The Effects of Letrozole And Clomiphene Citrate For Induction of Ovulation In Polycystic Ovarian Syndrome(PCOS)
Condition: Polycystic Ovarian Syndrome
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      As both medications i.e. CC and letrozole have been shown to be effective in inducing
      ovulation in PCOS patients, this study was performed in order to evaluate which regime
      (whether CC or letrozole) is the best to be used as the first line treatment for PCOS
      patients with infertility for local population. The best regime will therefore could be
      included in the protocol of management of infertility patients with PCOS so that the quality
      of patients' care could be improved.
    

Detailed description: 
      Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy among women of
      reproductive age group and is one of the leading causes of infertility. It is characterized
      by chronic anovulation and hyperandrogenism with variable clinical manifestations that
      include oligomenorrhea, infertility, hirsutism, and acne (Ehrmann DA 2005).

      Several methods have been described to induce ovulation in PCOS patients- weight reduction,
      laparoscopic ovarian drilling and the use of various induction ovulation agents like
      clomiphene citrate (CC), aromatase inhibitors (AIs) and gonadotrophins.

      Clomiphene citrate (CC) has been most widely used and standard drug for the treatment of
      infertility. It is known that clomiphene citrate results in an ovulation rate of 60-85%, but
      a conception rate of only around 20% (Bayar et al 2006, Sohrabvand et al 2006). About 20-25%
      of women are resistant to CC and do not ovulate. Discrepancy between ovulation and pregnancy
      rate is related to anti-estrogenic activity on endometrium and cervical mucus is due to CC
      has a long half life of 5 to 7 days.

      In view of disappointing result of CC treatment with many adverse effect and cost and
      possible complication of gonadotrophin, the concept of aromatase inhibition was proposed as a
      new method of ovulation that are easy to use, less expensive and more effective drugs.

      Letrozole is an oral, potent, reversible, and highly selective aromatase inhobitor that
      prevent androgen-to-estrogen (E) conversion. These aromatase inhibitors have a short half
      life (45 hours), hence is rapidly eliminated from the body. No adverse effect on E target
      tissues is seen with letrozole due to this short half life; furthermore, it does not down
      regulate the ER compare to CC.

      The main impetus for the development of aromatase inhibitor as ovulation induction agents was
      to avoid the peripheral antiestrogenic effects of CC, especially the frequent occurrence of a
      thin endometrial lining (Sohrabvand et al 2006).

      Rationale of performing the study As both medications i.e. CC and letrozole have been shown
      to be effective in inducing ovulation in PCOS patients, this study was performed in order to
      evaluate which regime (whether CC or letrozole) is the best to be used as the first line
      treatment for PCOS patients with infertility for local population. The best regime will
      therefore could be included in the protocol of management of infertility patients with PCOS
      so that the quality of patients' care could be improved.

      HYPOTHESIS

      Letrozole is more effective than clomiphene citrate as ovulation agent in PCOS patients.

      General Objective To compare the effectiveness of letrozole and clomiphene citrate as
      ovulation agent in PCOS.

      Specific Objectives

      i. To identify the ovulation percentage between letrozole and CC ii. To compare the
      endometrial thickness between letrozole and CC iii. To determine the pregnancy outcome
      between letrozole and CC iv. To study the associated factors that can affect the
      effectiveness of the treatment e.g. age, body weight, smoking, duration of marriage, duration
      of infertility and types of infertility either primary or secondary)

      Methodology

      1.0 Study design

      Prospective, multicenter, randomized control trial.

      2.0 Population and sample

      Reference population

      The reference population will be the female patient diagnosed to have polycystic ovarian
      syndrome at infertility clinic HSB, Kedah and infertility clinic HUSM, Kelantan and
      infertility Clinic, Hospital Tengku Ampuan Afzan (HTAA), Kuantan, Pahang.

      3.0 Selection criteria 3.1 Inclusion criteria i. Age > 18 years but < 40 years old ii. Was
      diagnosed PCOS iii. Patient is not illiterate. iv. Normal husband's seminal fluid analysis
      (SFA) - (Count > 20 million/ml, Motility > 40% and normal morphology > 30%) 3.2 Exclusion
      criteria : i. Having medical problem eg- renal disease, tyhroid disorder, hyperprolactinemia,
      liver disease.

      ii. Other causes of anovulatory infertility

      4.0 Sampling and Sample size

      4.1 Sample size

      Sample size calculation:

        1. Ovulation percentage

           From Hananel Holzer 2006

           Proportion of ovulation rate by using Clomiphene citrate (Po) = 0.60 Proportion of
           ovualtion rate by using Letrozole (P1) = 0.84

           P = P1 + Po = 0.83 + 0.64 = 0.72 zα = 1.96 zβ = 0.84 for 80% power 2 2 Significance
           level (α) = 5% (0.05) Power of study ( 1 - β )= 80% β =20% ( 0.2 ) n = (zα√2P(1-P) +
           zβ√P1(1-P1)+Po(1-Po))2 (P1-Po)2 n = ( 1.96√2(0.72)(1-0.72) + 0.84√0.83(1-0.84) +
           0.60(1-0.60))2 (0.75 - 0.50 )2 n = 54 Therefore sample size = 108 + 20 % drop out = 130
           By using PS software - sample size : 130

        2. Endomterial thickness between letrozole and CC From Mosammat Rhasid et al 2008 Letrozole
           2.5 mg, mean ± SD ratio -10.37 ± 1.2 CC 100mg, mean ± SD ratio - 9.03 ± 0.89

