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

NCT ID: NCT00427700

Last Updated: 2024-08-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-08-31
• Study Completion Date: 2009-08-31

Brief 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

Conditions

Polycystic Ovary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Clomiphene

Uso of 100mg of clomiphene citrate during days 5-9 of the menstrual cycle

Group Type: ACTIVE_COMPARATOR

clomiphene citrate

Intervention Type: DRUG

100mg PO on days 5-9 of the menstrual cycle

Raloxifene

Use of 100mg of raloxifene during days 5-9 of the menstrual cycle

Group Type: EXPERIMENTAL

raloxifene

Intervention Type: DRUG

100mg PO on days 5-9 of the menstrual cycle

Interventions

clomiphene citrate

100mg PO on days 5-9 of the menstrual cycle

Intervention Type: DRUG

raloxifene

100mg PO on days 5-9 of the menstrual cycle

Intervention Type: DRUG

Other Intervention Names

Clomid; Evista

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Hospital de Clinicas de Porto Alegre

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ricardo F Savaris, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Clínicas de Porto Alegre

Helena Corleta, MD, PhD

Role: STUDY_CHAIR

Hospital de Clínicas de Porto Alegre

Bruce A Lessey, MD, PhD

Role: STUDY_DIRECTOR

Greenville Hospital System

Locations

Hospital de Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Countries

Brazil

References

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Reference Type: BACKGROUND

PMID: 9385122 (View on PubMed)

Baker VL, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe RB. Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab. 1998 Jan;83(1):6-13. doi: 10.1210/jcem.83.1.4448.

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Savaris RF, Pedrini JL, Flores R, Fabris G, Zettler CG. Expression of alpha 1 and beta 3 integrins subunits in the endometrium of patients with tubal phimosis or hydrosalpinx. Fertil Steril. 2006 Jan;85(1):188-92. doi: 10.1016/j.fertnstert.2005.06.039.

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Reference Type: DERIVED

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Other Identifiers

RACLO

Identifier Type: -

Identifier Source: org_study_id