Background of the invention According to Harrison Dictionary, human infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. There is a spectrum of infertility, ranging from reduced conception rates or the need of medical intervention to irreversible causes of infertility. Infertility can be attributed primarily to male factors in 25%, female factors in 58%, and is unexplained in about 17% of couples.

Ovulation is the process where an ovum or ova are released from the ovaries. The timing of ovulation within the menstrual cycle is of foremost importance for fertilization. It is well known that follicles acquire the ability to ovulate following growth and maturation stimulated by the pituitary gonadotropins. Ovulation induction is a therapeutic procedure commonly used to manage infertile patients. Ovulation induction is employed in particular for the following two purposes: 1) to treat anovulation in patients with hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders and 2) to stimulate multiple folliculogenesis in patients (mostly with normal menstrual cycles) who are candidates for assisted reproduction techniques. These procedures are also termed controlled ovarian stimulation or hyperstimulation. However there are several complications caused by ovulation induction, including for instance multiple gestations and ovarian hyperstimulation syndrome. The complications mostly occur in polycystic ovary syndrome patients and/or full-dose gonadotropin regimens are employed.

The inventor of the present invention has found that exemestane can be safely used in ovarian follicular stimulation for treating infertility in a host in need thereof, namely without causing the above side effects.

Exemestane was first taught by US patent 4,808, 616 and it is currently administered orally at the dosage of 25 mg/day in treating breast cancer in postmenopausal women.

Exemestane is endowed with a peculiar mechanism of aromatase inhibition. The aromatase enzyme (450arom) is a specific form of cytochrome P450 hemoprotein composed of a P450 (heme) moiety and a peptidic moiety. The enzyme catalyzes a multistep reaction leading to aromatization of the A ring of the androgen substrate (mainly androstenedione) to estrone, requiring the presence of the cofactor NADPH.

After this enzymatic reaction, the enzyme molecule is once more available to perform a new aromatization. The exemestane's mechanism of aromatase inhibition has been extensively studied and the compound has been found to cause enzyme inactivation. In fact exemestane, structurally related to the natural substrate androstenedione, is initially recognized by the aromatase enzyme as a false substrate, therefore it competes with androstenedione at the active site of the enzyme. The compound is then transformed (through a NADPH-dependent mechanism) to an intermediate which binds irreversibly to the enzyme causing its inactivation (also known as suicide inhibition). Therefore the enzyme is definitely inactivated and de novo enzyme synthesis is required for oestrogen production.

The newly found therapeutic utility of exemestane is actually surprising. From the pharmacological point of view, the ovarian follicular stimulating activity of exemestane may be found in several concurrent factors, including its peculiar mechanism of aromatase inactivation, the dosage and the treatment schdule.

Description of the invention A first object of the present invention is to provide a method for treating infertility in a female host in need thereof comprising the administration of a therapeutical effective follicular stimulating amount of exemestane to said host.

According to a preferred embodiment of the invention, a method is provided for inducing ovarian follicular stimulation in a female host in need thereof comprising the administration and subsequent removal of a therapeutical effective follicular stimulating and/or inhibiting amount of exemestane to said host.

A female host, according to the invention, is for instance a mammalian female, in particular a woman. Preferred examples of such hosts are patients with hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders, and patients who otherwise are candidate for assisted reproduction techniques.

The clinical terms as used herein have their plain meanings, well known in the art.

In any case, anovulation refers to lack of ovulation, of course. Ovarian follicular stimulation refers to the process wherein exemestane is used to bring about ovulation in female hosts, who are otherwise anovulatory, resulting in induction of follicular rupture and ovulation of fertilizable oocytes.

As used herein, the term"a therapeutical effective follicular stimulating amount"refers to an amount which is effective, upon single or multiple dose administration to the patient, in treating infertility e. g. by inducing ovarian follicular stimulation either when being taken or after its stoppage causing a rebound hyperstimulation of the ovaries.

According to a further preferred embodiment of the invention, a method is provided for inducing ovarian follicular stimulation in a female host suffering from hypogonadotropic hypogonadism, polycystic ovary syndrome and other menstrual cycle disorders, or who is candidates for assisted reproduction techniques, comprising the administration of a therapeutical effective follicular stimulating amount of exemestane to said host.

A further object of the invention is the use of exemestane in the manufacture of a medicament for use in treating infertility in a female host.

The invention also provides the use of exemestane in the manufacture of a medicament for use in inducing ovarian follicular stimulation in a female host.

The effect of exemestane on ovarian follicular stimulation can for instance be seen in animal models once its administration is stopped with a resultant increase in follicle development and rupture.

In effecting treatment according to the invention, exemestane can be administered in any form or mode, which makes the compound bioavailable in therapeutical effective amounts. For example, routes of administration include oral, sublingual, intranasal, subcutaneous, intradermal, intraperitoneal, intramuscularly, intravenous, transdermal, vaginal, rectal and the like. Oral or intramuscular administration is generally preferred.

One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular circumstances. For instance, examples of suitable oral forms are tablets, capsules, sugar and film coated tablets.

The dosage of exemestane to be used is, of course, dependent on various factors such as the host to be treated (e. g. age, weight and general status of health), and the schdule of the treatment.

Exemestane can be administered to a woman, for instance orally, at a dosage range varying from about 5 mg/day to about 200 mg/day, possibly in divided doses, e. g. from 2 to 3 or 4.

According to a preferred schedule of treatment, exemestane is administered in the early part of the menstrual cycle (day 5 to day 7) and then stopped or it is administered throughout the entire cycle and then discontinued, in order to achieve the desired effective hematic follicular stimulating hormone level.