Primary ovarian insufficiency.

One World, One Woman: A<i>Kyosei</i>Approach to Primary Ovarian Insufficiency

How does the number of children in women with primary ovarian insufficiency (POI) compare to the number for control women across their reproductive lifespans? Approximately 14% fewer women with POI will have children, but for those able to have children the median number is 1 less than for age-matched controls. Women with POI are often identified when presenting for fertility treatment, but some women with POI already have children and there remains a low chance for pregnancy after the diagnosis. Further, POI is heritable, but it is not known whether relatives of women with POI have a smaller family size than relatives of controls. The study was a retrospective case-control study of women with POI diagnosed from 1995 to 2021 (n = 393) and age-matched controls (n = 393). Women with POI were identified using ICD9 and 10 codes in electronic medical records (1995-2021) from two major healthcare systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database. All POI cases (n = 393) were required to have genealogy information available for at least three generations of ancestors. Two sets of female controls were identified: one matched for birthplace (Utah or elsewhere) and 5-year birth cohort, and a second also matched for fertility status (children present). The number of children born and maternal age at each birth were ascertained by birth certificates (available from 1915 to 2020) for probands, controls, and their relatives. The Mann-Whitney U test was used for comparisons. A subset analysis was performed on women with POI and controls who delivered at least one child and on women who reached 45 years to capture reproductive lifespan. Of the 393 women with POI and controls, 211 women with POI (53.7%), and 266 controls (67.7%) had at least one child. There were fewer children born to women with POI versus controls (median (interquartile range) 1 (0-2) versus 2 (0-3); P = 3.33 × 10-6). There were no children born to women with POI and primary amenorrhea or those <25 years old before their diagnosis. When analyzing women with at least one child, women with POI had fewer children compared to controls overall (2 (1-3) versus 2 (2-4); P = 0.017) and when analyzing women who reached 45 years old (2 (1-3) versus 3 (2-4); P = 0.0073). Excluding known donor oocyte pregnancies, 7.1% of women with POI had children born after their diagnosis. There were no differences in the number of children born to relatives of women with POI, including those with familial POI. The data are limited based on inability to determine whether women were trying for pregnancy throughout their reproductive lifespan or were using contraception. Unassisted births after the diagnosis of POI may be slightly over-estimated based on incomplete data regarding use of donor oocytes. The results may not be generalizable to countries or states with late first births or lower birth rates. Approximately half of women with POI will bear children before diagnosis. Although women with POI had fewer children than age matched controls, the difference in number of children is one child per woman. The data suggest that fertility may not be compromised leading up to the diagnosis of POI for women diagnosed at 25 years or later and with secondary amenorrhea. However, the rate of pregnancy after the diagnosis is low and we confirm a birth rate of <10%. The smaller number of children did not extend to relatives when examined as a group, suggesting that it may be difficult to predict POI based on family history. The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. N/A.

Study question What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population? Summary answer Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI. What is known already Premature ovarian insufficiency (POI), defined as menopause before 40, has been associated with variants in over 70 genes. However, the evidence to support the causality of individual genetic variants varies between studies. As genomic data becomes more accessible, it is essential to ascertain the penetrance of variants in the absence of family history information. We identified 75 genes associated with POI from the literature, including family segregation studies, consanguineous pedigrees and cohort analyses of whole-exome/targeted sequencing data. Functional evaluation was also available for many of the genes. Study design, size, duration We used data from 101,127 females of European ancestry in the UK Biobank, to study the role of previously reported monogenic causal genes on ovarian function. We tested the association of 301 previously reported variants with POI and ANM, plus more than 2.5 million rare variants which were annotated and had not been implicated in POI previously. Genomic variants were tested individually and also combined into a gene burden test. Participants/materials, setting, methods Age at natural menopause (ANM) was derived from self-reported questionnaire data from the age at last menstrual period, excluding those with surgical menopause or taking hormone replacement therapy. POI cases were classified as women with ANM under 40 years (N = 2,213). Linked primary care records were used to identify a clinical cohort of POI cases, including primary amenorrhea (N = 113). Main results and the role of chance All of the previously reported individual variants we identified in our POI cases were also detected in the control group. Moreover, the gene burden tests were not associated with POI or ANM as a quantitative trait. Our results indicate that autosomal dominant causes of POI are rare; a single predicted loss-of-function (LOF) or non-synonymous genetic variant in one of the previously reported genes is generally not pathogenic. Limitations, reasons for caution The penetrance of monogenic disease-causing variants is likely to be lower in population-based cohorts such as UK Biobank than in clinically-ascertained cohorts. Wider implications of the findings Heterozygous LOF or non-synonymous variants in previously reported POI genes should be interpreted with caution and are unlikely to cause POI. The findings have implications for clinicians diagnosing causes of POI. Trial registration number Not applicable

