First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn's disease and 6-mercaptopurine chemotherapy

E. Scott Sills, Michael J. Tucker

Asian J Androl 2003 Mar; 5: 76-78             

Keywords: 6-mercaptopurine; chemotherapy; infertility; ICSI

Abstract

Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercaptopurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.

1 Introduction

ICSI has been used to treat an impressive array of male factor infertility etiologies [1], but thus far there have been no recorded births from ICSI using spermatozoa from oligozoospermic men with severe Crohn's disease and 6-MP immunosuppression. The impact 6-MP therapy may have on human semen parameters is controversial and remains incompletely characterized. Additionally, there is limited information available for counseling patients who suffer from this disease with regard to future reproductive potential. Here we present the first known successful case of ICSI applied in this clinical setting.

2 Case report

A non-smoking couple sought reproductive endocrinology evaluation at our center following approximately one year of secondary infertility. The woman was 30 years old and in good general health (BMI=31 kg/m²); her two previous spontaneous conceptions were established with the current partner over the three-year interval just prior to referral. The first pregnancy ended in spontaneous abortion at the 9th gestational week and the second resulted in the term vaginal delivery of a healthy male infant. About one year before their infertility evaluation, the husband (age 31) underwent a three-month course of 6-mercaptopurine (6-MP) for chronic Crohn's disease. Chemotherapy proceeded without complication with full remission of gastrointestinal symptoms. No other antimetabolite therapy was administered during this period. Because the two conceptions had been established without medical assistance, a semen analysis was not performed. However, during infertility evaluation at our institution, semen analysis one year after 6-MP exposure revealed an overall sperm concentration of 8,000/mL and 90 % total motility (forward progressive motility = 20 %). Morphology could not be precisely assessed due to insufficient sample. Serum testosterone was 271 ng/dL (low-normal).

Intrauterine insemination with donor sperm was declined and the couple elected in vitro fertilization with ICSI. Planned pretreatment evaluation of the husband included sperm chromatin structure assay [2], but the sperm concentration was too low for complete characterization of DNA fragmentation. The couple was encouraged to select anonymous donor sperm for use in the event that an unsuitable fresh specimen was produced on the day of planned oocyte retrieval. Ovarian reserve was determined as described previously [3].

Controlled ovarian hyperstimulation was undertaken using a combined rec-FSH + hMG protocol following late luteal pituitary downregulation [4]. After an uncomplicated 12-day follicular recruitment phase, the terminal serum estradiol was 1871 pg/mL and serum luteinizing hormone was 0.63 mIu/mL. Periovulatory hCG (10,000 IU) was administered subcutaneously [5] when sonographic findings suggested follicular maturity.

On the day of transvaginal oocyte aspiration, the husband produced a fresh 5.1 mL ejaculate with sperm concentration of approximately 10,000/mL and forward progressive motility of 15 %. Eighteen oocytes were retrieved and 11 of these were mature and advanced to the 2pn stage following ICSI. Anonymous donor sperm was not utilized. Assisted embryo hatching [6] was performed on three good quality 8-cell embryos and these were transferred three days later under direct transabdominal sonographic guidance via coaxial Frydman catheter (Laboratoire CCD, Paris, France). Four supernumary blastocysts were of sufficient quality for cryopre-servation. Supplementary progesterone followed a transmucosal protocol [7].

Seventeen days after embryo transfer, the serum hCG titer was 712 mIu/mL. On cycle day #50, a single intrauterine pregnancy with cardiac rate of 173/min was identified by transvaginal ultrasound. Following an uncomplicated obstetrical course including a normal genetic amniocentesis at 16 weeks, the patient was delivered of a 3288 g male infant (Apgar 8/9 at 1 and 5min, respectively) at 39 5/7 weeks gestation. Neonatal examination revealed no hypospadias or other urogenital anomaly. Six months after delivery, the mother and the baby continue to do well.

3 Discussion

Crohn's disease is a chronic, recurrent inflammatory condition that can involve any of the digestive system's deep mucosal tissues, from mouth to anus. The disease affects males and females in equal proportion and may be immunologically mediated. As Crohn's disease may affect the entire gastrointestinal tract, it is commonly associated with hypoproteinemia, caloric and vitamin deficiencies and a generalized undernourished state. Treatment is based on management of specific symptoms present in each case and typically includes control of inflammation, correction of nutritional inadequacies and relief of discomfort from diarrhea and abdominal cramping. In mild Crohn's disease, these therapeutic goals may be achieved by anti-inflammatory drugs or steroids, but for refractory cases, immunosuppressants (i.e., 6-mercaptopurine [6-MP]) are frequently required.

As an inhibitor of nucleic acid synthesis, 6-MP is a purine analog and potent immunosuppressant used to treat Crohn's disease over the last 20 years [8]. Although G2 arrest has been observed when cells are exposed to many anti-tumor agents, the exact mechanism of action for 6-MP is not known. In vitro research [9] has suggested the delayed cytotoxicity of 6-MP may result from substitution of 6-thioguanide (6TG) into DNA as a thioguanide nucoleotide (TGN). Despite these data and the theoretical risk for disrupted gametogenesis in humans, several clinical studies have shown that semen parameters may not be adversely affected by 6-MP therapy[8]. In some cases, the deleterious reproductive effects of 6-MP appear related to chromatid aberrations or deletions [10] with varying individual susceptibility.

For this patient, a comparison analysis of semen parameters before 6-MP administration would have been helpful, but pre-treatment fertility was probably normal in the three years just prior to 6-MP use when the two spontaneous conceptions were established. Whether the relationship between 6-MP and oligozoospermia is causative or associative in our patient cannot be known with certainty since the Crohn's disease process itself has been shown to influence semen parameters in some men with this disorder. Nevertheless, in this case (perhaps for reasons intimated above), the sperm concentration was profoundly reduced after immunosupressive therapy, necessitating either intrauterine insemination with donor sperm or IVF with ICSI.

As the curtain falls on the first decade of clinical experience with ICSI, its place in the treatment of severe oligozoospermia is now well-established. The full range of male factor etiologies satisfactorily treated with ICSI has yet to be cataloged. For men with lymphoma or other conditions requiring chemotherapy, recent advancements in IVF using surgically-retrieved spermatozoa for ICSI have enabled some couples to establish pregnancies with their own gametes [11]. As an extension of these developments, our report is the first to describe the successful implementation of ICSI specifically in the context of Crohn's disease and 6-MP associated oligozoospermia with a satisfactory reproductive outcome. It should be noted that after 6-MP immunosuppression, clinically important post-chemotherapy semen parameter changes may not always manifest. Yet, for those men with Crohn's disease who do experience impaired fertility (related either to the condition itself or its chemo-therapy), this report depicts another clinical setting where ICSI represents a safe and effective treatment.

References

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Correspondence to: Dr. E. Scott Sills, Georgia Reproductive Specialists LLC, Suite 270, 5445 Meridian Mark Road, Atlanta, Georgia 30342, USA.
Fax +1-404-843 0812
E-mail: dr.sills@ivf.com
Received 2002-10-10   Accepted 2002-12-17