Comparison Between Letrozole and Urinary Purified FSH in Women With Clomiphene Citrate Resistant Polycystic Ovarian Syndrome.
Condition: Infertility
MeSH terms: Polycystic Ovary Syndrome; Infertility
Study type: Interventional
Phase: Phase 3

Summary: 
      210 women with clomiphene resistant PCOS will be randomly divided into 3 equal groups using
      computer generated random numbers. Group 1 will receive FSH, group 2 will have Letrozole and
      group 3 will act as the control group with no intervention.
    

Detailed description: 
      Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age,
      with an incidence of 5 -10%. Classically clomiphene citrate (CC) is the first approach to
      induce ovulation in patients with PCOS. Although 70-80% of PCOS women can ovulate by the
      treatment with CC, only 40%of the PCOS women become pregnant. Women who do not ovulate with
      increasing doses of CC are described as being CC-resistant and remain a major challenge in
      gynecologic endocrinology. Traditional alternatives for CC-resistant patients include
      gonadotropin therapy and laparoscopic ovarian diathermy.

      Gonadotropin therapy is widely used for ovulation induction in CC-resistant PCOS patients.
      The use of purified FSH preparation virtually free of LH activity, is a recommendable
      treatment since there is evidence that pure FSH may significantly reduce tonic LH levels,
      favourably alter the intraovarian hormonal milieu, and promote the initial follicular
      development with minimal risk of multiple follicular growth or ovarian hyperstimulation.

      The use of metformin in PCOS is associated with cycle regulation, improved ovulation, and a
      reduction in circulating androgen levels. Metformin likely plays its role in improving
      ovulation induction in women with PCOS through a variety of actions, including reducing
      insulin levels and altering the effect of insulin on ovarian androgen biosynthesis, theca
      cell proliferation, and endometrial growth. In addition, potentially through a direct effect,
      it inhibits ovarian gluconeogenesis and thus reduces ovarian androgen production.

      Letrozole is an orally-active aromatase inhibitor, with good potential for ovulation
      induction. Letrozole acts by reducing estrogen production by blocking androgens to estrogens
      conversion. Additionally, it has no adverse effect on endometrium and cervical mucus (7).
      This releases the pituitary from negative feedback of estrogens and releases FSH. Also, an
      added positive effect is increased follicular sensitivity to FSH through amplification of FSH
      receptor gene expression.

      Hyper-insulinemia, which is closely associated with PCOS, is thought to be one of the
      causative factors for CC resistance. The prevalence of insulin resistance in PCOS is close to
      50%.

      All women with clomiphene resistant PCOS attending the subfertility clinic of Cairo
      university hospitals will be invited to participate in the study. PCOS diagnosis will be
      based on chronic anovulation and sonographic picture of polycystic ovaries (10). Clomiphene
      resistance will be defined as failure of ovulation in spite of receiving 150mg of clomiphene
      citrate for 5 days during the menstrual cycle.

      Exclusion criteria are age >40 years, other causes of infertility, hperprolactinaemia,
      allergy to FSH or metformin, previous FSH or LOD therapy, and body mass index (BMI)>35.

      The study will be explained to all the participants and a written informed consent will be
      obtained before participation.

      Full history will be taken followed by complete examination and sonographic evaluation.
      Sonographic picture of polycystic ovaries will be defined when there are at least 12
      follicles 2-9mm in the ovary and/or ovarian volume>10cm3 (10) 210 women with clomiphene
      resistant PCOS will be randomly divided into 3 equal groups using computer generated random
      numbers. Group 1 will receive FSH, group 2 will have Letrozole and group 3 will act as the
      control group with no intervention.

      Group 1 will receive urinary purified FSH (Fostimon® IBSA, Switzerland) 75IU daily for 7 days
      starting from the 3rd day of menstruation or progesterone withdrawal bleeding. If the
      follicle does not exceed 9mm the dose will be increased by 37.5IU every 7 days. The cycle
      will be cancelled if no follicles exceed 9mm 4 weeks after starting FSH. Group 2 will receive
      Letrozole (Femara®, Novartis, Switzerland) 2.5mg twice daily for 5 days starting from the 3rd
      day of menstruation or progesterone withdrawal bleeding.

      Group 3 will have regular progesterone withdrawal bleeding in the form of norethisterone
      (stereonate® Hi Pharm, Egypt).

      Serial vaginal ultrasound scans were done starting from the 10th day of menstruation, the
      frequency of monitoring will be individualized according to the women's response. When the
      dominant follicle reaches 17mm or more women will receive Human chorionic gonadotrophin
      (Choriomon® IBSA, Switzerland) 5000IU and a timed intercourse will be advised 36 hours later.
    

Intervention name(s): FSH; Letrozole
Intervention type(s): Drug; Drug
Intervention description(s): 75IU daily for 7 days starting from the 3rd day of menstruation or progesterone withdrawal bleeding. If the follicle does not exceed 9mm the dose will be increased by 37.5IU every 7 days; 70 women will receive Letrozole (Femara®, Novartis, Switzerland) 2.5mg twice daily for 5 days starting from the 3rd day of menstruation or progesterone withdrawal bleeding.
Intervention MeSH terms: Letrozole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment