Trial Information

Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome

-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 polycystics 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-menopausic women (Delmas PD et al., 1997). Recent studies have shown that this drug is
safe in healthy pre-menopausic 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