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    Better results with less medication

    Every woman who starts an IVF infertility treatment has two questions on her mind: “what are my success rates?” and “could I take less medication?”
    A new clinical research, which took place in University Gynaecology Clinics of the Netherlands and has been published in the international scientific magazine “Human Reproduction”, showed that embryos from IVF cycles which have yielded many oocytes have more chromosomal abnormalities (genetic material disorders). This has been found with preimplantation genetic diagnosis, a specialised technique that screens the embryo for possible genetic material problems before embryo transfer.
    “The study in question doesn’t surprise me, as it scientifically confirms the clinical observation of many years of experience, showing that patients who produce many oocytes (more than 16-20) during ovarian stimulation finally have lower fertilisation rates, as well as lower top quality embryo rates. Moreover, the endometrium is less receptive to embryonic implantation, due to high estrogen concentration”, said Mr. Evripidis Mantoudis FRCOG, reproduction gynaecologist. “Contrary to the “more drugs= more oocytes= more chances of achieving pregnancy” rationale, in the past few years, we have been using lower doses of medication and have excellent results of pregnancy achievement, without the ovarian hyperstimulation risk”. The ovarian hyperstimulation syndrome involves overreaction of the ovaries to medication, as well as unpleasant (and sometimes dangerous) symptoms experienced by the patient (abdominal bloating, pain, nausea, vomiting).
    Ideal candidates for IVF with lower medication dosage are patients with polycystic ovaries, those who produce many oocytes but whose embryos aren’t of top quality, as well as those who have experienced ovarian hyperstimulation in the past. Older women with few oocytes don’t benefit from high doses of medication either, which also makes them eligible candidates for IVF with lower medication dosage; this applies to all women who mustn’t take high doses of estrogens for medical reasons.

    “Until today, it hasn’t been found that hormones contained in ovulation drugs cause cancer; however, trying to administer less medication makes sense”, continued Mr. Mantoudis. “With lower doses of medication, fewer oocytes are produced (6-10), having though improved fertilisation rates and giving better embryos (better pregnancy potential). Moreover, the endometrium is more receptive. Besides optimal results, less medication guarantees a satisfaction rate of almost 100%, because “disturbance” in the patient’s system is the least possible. Thus, the whole procedure becomes easier, more comfortable and has no complications”.

    Today, IVF pregnancy rates are increased. With success being established, we aim at quality: contrary to past experience, IVF can now be a problem – free and stress – free procedure.  

    The role of hormones and medication in ovarian stimulation

    To prevent premature ovulation – i.e. before oocyte retrieval –, communication between ovaries and brain must be interrupted. This is accomplished with the use of GnRH-analogues; these are medicines closely resembling the gonadotropin-releasing hormone (GnRH), which is produced in the brain hypothalamus and controls FSH and LH hormones released by the hypophysis. There are 2 types of GnRH-analogues, agonists and antagonists, each type suppressing LH production in a different way.
    GnRH-agonists initially stimulate FSH and LH release, but then suppress the hypophysis.
    GnRH-antagonists constitute a newer class of injectable medicines, suppressing the hypophysis without having previously increased FSH and LH; thus, they are administered for fewer days.
    The selection of medication depends on various parameters, such as the woman’s age, ovarian response in previous cycles, as well as on other factors.
    To achieve final oocyte maturation before oocyte retrieval, a chorionic gonadotropin injection is administered (Pregnyl). In this way, we substitute LH release, naturally occurring before ovulation. For the time being, it is impossible to produce synthetic LH, which is thus replaced by chorionic gonadotropin, so as to enable final oocyte maturation.


    Is there a causal relationship between the use of medication for ovarian stimulation and the development of cancer?

    Recently, an epidemiological study from Denmark has been published, reassuring the medical community, as well as the public, as it definitely and clearly demonstrates that there is no correlation between the use of medication for infertility (ovarian stimulation) and the development of (breast or ovarian) cancer.

    The study has been recently published in 2 parts (‘Risk of Breast Cancer After Exposure to Fertility Drugs: Results from a Large Danish Cohort Study’ Jensen A et al 2007 Cancer Epidemiol Biomarkers Prev 16(7):1400-7 and ‘Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study’ Jensen A et al 2009 BMJ 338:b249). Denmark is the country with the highest percentage of children born with the aid of IVF. Within the framework of the study, there have been observed 54.362 women who have reached assisted reproduction clinics in Denmark, between 1963 and 1998. This is the study with the largest number of participants that has ever been carried out and the only one deemed reliable to give definite and clear answers due to its statistical validity. Namely: 

    Conclusion 1:
    “There is no significant correlation between the possibility of developing breast cancer and the use of medication for infertility. There is no correlation with the number of cycles or the number of years since the first use of medication”. 

