Preservation of Ovarian Tissue and Chemo-Radiotherapy
Condition: Endocrine Disorders of Female Reproductive System; Secondary Infertility; Infertility Involuntary
MeSH terms: Infertility; Endocrine System Diseases
Study type: Interventional

Summary: 
      The purpose of this study is to assess the results of ovarian tissue freezing, such as
      resumption or initiation of menses (menstruation: the discharge of blood and tissue from the
      uterus that happens about every 4 weeks in females who are not pregnant) and pregnancy, prior
      to starting chemotherapy or radiation treatment (commonly used for cancer treatment or for
      other conditions such as multiple sclerosis, psoriasis, rheumatoid arthritis). Females who
      are about to undergo chemotherapy or radiation therapy for cancer or these other medical
      conditions may stop having menses and may not be able to produce a biological child. Girls
      who have not achieved puberty and are exposed to chemotherapy (alkylating agents) or
      radiation treatment, the risk is up to 22-50%. In contrast, girls older than 10 years, or who
      have achieved puberty, experience acute ovarian failure in over 50% of the cases. By freezing
      and preserving ovarian tissue will help prevent these outcomes. In fact, when you are
      considered cured of your disease, you will have another surgical procedure where your own
      ovarian tissue will be transplanted back to you. This surgery will increase the possibility
      of resuming/initiating menses and the chance to have a pregnancy.
    

Detailed description: 
      At the present time, freezing of ovarian tissue is considered experimental and so thawing and
      future use of the tissue to initiate a pregnancy must be performed as part of a research
      program. With the patient's permission, a portion of her ovarian tissue will be frozen for
      her own use and a portion will be donated to a research pool.

      Twenty subjects/year will be participating in this study.

      Participation in this study will last until the patient's ovarian tissue is all used, or the
      patient decides to drop out of the study, or for the rest of her life. Freezing of ovarian
      tissue can be done only for research. Thawing and future use of the tissue to start a
      pregnancy must be done as part of a research program. After the age of 18, the patient will
      decide how and at what institution she wishes to use her own tissue in the future, for the
      purposes of becoming pregnant. The number of visits will be decided by the surgical procedure
      performed. The Investigators will contact the patient by phone, email, or mail until she has
      turned 18 years old, used her tissue or dropped out of the study (whichever comes first) to
      follow the patient's medical and fertility status over time and to ask questions about any
      future use of her frozen tissue and the possible results of the treatment. Depending on the
      patient's age at the time of enrollment, follow-up might be up to 30 years.

      PURPOSE Primary objective: To assess resumption/initiation of menses after surgical ovarian
      preservation (ovarian tissue explant followed by freezing and autologous transplantation).

      Secondary objective: To assess pre- and post-treatment production of various hormones, i.e.,
      anti-mullerian hormone (AMH), insulin-like growth factor-1 (IGF-1), inhibin-B, follicle
      stimulating hormone (FSH), luteinizing hormone (LH), and estradiol, by serum and histological
      measurements.

      Tertiary objective: To assess long-term sexual development, fertility competence, and
      lifespan of ovarian preservation via surgical autotransplant.

      RATIONALE Chemotherapy treatment with alkylating agents and/or total body irradiation will
      prevent normal pubertal development of uterus, ovaries, and breasts because of primary
      ovarian insufficiency (POI). Explant and autologous transplantation of ovarian tissue will
      prevent ovarian insufficiency and allow normal sexual development through puberty and
      fertility competence.

      RESEARCH DESIGN Prospective cohort study.

      STUDY PROCEDURES Subject Recruitment and Screening- Subjects will be recruited by referral
      from the St. Jude Children's Research Hospital (SJCRH) and Methodist-Le Bonheur physicians to
      the Reproductive Medicine clinics held by Dr. Laura Detti. Patients will undergo an informed
      consent process in accordance with St. Jude Children's Research Hospital (SJCRH) and
      Methodist-Le Bonheur Institutional Review Boards.

      Screening Visit- Complete medical history and physical exam; vital signs, height, and weight.
      Psychological Consult on impact of therapy.

