Does IVF Increase Risk for Gynaecological Cancer?: What Is the Limit?

Introduction

Whether fertility treatments and in particular IVF are related to carcinogenesis in women, is a rather interesting issue, which involves apparently more than one medical specialties. Gynecologists, surgeons, oncologists, mastologists, being some of them but certainly concerns all those involved in malignancies in the females and assisted reproduction.

The malignancies we refer to, are mainly those of the breast, endometrium and ovary, with breast cancer being the most common in the female population, affecting 1 in 8 women worldwide, ovarian cancer which is the 6th in frequency representing 4% of malignancies and endometrial cancer which is the most common gynecological cancer excluding breast cancer presenting an incidence of 8% of all malignant diseases. Furthermore, it will be of great interest the possible relation of IVF treatments and non-gynecological malignancies like thyroid and colon cancer, melanoma and non-Hodgkin lymphomas.

Estrogens, and progestogens, have long been associated with the development of breast cancer. In fact, this relationship was first described and published in 1896 in Lancet. Of course, this theory was confirmed after many years of research and after the discovery of estrogen and progesterone receptors in the human body. It is well known, that about two-thirds of breast cancers have positive estrogen receptors and 70% have positive progesterone receptors, but then again more than half of them will become resistant to hormone therapy. The truth is that, estrogens are not exactly what causes mutations or breast cancer. However, it is very well known that they have a potent mitogenic activity. Thus, they can develop endometrial cancer after prolonged action upon the endometrium, whereas progesterone, on the contrary, may act protectively on it. In addition, endometrial cancer may be due to various hormonal changes in the secretory phase, to high concentrations of substances due to the action of gonadotropins, to polycystic ovaries, to obesity and after prolonged SERMs administration.

On the other hand, recurrent ovarian epithelial superficial damage, the prolonged action of gonadotropins with corresponding growth factors upon the ovary and finally the dispersal of malignancy by descending epithelial cells from the salpingeal epithelium, have long been proposed as the possible pathogenesis of epithelial ovarian cancer.

Studies have shown that the longer the female body is exposed to the action of female hormones (such as early menstruation and delayed onset of menopause, long-term use of contraceptive or hormone replacement therapy, elevated estrogen levels, or progestogen levels) is associated with an increased risk of developing breast or endometrial cancer. On the other hand, the reduced duration of exposure to these hormones such as the removal of the ovaries while they are active, or the use of anti-estrogens, reduces it.

In IVF, it is well known that we have 2 basic points. First, a brief, transient but significant increase in circulating estrogen levels during ovarian stimulation, as well as a large increase in progesterone levels during luteal phase support. Thus, estrogen levels in an IVF cycle can easily reach 3,000 - 4,000 pg/mL in women with a good ovarian response, which is significantly higher than 300 pg/ml in a normal physical cycle, without any pharmaceutical intervention. Correspondingly, Progesterone levels in a mildly supported luteal phase in IVF are similarly higher than levels in unsupported.

So the logical question to be elucidated is, if this short-term increase in estrogen and progesterone levels, along with the possible additional changes in other reproductive hormones, might increase the risk of breast, endometrial, ovarian cancer or other non-gynecologic female malignancies in patients undergoing IVF.

The answer to this question is very important, as there is a large number of women, counting about one million per year, who want to achieve pregnancy with assisted reproduction techniques and should be properly informed with up-to-date knowledge of their risk (if there is any) regarding the drugs to be used. On the other hand, health professionals need to know what applies to the treatments they submit to their patients, so that they may benefit and not harm them.