. 2022 May 25;11(5):e220024.

doi: 10.1530/EC-22-0024.

Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts

Elinor Chelsom Vogt^{1

2

3}, Francisco Gómez Real^{1

4}, Eystein Sverre Husebye^{1

2

3}, Sigridur Björnsdottir^{5

6}, Bryndis Benediktsdottir^{7

8}, Randi Jacobsen Bertelsen¹, Pascal Demoly⁹, Karl Anders Franklin¹⁰, Leire Sainz de Aja Gallastegui¹¹, Francisco Javier Callejas González¹², Joachim Heinrich^{13

14}, Mathias Holm¹⁵, Nils Oscar Jogi¹, Benedicte Leynaert¹⁶, Eva Lindberg¹⁷, Andrei Malinovschi¹⁸, Jesús Martínez-Moratalla^{19

20}, Raúl Godoy Mayoral¹², Anna Oudin²¹, Antonio Pereira-Vega²², Chantal Raherison Semjen²³, Vivi Schlünssen^{24

25}, Kai Triebner¹, Marianne Øksnes^{1

2

3}

Affiliations

¹ Department of Clinical Science, University of Bergen, Bergen, Norway.
² K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway.
³ Department of Medicine, Haukeland University Hospital, Bergen, Norway.
⁴ Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
⁷ Medical Faculty, University of Iceland, Reykjavik, Iceland.
⁸ Department of Sleep, Landspitali University Hospital Reykjavík, Reykjavik, Iceland.
⁹ University Hospital of Montpellier, IDESP, Univ Montpellier-Inserm, Montpellier, France.
¹⁰ Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
¹¹ Unit of Epidemiology and Public Health, Department of Health, Basque Government, Vitoria-Gasteiz, Spain.
¹² Department of Respiratory Medicine, Albacete University Hospital, Albacete, Spain.
¹³ Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁴ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁵ Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Université Paris-Saclay, Inserm U1018, Center for Epidemiology and Population Health, Integrative Respiratory Epidemiology Team, Villejuif, France.
¹⁷ Department of Medical Sciences, Respiratory, Allergy and Sleep Medicine, Uppsala University, Uppsala, Sweden.
¹⁸ Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden.
¹⁹ Pneumology Service of the General University Hospital of Albacete, Albacete, Spain.
²⁰ Albacete Faculty of Medicine, Castilla-La Mancha University, Albacete, Spain.
²¹ Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
²² Juan Ramón Jiménez University Hospital in Huelva, Huelva, Spain.
²³ INSERM, EpiCene Team U1219, University of Bordeaux, Talence, France.
²⁴ Department of Public Health, Environment, Work and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark.
²⁵ The National Research Center for the Working Environment, Copenhagen, Denmark.

PMID: 35521804
PMCID: PMC9175594
DOI: 10.1530/EC-22-0024

Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts

Elinor Chelsom Vogt et al. Endocr Connect. 2022.

. 2022 May 25;11(5):e220024.

doi: 10.1530/EC-22-0024.

Authors

Affiliations

¹ Department of Clinical Science, University of Bergen, Bergen, Norway.
² K.G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway.
³ Department of Medicine, Haukeland University Hospital, Bergen, Norway.
⁴ Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
⁷ Medical Faculty, University of Iceland, Reykjavik, Iceland.
⁸ Department of Sleep, Landspitali University Hospital Reykjavík, Reykjavik, Iceland.
⁹ University Hospital of Montpellier, IDESP, Univ Montpellier-Inserm, Montpellier, France.
¹⁰ Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
¹¹ Unit of Epidemiology and Public Health, Department of Health, Basque Government, Vitoria-Gasteiz, Spain.
¹² Department of Respiratory Medicine, Albacete University Hospital, Albacete, Spain.
¹³ Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁴ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁵ Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Université Paris-Saclay, Inserm U1018, Center for Epidemiology and Population Health, Integrative Respiratory Epidemiology Team, Villejuif, France.
¹⁷ Department of Medical Sciences, Respiratory, Allergy and Sleep Medicine, Uppsala University, Uppsala, Sweden.
¹⁸ Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden.
¹⁹ Pneumology Service of the General University Hospital of Albacete, Albacete, Spain.
²⁰ Albacete Faculty of Medicine, Castilla-La Mancha University, Albacete, Spain.
²¹ Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
²² Juan Ramón Jiménez University Hospital in Huelva, Huelva, Spain.
²³ INSERM, EpiCene Team U1219, University of Bordeaux, Talence, France.
²⁴ Department of Public Health, Environment, Work and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark.
²⁵ The National Research Center for the Working Environment, Copenhagen, Denmark.

PMID: 35521804
PMCID: PMC9175594
DOI: 10.1530/EC-22-0024

Abstract

Objective: To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women.

Design: Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women.

Methods: Variables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI.

Results: Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63-3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin.

Conclusion: Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.

Keywords: autoimmune; premature menopause; premature ovarian failure; premature ovarian insufficiency; primary ovarian insufficiency.

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Figures

**Figure 1**
Study design. European Community Respiratory Health Survey (ECRHS3S). The Respiratory Health in Northern Europe, Spain and Australia (Rhinessa). Idiopathic premature ovarian insufficiency (POI).

**Figure 2**
Timing and etiology of menopause.

**Figure 3**
17β-estradiol and follicle-stimulating hormone (FSH) by (A) time since menopause and (B) BMI in all post-menopausal women (n = 1134). Hormone levels reported in mean and 95% CI.

**Figure 4**
Multivariable logistic regression of reproductive and lifestyle factors associated with idiopathic primary ovarian insufficiency (POI) compared to menopause ≥40 years. Odds ratio adjusted for BMI, smoking, age and study affiliation (adOR) and 95% CI. Excluding women with surgically induced menopause ≥40 years (n = 261) or women with menopause at 40–44 years (n = 361) did not alter the results of the multivariable logistic regression analysis.

**Figure 5**
Hormonal patterns of 17β-estradiol and follicle-stimulating hormone (FSH) in three groups of women with different reasons for premature menopause. Idiopathic primary ovarian insufficiency (POI), iatrogenic and non-ovarian premature menopause.

**Figure 6**
Autoantibody index levels in 66 women with idiopathic primary ovarian insufficiency (POI) and a control group of 64 age-matched women with iatrogenic premature menopause (bilateral ovariectomized). Dotted line shows the cut-off threshold for positive test in this radio-binding ligand assay.

See this image and copyright information in PMC

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Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts

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Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts

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