STUDY QUESTIONIs there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis?SUMMARY ANSWERWomen with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis.WHAT IS KNOWN ALREADYIt has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%.STUDY DESIGN, SIZE, DURATIONThis population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case–control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970–2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls.MAIN RESULTS AND THE ROLE OF CHANCEThe prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison’s disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years.LIMITATIONS, REASONS FOR CAUTIONThis study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher.WIDER IMPLICATIONS OF THE FINDINGSSevere autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives.STUDY FUNDING/COMPETING INTEREST(S)This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report.TRIAL REGISTRATION NUMBERN/A.

BackgroundChemotherapy can induce premature ovarian insufficiency (POI). POI causes multiple sequelae and is currently incurable. As shown in our previous studies, systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) home to ovaries with chemotherapy-induced POI and subsequently reduce ovarian injury and improve ovarian function in rats with POI. However, the cellular mechanisms that direct the migration and homing of hAD-MSCs to ovaries with chemotherapy-induced POI are incompletely understood. This study investigated the role of the SDF-1/CXCR4 axis in the migration and homing of systemically transplanted hAD-MSCs to ovaries with chemotherapy-induced POI and its relevant downstream signalling pathways.MethodsCXCR4 expression in hAD-MSCs was assessed using Western blotting and immunofluorescence staining. hAD-MSC migration was tested using Transwell migration assays. SDF-1 levels were detected using ELISA. Seventy-two female SD rats were randomly divided into the control, POI, hAD-MSCs and hAD-MSCs + AMD3100 groups. Cyclophosphamide was used to establish rat POI models. For inhibitor treatment, hAD-MSCs were pretreated with AMD3100 before transplantation. PKH26-labeled hAD-MSCs were injected into the tail vein of POI rats 24 h after chemotherapy. After hAD-MSC transplantation, the homing of hAD-MSCs to ovaries and ovarian function and pathological changes were examined. We further investigated the molecular mechanisms by detecting the PI3K/Akt and ERK1/2 signalling pathways.ResultshAD-MSCs expressed CXCR4. SDF-1 induced hAD-MSC migration in vitro. SDF-1 levels in ovaries and serum were significantly increased in rats with chemotherapy-induced POI, and ovaries with POI induced the homing of hAD-MSCs expressing CXCR4. Blocking the SDF-1/CXCR4 axis with AMD3100 significantly reduced the number of hAD-MSCs homing to ovaries with POI and further reduced their efficacy in POI treatment. The binding of SDF-1 to CXCR4 activated the PI3K/Akt signalling pathway, and LY294002 significantly inhibited hAD-MSC migration induced by SDF-1 in vitro. Moreover, inhibition of the PI3K/Akt signalling pathway significantly reduced the number of systemically transplanted hAD-MSCs homing to chemotherapy-induced ovaries in rats with POI.ConclusionsSDF-1/CXCR4 axis partially mediates the migration and homing of systemically transplanted hAD-MSCs to the ovaries of rats with chemotherapy-induced POI, and the PI3K/Akt signalling pathway might be involved in the migration and homing of hAD-MSCs mediated by the SDF-1/CXCR4 axis.

STUDY QUESTIONAre genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)?SUMMARY ANSWERA wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI.WHAT IS KNOWN ALREADYPOI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7–15% of POI cases.STUDY DESIGN, SIZE, DURATIONThis population-based study included 5011 women diagnosed with POI in 1988–2017. The data were collected from various national registries and covers women with POI nationwide.PARTICIPANTS/MATERIALS, SETTING, METHODSWe identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date.MAIN RESULTS AND THE ROLE OF CHANCEOf the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1–1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1–39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2–43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10–14 years old, OR 24.1, 95% CI 15.1–38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had.LIMITATIONS, REASONS FOR CAUTIONSome women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers.WIDER IMPLICATIONS OF THE FINDINGSGD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations.STUDY FUNDING/COMPETING INTEREST(S)Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare.TRIAL REGISTRATION NUMBERN/A.

