Locations

TU (1)