Learning Objectives
After completing this course, the reader will be able to:
Discuss the possibilities for preserving fertility in women exposed to chemotherapy.
List the possible mechanisms put ...forward to explain the beneficial effect of GnRH agonists in minimizing the gonadotoxic effect of chemotherapy, in particular that of alkylating agents.
Identify the advantages and possible risks and shortcomings of each of the proposed methods for fertility preservation in women exposed to gonadotoxic chemotherapy.
Discuss the possibility of combining several methods to maximize the chances of fertility preservation in these patients.
Explain the gender differences between male and female patients regarding the methods of fertility preservation.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
The possibilities to preserve fertility in women exposed to chemotherapy are: in vitro fertilization plus embryo cryopreservation, ovarian cryopreservation, unfertilized ova cryopreservation, and the administration of a gonadotropin‐releasing hormone (GnRH) agonist. Because none of these methods is ideal, combination of several methods should be considered. Because the chances of preserving gonadal function following combined‐modality treatment are significantly better for girls than for boys, simulation of a prepubertal milieu was applied only to women of reproductive age. The administration of GnRH agonists to women with Hodgkin's disease, breast cancer, and other malignancies, or to patients with lupus nephropathy, in parallel with chemotherapy, by others and by us, has demonstrated a significantly lower rate of premature ovarian failure in survivors than in nonrandomized controls. Several prospective, randomized studies are ongoing. A recent meta‐analysis found that the administration of a GnRH agonist, in addition to chemotherapy, to patients with breast cancer was associated with less recurrence and superior survival. Several possibilities to explain the beneficial effect of GnRH agonists to minimize chemotherapy‐associated gonadotoxicity are suggested: (a) The hypogonadotropic milieu decreases the number of primordial follicles entering the differentiation stage, which is more vulnerable to chemotherapy; (b) The hypoestrogenic state decreases ovarian perfusion and delivery of chemotherapy to the ovaries; (c) A direct effect of the GnRH agonist on the ovary occurs independently of the gonadotropin level; (d) GnRH agonists may upregulate an intragonadal antiapoptotic molecule such as sphingosine‐1‐phosphate; (e) The GnRH agonist may protect ovarian germline stem cells.
The infertile patients with aging ovaries-also sometimes referred to as impending premature ovarian insufficiency (POI), impending premature ovarian failure (POF), or poor ovarian responders (POR), ...constitute a significant and increasing bulk of the patients appealing to IVF/ART. Different causes have been cited in the literature, among the identified etiologies, including chromosomal and genetic etiology, metabolic, enzymatic, iatrogenic, toxic, autoimmune, and infectious causes. Although the most successful and ultimate treatment of POI/POF/POR patients is egg donation (ED), many, if not most, of these infertile women are reluctant to consent to ED upon the initial diagnostic interview, requesting alternative solutions despite the low odds for success. Despite anecdotal case reports, no unequivocal treatment proved to be successful for these patients in prospective randomized controlled trials. Nevertheless, the addition of growth hormone (GH) to ovarian stimulation in POR with GH deficiency may improve the results of controlled ovarian hyperstimulation (COH) and the IVF success. In patients with autoimmune etiology for POR/POI, the combination of glucocorticosteroids, pituitary-ovarian suppression, and COH may be successful in achieving the desired conception.
Background.
The use of gonadotropin‐releasing hormone analogs (GnRHas) for fertility preservation is not unequivocally accepted. It is controversial whether GnRHa can increase the pregnancy rate in ...survivors.
Patients and Methods.
This is a retrospective cohort study. Every patient referred for fertility preservation was offered cryopreservation of embryos, ova, and ovarian tissue and GnRHa. The patients were consecutively included. The primary outcome was spontaneous pregnancies. The secondary outcome was cyclic ovarian function (COF) versus premature ovarian failure (POF). These outcomes were assessed 2 years or more after chemotherapy.
Results.
We compared 286 patients who received gonadotropin‐releasing hormone agonist (GnRHa) with chemotherapy with 188 patients who were treated with chemotherapy alone. Ovarian function could be determined in 217 patients. Overall, 87% (127 of 146) of the patients in the GnRHa group retained COF and 13% (19 of 146) suffered POF, whereas in the control group, 49% (35 of 71) experienced COF and 51% (36 of 71) suffered POF (p = .0001). The odds ratio (OR) for preserving COF was 6.87 for the patients who received GnRHa (95% confidence interval CI 3.4–13.4). Overall 60% (112 of 188) of the survivors conceived: 69.3% (84 of 122) of the patients in the GnRHa group compared with 42.4% (28 of 66) in the control group (p = .006). In the GnRHa group, 123 healthy newborns were delivered, versus 40 in the controls. Spontaneous pregnancies occurred in 65.6% (80 of 122) of the survivors in the GnRHa group versus 37.9% (25 of 66) in the control group (p = .0004, OR 3.12, 95% CI 1.7–5.8).
Conclusion.
Adding GnRHa to chemotherapy significantly increases the OR for spontaneous conception, in addition to COF. It is suggested that GnRHa cotreatment should be added before and during gonadotoxic chemotherapy.
Implications for Practice:
The use of gonadotropin‐releasing hormone analogs (GnRHa) for fertility preservation is not unequivocally accepted and is even controversial. This study compared 286 patients who received GnRHa with chemotherapy with 188 patients who were treated with chemotherapy alone. Ovarian function could be determined in 217 patients. The odds ratio for preserving cyclic ovarian function was 6.87 for the patients who received GnRHa. Furthermore, the total and spontaneous pregnancy rate was significantly higher for those who received the agonist (p = .006). Adding GnRHa to chemotherapy significantly increased the odds ratio for spontaneous conception, in addition to preserving regular ovarian function. It is suggested that GnRHa cotreatment should be administered to young women in conjunction with gonadotoxic chemotherapy.
Patients who received gonadotropin‐releasing hormone agonist (GnRHa) with chemotherapy were compared with patients who were treated with chemotherapy alone to determine whether GnRHa can increase the pregnancy rate in survivors. The results indicated that adding GnRHa to chemotherapy significantly increases the odds ratio for spontaneous conception, in addition to cyclic ovarian function. It is suggested that GnRHa cotreatment should be added before and during gonadotoxic chemotherapy.
To compare the rate of premature ovarian failure (POF) after stem cell transplantation (SCT) in young women receiving GnRH-agonist (GnRH-a) in conjunction with gonadotoxic chemotherapy.
Prospective, ...nonrandomized study.
Tertiary university hospital.
Ninety-five women received conditioning chemotherapy, with or without GnRH-a before SCT. Complete information was available for only 83 patients.
Conditioning chemotherapy, with or without GnRH-a before SCT.
Cyclic ovarian function (COF) or POF after SCT.
There were no significant differences in age, chemotherapy treatment, or diagnoses between the study and control groups. In the GnRH-a group, 38.3% (18/47) patients resumed COF, compared with 11.1% (4/36) for patients who did not receive GnRH-a. Patients who resumed COF were on average 3.7 years (median, 3 years) younger at the time of transplantation than those who experienced POF. GnRH-a had a significant effect on long-term COF in patients with lymphomas (66.7% 14/21 for GnRH-a group vs. 18.2% 2/11 for control) but not for leukemia patients.
GnRH-a cotreatment in conjunction with conditioning chemotherapy before SCT may significantly decrease the gonadotoxicity and POF from 82% to 33% in lymphoma but not in leukemia patients.
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