Background: Premature ovarian failure (POF) is a common long-term consequence of chemotherapy. Whereas the cytotoxic-induced damage is reversible in other tissues of rapidly dividing cells such as bone marrow, gastrointestinal tract and thymus, it appears to be progressive and irreversible in the ovary, where the number of germ cells is limited, fixed since the fetal life, and cannot be regenerated. The gonadal toxicity of cyclophosphamide is well known. In patients with lupus nephritis, premature ovarian failure (POF) was reported in half of all treated women after cyclophosphamide pulse therapy, affecting 100% of those older than 30 y, about 50% of the patients between 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 lymphoma, whereby the temporary induction of a prepubertal hormonal milieu, during chemotherapy. has significantly decreased the risk of POF, we have administered a monthly injection of gonadotropin-releasing hormone agonistic analogue (GnRH-a) to eight young women in parallel to alkylating agent chemotherapy. 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 eight women with autoimmune, severe connective tissue diseases (seven SLE patients 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-β-estradiol (E2) were measured before, during and after the GnRH-a/chemotherapy 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 treated by cyclophosphamide pulses (CPT) or chlorambucil for SLE/connective tissue disease but were not referred for the GnRH-a adjuvant treatment. Results: Whereas none of the eight women receiving GnRH-a in parallel to alkylating agent chemotherapy (cyclophosphamide (7) or chlorambucil (1)) suffered POF and hypergonadotropic amenorrhea, five of the nine (> 50%) patients treated by alkylating agents (cyclophosphamide (8) or chlorambucil (1)) experienced POF. Whereas two of these five women were 35 y old, the other three were 23 y old at the time of the chemotherapeutic 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 beneficial effect of GnRH-a co-treatment may be exploited towards preservation of future fertility and ovarian function in every young woman of reproductive age, exposed to alkylating agents, such as cyclophosphamide and chlorambucil.