Clinical trial NCT00427700: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome
Keywords: Polycystic Ovary Syndrome
clomiphene citrate
Raloxifene
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
First posted: 2007-01-29
Enrollment: 82
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 38
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Percentage of Participants With Ovulation Detected by Ultrasound
timeFrame: cycle day 14-20
Secondary outcomes:
measure: Serum Levels of Progesterone
timeFrame: 8-10 days after ovulation
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: Hospital de Clínicas de Porto Alegre
name: Ricardo F Savaris, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Clínicas de Porto Alegre
name: Helena Corleta, MD, PhD
role: STUDY_CHAIR
affiliation: Greenville Hospital System
name: Bruce A Lessey, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997 Dec 4;337(23):1641-7. doi: 10.1056/NEJM199712043372301.
citation: 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.
citation: Grimes DA. The "CONSORT" guidelines for randomized controlled trials in Obstetrics & Gynecology. Obstet Gynecol. 2002 Oct;100(4):631-2. doi: 10.1016/s0029-7844(02)02233-0. No abstract available.
citation: Moher D, Schulz KF, Altman D; CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001 Apr 18;285(15):1987-91. doi: 10.1001/jama.285.15.1987.
citation: Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab. 2006 Mar;91(3):781-5. doi: 10.1210/jc.2005-2153. Epub 2006 Jan 17.
citation: Lessey BA, Ilesanmi AO, Lessey MA, Riben M, Harris JE, Chwalisz K. Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol. 1996 Mar;35(3):195-204. doi: 10.1111/j.1600-0897.1996.tb00031.x.
citation: Lessey BA, Castelbaum AJ, Buck CA, Lei Y, Yowell CW, Sun J. Further characterization of endometrial integrins during the menstrual cycle and in pregnancy. Fertil Steril. 1994 Sep;62(3):497-506.
citation: Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S. Time of initiation of clomiphene citrate and pregnancy rate in polycystic ovarian syndrome. Int J Gynaecol Obstet. 2006 Apr;93(1):44-8. doi: 10.1016/j.ijgo.2005.10.015. Epub 2006 Mar 10.
citation: Bayar U, Tanriverdi HA, Barut A, Ayoglu F, Ozcan O, Kaya E. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006 Apr;85(4):1045-8. doi: 10.1016/j.fertnstert.2005.09.045. Epub 2006 Mar 9.
citation: Lessey BA, Castelbaum AJ, Sawin SW, Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril. 1995 Mar;63(3):535-42.
citation: 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.
citation: Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999 Sep 11;319(7211):670-4. doi: 10.1136/bmj.319.7211.670.
citation: de Paula Guedes Neto E, Savaris RF, von Eye Corleta H, de Moraes GS, do Amaral Cristovam R, Lessey BA. Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome. Fertil Steril. 2011 Sep;96(3):769-73. doi: 10.1016/j.fertnstert.2011.06.067. Epub 2011 Jul 22.