Adolescence and puberty are associated with significant physical, physiological, psychological and immunological changes which are initiated and mediated by sex hormones. There is evidence that sex hormones also influence the development and regulation of the immune system(1). Epidemiological studies have shown that pubescent and post-pubescent males and females are at risk of developing autoimmune rheumatic diseases (ARDs) in a sex-biased manner, and that the age at disease onset often differs between sexes(2, 3).
The sex bias in the incidence of autoimmune diseases has long been recognised, with females being at significantly higher risk of developing conditions such as systemic lupus erythematosus (SLE), scleroderma, Sjögren’s syndrome, rheumatoid arthritis (RA), autoimmune thyroid disease, multiple sclerosis (MS), and polyautoimmunity (1, 4). Furthermore, in many ARDs, the average age of disease onset is significantly earlier in females than in males. The female population undergoes at least two major endocrinological changes in their lifetimes: puberty and the menopause, between which there are constant cyclical hormonal changes. Women may also experience pregnancy and breastfeeding. The endocrinological changes at each of these milestones exert effects on both the innate and adaptive immune systems. T-cell autoimmunity in particular has been shown to be upregulated post-puberty in animal models (4); however, there is a limited understanding of the physiological (molecular and cellular) mechanisms for sex-specific immune modulation.
Previous research has observed a relationship between puberty and the onset of various autoimmune conditions. The incidence of SLE, autoimmune thyroid disease, and MS increases in peri- and post-pubescent females, suggesting that sex hormone changes at puberty play an immunomodulatory role in triggering ARD onset and development (4). The prevalence of juvenile SLE (JSLE) in females has been observed to rise from 6.7 per 100,000 at age seven to 34.6 per 100,000 at age fifteen (versus almost zero per 100,000 at age seven and 7.8 per 100,000 at age fifteen in males) (5). The female: male incidence ratio in SLE is most pronounced after puberty and before the menopause (from 2:1 to 6:1 pre-puberty, 7:1 to 15:1 post-puberty, and 3:1 to 8:1 post-menopause) (6, 7) suggesting that the increased sex hormone levels present from puberty to the menopause increase susceptibility to an autoimmune state. Similarly, MS is rarely seen pre-puberty, and the female: male ratio of MS onset in pre-pubertal children is near equal. Post-puberty, MS incidence increases in both sexes with a 2.2:1 female: male ratios (8). Furthermore, there is emerging evidence which links the age at menarche with the risk of autoimmunity in females. Studies have found that an earlier age at menarche increases the risk of RA (9); later age at menarche decreases the risk of MS (10); JSLE is associated with a trend for later onset menarche (11); and the incidence of psoriasis in females increases during the peri-menarchal period (12).
In addition to triggering autoimmunity, sex hormones can influence the outcome of autoimmune diseases. Testosterone is thought to exert a protective effect against the development of autoimmunity. This has been replicated in animal models, which showed protective effects of testosterone in models of both SLE (13) and arthritis (14, 15). Oestriol, a sex hormone that is only detectable during pregnancy, is thought to have a protective effect in MS, and may account for the reduced relapse rates observed during pregnancy (3). Previous research has been directed at understanding the impact of hormonal treatment in autoimmune disease: benefits associated with testosterone treatment have been seen in SLE (16) and arthritis (17); ongoing clinical trials are finding reduced relapse rates with oestriol treatment in MS (18).
Apart from influencing autoimmune disease onset and outcomes, sex hormones impact the physiological development of bones and muscles during puberty (19). This is frequently accompanied by non-specific musculoskeletal symptoms (20), and changes in bone and muscle biomarker levels (21, 22), further complicating the assessment of ARD-related symptoms in teenagers.
No previous systematic reviews have addressed the impact of puberty on disease outcome measures in autoimmune rheumatic diseases, or the impact of ARDs on puberty-related outcomes. Few studies are available that have looked at the epidemiology of ARDs during adolescence or focused on the gender bias in autoimmunity in adolescent populations. Understanding the interplay between the neuroendocrine and immune systems will provide insights into the pathogenesis of the peri-pubertal onset of ARDs and may change the clinical approach to treatment of these patients in the long term.
With this systematic review we aim to elucidate how rheumatological conditions impact puberty, and how physiological changes of puberty influence incidence and manifestations of autoimmune rheumatic diseases.
The objectives of this systematic review are to:
Identify and describe the evidence exploring the bidirectional relationship between puberty and ARDs in adolescence and adulthood;
Determine the strength of such evidence.
We hope that the findings of this review will help to inform policy, practice, and future research priorities in the field of puberty and autoimmunity.