             -  - 0.5 n = 2 α2 (zα + zβ)2

             -  2 = 2 (1.2)2 ( 1.96 + 0.84) 2 (0.5)2 = 49 per group Therefore sample size = 98 + 20
                % drop out Total n = 117 By using software, n = 51 per group, total n = 122

        3. Pregnancy rate between letrozole and CC From Mosammat Rashida Begum 2008 Letrozole 2.5mg
           - pregnancy rate - 40.6% CC 100mg - pregnancy rate - 18.7% ( Po ) = 0.18 (P1) = 0.41 P =
           P1 + Po = 0.41 + 0.18 = 0.30 zα = 1.96 zβ = 0.84 for 80% power 2 2 Significance level
           (α) = 5% (0.05) Power of study ( 1 - β )= 80% β =20% ( 0.2 ) n = (zα√2P(1-P) +
           zβ√P1(1-P1)+Po(1-Po))2 (P1-Po)2 n = ( 1.96√2(0.30)(1-0.30) + 0.84√0.41(1-0.41) +
           0.18(1-0.18))2 (0.41-0.18 )2 n = 61 Therefore sample size = 120 + 20 % drop out n= 146

             -  The maximun sample size that were calculated for this study is 146. Therefore
                sample size that were decided for the the study = 150 patients

      4.2 Sampling frame All PCOS patients attending Infertility Clinic Hospital Sultanah Bahiyah
      (HSB), Kedah, Infertility Clinic Hospital Universiti Sains Malaysia (HUSM), Kelantan and
      Infertility Clinic Hospital Tengku Ampuan Afzan (HTAA), Kuantan, Pahang who fulfill inclusion
      and exclusion criteria will be recruited in the study.

      5.0 Methods of data collection

      The study will be conducted after the approval from Hospital Sultanah Bahiyah, Kedah, USM and
      HTAA, Pahang ethical committee.

      All PCOS patients, age more than 18 years old at Gynecology Clinic, HUSM were given
      information form regarding the study conducted. When the participants agree to involve in
      this study, the consent form will be given to them. Participants are required to fill the
      social demographic data which includes age, address, occupation, monthly family income,
      education status, and duration of marriage, number of parity and year of last child birth.
      Measurement such as waist circumference, weight, height and blood pressure reading will be
      recorded. Then patients will be randomized into two groups

      Randomization PCOS women who are eligible and fulfilling the criteria of the study will
      recruit. After they had given inform consent, they will assigned to one of the groups of
      sealed opaque envelope labelled as C and L. Women in group C will assigned CC 100mg and those
      in L assigned Letrozole 2.5 mg. The randomization will be done by computer- generated
      randomization using http://www.randomization.com according to the random sequence.

      Group 1- Letrozole group

        -  The patients will be given letrozole 2.5 mg from D5-D9 of menses.

        -  Base line TVS at D2 will be done, following spontaneous menses/induction with MPA 10 mg
           Daily for 1 week.

        -  Transvaginal scan was done to document the evidence of ovulation only if patient having
           menses (D8 -10 onwards ).

        -  If dominant follicle (DF) present (DF> 12mm), repeat TVS every 2 days,

        -  ovulation is diagnosed when the mature DF is about 18 to 22 mm and then evidence of
           ruptured about 3 to 4 days later

           o If dominant follicle (DF) absent (DF<12mm), repeat TVS every 3-4 days later.

        -  Measure Endometrial thickness (ET) for every follow-up.

        -  If absent of Dominant follicle (DF<12mm up to Days 20), consider failed or anovulation.

      Group 2 Clomiphene Citrate Group

        -  The patients will be given CC 100 mg from D5-D9 of menses.

        -  Base line TVS at D2 will be done, following spontaneous menses /induction with MPA 10 mg
           Daily for 1 week.

        -  Transvaginal scan was done to document the evidence of ovulation only if patient having
           menses (D8 -10 onwards).

        -  If dominant follicle (DF) present (DF> 12mm), repeat TVS every 2 days,

        -  ovulation is diagnosed when the mature DF is about 18 to 22 mm and then evidence of
           ruptured about 3 to 4 days later

        -  If dominant follicle (DF) absent (DF<12mm), repeat TVS every 3-4 days later.

        -  Measure Endometrial thickness (ET) for every follow-up.

        -  If absent of dominant follicle (DF<12mm up to Days 20), consider failed or anovulation.

      In all groups a urine pregnancy test was done 3 weeks after documented ovulation and the
      patient remained amenorrheic. All study medications will be discontinued when there was a
      positive pregnancy test. Pregnant patients were then will be followed up until an ultrasound
      could document the viability of pregnancy. Copies of patients' obstetric records, including
      delivery records, were reviewed by the investigators to obtain obstetrics outcomes e.g:
      miscarriage, ectopic pregnancy, molar pregnancy, preterm delivery etc).

      Research tool

        -  General Questionnaire

        -  Weighing scale using Seca weighing machine

        -  Measuring tape

        -  Ultrasound machine

        -  BP set Investigations Urine pregnancy test Hormonal and biochemical profiles
    

Intervention name(s): Letrozole
Intervention type(s): Drug
Intervention description(s): Women in group L will be assigned with Letrozole on night at day 5 to day 9 of the cycle
Other intervention name(s): Femara (Aromatase Inhibitor)
Intervention MeSH terms: Letrozole; Aromatase Inhibitors
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ovulation induction, clomiphene citrate, letrozole