Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome
Condition: Polycystic Ovary Syndrome
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      The Polycystic Ovarian Syndrome (PCOS) is a common disorder related to ovulation problems.
      Clomiphene citrate (CC) is the drug of first choice for this condition. Nevertheless, CC has
      a detrimental effect over uterine receptivity.

      Raloxifene is a Selective Estrogen Receptor Modulator, that does not have a detrimental
      effect over the endometrium, and also increase the serum levels of FSH, thus, inducting
      ovulation.

      The objective of this study is to compare the ovulation rate in PCOS patients between
      clomiphene citrate and raloxifene in a double blind randomized trial.
    

Detailed description: 
      -Introduction The Polycystic Ovarian Syndrome (PCOS) is a frequent endocrine among women in
      reproductive ages, with a prevalence of 10%. In 2003, a consensus among the European and
      American Society of Human Reproduction (ESRHE and ASRM) defined that PCOS is a ovarian
      disfunction which present at least 2 out of 3 criteria: oligomenorrhea or anovulation;
      clinical or laboratorial signs of hyperandrogenism and polycystic ovaries on ultrasound;
      other causes, such as congenital adrenal hyperplasia, androgen secretory tumors, Cushing
      syndrome and hyperprolactinemia must be rule out.

      Patients with PCOS who desire to became pregnant need, in their majority, induction of
      ovulation. Traditionally, clomiphene citrate, an estrogen receptor agonist, is the most used
      drug for this type of anovulation. The mechanism of action of clomiphene is related to a
      negative feedback to the endogenous estrogen, resulting in a higher amplitude of
      gonadotrophin surges, i.e., luteinizing hormone(LH) and follicle stimulating hormone(FSH).
      Nevertheless, recent studies have been shown that clomiphene citrate has a deleterious effect
      in the endometrium. The markers of uterine receptivity, among them, the integrin beta3
      subunit, has its expression diminished, which implicate in a reduced fecundation rate.

      The raloxifene is a selective estrogen receptor modulator. It has an agonist and antagonist
      activity over different organs. The daily therapy with raloxifene increase bone density,
      reduce cholesterol serum concentrations (LDL) and do not stimulate the endometrium in
      post-menopausal women (Delmas PD et al., 1997). Recent studies have shown that this drug is
      safe in healthy pre-menopausal women (Baker VL et al., 1998). A daily dosi of 100mg per 28
      days, beginning on the 3rd day of the cycle, has shown that FSH and LH levels were not
      affected when compared to controls during the menstrual cycle. However, women who had
      received 100mg of raloxifene had a 31% increase in their FSH serum levels during the
      follicular phase, when compared to controls. An increase to 200mg did not increase FSH levels
      (Baker VL et al, 1998). Furthermore, it has been shown that raloxifene significantly increase
      the in vitro expression of αvβ3 integrin, suggesting a beneficial effect over the endometrium
      in relation to clomiphene (Lessey BA, personal communication, 2006).

      -Objective To compare the ovulation rate between raloxifene and clomiphene among women with
      polycystic ovarian syndrome.

      To identify the endometrial alterations compatible with ovulations, i.e., secretory
      endometrium, through endometrial biopsy between the women who used raloxifene or clomiphene.

      -Patients and Methods

      Patients with the diagnosis of polycystic ovarian syndrome (because of infertility or
      hirsutism) who had a consultation at outpatient clinic of Hospital de Clínicas de Porto
      Alegre will be invited to participate in the study, after signing the informed consent. A
      standard interview will be performed. In the first consultation, the laboratorial exams will
      reviewed: total testosterone, 17 OH-progesterone, fasting glucose, TSH, prolactin. After the
      interview, the patient will be randomized for one of the treatments:

      100mg of clomiphene or 100mg of raloxifene from day 3 of the menstrual cycle, for 5 days.
      Menstruation will be induced with 10mg of oral medroxyprogesterone per 10 days. On day 10,
      urinary LH will be collected daily along with endovaginal ultrasound for assessing follicular
      development. On post-ovulatory day 8~10, progesterone levels will be measured from blood. An
      endometrial biopsy on day 8~10 post-ovulation will be performed in those patients who do not
      wish to became pregnant. The endometrial biopsy will divided into 2 parts and kept in liquid
      nitrogen and formol for immunohistochemistry and histological analysis respectively.

      Sample size and statistical analysis

      Ethical aspects
    

Intervention name(s): clomiphene citrate; raloxifene
Intervention type(s): Drug; Drug
Intervention description(s): 100mg PO on days 5-9 of the menstrual cycle; 100mg PO on days 5-9 of the menstrual cycle
Other intervention name(s): Clomid; Evista
Intervention MeSH terms: Raloxifene Hydrochloride; Clomiphene; Enclomiphene; Zuclomiphene
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Polycystic Ovary Syndrome; clomiphene citrate; Raloxifene