Autoimmune conditions

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In the context of autoimmune diseases, women face two major challenges to their reproductive potential. The first is the increased risk of autoimmune oophoritis, in which immune-mediated injury to ovarian tissue accelerates follicular depletion and can lead to premature ovarian insufficiency (POI). The second is the gonadotoxic effect of certain treatments, particularly cytotoxic or immunosuppressive agents such as cyclophosphamide, which may irreversibly compromise ovarian function.

Autoimmune oophoritis

Autoimmune oophoritis is a rare but significant cause of premature ovarian insufficiency (POI), arising from an immune-mediated attack on ovarian tissue that results in follicular loss and endocrine failure [1,2]. It may occur as an isolated condition or in association with systemic and organ-specific autoimmune diseases, including autoimmune thyroiditis, Graves’ disease, Addison’s disease, autoimmune polyglandular syndromes, type 1 diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and celiac disease [3-5].

The pathogenesis of autoimmune oophoritis reflects a breakdown of ovarian immune privilege and local tolerance mechanisms. In susceptible individuals, autoreactive T and B lymphocytes are activated against steroidogenic antigens—including 21-hydroxylase, 17-hydroxylase, and P450 side-chain cleavage enzymes— and also granulosa cell and oocyte-associated epitopes expressed during follicular maturation.  Loss of immune regulation within the ovarian microenvironment leads to immune infiltration triggering a local pro-inflammatory milieu that promotes granulosa cell apoptosis, theca cell destruction, and stromal fibrosis. The results in progressive depletion or preantral follicles at growing stage and functional failure of the organ [2].

Clinically, autoimmune oophoritis manifests with secondary amenorrhea, menopausal-range FSH/LH, low estradiol, and—characteristically in early stages—preserved antral follicles with impaired responsiveness to gonadotropins [1].

Which pathologies are at risk of needing gonadotoxic treatments?

Among autoimmune diseases, the highest fertility risk is due to the use of gonadotoxic agents like cyclophosphamide and it is consistently observed in:

  • Systemic lupus erythematosus (SLE)
  • Autoimmune glomerulonephritis (Lupus Nephritis)
  • Systemic vasculitis (e.g. Wegener’s, polyarteritis nodosa)
  • Rheumatoid arthritis
  • Multiple sclerosis
  • Autoimmune hematological disorders (e.g. autoimmune hemolyitic anemia)

Management and Future Challenges

Although women with autoimmune diseases are at increased risk of developing autoimmune oophoritis and premature ovarian insufficiency, periodic monitoring of ovarian reserve markers such as AMH or antral follicle count is not recommended, as these tests have limited predictive value outside the context of infertility treatment. Current evidence indicates that AntiMüllerian hormone (AMH) and antral follicle count (AFC) reflect the quantitative ovarian response to stimulation in IVF settings, but do not reliably predict the timing or likelihood of ovarian failure in otherwise healthy or at-risk women (according to ESHRE and ASRM guidelines). Therefore, ovarian-reserve testing should be reserved for specific clinical indications, such as fertility preservation counseling prior to gonadotoxic therapy or evaluation of menstrual irregularity suggestive of declining function, rather than used for routine surveillance in autoimmune populations.Fertility preservation should be discussed proactively with an integrated counselling of rheumatology, reproductive endocrinology, and fertility preservation specialists, ideally before the onset of amenorrhea or initiation of gonadotoxic therapy. Oocyte cryopreservation after controlled ovarian stimulation remains the standard and most effective option, provided sufficient follicular responsiveness to FSH can be achieved. However, in autoimmune oophoritis or in cases showing FSH resistance with persistent small antral follicles, in-vitro maturation (IVM) may represent a valuable emerging alternative. The first live birth from IVM in autoimmune POI was reported in 2020, highlighting that competent oocytes can sometimes be retrieved and matured even in the setting of apparent ovarian failure [1].

Once ovarian failure is established, hormone replacement therapy is essential for bone and cardiovascular long-term protection.

 

References:

1. Grynberg M, Jacquesson L, Sifer C. In vitro maturation of oocytes for preserving fertility in autoimmune premature ovarian insufficiency. Fertil Steril. 2020;114(4):848-853.

  1. 2. Cacciottola L, Camboni A, Dolmans MM. Immune system regulation of physiological and pathological aspects of the ovarian follicle pool throughout the female reproductive lifespan. Hum Reprod. 2025;40(1):12-22.
  2. 3. Stamm B, Barbhaiya M, Siegel C, Lieber S, Lockshin M, Sammaritano L. Infertility in systemic lupus erythematosus: what rheumatologists need to know in a new age of assisted reproductive technology. Lupus Sci Med. 2022;9(1):e000840.
  3. 4. Leavitt M, Adeleye A, Edens C. Preserving Fertility in People With Rheumatic Diseases. J Clin Rheumatol. 2024;30(7S Suppl 1):S13-S24.
  4. 5. Notaro ALG, Lira Neto FT, Bedoschi GM, et al. Evaluation of ovarian reserve in women with thyroid autoimmunity. JBRA Assist Reprod. 2024;28(3):442-449. Published 2024 Jun 28.
  5. 6. Saito S, Yamada M, Yano R, et al. Fertility preservation after gonadotoxic treatments for cancer and autoimmune diseases. J Ovarian Res. 2023;16(1):159. Published 2023 Aug 10.

 

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