      Laboratory testing- Lab results for Estradiol, follicle stimulating hormone (FSH),
      luteinizing hormone (LH), Anti-Mullerian hormone (AMH), Inhibin B, will be obtained from the
      patients' clinical charts. In addition, Electrocardiogram (ECG) (12-lead); Bone age scan (if
      pre-pubertal), Pelvic ultrasound (transabdominal or transvaginal, depending on the patient's
      age) will be obtained from the patients' clinical charts. If a pelvic ultrasound has not been
      obtained prior to surgery, the procedure will be performed under anesthesia prior to the
      patient undergoing surgery for ovarian tissue harvesting).

      Surgical Procedures- Unilateral oophorectomy will be performed by laparoscopy prior to
      undergoing chemo-radiation treatment as specified above. Subsequent ovarian cortex
      autotransplant will be performed by laparoscopy after the patients have been declared cured
      by their physicians.

      Laparoscopic procedures- Upon general anesthesia is induced, attention will be turned to the
      patient's abdomen where 3-4 0.5 cm skin incisions will be performed (one in the umbilical
      fold and 2 lateral incisions; possibly, a 4th suprapubic incision). Disposable, bladed,
      trocars will be inserted in the abdominal cavity. The ovaries will be identified and a
      unilateral oophorectomy will be performed by retroperitoneal clamping/dissection of the
      infundibulo-pelvic and utero-ovarian ligaments.

      A bipolar electrode will be used to assure accurate hemostasis and irrigation will be
      performed as needed. Upon retrieval of the trocars from the abdomen, the skin incisions will
      be reapproximated with 4-0 vycril sutures.

      The second laparoscopic procedure will be done to perform autologous ovarian tissue
      transplant by suturing the thawed cortex fragments to the recipient ovary using 7-0 Prolene
      (Ethicon, Johnson and Johnson, USA), using the technique described by Silber et al. (Silber
      et al., 2005; Silber and Gosden, 2007) applied during laparotomy for transplantation.

      As the transplanted tissue exhausts its function after the 1st autologous transplant, other
      laparoscopic procedures might become necessary over the years to transplant the rest of the
      cryopreserved tissue until no more tissue is available in the cryobank storage.

      Freezing Procedure- The process of vitrification will be started in the Operating Room or in
      the lab within 120 minutes from collection of the sample and will be completed in the
      University of Tennessee Center for Reproductive Medicine laboratory. The tissue will be
      subdivided into numerous vials for individual storage/thawing. This will allow selective
      thawing for autotransplant over multiple procedures, if necessary.

      Embryology laboratory procedures- The ovarian tissue that is stored for the patients will be
      used for autologous transplant. However, other techniques that are performed in the
      embryology laboratory may be available to the patients in the near future and might represent
      the best option for fertility preservation in patients with blood-borne cancers (i.e.:
      leukemia), in whom the risk of re-seeding cancer cells with tissue transplant is high.

      Follow-Up Evaluation- Study treatment will include a post-operative visit and following
      scheduled follow-up visits for the patients' initial disease during which a complete physical
      exam and psychological evaluation will be conducted, and laboratory testing will be obtained
      for follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone
      (AMH), and Inhibin B.

      Visits will be scheduled one month after explant and every 6-12 months until autotransplant
      of tissue and afterwards.

      Laboratory testing, Electrocardiogram (ECG) (12-lead), Bone age, Pelvic ultrasound may be
      repeated yearly, as part of the patient's scheduled follow-ups. Bone age assessment will stop
      when a bone age of 18 years is achieved.

      Patients who are going to develop ovarian insufficiency prior to or after puberty will
      undergo estrogen/progesterone therapy as per our institutional protocols.

      Follow-up will continue until the patient stays enrolled in the study or until she reaches 40
      years of age, or she goes in menopause and does not have, or does not desire, further tissue
      for transplantation.
    

Intervention name(s): surgery
Intervention type(s): Procedure
Intervention description(s): Surgical Procedures- Unilateral oophorectomy will be performed by laparoscopy prior to undergoing chemo-radiation treatment as specified above. Subsequent ovarian cortex autotransplant will be performed by laparoscopy after the patients have been declared cured by their physicians.
Other intervention name(s): surgical removal-ovary, freezing-tissue, autotransplant
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment