Systemic Lupus Erythematosus (SLE)

Many women with SLE experience menstrual disturbances ranging from amenorrhoea to menorrhagia[4]. Women who receive anti-coagulation therapy for thrombotic complications may experience menorrhagia. Amenorrhoea may occur as the result of cyclophosphamide (CYC) treatment, which can cause ovarian failure, but also as a result of the disease itself. Amenorrhoea in women with SLE is also associated with anti-corpus luteum antibodies with raised FSH levels, suggestive of an autoimmune-SLE related menstrual dysfunction[5]. Pasoto et al. (2002) found 53% of adult women under the age of 40 years with SLE had menstrual irregularity in the absence of alkylating agents[6]. Those with high disease activity were found more likely to have menstrual disturbances than those with less disease activity

Reproductive System Impairment

Impairment of the reproductive system of women with SLE may result due to disease activity, autoantibodies, and through iatrogenic cytotoxic treatments[7-8]. Impairment of the reproductive system may cause:

• problems preventing successful fertilization thus leading to infertility
• obstacles in effective implantation to the uterine wall
• difficulties in maintaining pregnancy post-implantation
• complications during labor

Drug-Related Infertility

Despite improvements in the treatment options for SLE, the disease can be therapeutically challenging for rheumatologists. Patients with acute exacerbations with severe organ manifestation may need cyclophosphamide (CYC). CYC is an alkylating chemotherapeutic agent shown to cause premature ovarian insufficiency (POI) and deplete healthy oocytes[7,9]. It’s toxicity is associated with many secondary risk factors, including: the cumulative dose of CYC, the age at which the drug is administered, history of thyroid disease, disease duration, and presence of anti-Ro and anti-U1RNP antibodies[7,9-10]. Therefore, CYC should be prescribed at the lowest effective dose possible and for the shortest duration, particularly in older women. Boumpas et al. (1993) found that 17% of patients under age 25 years with > 15 cycles of CYC developed POI. Of those over the age of 30 years, 100% developed POI[11].

Antiphospholipid Antibody syndrome (APS) 

Approximately 30% of women with SLE also have Antiphospholipid Antibody syndrome (APS), or Hughes’ syndrome. Traditionally, APS is known for causing spontaneous abortions, stillbirths, and premature births. However, APS can lead to venous and arterial thrombotic events, which may restrict the blood supply to reproductive organs, thereby affecting fertility. APS should be considered a risk factor for infertility in women with SLE[4].

Lupus Nephritis 

Approximately 30-75% of women with SLE, dependent on ethnic and racial background, develop Lupus nephritis- chronic renal failure. Women with chronic renal failure are likely to develop infertility through hypothalamic-pituitary dysfunction, because renal failure and/or haemodialysis tend to raise prolactin levels- which reduces the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. Women with Lupus nephritis tend to have menstrual irregularity with anovulatory cycles[4].

Leuprolide, a gonadotrophic receptor hormone (GnRH) agonist, is protective against POI when administered 10-14 days before each CYC pulse. Leuprolide causes a drastic reduction in oestrogen and progesterone levels, which significantly reduces the risk of POI in patients with SLE from 30% to 5%[15].

GnRH agonists

Oocyte or Embryo Cryopreservation

Ooctyte and embryo cyropreservation are the most effective methods to preserve fertility, however in women with SLE hormonal manipulation may trigger exacerbation of SLE as a result of raised oestrogen levels following ovarian stimulation. Exogenous oesterogen therapy is also associated with an increased risk of thrombosis. The safest approach is to avoid overt ovarian hyperstimulation syndrome (OHSS) and administer co-adjuvant therapy and use of natural E(2) or P through non-oral route[7].

Ooctye Cryopreservation

Embryo Cryopreservation

Ovarian Tissue Cryopreservation

One entire ovary is removed surgically and the outer surface (cortex), which contains the eggs, is frozen in strips for later use. Women who have underwent CYC can have pieces of the tissue thawed and transplanted back. A number of pregnancies have resulted from using this technique.

Ovarian Tissue Cryopreservation

SLE patients are young and have an excellent response to treatment as well as long-term survival. The Henes et al. (2012) FertiPROTEKT study enrolled 68 women with SLE, with an average patient age of 25 and 91.2% of participants did not have children. Of the 68 women enrolled, only 5 chose not to preserve fertility prior to CYC treatment. Of those who did elect to preserve fertility, 91.2% had GnRH analogue treatment and 25% cryopreserved ovarian tissue, of which 4.4% retrieved and froze oocytes. Henes et al. (2012) made fertility preservation recommendations for women with SLE based on study results and literature review:

• All women after menarche and less than 40 years of age who receive CYC for SLE or any autoimmune disease should be counseled by a docor trained in reproductive medicine on fertility preservation methods, in agreement with a responsible rheumatologist.
• Use of GnRH analogues prior to CYC treatment can be recommended for all patients up to the age of 40 years.
• GnRH administration can be combined with ovarian tissue cryopreservation, especially in patients under the age of 35 years.
• Stimulation therapy and subsequent cryopreservation of oocytes or embryos should be critically evaluated. In the case of advanced age and urgent desire to conceive, as well as maintained by disease activity and associated diseases, this method is still the most effective at preserving fertility.