GnRH ANALOGUES DO NOT PREVENT CHEMOTHERAPY INDUCED OVARIAN FAILURE 

NEW YORK (Reuters Health) Jan 01 - Cotreatment with gonadotropin-releasing hormone (GnRH) analogues does not protect against ovarian damage in patients treated with cyclophosphamide-based chemotherapy, according to a new study.

The findings, published in the January issue of Obstetrics & Gynecology, contradict earlier studies suggesting ovarian suppression with GnRH agonists would help prevent chemotherapy-induced amenorrhea.

"I was deeply surprised at this evident lack of benefit," Dr. Eman A. Elgindy from Zagazig University School of Medicine in Egypt told Reuters Health by email. "What I recommend for preserving ovarian function in women like these are the established fertility preservation methods like oocyte and embryo cryopreservation. Indeed, this has been widely used in infertility treatment."

She and her colleagues tested a GnRH agonist or a combination of a GnRH agonist and an antagonist in a trial of 100 young (18-40 years old) women treated for hormone-insensitive breast cancer with cyclophosphamide-based chemotherapy.

Fifty women ready for early chemotherapy within one week of enrollment were randomized to early chemotherapy alone or chemotherapy after downregulation by a combined GnRH antagonist and agonist cotreatment.

The other 50 women (who were to start chemotherapy at least 10 days later) were randomized to receive chemotherapy alone or chemotherapy after downregulation with a GnRH agonist.

Menstruation resumption rates (ranging from 80% to 84%) did not differ significantly between patients treated with GnRH analogues and their respective controls at 12 months (the primary endpoint).

Among 68 women followed up for 18 months, cycle resumption and regularity were similar in women receiving GnRH analogues and their respective controls. There were three spontaneous pregnancies during this period, including one in each group except for the delayed chemotherapy control group.

Hormonal and ultrasound markers for ovarian reserve showed no significant differences among the groups at 6, 12, and 18 months.

Moreover, multivariable logistic regression analysis showed no significant correlation between tested variables and resumption of menstruation at 12 months post-chemotherapy (including age, chemotherapy dose, treatment modality using GnRH antagonist and agonist or GnRH agonist alone, and participating center).

"There are 2 main messages for physicians," Dr. Elgindy concluded. "First, in women younger than 40 years receiving the most toxic chemotherapy for treatment of breast cancer, these women should be counseled that amenorrhea ranges from 16-20% after one year of the end of chemotherapy (as there were marked variations in literature, from 21-71%, and these women have the right to be properly counseled). Second, GnRH analogues offer no benefit and alternative established measures must be done."

Dr. Kutluk Oktay from Reproductive Specialists of New York in Rye, New York, said numerous other well-designed studies have reached the same conclusions.

"Unfortunately there have been few others with certain design flaws which suggested this treatment may delay menopause, but even those did not show that fertility was preserved," Dr. Oktay told Reuters Health by email.

"Possible protection by hormonal suppression is not plausible because the reserve eggs (primordial follicles) are not hormone (FSH) sensitive; hence, hormonal manipulations cannot have direct effect on this cell population," he said. "It is time to consider the overwhelming evidence and ovarian biological facts to remove ovarian suppression from possible treatments of fertility preservation."

"We have shown that ovarian stimulation can be performed with aromatase inhibitors which keep estrogen levels low to alleviate the concerns with estrogen exposure in cancer patients while undergoing oocyte or embryo cryopreservation," Dr. Oktay added. "In addition, those who do not have sufficient time to undergo ovarian stimulation can resort to other experimental approaches, such as ovarian tissue freezing and in vitro maturation."

Other experts agreed the GnRH agonists have not been proven to protect the ovaries from chemotherapy.

"We recommend cryopreservation of 50% of one ovary in women up to around 35 years of age or ovarian stimulation and cryopreservation of oocytes in women up to around 38 years of age and if the tumor is not estrogen dependent," Dr. Michael von Wolff from University Hospital Berne in Switzerland told Reuters Health by email. "In some chemotherapies and in young patients no fertility preserving therapy is necessary."

Dr. Sam Kim from the University of Kansas Medical Center in Kansas City said ovarian suppression in chemotherapy has always been controversial and that newer studies have found no or only marginal benefit.

"Indeed," Dr. Kim said in an email to Reuters Health, "we need prospective randomized studies with a larger sample size to reach a definite answer for this issue. I am waiting for the results of the SWOG trial that is supposed to complete by 2014."

SOURCE: http://bit.ly/W6Lnpx

Obstet Gynecol 2013;121:78-86.