Current Clinical Approaches to Protecting the Ovary: GnRH Analogues

8.1 Introduction

Cancer is not uncommon and no longer considered as an incurable disease among reproductive-age women. Indeed, cancer is estimated to occur in approximately 2% of women under the age 40. Over the past decades, there has been a remarkable improvement in the survival rates due to the marked progress in detecting cancer at earlier stages and the improvement in treatment modalities. With improvements in treatment outcomes, 83% of women younger than 45 years diagnosed with cancer in the USA survived between 2002 and 2012. As a consequence of the increase in the number of patients surviving cancer, greater attention has been focused on the delayed effects of cancer treatments on the quality of future life of the survivor.

The treatment for most of the cancer types in reproductive-age women involves either removal of the reproductive organs or cytotoxic treatment (chemotherapy and/or radiotherapy) that may partially or definitively affect reproductive function. The irreversible gonadotoxic effects of chemotherapeutic agents on the ovary are well documented, especially for anthracyclines and alkylating agents (e.g., cyclophosphamide, busulfan and ifosfamide), which are the backbone of chemotherapy for breast cancer, lymphomas, leukaemia and sarcomas (see also Chapter 4 ). Pelvic radiation therapy also causes follicular destruction and less than 2 Gy of radiation can deplete at least 50% of the follicles. In addition, exposure to 5–10 Gy of pelvic radiation results in premature ovarian insufficiency (POI) in many women. The risk of ovarian failure following chemotherapy is highly correlated with the woman’s age and ovarian reserve at the time of treatment, type and dosage of drug administered, and the duration of drug exposure. After chemotherapy, the long-term incidence of amenorrhoea is at least 25% at age 30 years and is 50% in women aged 35–40 years, whereas most women over 40 years of age become amenorrhoeic, and their chances of restoring ovarian function is dismal. In addition, temporary amenorrhoea post-chemotherapy, but not duration of amenorrhoea, predicted a trend toward increased rates of infertility.

Currently, the most widely used and effective strategies for fertility preservation in cancer patients are oocyte and embryo cryopreservation, which require the patient to undergo controlled ovarian stimulation in preparation for oocyte retrieval. Historically, this treatment option was often associated with significant delays in starting cancer treatment, which led to anxiety on the part of both the patient and medical team. However, with a random start ovarian stimulation, there are now minimal delays, but it is potentially costly and invasive.

Another option, which has resulted in live births but is still considered experimental according to the American Society for Reproductive Medicine, is the cryopreservation of ovarian tissue. With this procedure, ovarian tissue is surgically removed and cryopreserved. The tissue can then be re-transplanted into the patient at a later time. Although pregnancies have been achieved, the efficiency of this method is controversial : this is discussed further in Chapter 7 .

Another option for fertility preservation that does not require cryopreservation of reproductive cells/tissues involves medical treatments that may protect the ovary. The most widely used agents are gonadotropin-releasing hormone (GnRH) agonists. Multiple clinical studies suggest a potential protective effect in patients receiving gonadotoxic chemotherapy, while others demonstrate no benefit. However, there are no data to support the use of GnRH agonists to protect the ovary from radiotherapy. In this chapter, we review the physiology of GnRH and the role of GnRH agonist co-treatment with chemotherapy for the protection of the ovary.

8.2 Distribution and Roles of the GnRH/GnRH Receptor System

8.2.1 GnRH

GnRH is a decapeptide synthesized by specific neurons located in the arcuate nucleus and in the preoptic area of the hypothalamus, and is released into the portal blood in a pulsatile fashion. GnRH binds with high affinity to specific G protein-coupled receptors on the surface of gonadotrope cells in the anterior pituitary, and induces biosynthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones act directly on the ovary, stimulating steroidogenesis and gametogenesis.

Twenty-three different isoforms of GnRH have been identified in various vertebrate species. All of these peptides consist of 10 amino acids and have a similar structure, with at least 50% sequence identity ; they have been named according to the species from which they were initially isolated. In mammals, the hypophysiotropic GnRH that stimulates the hypophysiotropic gonadotropin release was first isolated in pigs and is designated as GnRH-I (mammalian GnRH), while an early evolved and highly conserved new isoform that was discovered in the chicken is designated as GnRH-II (chicken GnRH). In addition, in mammals, a third isoform, the salmon GnRH, named GnRH-III, has been reported. In the human genome, only the GnRH-I and GnRH-II have been found. In humans, the expression of both GnRH-I and -II messenger RNA (mRNA) has been demonstrated in somatic and gonadal tissues such as the placenta, ovary, endometrium, trophoblast and the fallopian tubes in addition to in the hypothalamus.

8.2.2 GnRH Receptor

The GnRH receptor (GnRHR) is a member of the G protein-coupled serpent-like membrane receptors, which consist of seven hydrophobic transmembrane chains, connected to each other with extracellular and intracellular loops. Transmembrane chains participate in receptor activation and the transmission of signals, and intracellular loops are involved in the interaction with G proteins and also other proteins participating in the intracellular signal transmission. Upon GnRH binding, the GnRHR undergoes a conformational change and stimulates G proteins, which in turn produces downstream activation of several signalling cascades, mainly inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), MAPK and adenylyl cyclase pathways. Two homologous GnRHR have been identified: type I and type II. The absence of the carboxyl terminal tail results in slow internalization of type I GnRHR, and prevents rapid desensitization of the receptor. In humans, the conventional type I GnRHR is mainly expressed in gonadotropes in the anterior pituitary. However, it is also expressed in numerous extrapituitary tissues including placenta, breast, ovary, uterus, prostate and the corresponding cancer cells. The type II GnRHR has been cloned in marmoset as well as in non-human primates. This receptor does have the characteristic carboxyl terminal tail, which allows its rapid desensitization. However, a full-length type II GnRHR mRNA is absent in humans, as the open reading frame from the putative human type II GnRHR gene is disrupted by a frame shift, resulting in a premature stop codon.

8.2.3 You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here