Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome
Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome
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.
-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
Inclusion Criteria:

 -  All patients with polycystic ovarian syndrome will be invited to participate in the
 study. The PCOS criteria are according to modified Rotterdam criteria (7); i.e.,
 oligoovulation defined as < 6 menstrual periods per year, signs of clinical
 hyperandrogenism (Ferriman and Gallwey >8) or laboratorial (total Testosterone >=0.81
 ng/dL) or polycystic ovary > 10cm3.

 Furthermore, all patients with infertility diagnosis based solely on ovulation factor will
 included in the protocol

 -  Age >18 years old and <= 38 years old.

 -  No endometriosis on laparoscopy

 Exclusion Criteria:

 -  Not willing to participate in the study

 -  use of IUD or contraceptive pill within 2 months before the study.

 -  Hyperprolactinemia (>20ng/mL)

 -  Abnormal serum levels of TSH(normal range:0.4-40 mUI/mL).

 -  High 17-OH progesterone (>=4.9ng/mL)

 -  Endometriosis

 -  Known allergy to clomiphene or raloxifene