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

Official Title: “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 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

Intervention(s) in this Clinical Trial

• Drug: clomiphene citrate
  • 100mg PO on days 5-9 of the menstrual cycle
• Drug: raloxifene
  • 100mg PO on days 5-9 of the menstrual cycle

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle
• Experimental: 2
  • Use of 100mg of raloxifene during days 5-9 of the menstrual cycle

Primary Measures

• Ultrasound sign of ovulation
  • Time Frame: cycle day 14-20
    Safety Issue?: No

Secondary Measures

• endometrial biopsy compatible with the +/- 3days of the cycle
  • Time Frame: 8-10 days post-ovulation
    Safety Issue?: No
• Serum levels of Progesterone
  • Time Frame: 8-10 days after ovulation
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 38 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Investigator: Hospital de Clinicas de Porto Alegre Other

Overall Clinical Trial Officials and Contacts

Ricardo F Savaris, MD, PhD Principal Investigator Hospital de Clínicas de Porto Alegre  

Overall Contact: Ricardo F Savaris, MD, PhD 55 51 91122184 rsavaris@hcpa.ufrgs.br

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00427700

Study ID Number: RACLO

ClinicalTrials.gov Identifier: NCT00427700

Health Authority: Brazil: Ministry of Health