Role of vasculitis in fertility

Vasculitides such as granulomatosis with polyangiitis (GPA), polyarteritis nodosa (PAN) or Behçet’s disease rarely involve female reproductive organs . Functional neuroendocrine dysregulation of the hypothalamic–pituitary–ovary axis is possible, as in any stressful situation, but is usually transient . In men, orchitis (or epididymo-orchitis) is a classic manifestation of PAN but can also be observed in GPA (due to granulomatous inflammation and ischaemia), Behçet’s disease or IgA vasculitis (IgAv; Henoch–Schönlein purpura) . Intra-testicular inflammation is usually reversible with treatment, with no overt clinical consequences, but testicular ischaemic necrosis is possible . In a study of 19 GPA patients, more than half had some biological evidence of hypogonadism (defined by an increase in follicle-stimulating hormone >2 times the upper reference limit and low serum testosterone level), regardless of previously received treatment.

Impact of previous (cytotoxic) treatments

CYC is the most potent drug used to treat vasculitis but is associated with high risk of inducing infertility or subfertility in 20–85% of women of childbearing age depending on the cumulative dose received and the patient age . The cumulative dose of CYC associated with premature ovarian failure in women (without vasculitis) decreases with increasing age: 20.4 g for women 20–30 years old, 9.3 g for women 30–40 years old and only 5.2 g for women older than 40 years . This finding is due to the reduced number of viable oocytes at the time of therapy. Thus, receipt of 12 g CYC at age 38 years does not have the same impact as at age 18 years, but the exact dose above which subfertility can occur in an individual patient cannot be accurately determined. The anti-Müllerian hormone (AMH) level has recently been found to be a potential marker of ovarian reserve in women with subfertility . In this study of 42 women with GPA, changes in AMH level were inversely correlated with cumulative CYC dose, with a 0.74-ng ml ⁻¹ decrease in level for each 10 g CYC consumed. However, further trials are required to ascertain how accurately AMH level can be used to assess fertility and estimate the risk of CYC-induced infertility in vasculitis.

The detrimental impact of CYC on fertility is a concern for men. Sterility, subfertility, and oligo- or azoospermia were observed in 50–90% of men previously given CYC . There is an age-dependent association with reversibility of CYC impact, with men younger than 40 years more likely to recover from oligo- or azoospermia with discontinued CYC therapy .

Other drugs used to treat vasculitides and/or during specific treatment phases do not seem responsible for subfertility or infertility; these drugs include corticosteroids, colchicine, azathioprine (AZA), mycophenolate mofetil (MMF), leflunomide, tumour necrosis factor α (TNF-α) blockers or anti-CD20 monoclonal antibodies (rituximab, RIT) . A few reports for conditions other than vasculitis suggest that methotrexate (MTX) may induce reversible oligospermia .

Gonad preservation and treatment options for sub- and infertility

For severe forms of systemic vasculitis, especially vasculitis associated with autoantibodies directed against anti-neutrophil cytoplasmic antibody (ANCA) or PAN with factor(s) of poor prognosis , treatment with the combination of corticosteroids and CYC remains the gold standard. AZA and MTX or MMF are considered less potent and are not considered first-line induction immunosuppressants for such severe/systemic forms . For adults with severe GPA and microscopic polyangiitis (MPA), the only alternative to CYC, when indicated and as approved by the US Food and Drug Administration in April 2011, is RIT. Published data are insufficient for children, and only case reports or small series of RIT for some other vasculitides have been reported. Whether RIT is preferred over CYC for young patients should be based on individual patient characteristics and treatment history. RIT seems to be a better choice to preserve fertility in a 25-year-old GPA patient who had previously received 25 g CYC and is experiencing a severe vasculitis relapse but could be debated for an 18-year-old patient just diagnosed with severe GPA and with no other contraindication for CYC use.

For male patients, cryopreservation of sperm (i.e., sperm banking) should be suggested before the initiation of CYC. This procedure is typically easy to arrange within a timely manner and is cost effective. For women, cryopreservation of oocytes, ovarian tissue (or strips) and/or embryos are potential options. In general, cryopreservation of embryos is preferred, due to increased tissue stability. However, it should be noted that these practices are expensive and restricted to a few specialised centres. Furthermore, it is not often possible to consider cryopreservation prior to the initiation of CYC due to the urgent need to treat the vasculitis . The use of progesterone, in forms such as long-acting depot medroxyprogesterone acetate and the combined oral contraceptive pill, at least during active vasculitis and initial treatment phases, may reduce the risk of infertility induced by CYC. This is postulated to occur by decreasing ovarian activity and thus exposure to the cytotoxic drug. Analogues of gonadotropin-releasing hormone (GnRHa), such as leuprolide acetate for depot suspension, may be effective in blocking, at least in part, menstrual cycles and limiting CYC diffusion into ovaries. This in turn would help to preserve ovarian function . However, GnRHa side effects include menopausal symptoms and depression. Furthermore, the initial increase in gonadotrophin level is associated with transient ovarian stimulation and thus sensitivity to CYC, before its down-regulation and suppression effects. GnRH antagonists such as cetrorelix are an option because they compete directly with GnRH binding to GnRH receptors. The initial surge in gonadotrophin level seen with GnRH agonists is absent with GnRH antagonists. GnRH agonists and antagonists can also be used in combination after ovarian tissue cryopreservation . However, despite their efficacy with chemotherapy co-treatment in ovarian function preservation, their impact on subsequent pregnancy rates is unknown . For subfertile women, ovarian stimulation for in vitro fertilisation is possible with no overt risk or additional cautions than in other populations; isolated cases of venous thrombosis, including of the jugular veins, necrotising ovarian vasculitis or allergic cutaneous vasculitis following ovarian stimulation have been reported .