The effect of clomiphene citrate on blastocyst development and implantation in the rabbit

Abstract

The induction of ovulation with clomiphene citrate (CC) in human patients results in a high ovulation rate but achieves a relatively low pregnancy rate. To clarify the possible role of CC in interfering with the normal reproductive physiology and embryology, we have used our rabbit model and transferred 4-day-old blastocysts from untreated donors to CC-treated pseudopregnant recipients and from CC-treated donors to untreated pseudopregnant recipients to study embryonic development and implantation. Each group was further subdivided into two subgroups, one receiving CC before and the other after ovulation. CC was administered subcutaneously in three consecutive doses of 10 mg/kg body weight. Ovulation was induced with pregnant mare serum gonadotropin (PMS) and human chorionic gonadotropin (hCG). The implantation rate of the control group, evaluated on day 8 of pregnancy, reached 62.0%. When recipients were treated with CC before ovulation, implantation rate was reduced to 18.8% (P less than 0.0002), and to 20.0% (P less than 0.003) when CC was administered after ovulation. The implantation rate of blastocysts transferred from donors, treated before ovulation, is 22.2% (P less than 0.0055), however, reached 70.8% when treatment was started after ovulation. All implantations were analysed microscopically and showed normal morphological features. Our results demonstrate a potential multiple effect of CC, first on the endometrium by altering its receptivity for the implanting conceptus, second, on tubal physiology by altering egg transport, and finally on ovum maturation before ovulation interfering with development of blastocysts. These parameters may all result in rapid decrease in establishment of implantations and in turn in very low pregnancy rates.

Endometrial Development Was Improved by Transdermal Estradiol in Patients Treated with Clomiphene Citrate

“…It is generally accepted that CC exerts its ovulation-inducing effect by acting as an antiestrogen at the level of the hypothalamus and competing with endogenous estradiol (E 2 ) for binding to the estrogen receptor [2,3]. The success rate in inducing ovulation was 57-91% [4][5][6][7][8][9]. However, conception occurs in only 27-40% of the cases and approximately 25% of these pregnancies terminate in miscarriage [10].…”

Intrauterine insemination in natural cycle may give better results in older women

“…Clomiphene citrate has been shown to have an adverse effect on early embryonic development [7,8], on the endometrium, as well as implantation. Its antagonistic effect on the endometrium is well recognised [9].…”

Die Pseudogravidität des Kaninchens als Lutealphasenmodell: Steroid- und Proteohormonspiegel nach Clomiphencitrat-Behandlung

“…Nach peripherer ven6ser Blutentnahme im 48-Stunden Abstand wurden daran anschliei3end die Progesteron-, FSH-und LH-Werte analysiert. Beim Menschen bewirkt CC zudem sowohl an Hypophyse und Hypothalamus als auch am Endometrium eine Alteration der zytosolischen Ostradiol-und Progesteronrezeptorkonzentrationen [1,3]. Dank der M6glichkeit der exakten zeitlichen Zuordnung der endokrinen und histomorphologischen Effekte von CC/Gonadotropin-Medikationsschemata im Rahmen des Versuchskonzepts der Pseudograviditfit des Kaninchens sind weiterffihrende Untersuchungen, speziell der steroidalen Rezeptorkinetik, an den unterschiedlichen Zielorganen dieser Substanz unbedingt erforderlich.…”