Women with premature ovarian insufficiency, whose periods stop before 40, have a much greater risk of severe autoimmune diseases like diabetes and lupus, according to researchers who followed nearly 20 000 women for a dozen years.
Premature ovarian insufficiency (POI) occurs when women under 40 no longer produce eggs because their ovaries have stopped working properly. Periods become irregular and then stop, and some women experience menopause symptoms. It affects 1% of women globally.
In the largest study ever to investigate the link between autoimmune conditions and POI, the scientists suggested that women with POI are twice to three times as likely to develop severe conditions like type 1 diabetes, overactive thyroid, lupus and inflammatory bowel disease, compared with the general population.
Their findings, published in Human Reproduction, significantly strengthen the hypothesis that autoimmune processes play a “pivotal role” in the onset of POI, wrote the authors.
The Guardian reports that for their study, in which they tracked almost 20 000 women for at least 12 years, the academics analysed health data from Finland’s comprehensive registries and identified almost 4 000 women under 40 with a POI diagnosis between 1988 and 2017.
Each was matched with four women of similar ages. They then studied how many developed severe autoimmune conditions between 1970 and 2017. They found that 5.6% of women with POI had been diagnosed with at least one autoimmune disorder before their diagnosis and 12.7% after diagnosis with POI.
Overall, women were 2.6 times more likely to have an autoimmune disease before a POI diagnosis when compared with the control group. These risks varied from nearly double for overactive thyroid glands and rheumatoid arthritis to nearly 26 times for polyglandular autoimmune diseases.
Women with POI who did not have a pre-existing autoimmune condition were nearly three times as likely to be diagnosed with one in the next three years.
These links are likely to be an underestimation, the authors say, because the study only included autoimmune disorders diagnosed in specialist health centres: less severe conditions such as coeliac disease and underactive thyroid glands are often diagnosed and treated in primary healthcare, so the overall prevalence of autoimmune disorders in women with POI is higher.
Dr Susanna Savukoski, a gynaecology and obstetrics doctor at Oulu University Hospital and the University of Oulu, Finland, who led the study, said: “It is important to stress that most women with POI do not develop severe autoimmune conditions, and most women with severe autoimmune diseases do not develop POI. However, medical professionals should be aware of the increased risk, and patients should be informed about it as well.”
As POI threatens fertility, women with an increased risk of the condition should consider trying to conceive when they are young, she said, although some autoimmune diseases could significantly increase the risk of pregnancy complications and should be considered.
The authors want to study the biological mechanisms of POI and autoimmune diseases to help the development of preventive treatments, Savukoski said.
“We are investigating whether long-term use of (hormone replacement therapy) can prevent other conditions developing among women with POI.”
Responding to the findings, Louise Kenny, a professor of maternal and foetal health at the University of Liverpool, said: “POI is poorly understood and devastating. It limits the possibility of young women carrying their own biological child as well as increasing their risk of menopausal-related complications such as osteoporosis.”
New research was needed to confirm the role of the immune system, she added.
Bassel Wattar, an associate professor of reproductive medicine at Anglia Ruskin University, said the research highlighted the need for multidisciplinary and holistic care for women with POI due to the increased risk of long-term health complications.
He added: “This study does not help us to understand the causality of POI and therefore it remains to be answered if it is a consequence of autoimmune disorders or if the lack of ovarian activity can exaggerate an autoimmune response among affected women.”
Study details
Excess of severe autoimmune diseases in women with premature ovarian insufficiency: a population-based study
S M Savukoski, H Silvén, P Pesonen et al.
Published in Human Reproduction on 24 September 2024
Abstract
Question
Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis?
Answer
Women 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 two- to three-fold risk for these diseases for several years after POI diagnosis.
What is known already
It 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
This population-based registry study included 3 972 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, methods
Women 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. Standardised 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 chance
The 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 caution
This 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 findings
Severe 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.
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