Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy

Background: Premature ovarian failure (POF) is a common long-term consequen ce of chemotherapy. Whereas the cytotoxic-induced damage is reversible in o ther tissues of rapidly dividing cells such as bone marrow, gastrointestina l tract and thymus, it appears to be progressive and irreversible in the ov ary, where the number of germ cells is limited, fixed since the fetal life, and cannot be regenerated. The gonadal toxicity of cyclophosphamide is wel l known. In patients with lupus nephritis, premature ovarian failure (POF) was reported in half of all treated women after cyclophosphamide pulse ther apy, affecting 100% of those older than 30 y, about 50% of the patients bet ween the ages of 20-30 y and only 13% of the patients younger than 20 y of age. Following our preliminary encouraging experience in women with lymphom a, whereby the temporary induction of a prepubertal hormonal milieu, during chemotherapy, has significantly decreased the risk of POF, we have adminis tered a monthly injection of gonadotropin-releasing hormone agonistic analo gue (GnRH-a) to eight young women in parallel to alkylating agent chemother apy. Materials and methods: A monthly intramuscular depot injection of 3.75 mg D -TRP6-GnRH-a (Decapeptyl C.R.) was administered after informed consent to e ight women with autoimmune, severe connective tissue diseases (seven SLE pa tients and one woman with nephrotic syndrome) in parallel to chemotherapy, for up to six months. The institutional committee for human experimentation approved the protocol. The concentrations of FSH, LH, progesterone, and 17 -beta-estradiol (E2) were measured before, during and after the GnRH-a/chem otherapy treatment. A transvaginal (or transabdominal) sonography (TVS) was performed on each patient before and after treatment. These eight treated patients (study group) were compared to a group of nine women similarly tre ated by cyclophosphamide pulses (CPT) or chlorambucil for SLE/connective ti ssue disease but were not referred for the GnRH-a adjuvant treatment. Results: Whereas none of the right women receiving GnRH-a in parallel to al kylating agent chemotherapy (cyclophosphamide (7) or chlorambucil (1)) suff ered POF and hypergonadotropic amenorrhea, five of the nine ( > 50%) patien ts treated by alkylating agents (cyclophosphamide (8) or chlorambucil (1)) experienced POF. Whereas two of these five women were 35 y old, the other t hree were less than or equal to 23 y old at the rime of the chemotherapeuti c insult. Conclusions: Our present results, extrapolating this encouraging experience from hematological malignant diseases to severe connective tissue diseases , such as SLE associated nephropathy or others, suggests that the beneficia l effect of GnRH-a co-treatment may be exploited towards preservation of fu ture fertility and ovarian function in every young woman of reproductive ag e, exposed to alkylating agents, such as cyclophosphamide and chlorambucil.