Primary Ovarian Insufficiency Incidence Rate and Etiology Among Israeli Adolescents Between the years 2000-2016 – A Nationwide Study

נועה גרובר ^1,2 Shir Kugler ¹ Liat De Vries ^2,3 Avivit Brener ² Amnon Zung ^4,5 Ori Eyal ^2,6 Marianna Rachmiel ^2,7 Ilana Koren ⁸ Yardena Tenenbaum-Rakover ^9,10 Eli Hershkovitz ¹¹ Zohar Landau ^2,12 Meirav Oren ¹³ Alon Eliakim ^2,14 David Zangen ^5,15 Alina German ¹⁶ Hussein Majdoub ⁸ Kineret Mazor-Aronovitch ^1,2 Dalit Modan-Moses ^1,2 Yonatan Yeshayahu ^1,2 Larisa Naugolni ⁷ Yael Levy-Shraga ^1,2 Michal Ben-Ami ^1,2 Gherta Brill ¹⁷ Nehama Zuckerman-Levin ^10,18 Floris Levy-Khademi ^5,19 Carmit Avnon-Ziv ^5,19 Dov Tiosano ^10,13 Shira Harel ²⁰ Einat Kedem ¹² Anat Segev-Becker ⁶ Yehuda Shoenfeld ²¹ Orit Pinhas-Hamiel ^1,2

¹Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan
²Sackler School of Medicine, Tel-Aviv University, Israel
³The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva
⁴Pediatric Endocrinology Unit, Kaplan Medical Center, Rehovot
⁵The School of Medicine, The Hebrew University of Jerusalem
⁶Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children Hospital, Tel Aviv Sourasky Medical Center
⁷Pediatric Endocrinology Unit, Assaf Haroffeh Medical Center, Zerifin
⁸Pediatric Endocrinology Clinic, Armon Child Center, Clalit Health Services
⁹Pediatric Endocrine Unit, Ha'Emek Medical Center, Affula
¹⁰The Rappaport Faculty of Medicine, Technion, Haifa
¹¹The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Pediatric Endocrinology and Metabolic Unit, Soroka University Medical Center
¹²Pediatric Endocrine and Diabetes Unit, E. Wolfson Medical Center, Holon
¹³Paediatric Endocrine Unit, Rambam Health Care Campus, Haifa
¹⁴Kfar Saba, Meir Medical Center
¹⁵Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center
¹⁶Pediatric Department, Bnei Zion Medical Center, Haifa
¹⁷Migdal Hamea, Tel Aviv District, Clalit Health Services
¹⁸Institute of Diabetes, Endocrinology and Metabolism, Rambam Medical Center
¹⁹Division of Pediatric Endocrinology, Shaare Zedek Medical Center
²⁰Central District, Maccabi Health Services
²¹Sheba Medical Center, Tel-Hashomer, Zabludowicz Center for Autoimmune Diseases

Introduction: Primary ovarian insufficiency (POI) occurring in youth is a devastating condition. POI is characterized by at least 4 months of disordered menses in association with menopausal follicle stimulating hormone (FSH) levels. Data are scarce regarding the incidence of POI in adolescents.

Objectives: We estimated the current incidence and the distribution of etiologies of POI in a nationwide study in Israel.

Methods: Data regarding girls under age 21 years presenting with POI during the years 2000-2016 were collected from all the pediatric endocrine units (14 centers). Iatrogenic cases were excluded. The incidence rate of new POI cases was calculated based on birthrate information from the Israeli Central Bureau of Statistics.

Results: 113 girls met the criteria of POI. The distribution of etiologies was: Turner syndrome/mosaicism in 49/113 (43%), idiopathic in 36/113 (32%) and other (genetic, autoimmune, etc.) in 28/113 (25%). During the years 2009-2016 compared to 2000-2008, the incidence rate of new POI diagnoses per 100,000 births doubled (3.8 versus 1.8, P=0.0003), and incidence rates of both idiopathic and other etiologies tripled (P=0.003 and 0.01 respectively). In contrast, the incidence of Turner syndrome was constant (P=0.3). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is 1 per 100,000 person-years.

Conclusions: The current study was the largest scale multi-center study in adolescents and a significant increase in the rate of POI was observed over the last decade, among non-Turner cases. The contribution of environmental and epigenetic factors to this remarkable increase should be studied.