tacrolimus and Infertility--Female

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.

Topics: Dose-Response Relationship, Drug; Endometrium; Female; Humans; Infertility, Female; Insulin Resistance; Polycystic Ovary Syndrome; Pregnancy; Tacrolimus; Uterine Diseases

Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility.. This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously.. Japan Registry of Clinical Trials (jRCT; jRCTs031220235).

Topics: Abortion, Spontaneous; Adult; Embryo Transfer; Female; Fertilization in Vitro; Humans; Infertility, Female; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Tacrolimus

What are the pregnancy outcomes after the OPtimization of Thyroid function, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)?. The 116 women with RIF after the OPTIMUM treatment strategy were 38.3 ± 3.8 years old and had an implantation failure history over 5 (3-19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged < 40 and ≥ 40 years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control.. The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.

Topics: Adult; Anti-Bacterial Agents; Anticoagulants; Aspirin; Autoantibodies; Embryo Implantation; Endometritis; Female; Humans; Immunosuppressive Agents; Infertility, Female; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Retrospective Studies; Risk Factors; Tacrolimus; Th1 Cells; Th2 Cells; Thrombophilia; Thyroid Diseases; Thyrotropin; Thyroxine; Vitamin D; Vitamin D Deficiency; Vitamins

Many approaches have been used to achieve successful pregnancies in patients with infertility, though existing treatments remain unsatisfactory in patients with infertility caused by abnormal maternal-fetal immunity. However, our understanding of the immunological aspects of infertility has steadily progressed, aided by recent research into organ transplantation and cancer. The results of these recent analyses have led to the development and evaluation of several candidate immunological treatments, but the use of immunological treatments remains a novel approach. The current paper presents the hypothesis that tacrolimus may have potential as a candidate agent for the treatment of maternal-fetal immunity-related infertility.

Topics: Biomarkers; Female; Humans; Immune Tolerance; Immunity, Maternally-Acquired; Immunosuppressive Agents; Infertility, Female; Maternal-Fetal Exchange; Models, Immunological; Placenta; Pregnancy; Tacrolimus

Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?. Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used.. UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks.. Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated.. The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity.. This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection.. The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed.. The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Topics: Adrenal Cortex Hormones; Animals; Antilymphocyte Serum; Disease Models, Animal; Drug Therapy, Combination; Feasibility Studies; Female; Graft Rejection; Graft Survival; Immunosuppression Therapy; Induction Chemotherapy; Infertility, Female; Living Donors; Maintenance Chemotherapy; Mycophenolic Acid; Papio; Tacrolimus; Transplantation, Homologous; Uterine Diseases; Uterus

Uterus transplantation may become the first available treatment for uterine factor infertility, which is due to the absence or malfunction of the uterus. Here we describe for the first time pregnancy after allogeneic uterus transplantation, as a proof of concept of uterine function in a transplanted uterus in a standardized animal model (rat) under immunosuppression.

Topics: Animals; Female; Fertility; Graft Rejection; Immunosuppressive Agents; Infertility, Female; Male; Pregnancy; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Tacrolimus; Transplantation, Homologous; Uterus