Primary ovarian insufficiency (POI) refers to the cessation of menses before the age of 40 years and occurs in 1% to 2% of women. The specific cause of POI is unknown in the majority of cases. Known causes include gene mutations of fragile X mental retardation 1 (FMR1), a gene located on the X chromosome. This gene codes for a protein essential for normal cognitive development and female reproductive function. FMR1 contains a CCG trinucleotide segment in an untranslated region of its DNA that is repeated less than 45 times in normal individuals (normal range of repeats). Mutation of FMR1 results in abnormal expansion of an unstable CGG triplet, leading to impaired cognitive and reproductive function. Between 55 and 200 CCG repeats is called premutation; affected individuals with premutation are at risk for POI and further expansion of repeats in subsequent generations. People with 45 to 54 CCG repeats (intermediate range of repeats) are considered to be at borderline risk for POI and further expansion of repeats. This case-control study was designed to determine whether the risk of POI is associated with CGG repeat length of normal and intermediate range (up to 55 repeats) in a large cohort of Dutch women with idiopathic POI. The second aim of the study was to examine a possible association between the number of CGG repeats and age at first manifestation of POI as a measurement for the severity of POI. The study population was composed of 375 well-phenotyped Dutch women diagnosed with POI; control subjects were 3368 women with natural menopause at 40 years or older. The FMR1 CGG repeat number was determined by polymerase chain reaction amplification of DNA extracted from blood samples drawn from each patient. Fisher exact test was used to assess the prevalence of intermediate-size CGG repeats in POI cases and control subjects. Analysis of variance tested differences in mean CGG repeat lengths on alleles 1 and 2 between POI cases and control subjects. Allele 1 has the lowest triple repeat number, and allele 2 has the highest triple repeat number. There was no significant difference between POI cases and control subjects in the frequency of intermediate-size CGG repeats on allele 2 (POI 2.7 vs control subjects 3.8%; the odds ratio was 0.72, with a 95% confidence interval of 0.38–1.39; P = 0.38). Linear regression analysis showed no association between the number of CGG repeats and age at first POI manifestation (β = 20.019, P = 0.72). These data suggest that intermediate-size CGG repeats are not associated with risk of POI. Therefore, evaluation of normal and intermediate FMR1 repeat size appears to be of little or no value in the diagnostic workup of women affected by POI or in the prognostic assessment of women at risk of developing POI. Reasons for caution in interpreting these results are as follows: (1) FMR1 CGG repeat lengths in POI cases and control subjects were genotyped in 2 different laboratories; technical differences could have affected the results; (2) distributions of CGG repeats could vary among ethnic populations; (3) women with primary amenorrhea (n = 17) were included in the POI group. The last 2 possible limitations were unlikely because exclusion of data from nonwhite women or women with primary amenorrhea did not affect the results.

STUDY QUESTIONWhat is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women?SUMMARY ANSWERThe incidence of POI increased among females aged 15–19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased.WHAT IS KNOWN ALREADYSo far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause.STUDY DESIGN, SIZE, DURATIONPopulation-based study with 5011 women diagnosed with POI in 1988–2017. The data were collected from national registries and covers POI subjects in entire Finland.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model.MAIN RESULTS AND THE ROLE OF CHANCEThe incidence was highest in the 35–39 age group, ranging from 73.8/100 000 women-years in 1993–1997 to 39.9/100 000 women-years in 2013–2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015–2017. Cumulative incidence of POI for women under 40 years in 1988–2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3–6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls.LIMITATIONS, REASONS FOR CAUTIONFor some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria.WIDER IMPLICATIONS OF THE FINDINGSThe risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis.STUDY FUNDING/COMPETING INTEREST(S)This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare.TRIAL REGISTRATION NUMBERN/A.