    Researchers have found out 331 cases and note that the group of patients who remain childless must be further studied, due to the limeted number of women who constitute it.

    Conclusion 2:

    “No increase is recorded in the possibility of developing ovarian cancer after the use of gonadotropins. There is no correlation with medication for infertility, regardless of the number of cycles, time of monitoring or number of children of every patient”.


    Researchers have found out 156 cases and note that previous studies of that kind couldn’t have given definite and clear answers due to inaccurate statistical analysis (risk factor evaluation) and to comparison being made to the wrong population (women with infertility who have used medication have been compared to the general population, while they should have been compared to women with infertility who haven’t used any medication).
    They conclude that the possibility of developing cancer seems to increase rather due to the patient’s infertility itself than to the use of medication for ovarian stimulation (it has been suggested in the past that endometriosis constitutes a risk factor). They stress that research must now turn towards that direction. 

    Personal opinion of Mr. Evripidis Mantoudis

    “The study from Denmark confirms my personal clinical experience. Nowadays, too many women are using IVF medication. If it caused cancer, every reproduction gynaecologist who applies IVF treatments would face cases of cancer among his patients on a daily basis. Of course, nothing like that happens. Besides, no large study showing a clear correlation between medication and cancer occurrence has ever been published in the international scientific bibliography. All relevant references concerned studies that involved a limited number of patients, thus their results couldn’t be statistically reliable. In any case, cancer development is multifactorial, which means that many different factors must coexist.
    Epidemiological studies endorse clinical experience: medication for ovarian stimulation is necessary in order for the infertility treatment to succeed. It is self-evident though that we prescribe the fewest possible medicines, as we achieve in this way the “ideal” ovarian stimulation. Moreover, we thus avoid side effects, such as ovarian hyper-stimulation. Our aim is to achieve a positive result as soon as possible, that is with the fewest possible IVF cycles”.

    Past concerns

    Safety has always been a big question when it comes to the use of medication for ovarian stimulation. Some types of cancer in women (e.g. some types of breast cancer) are known to be hormone-dependent, i.e. to “grow” due to the existence of reproductive hormones. In such cases, part of the treatment consists in suppressing the production of these hormones, in order for the tumour to shrink. So, the reasonable question is: could the external administration of hormones with the aim to stimulate the ovaries during the assisted reproduction treatment cause cancer, either in the short or in the long run in a woman’s life? This matter is being monitored with consecutive clinical studies from the first years of assisted reproduction treatments until today.

    In the early 90s, 2 clinical studies (Whittemore AS et al 1992 Am J Epidemiol 136:1184-203 and Rossing MA et al 1994 N Engl J Med 331:771-6) made an impact, as they showed that the use of medication for ovarian stimulation increases the possibilities of developing ovarian cancer. The first study reported 12 cases, while the second one reported 9 cases. After these two studies, and given their extremely limited sample of cases, there has been an outbreak of relevant epidemiological studies with the aim to definitively confirm or refute the results.
    All those years that the assisted reproduction treatments are being applied, bibliography reports cases of patients who have developed ovarian or breast cancer after having taken in the past medication for ovarian stimulation within the framework of an infertility treatment. Epidemiological studies aimed at conducting researches including large numbers of participants and accurate statistical analysis, in order either to confirm the causal relationship between the use of medication for ovarian stimulation and the development of cancer or to definitively deem the cases of cancer “random”.
    However, according to Brinton LA et al (Fertility & Sterility 2005; 83:261-74), most such studies had to solve basic problems:
    • Limited number of participants (thus not permitting statistical analysis so as to draw definitive conclusions),
    • Patients monitored for a short period of time (thus a large amount of “missed” information), 
    • Inaccurate information on medication and its indications of use.
    • Inability to tell whether medication or infertility itself was finally responsible for the development of cancer (i.e. whether infertility and the development of cancer have a common genetic cause). 

    In general, studies were reassuring, although slightly increaded rates of cancer development have been reported among some specific populations of patients, e.g. among those who remain childless, those monitored for a long period of time or those who take medication for many menstrual cycles. Thus, an epidemiological study which would give an answer about all the cases, in a definitive and clear way, was imperative. The study that gave clear answers due to the large number of participants and the strength of statistical analysis is the aforementioned study carried out in Denmark. 


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