Short Communication
Gonadotropin-Releasing Hormone Agonist Debate
Zeev Blumenfeld*
Department of Reproductive Endocrinology, Israel Institute of Technology, Haifa, Israel
*Corresponding author: Zeev Blumenfeld, Department of Reproductive Endocrinology, Israel Institute of Technology, Haifa, Israel 31096
Published: 10 Jul, 2017
Cite this article as: Blumenfeld Z. Gonadotropin-Releasing
Hormone Agonist Debate. Clin Oncol.
2017; 2: 1315.
Keywords
Fertility preservation; pregnancies after gonadotoxic chemotherapy; GnRH-agonist; premature ovarian failure
Gonadotropin-Releasing Hormone Agonist Debate
The recent publications by Demeestereet a land the accompanying editorial in the journal of
clinical oncology are intriguing [1,2]. We agree with the authors’ statement: “… pregnancy is the
most accurate …for evaluating the efficiency of fertility preservation.” We have shown that GnRH
a increased spontaneous conceptions (P <0.006), in addition to preserving Cyclic Ovarian Function
(COF) (OR = 6.87) [3], in a large group of young women followed up for up to two decades. Ninety
patients (62%) conceived 178 times in the GnRHa group vs. 31 patients experiencing 55 pregnancies
(42%) in the controls (P <0.0003), generating 131 and 41 newborns (P <0.01), respectively [3].
Spontaneous pregnancies occurred in 58% of the survivors in the GnRHa group, vs 34.9% of the
controls (P = 0.009). Similarly, two recent RCT’s publications, in the NEJM and JAMA [cited in
1] assessed the efficacy of GnRHa reporting promising data on fertility outcomes [1]. Both studies
found significant reduction in premature ovarian failure (POF) in the GnRHa arms (OR: 0.28-0.3;
P <0.001-0.04) [3].
The authors [1] mention their study limitations: dropout rate of 50%, and 25% loss of follow-up
or data unavailability. Although the original study “mandated the accrual of 157 patients to ensure a
power of 80% and a type error I probability of 5%, enrolment was discontinued after the assignment
of129 patients,” but only 63 patients were evaluated for POF, 31-32 in each arm, in 15 centers (1-3
patients/arm/center). Furthermore, five pregnancies occurred in patients with protocol-defined
POF of “one FSH >40U/L measurement” challenging the accuracy of POF definition, and the
resulting conclusions.
Indeed, the study initially did not find a difference in POF rate after one year [4], but two years
follow-up [5] claimed: "… the number of patients who totally restored their ovarian function was
significantly higher in the GnRHa group (P = 0.049) confirming results of AMH", (mean AMH
was 1.4±0.35 ng/ml in the GnRHa arm vs. 0.5 ± 0.15ng/ml in the controls (P <0.04)) [4]. The small
number of the evaluated patients (type-I error) may explain the “negative” results after one year
[4], the pendulum swinging to “positive” result at 2 years [5], and again switching back to negative
conclusion at 5 years [1].
Relevant to this equivocal issue, a publication [6] from one of the previous opponents to
GnRH-a, has found that the use of GnRHa during chemotherapy has significantly increased the
probability to become pregnant (OR = 12.87 P = 0.001); They [6], "…found strong (OR (12
Oktay and Bedoschi [2] claim that none of the studies favoring GnRHa effect for fertility
preservation was blinded or placebo controlled, therefore unacceptable. On the other hand, they [2]
claim that the successful reports on ovarian cryopreservation should lead to accepting this method
as an unequivocally established method for fertility preservation. How many of these reports were
“blinded or placebo controlled” or even RCT’s? None. What is the
justification of their double standard?
Furthermore, Oktay and Bedoschi [2] claim that primordial
follicles do not have FSH receptors and their growth is unaffected
by GnRHa. In contradiction, Zheng et al. [9] demonstrated FSH
receptorm RNA expression, by RT-PCR, in primordial follicles.
More recently, Bhartiya and Singh [10], have identified two distinct
populations of stem cells including very small embryonic-like stem
cells (VSELs) and ovarian stem cells in OSE, responsible for neooogenesis
and Primordial Follicle (PF) assembly in adult life, being
modulated by FSH via its alternatively spliced receptor variant
FSH-R3. If indeed FSH-R3 (lacking exon 10) is the key player to
mediate FSH action on stem cells, one could easily explain why the
extensive studies undertaken to search for mutations in exon 10 of
FSH receptor have failed. Failure to detect FSH receptors on PF’s
incorrectly suggested that initial PF growth is GN independent.
However, the primers used for rt-PCR were selected from exon 10
whereas PF’s express FSH-R3 that lacks exon 10.
Due to these and several other inaccurate points, these publications
[1,2], are unconvincing and intriguing. The recent publication [11],
by several leaders in fertility preservation seems to be in keeping with
our opinion.
References
- Demeestere I, Brice P, Peccatori FA, Kentos A, Dupuis J, Zachee P, et al. No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial. J Clin Oncol. J Clin Oncol. 2016; 34: 2568-2574.
- Oktay K, Bedoschi G. Appraising the Biological Evidence for and Against the Utility of GnRHa for Preservation of Fertility in Patients with Cancer. J Clin Oncol. 2016; 34: 2563-2565.
- Blumenfeld Z, Zur H, Dann EJ. Gonadotropin-Releasing Hormone Agonist Co treatment During Chemotherapy May Increase Pregnancy Rate in Survivors. Oncologist. 2015; 20: 1283-1289.
- Demeestere I, Brice P, Peccatori FA, Kentos A, Gaillard I, Zachee P, et al. Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol. 2013; 31: 903- 909.
- Demeestere I, Brice P, Peccatori FA. Triptorelin to prevent chemotherapyinduced ovarian failure in lymphoma patients: a prospective randomized study. Paper presented at: Third World Congress of the International Society for Fertility Preservation; November, 2013; Valencia, Spain.
- Behringer K, Thielen I, Mueller H, Goergen H, Eibl AD, Rosenbrock J, et al. Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial. AnnOncol. 2012; 23: 1818-1825.
- Lambertini M, Del Mastro L, Pescio MC. Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med. 2016; 14: 1.
- Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.Ann Oncol. 2015; 26: 1533-1546.
- Zheng W, Magid MS, Kramer EE, Chen YT. Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube.Am J Pathol. 1996; 148: 47-53.
- Bhartiya D, Singh J. FSH-FSHR3-stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer. Reproduction. 2015; 149: R35-R48.
- Lambertini M, Falcone T, Unger JM, Phillips KA, Del Mastro L, Moore HC. Debated Role of Ovarian Protection With Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women With Cancer. J Clin Oncol. 2017; 35: 804-805.