Study question Do the Edinburgh selection criteria correctly identify females, diagnosed with cancer under 18 years old, at high risk of future premature ovarian insufficiency (POI)? Summary answer Patient assessment using these criteria accurately identifies those at risk of POI. Ovarian tissue cryopreservation with future transplantation can be offered, providing future fertility options. What is known already Cancer treatments can be gonadotoxic and future fertility and reproductive health should be considered at the time of diagnosis and treatment planning. Correct identification of patients at high risk allows appropriate discussion of fertility preservation with ovarian tissue cryopreservation (OTC) and future transplantation. The Edinburgh selection criteria have been proposed as a tool to identify those patients at high risk. However, the surgical procedure is not without risk and reproductive outcomes remain uncertain in girls. Therefore, long-term follow up of reproductive function is crucial to ensure that this treatment strategy is offered appropriately. Study design, size, duration All females diagnosed with cancer less than 18 years old, in South East Scotland, between 01/01/96 and 30/10/20 were included. They were assessed using the Edinburgh selection criteria and offered OTC, if appropriate. Ongoing long-term follow up of reproductive outcomes has been undertaken for the whole patient cohort to detect those who develop POI. Participants/materials, setting, methods A total of 639 eligible patients were identified from the Cancer registry and their electronic records reviewed. Reproductive function was assessed by the presence of menstruation, pregnancy, hormonal measurements, evidence of puberty or diagnosis of POI. Patients on hormonal contraception (other than for the treatment of POI) were considered unsuitable for analysis. Data were analysed using the Kaplan Meier method, with POI as the event, and the Cox proportional hazards model to calculate hazard ratios. Main results and the role of chance Of the 639 patients diagnosed with cancer during the study period, those deceased before age 12 years old (n = 73) or under 12 years old (n = 134) at the date of analysis were excluded; also excluding those on hormonal contraception (n = 9) gave a study population of 423. Data were analysed including those with unknown reproductive outcomes (n = 143), assuming they did not have POI. A subgroup analysis excluding these patients was also performed. Mean age at diagnosis and analysis was 8.8 years and 22.5 years respectively. OTC was offered to 37 patients, 26 of whom underwent the procedure. Nine patients developed POI (24.3%). Of the 386 not offered OTC, 11 developed POI (2.85%). The hazard ratio for developing POI was 8.8 (CI 3.6-21). Excluding the patients with unknown outcomes (n = 143) left a study population of 280. Within this group, 9 of 29 offered OTC developed POI (31.0%) versus 11 of 251 not offered OTC (4.4%); hazard ratio 8.2 (CI 3.4-20). In the group offered OTC, all cases of POI developed after the primary treatment. In those not offered OTC, POI developed after secondary treatment for disease relapse in 5 patients (45.5%). Limitations, reasons for caution A significant number of patients had unknown reproductive outcomes; this is likely to reflect a lack of recording of normal menstrual function in oncology/haematology clinics but may have biased the analysis. The duration of follow up is also short for some patients, highlighting the need for further follow up. Wider implications of the findings The overall prevalence of POI after childhood cancer is low, but the Edinburgh selection criteria are a robust tool for selecting those at high risk at the time of diagnosis, who can be offered OTC. However, many patients had incomplete information on current reproductive status, which should be assessed routinely. Trial registration number N/A

To investigate the occurrence of previous cancer diagnoses in women suffering from premature ovarian insufficiency (POI) and compare it with the general population, shedding light on the association between cancer, cancer treatments, and POI. We conducted a nationwide case-control study based on registry data from various sources, including the Social Insurance Institution, Finnish Population Information System, and Finnish Cancer Registry spanning from 1953 to 2018. Our participants comprised all women in Finland who, between 1988 and 2017, received hormone replacement therapy reimbursement for ovarian insufficiency before the age of 40 years (n = 5221). Controls, matched in terms of age and municipality of residence, were selected from the Finnish Population Information System (n = 20 822). Our main exposure variable was a history of cancer diagnosis preceding the diagnosis of POI. We analyzed odds ratios (OR) to compare the prevalence of previous cancers in women with POI with that in controls, stratifying results based on cancer type, age at cancer diagnosis, and the time interval between cancer diagnosis and POI. We also assessed changes in OR for previous cancer diagnoses over the follow-up period. Out of the women diagnosed with POI, 21.9% had previously been diagnosed with cancer, resulting in an elevated OR of 36.5 (95% confidence interval [CI] 30.9 to 43.3) compared with 0.8% of the controls. The risk of developing POI was most pronounced during the first 2 years following a cancer diagnosis, with an OR of 103 (95% CI 74.1 to 144). Importantly, this risk remained elevated even when the time interval between cancer and POI exceeded 10 years, with an OR of 5.40 (95% CI 3.54 to 8.23). This study reveals that 21.9% of women with POI have a history of cancer, making the prevalence of cancer among these women 27.5 times higher than age-matched controls in the Finnish population. The risk of developing POI is most substantial in the first 2 years following a cancer diagnosis. These findings underscore the role of cancer treatments as an etiological factor for POI and emphasize the importance of recognizing the risk of POI in cancer survivors for early diagnosis and intervention.

