Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation
Condition: Pregnancy; Unexplained Infertility
MeSH terms: Infertility
Intervention: Letrozole (aromatase inhibitor); Clomiphene Citrate; Follicle Stimulating Hormone (gonadotropin)
Intervention description: A daily dose of 5 mg of the AI, letrozole, will be administered orally for five days starting on day three of the menstrual cycle. Future cycles can be started at 2.5-7.5 mg/d. FDA approval (IND) will be obtained.; CC will be administered at a dose of 100 mg/d on cycle days 3-7. Future cycles can be started at 50-150 mg/d.; A daily injection of 150 IU of FSH will be administered subcutaneously starting on day three of the menstrual cycle and continuing until the day of hCG administration. Dosage will be able to be increased or decreased 37.5-75 IU/d beginning cycle day 7. Future cycles can be started at doses ranging from 75-225 IU/d. The same type of FSH injections will be used.
Intervention MeSH terms: Letrozole; Clomiphene; Enclomiphene; Zuclomiphene; Hormones; Follicle Stimulating Hormone; Aromatase Inhibitors
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 900.0
Sex: Female
Minimum age: 18 Years
Maximum age: 40 Years
Healthy volunteers: No
Keywords: Pregnancy; Infertility; Ovarian stimulation; Aromatase inhibitors; Follicle Stimulating Hormone

Summary:

      The objective of this application is to identify a pharmacologic agent which helps couples in
      whom the female partner ovulates regularly successfully obtain their goal of delivering a
      healthy child, whose use will result in low rates of multiple gestations. The central
      hypothesis is that, in infertile ovulatory women undergoing ovarian stimulation (OS) and
      intrauterine insemination (IUI), the use of aromatase inhibitors (AI) will stimulate the
      ovaries sufficiently to produce no reduction in the rate of pregnancy, while significantly
      reducing the numbers of multiple gestational pregnancies that result from stimulation with
      clomiphene citrate (CC) or follicle stimulating hormone (FSH). The rationale for the proposed
      research is that reduction of multiple pregnancy rates could significantly reduce maternal
      and neonatal morbidity and mortality, as well as the cost of healthcare for these individuals
      and society.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Women ≥18 to ≤40 years of age, with one or more years infertility history, desirous of
             conceiving, regularly ovulating (defined as 9 or more menses per year), at initiation
             of participation.

          2. Normal uterine cavity and at least one open fallopian tube confirmed by
             hysterosalpingography (HSG), sonohysterography, or laparoscopy/hysteroscopy in the
             last three years preceding enrollment into the study. An uncomplicated intrauterine
             non-IVF pregnancy and uncomplicated delivery and postpartum course resulting in live
             birth within the last three years will also serve as sufficient evidence of a patent
             tube and normal uterine cavity as long as the subject did not have, during the
             pregnancy or subsequently, risk factors for Asherman's syndrome or tubal disease or
             other disorder leading to an increased suspicion for intrauterine abnormality or tubal
             occlusion.

          3. Evidence of ovarian function/reserve as assessed by day 3 (+/-2 days) FSH ≤12 IU/L
             within one year prior to study initiation.

          4. Normal or corrected thyroid function within one year of study initiation.

          5. Normal prolactin level within one year of study initiation.

          6. In general good health, not taking any medications which could interfere with the
             study (e.g., FSH, insulin sensitizers).

          7. Ability to have inseminations following hCG administration.

          8. Male partner with total motile sperm in the ejaculate of at least 5 million sperm,
             within one year of study initiation.

        Exclusion Criteria:

          1. Currently pregnant or successful pregnancies within 12 months of initiating
             participation. Clinical intrauterine miscarriages prior to initiating participation,
             within ASRM guidelines: subjects over 35 must wait six months, while subjects under 35
             must wait 12 months. No exclusion for biochemical pregnancies.

          2. Undiagnosed abnormal uterine bleeding.

          3. Suspicious ovarian mass.

          4. Patients on oral contraceptives, depo-progestins, or hormonal implants (including
             Implanon). A two month washout period will be required prior to screening for patients
             on these agents. Longer washouts may be necessary for certain depot contraceptive
             forms or implants, especially when the implants are still in place. A one-month
             washout will be required for patients on oral cyclic progestins.

          5. Known 21-hydroxylase deficiency or other enzyme defect causing congenital adrenal
             hyperplasia.

          6. Type I or Type II diabetes mellitus, or if receiving antidiabetic medications.

          7. Known significant anemia (Hemoglobin <10 g/dL).

          8. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular event.

          9. Known heart disease (New York Heart Association Class II or higher).

         10. Known Liver disease (defined as AST or ALT>2 times normal, or total bilirubin >2.5
             mg/dL).

         11. Known Renal disease (defined as BUN >30 mg/dL or serum creatinine > 1.4 mg/dL).

         12. History of, or suspected cervical carcinoma, endometrial carcinoma or breast
             carcinoma.

         13. History of alcohol abuse (defined as >14 drinks/week) or binge drinking of ≥ 6 drinks
             at one time).

         14. Known Cushing's disease.

         15. Known or suspected adrenal or ovarian androgen secreting tumors.

         16. Allergy or contraindication to the treatment medications: AI, gonadotropins, CC or
             hCG.

         17. Couples with previous sterilization procedures (e.g. vasectomy, tubal ligation) which
             have been reversed.

         18. Patients with untreated poorly controlled hypertension defined as a systolic blood
             pressure ≥ 160 mm Hg or a diastolic ≥ 100 mm Hg obtained on two measures obtained at
             least 60 minutes apart.

         19. Subjects who have undergone a bariatric surgery procedure in the recent past (< 12
             months) and are in a period of acute weight loss or have been advised against
             pregnancy by their bariatric surgeon.

         20. Known moderate or severe endometriosis

         21. Known polycystic ovarian syndrome as evidenced by anovulation or oligoovulation,
             hirsutism and/or elevated testosterone levels, and ovarian morphology on ultrasound
             examination.

         22. Donated semen.

         23. Couples in which either partner is legally married to someone else.

         24. Medical conditions that are contraindications to pregnancy.