Ovarian protection with gonadotropin-releasing hormone agonists during chemotherapy in cancer patients: From biological evidence to clinical application

doi:10.1016/j.ctrv.2018.11.006

Cancer Treatment Reviews

Volume 72, January 2019, Pages 65-77

https://doi.org/10.1016/j.ctrv.2018.11.006 Get rights and content

Highlights

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In premenopausal cancer patients, chemotherapy can cause premature ovarian insufficiency (POI).
•
GnRHa administration during chemotherapy is an available strategy to reduce POI risk.
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This strategy is now endorsed for clinical use by several guidelines.
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Long-term follow-up data from the available randomized trials is awaited.
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The protective mechanism of action of this strategy remains not clearly identified.
•
Adequately conducted in vitro and in vivo animal experiments should be further encouraged.

Abstract

Survivorship issues are an area of crucial importance to be addressed as early as possible by all health care providers dealing with cancer patients. In women diagnosed during their reproductive years, the possible occurrence of chemotherapy-induced premature ovarian insufficiency (POI) is of particular concern being associated with important menopause-related symptoms, psychosocial issues as well as infertility. Temporary ovarian suppression by administering a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been studied to reduce the gonadotoxic impact of chemotherapy thus diminishing the chance of developing POI. Despite more than 30 years of research in both preclinical and clinical settings, the performance of this strategy has remained highly debated until recently. In particular, the potential mechanisms of action for the protective effects of GnRHa during chemotherapy are still not clearly identified. Nevertheless, important novel research efforts in the field have better elucidated the role of this option that is now endorsed for clinical use by several guidelines.

This manuscript aims at providing an extensive overview of the literature on the use of temporary ovarian suppression with GnRHa during chemotherapy in cancer patients by addressing its biological rationale, the available preclinical and clinical evidence as well as the still existing grey zones in this field that future research efforts should address.

Introduction

As a consequence of the improved survival outcomes, a significant proportion of cancer survivors face the long-term side-effect of anticancer treatments making survivorship issues an area of crucial importance to be addressed by all health care providers dealing with these patients. In women diagnosed during their reproductive years, a possible additional side effect associated with the use of anticancer therapies is the occurrence of chemotherapy-induced premature ovarian insufficiency (POI) [1]. Importantly, besides infertility, POI development has several other negative consequences on the quality of life and wellbeing of young patients being associated with menopausal symptoms as well as risk of osteoporosis, cognitive dysfunction and cardiovascular disease [2]. According to major international guidelines, POI risk should be discussed as early as possible after diagnosis with all young patients for then offering the available strategies to reduce the burden of this side effect to those who are interested [3], [4].

Embryo and oocyte cryopreservation are available strategies for fertility preservation in cancer patients but they cannot prevent the risk of chemotherapy-induced POI with its associated psychosocial and menopause-related concerns beyond infertility. Temporary ovarian suppression obtained by administering a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been studied as a strategy to reduce the gonadotoxic impact of chemotherapy thus diminishing the chance of developing POI. Despite a long debate on this topic, important novel research efforts in the field have better clarified the role of temporary ovarian suppression with GnRHa during chemotherapy that is now endorsed for clinical use by several guidelines [4], [5], [6].

Section snippets

Biological rationale

In human adult ovaries, the large majority of the follicles are quiescent, at the primordial stage. The activation of these follicles is precisely controlled to maintain an equilibrium between growing and quiescent follicles during the reproductive life. After reaching preantral stage, follicle development is dependent on gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) that stimulate the proliferation of granulosa cells, the differentiation of theca cells and

Preclinical evidence

In the 80s–90s, several experiments in rats and monkeys provided evidence on the efficacy of GnRHa use in protecting the ovaries from chemotherapy-induced damage [38], [39], [40], [41], [42] opening the door to its subsequent clinical development. However, subsequent preclinical experiments reported conflicting results so that after more than 30 years of research in the field, the mechanism of action of this strategy remains controversial.