Disclosure: K.L. Allen-Brady: None. L. Verrilli: None. M. Alvord: None. M. Kern: None. N. Camp: None. K. Kelley: Consulting Fee; Self; Immunogen. J. Letourneau: None. L. Cannon-Albright: None. E.B. Johnstone: Stock Owner; Self; Abbott Laboratories, Abbvie. C.K. Welt: None. Introduction: Next generation sequencing in women with primary ovarian insufficiency (POI) identified deleterious variants in DNA damage repair and transcription fidelity genes. Based on underlying genetics, we hypothesized that a subset of women with POI may also be predisposed to reproductive or hormonally influenced cancers and that family members may be at risk. Methods: Women with POI (≤40 years) and early menopause &amp;gt;40 and &amp;lt;45 years) were identified using ICD9 and 10 codes in electronic medical records (1995-2021) from two major healthcare systems in Utah and reviewed for accuracy. Women with POI and their relatives were linked to genealogy information using the Utah Population Database (UPDB) and to cancer diagnoses (breast, ovarian, endometrial, colon, testicular and prostate) using the Utah Cancer Registry. The relative risk (RR) of cancer in women with POI and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. We also identified POI pedigrees with an excess number of observed cancer cases compared to the expected number in population controls. Results: We identified 613 women with POI and 165 women with early menopause. Of these, 416 women with POI had at least three generations of genealogical data with 2,405 first-degree relatives, 6,798 second-degree relatives and 17,666 third-degree relatives. Breast cancer was significantly increased in women with POI (OR [95%CI] 1.89 [1.20, 2.84]; p=0.0056) and there was a borderline increase in ovarian cancer. Probands were 36.5±4.3 years when diagnosed with POI and 59.5±12.7 years (range 43-80 years) at the time of breast cancer diagnosis and only 2 women took hormone replacement therapy after age 50 years. When women with early menopause were added, breast cancer risk remained increased and ovarian cancer was also nominally significant (3.38 [1.15, 8.65]; p=0.032). There was no increased risk of endometrial cancer and there were no cases of colon cancer. Among second-degree relatives of women with POI and 3 generations of family members, there was a significantly increased risk of breast (1.28 [1.08, 1.71]; p=0.0078) and colon cancer (1.50 [1.14, 1.94]; p=0.0036). Prostate cancer was increased in first- (1.64 [1.18, 2.23]; p=0.0026), second- (1.54 [1.32, 1.79]; p&amp;lt;0.001), and third-degree relatives (1.33 [1.20, 1.48]; p&amp;lt;0.001). There were 27 POI pedigrees that were high risk for these reproductive or hormonally influenced cancer diagnoses. Conclusions: Our data suggest common risk factors for POI and reproductive or hormonally influenced cancers. Therefore, clinicians need tools to predict cancer risk and comorbid disease in women with POI and early menopause to adequately counsel about future health risk. This understanding may change recommendations for hormone replacement based on the underlying genetic cause of POI for an individual. Presentation: 6/3/2024

Premature ovarian insufficiency: step-by-step genetics bring new insights

New theca-cell marker insulin-like factor 3 is associated with premature ovarian insufficiency

Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility

Primary ovarian insufficiency (POI) represents ovarian dysfunction related to very early aging of the ovaries. While the cause of POI in a majority of clinical cases remains undefined, autoimmunity is responsible for approximately 4-30% of POI cases. In the present paper, we aim to provide a critical appraisal and update review on the role of autoimmunity in POI patients. A literature review was conducted for all relevant articles reporting on POI and autoimmunity. PubMed/MEDLINE and the Cochrane library were searched for the best available evidence on this topic. Patients with POI and coexisting autoimmunity are indistinguishable from those with negative autoimmune screen with regard to age of onset, prevalence of primary amenorrhea, or their endocrine profiles. A specific noninvasive reliable diagnostic test for the diagnosis of an autoimmune etiology is lacking; therefore, patients should be screened for the most common autoantibodies, i.e., steroid cell antibodies, anti-ovarian antibodies, and anti-thyroid antibodies. Moreover, treatment strategies to POI infertility are lacking and controversial. Nowadays, guidelines for the treatment of autoimmune POI are not available. Moreover, since diagnostic and treatment strategies to POI infertility are still lacking and controversial, further large clinical studies are needed to investigate the true impact of autoimmunity on POI and to identify the selected groups of patients who are most likely to benefit from immunossuprresive treatment.