Gonadotropins as an approach to couple infertility: the new guidelines

What are gonadotropins, how do they work and how are they used to treat infertility in couples?

The Italian Medicines Agency (AIFA) has published a Position Paper on the use of gonadotropins in the pharmacological approach to couple infertility (see link at the bottom of the article to download the complete document).

We remind you that infertility means the inability to conceive within the first 12-18 months of targeted attempts, a condition which currently affects 8-20% of couples who are of childbearing age.

The causes of infertility, from the recent data of the Italian PMA register are divided as follows:

• 35.5% female causes (ovulation disorders, endometriosis, malformation of sexual organs)
• 35.4% male causes
• 15% couple lawsuits
• 13.2% idiopathic causes (= without apparent cause)
• 1% other causes

Gonadotropins as an approach to the treatment of infertility

What are gonadotropins?

These are glycoprotein hormones (as the name suggests). They have partially similar structures, human gonadotropins FSH, LH or HCG can be used, alone or in combination with other molecules.

Gonadoropins have a stimulating effect on the gonads (ovaries and testicles).

Gonadotropins for pharmacological purposes can be obtained by extraction from human urine, or by recombinant DNA technology.

A new form of recombinant FSH has recently been developed, corifollitropin alfa which allows for a single weekly administration compared to the daily administrations of other types of FSH.

Gonadotropins currently on the market in Italy and reimbursement

The gonadotropins on the market (Corifollitropin alfa, Choriogonadotropin alfa, Follitropin alfa, Follitropin alfa/ Lutropin alfa, Follitropin beta, Lutropin alfa, Menotropin, Urofollitropin) are reimbursable by the NHS on the basis of AIFA note 74 (see reference below) which provides for the following conditions:

• treatment of female infertility : in women aged up to 45 years with FSH values, on the 3rd day of the cycle, no higher than 30 mUl/ml
• treatment of male infertility: in males with hypogonadotropic hypogonadism with low or normal gonadotropin levels and in any case with FSH not exceeding 8 mIU/ml

• preservation of female fertility : in women aged up to 45 years affected by neoplastic diseases who have to undergo oncological therapies capable of causing transient or permanent infertility.

Use of gonadotropins

FSH

The pharmacological active ingredient of FSH   stimulates the growth of follicles in women (in men it is instead used for the treatment of hypogonadotropic hypogonadism).

Active ingredients of recombinant FSH:

• Follitropina alfa
• Follitropina beta
• Corifollitropin alfa

Active principles of extractive FSH: Urofollitropin

LH

In women with endogenous LH below 1.2 IU/l it is used in the recombinant formulation (Lutropin alfa), in association with a preparation based on FSH, to stimulate follicular development.

FSH+LH

Follitropin alfa + Lutropin alfa are used for pharmacological stimulation of follicular growth in women with low endogenous LH levels (less than 12 IU/L).

For anovulation, including PCOS anovulation, manotropin (extractive origin) is used in women unresponsive to clomiphene citrate.

The FSH + LH combination in the form of Menotropin is also used in the case of controlled ovarian hyperstimulation for multiple follicular development during a PMA process.

HCG

Gonadotropin HCG in its recombinant form Choriogonadotropin alfa is used for the final induction of ovulation of the matured follicle (or follicles) after stimulation of follicular growth.

Chorionic gonadotropin, of extractive origin, is used for the induction of ovulation and in cases of infertility due to anovulation or lack of maturation of the follicle. It can also be used to prepare for follicle harvesting in an ovarian hyperstimulation programme. Finally, it can be used as a support for the luteal phase.

In humans it is used in case of hypogonadotropic hypogonadism.

Personalized therapy

Ovarian aging is a determining factor for the effectiveness and success of assisted reproduction treatments.

For this reason, before setting up a therapeutic plan, it is necessary to accurately establish the woman’s ovarian reserve .

As we have seen, the main molecule for stimulating follicular growth is FSH. FSH can be administered daily or weekly (corifollitropin alfa).

A key issue is establishing the optimal dose of FSH to use to minimize risk. The customization of the stimulation protocol should be based on the prediction of the ovarian response of each individual woman.