Clinical evidence

In premenopausal women, several clinical research efforts have been conducted in this setting, not only in cancer patients but also in women receiving chemotherapy for autoimmune diseases. For premenopausal cancer patients, the majority of the studies have been conducted in young women with breast cancer but important evidence exists also for those with hematological malignancies; conversely, limited data are available for cancer patients diagnosed with other solid tumors.

Conclusions and future perspectives

After more than 30 years of research in the field, recently updated guidelines recommend the use of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal breast cancer patients through systemic cytotoxic therapy [4], [5], [6]. The best candidates for this strategy are women aiming to reduce the risk of developing chemotherapy-induced POI irrespectively of their pregnancy desire. For women interested in fertility preservation, temporary ovarian suppression with GnRHa

Acknowledgments

Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at the Institut Jules Bordet in Brussels (Belgium).

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

Matteo Lambertini served as a consultant for Teva and received speaker honoraria from Theramex outside the submitted work. All remaining authors declare no conflicts of interest.

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Approaches to Fertility Preservation for Young Women With Breast Cancer
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Breast cancer treatment and ovarian function
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Citation Excerpt :
If GnRH has the potential to protect the ovary from CIA, what is the mechanism of its action? Although the mechanism is unknown (or does not exist), there are some proposed mechanisms, such as decreased delivery of chemotherapeutics into ovarian tissue due to reduced ovarian blood flow, pseudomenopausal state created by GnRH administration, or other actions of GnRH in the ovary (Lambertini et al., 2019b). Follicle development from the primordial to the antral stage is a continuous process in the ovary.
The aim of this study was to provide an update on ovarian function and the mechanisms of gonadal damage after exposure to chemotherapy in breast cancer survivors. The alkylating agents are toxic to both primordial and growing follicles. However, anti-metabolite drugs are more likely to destroy preantral and antral follicles. Younger patients are more likely to have a higher ovarian reserve, and therefore, more likely to retain some residual ovarian function after exposure to gonadotoxic regimens. However, there can be significant variability in ovarian reserve among patients of the same age. Furthermore, patients with critically diminished ovarian reserve may continue to menstruate regularly. Therefore age and menstrual status are not reliable indicators of good ovarian reserve and might give a false sense of security and result in an adverse outcome if the patient is consulted without considering more reliable quantitative markers of ovarian reserve (antral follicle count and anti-Müllerian hormone) and fertility preservation is not pursued. In contrast to well-documented ovarian toxicity of older chemotherapy regimens, data for newer taxane-containing protocols have only accumulated in the last decade and data are still very limited regarding the impact of targeted therapies on ovarian function.
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Ovarian reserve in premenopausal women with breast cancer
2022, Breast
Citation Excerpt :
The treatment-related reproductive toxicity and ovarian function protection of women with cancer will be an important issue in the present and for a long time in the future [1–3].
As a special reproductive hormone and ovarian reserve indicator, the role of anti-Müllerian hormone (AMH) in premenopausal women with breast cancer deserves further study.
We conducted an in-depth analysis of the data from the EGOFACT study (NCT02518191), a phase Ⅲ, randomized, controlled trial involving premenopausal female breast cancer patients in two parallel groups: chemotherapy with or without gonadotropin-releasing hormone analogs (GnRHa). Three hundred thirty premenopausal women aged 25–49 years with operable stage I to III breast cancer were included in this study. The characteristics of ovarian reserve changes marked by AMH in the EGOFACT study and the factors affecting ovarian function in premenopausal women with breast cancer were analyzed.
The AMH level of the chemotherapy alone group decreased gradually within one year, while the AMH level of the GnRHa group was significantly higher as early as 6 months after chemotherapy and recovered to close to the baseline level 12 months after chemotherapy (F = 34.991, P < 0.001). Correlation analysis showed that the factors affecting AMH levels mainly included age, menarche age, body mass index (BMI), reproductive history, baseline follicle stimulating hormone (FSH) level, pathological stage and GnRHa application, but they had different effects on the incidence of premature ovarian insufficiency (POI) at different periods. Multivariate logistic regression analysis showed that menarche age younger than 14 years (OR 0.470 [0.259, 0.852], P = 0.013), baseline AMH level higher than 0.5 ng/mL (OR 9.590 [3.366, 27.320], P < 0.001), pathological stage Ⅰ(OR 0.315 [0.124, 0.798], P = 0.015) and GnRHa application (OR 0.090 [0.045, 0.183], P < 0.001) were independent factors conducive to protection of ovarian reserve, as well as to recovery of ovarian reserve.
Age, menarche age, baseline AMH level, and GnRHa application are the most important influencing factors for ovarian reserve in premenopausal women with breast cancer.
ClinicalTrials.gov, NCT02518191, registered on Aug 5, 2015.

