Luteal Phase Versus Follicular Phase Administration of Clomiphene Citrate in Polycystic Ovary Syndrome. A Randomized Controlled Trial

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders. It is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can, to a large degree, be classified as a genetic disease. Genetic and environmental contributors to hormonal disturbances combine with other factors, including obesity. Ovarian dysfunction and hypothalamic pituitary abnormalities contribute to the etiology of PCOS. It produces symptoms in approximately 5% to 10% of women of reproductive age 12-45 years old. It is thought to be one of the leading causes of female subfertility. Clomiphene citrate is a first line pharmacological treatment of ovulatory dysfunction associated with PCOS, because it is easily administered, relatively safe, and inexpensive. It is a selective estrogen receptor modulator (SERM) that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus. It is used in the form of its citrate to induce ovulation. It is known to be both an estrogen agonist and antagonist; however, its agonist properties manifest only when endogenous estrogen levels are extremely low. Its administration leads to depletion of estrogen receptors at the level of the pituitary and hypothalamus, interrupting the negative feedback that estrogen normally produces. As a result, GnRH secretion is improved and stimulates pituitary production of follicle-stimulating hormone (FSH), which in turn drives follicular growth and maturation with emergence of 1 or more dominant follicles. Although CC is very successful in inducing ovulation, there is usually a discrepancy between ovulation and pregnancy rates (PR) (CC failure), and also the lack of response found in a number of treated individuals (CC resistance). Several studies made it evident that the earlier the day of starting CC the better the results. Early administration of CC in patients with PCOS will lead to more follicular growth and endometrial thickness, which might result in a higher pregnancy rate (PR). Hence this study had been done to compare between the effect of starting CC early on the luteal phase and starting CC late on the second day of menstrual cycle which was used for years, and the anti-estrogenic effect of CC on ovulation, endometrium and pregnancy rate in the two regimens. This study had shown that the total number of follicles, mean follicular diameter and endometrial thickness during stimulation was significantly more when starting CC in (luteal phase) than (follicular phase).

In conclusion, it is well documented that the early administration of CC in late luteal phase (before withdrawal shedding) in patients with PCOS might lead to more follicular growth, ovulatory patients and endometrial thickness which might reflect on higher pregnancy rate than administration of CC in early follicular phase (from 2nd day to 6th day of cycle). Recommendation: Further large-scale studies are required to confirm the findings of the present study and determine the optimal duration of the administration of CC for ovulation induction in patients with PCOS.