The Role of Aromatase Inhibitor (Letrozole) in Minimal Ovarian Stimulation Protocols in Assisted Reproductive Technology. A Randomized Controlled Trial

Infertility in not a health problem and that infertile couples are not really ill. However, this narrow interpretation of the problem is refuted by the world community. The WHO defines health as a "state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity". It has also been argued that overpopulation is the main problem in the developing countries and that helping infertile couples contradicts the interests of the countries and the world at large. However, this narrow approach contradicts human rights in general and reproductive rights in particular.

In 1994, the United Nations International Conference on Population and Development in Cairo mentioned issues on future actions on 'prevention and appropriate treatment of infertility where feasible'. However, no guidelines or concrete actions and programmes were given for developing countries.

Worldwide, more than 80 million couples suffer from infertility; the majority of this population are residents of developing countries.

In September 2001, a meeting on 'Medical, Ethical and Social Aspects of Assisted Reproduction' was organized by the WHO. For the first time, major attention was paid to ongoing developments in assisted reproduction technology together with their social and ethical implications in developing countries . It was the first time that the WHO highlighted the issue of assisted reproduction in developing countries.

ART in developed countries is highly expensive one of steps is ovulation induction the most common protocol for induction is the long gonadotrophin-releasing hormone (GnRH) agonist pituitary suppression regimen combined with relatively high doses of exogenous follicle-stimulating hormone (FSH) remains the most frequently used stimulation protocol which is expensive. in our study we will use a mild ovarian stimulating protocol letrozole adjuvant to gonadotrophins which is less expensive

The use of aromatase inhibitor have only recently been introduced in infertility treatment, especially for ovulation induction.

An aromatase inhibitor blocks the conversion of androgens to estrogens in the ovarian follicles, peripheral tissues, and in the brain. This result in two things: (a) Fall in circulating and local estrogens and (b) Rise in intraovarian androgens. Fall in estrogen levels, releases the hypothalamopituitary axis from the negative feedback of estrogens. Thus, there is a surge in follicle stimulating hormone (FSH) release, which results in follicular growth. Since, the feedback mechanism is intact; normal follicular growth, selection of dominant follicle, and atresia of smaller growing follicle occurs; and thereby facilitating monofollicular growth and ovulation.Another mechanism of action of the aromatase inhibitors is by the increasing intraovarian androgens. This increases the follicular sensitivity to FSH. Recent data shows the role of androgens in early follicular developments. by augmenting FSH receptors and stimulating insulin-like growth factor (IGF)-I; FSH and IGF-I act synergistically to promote follicular growth. This pharmacodynamics of letrozole ensures improved endometrial thickness, cervical mucus, monofollicular, and better folliculogenesis. So , these factors may lead to higher pregnancy rates and greater likelihood of singleton pregnancy.

Letrozole has been tried for ovarian stimulation for assisted reproduction. With the concept of mild stimulation in IVF to improve implantation rate, letrozole is a potential agent. Letrozole has two potential uses in IVF: First, where it is used in the follicular phase usually with FSH/human menopausal gonadotropin (HMG) for ovulation induction; second, it has also been used in luteal phase of stimulated IVF cycle and to reduce circulating E2 levels; thus, potentially reducing ovarian hyperstimulation syndrome (OHSS) risk.

A significant reduction in the total dose of gonadotrophins was found when aromatase inhibitor was added in controlled ovarian hyperstimulation (COH) cycles.

Some studies evaluated the addition of letrozole in patients with normal ovarian response undergoing IVF or Intracytoplasmic sperm injection( ICSI). They showed higher implantation and ongoing pregnancy rates in the letrozole cotreatment group.