Alterations of the Female Reproductive System in Islet Recipient Receiving Immunosuppression

Abstract

Pancreatic islet allotransplantation is an option for patients with unstable type 1 diabetes mellitus (T1DM). Major improvements in islet isolation techniques and the implementation of steroid-free immunosuppressive regimens can maintain insulin independence in the majority of T1DM for at least 1 year after transplantation. Recent studies have emphasized the impact of sirolimus on female reproductive tract. In this communication we report on the alterations of the female reproductive tract in 18 chronically immunosuppressed patients with T1DM following allogenic islet transplantation. Previous research has shown development of ovarian cysts in islet transplant patients receiving sirolimus. We extensively reevaluated this and other possible side effects on the female reproductive system. These side effects have been underestimated, although they are significant, requiring surgical or intensive medical treatment. Pre- and posttransplant gynecological evaluation should be performed to address the development of complications secondary to sirolimus in order to intervene sooner with alternative therapies.

Islet transplantation in selected type 1 diabetes mellitus (T1DM) patients has proved to be an alternative therapy. Transplantation protocols are currently safer and allow higher survival rates of both graft and recipients, thanks to the implementation of novel organ procurement and transplantation procedures and to improvements in the management of immunosuppressive drugs (4).

Recent studies have emphasized a potential impact of immunosuppression on female reproductive tract. There has been reported a high prevalence of ovarian cysts in women undergoing islet transplantation and receiving tacrolimus and sirolimus (1,3). On the other hand, menstrual changes after organ transplantation have been recognized, including different patterns from normal oligomenorrhea, and amenorrhea. These alterations have been considered as minor adverse secondary effects of the drug but may have a significant impact, as they may require surgical or intensive medical treatment.

Until the present day, pathological changes of the reproductive system in islet transplantation patients treated with new immunosuppressive drugs are still poorly documented and probably underestimated. In the present study we report an update on the alterations of the female reproductive tract in chronically immunosuppressed patients with T1DM following allogenic islet transplantation at our center (3).

From 2000 to 2009, a total of 18 subjects with T1DM underwent allogeneic transplantation at our center using a steroid-free immunosuppressive protocol that included the use of sirolimus.

The mean age at the moment of transplant was of 48.5 (8.00) years with a mean duration of T1DM of 33.81 (10.13) years. They were followed during a mean time after the transplant of 7.9 (1.13) years.

Sirolimus was given orally pretransplant at 0.2 mg/ kg and then adjusted to achieve trough levels of 12–15 ng/ml for the first 90 days and 7–12 ng/ml thereafter.

Data from the patients were collected using a web-based electronic case record form. Peritransplant gynecological surveys were taken, including age of menarche and menopause; menstrual pattern that included duration, interval, and dysmenorrheal symptoms; obstetrical and surgical gynecological history, metrorrhagia, and history of adnexal and uterine masses. Patient evaluation included serial pelvic ultrasounds to evaluate the adnexa and uterus.

Statistical analysis was conducted using SAS 9.2. Categorical data are reported as proportions and continuous data as mean values with standard deviation. Paired outcome variables pre- and posttransplant were compared with McNamar's test for dependent proportions, and Wilcoxon rank sign tests. A Type 1 error rate 0.05 was used to determine significance.

De novo formation of ovarian cysts were observed posttransplant after initiation of immunosuppression in 10 of the subjects (p = 0.01). The cysts were either unilateral or bilateral cysts (56%). Five of the patients with history of ovarian cysts presented recurrency throughout the follow-up. All of the cysts were benign, but eight of them were considered complex because of size (>6 cm), hydrosalpinx, haemorrhage, spontaneous rupture causing abdominal pain, or the need of surgery for the resolution. Four of the subjects (40%) underwent surgical treatment because of poor response to medical treatment that required cystectomy. One of the patients developed a unilateral complex cyst that resolved surgically and 2 years later she presented new cysts with benign characteristics that responded to medical treatment.

Menstrual cycle abnormalities increased in the post-transplant period, although they resulted nonsignificant (p < 0.065). Five of the patients that presented regular cycles at baseline developed oligomenorrhea or amenorrhea after the transplant. None of the patients presented metrorrhagia before the transplant but six of them (33.3%) developed it posteriorly (p = 0.03). The metrorrhagia was attributed to dysfunctional uterine bleeding (n = 3), cervical polyposis (n = 1), or miomatosis (n = 2). Of these six patients, two underwent endometrial ablation and other two hysterectomy.

Since the immunosuppressant treatment was started, a total of eight surgical major procedures (44.4%) were necessary to resolve the gynecologycal abnormalities in our cohort. About 50% of all of the subjects had to start combined estrogen-gestagen or gestagen alone treatment during their follow-up with regular response.

The long-term effects of chronic immunosuppression have an important impact on the management of transplanted patients. They have numerous side effects that are a major concern for the physicians such as infections, higher incidences of de novo malignancies, or metabolic alterations. The incidence of gynecological abnormalities, considered as minor side effects, has proved to be high not only in incidence but also in complexity. About 44.4% of the patients in our cohort required gynecological surgery in their follow-up, one third developed metrorrhagia and/or menstrual irregularities, and two thirds developed ovarian cysts.

Other alternative agents that do not include sirolimus are being used in islet transplantation but the number of cases too low to make any comparison. As reported in the CITR (2) approximately 4% (12/347) of the subjects undergoing islet transplantation do not use sirolimus as immunosuppressive agent. We recognize that one of the weaknesses of this study is the lack of a cohort of subjects with long-term type 1 diabetes or other organ transplants under sirolimus immunosuppression to compare with our findings. The preferential use of sirolimus in islet transplantation and the higher trough levels achieved may be responsible for the increased incidence of alterations in the reproductive system. There is no literature on sirolimus and alteration of the female reproductive system in subjects receiving other organ transplants.

Pre- and posttransplant gynecological evaluation should be performed, including a serial pelvic ultrasound, paying attention especially to the development of ovarian cysts or uterine bleeding as the morbidity of these diseases is high and their consequences may be significant.