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General and Supportive CareOvarian protection with gonadotropin-releasing hormone agonists during chemotherapy in cancer patients: From biological evidence to clinical application

Highlights

Abstract

Introduction

Section snippets

Biological rationale

Preclinical evidence

Clinical evidence

Conclusions and future perspectives

Acknowledgments

Funding

Disclosure

Ann Oncol

Eur J Cancer

Breast

Blood

Biochim Biophys Acta

Fertil Steril

Fertil Steril

Mol Cell Endocrinol

Fertil Steril

Eur J Obstet Gynecol Reprod Biol

Reprod Toxicol

Reprod Biol Endocrinol

Fertil Steril

Front Neuroendocrinol

Fertil Steril

Ann Oncol

Ann Oncol

Cancer Treat Rev

Ann Oncol

Ann Oncol

Cancer and fertility preservation: international recommendations from an expert meeting

BMC Med

Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review

J Natl Cancer Inst

Fertility preservation in patients with cancer: ASCO clinical practice guideline update

J Clin Oncol

What lies behind chemotherapy-induced ovarian toxicity?

Reprod

Declines in levels of hyperpolarization-activated cation (HCN) channels in the rat ovary after cisplatin exposure

Reprod Sci

Folliculogenesis is not fully inhibited during GnRH analogues treatment in mice challenging their efficiency to preserve the ovarian reserve during chemotherapy in this model

PLoS ONE

Initial and cyclic recruitment of ovarian follicles

Endocr Rev

Follicle-stimulating hormone accelerates mouse oocyte development in vivo

Biol Reprod

How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries

Oncologist

LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

Cell Death Differ

The impact of depot GnRH agonist on AMH levels in healthy reproductive-aged women

J Clin Endocrinol Metab

Ovarian follicle burnout: a universal phenomenon?

Cell Cycle

Gonadotrophin-releasing hormone agonists for fertility preservation: unraveling the enigma?

Hum Reprod

Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5

Endocrinology

Effect of pituitary desensitization on the early growing follicular cohort estimated using anti-Mullerian hormone

Hum Reprod

Utero-ovarian blood flow characteristics of pituitary desensitization

Hum Reprod

Effect of pituitary downregulation on antral follicle count, ovarian volume and stromal blood flow measured by three-dimensional ultrasound with power Doppler prior to ovarian stimulation

Hum Reprod

Long-term follow-up of chemotherapy-induced ovarian failure in young breast cancer patients: the role of vascular toxicity

Oncologist

Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury

Hum Reprod

Gonadotropin-releasing hormone and its receptor in normal and malignant cells

Endocr Relat Cancer

Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in rat ovary

Endocrinology

Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer

Reprod Biol Endocrinol

GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy

Hum Reprod Update

Enhancement of neoangiogenesis and follicle survival by sphingosine-1-phosphate in human ovarian tissue xenotransplants

PLoS ONE

General and Supportive Care
Ovarian protection with gonadotropin-releasing hormone agonists during chemotherapy in cancer patients: From biological evidence to clinical application