Chemotherapy-Induced Damage to Ovary: Mechanisms and Clinical Impact

Abstract

Cancer is a major public health problem around the world. Currently, about 5% of women diagnosed with cancer are of reproductive age. These young survivors may face compromised fertility. The effects of chemotherapeutic agents on ovarian reserve and its clinical consequences are generally inferred from a variety of surrogate markers of ovarian reserve, all aiming to provide prognostic information on fertility or the likelihood of success of infertility treatment. Until recently, the mechanisms that are responsible for chemotherapy-induced ovarian damage were not fully elucidated. The understanding of these mechanisms may lead to targeted treatments to preserve fertility. In this manuscript, we will review the current knowledge on the mechanism of ovarian damage and clinical impact of chemotherapy agents on fertility. Cancer is a major public health problem around the world and is the second leading cause of death in the USA [1]. In 2016, approximately 844,000 new cases of cancer will be diagnosed in women in the USA [1]. In recent years, the remarkable screening, diagnostic and therapeutic advances in oncology practice improved the prognosis for many cancer patients, adding years to their anticipated survival. In fact, all these measures have resulted in a 23% drop in the cancer death rates from 1991 to 2012 [1].Currently, about 5% of cancers affects women younger than 50 years [1]. As young patients with these once-fatal malignancies become long-term survivors, many must face the potentially devastating complications of the treatment. Young survivors will likely face compromised fertility that is now recognized as among the most prevalent long-term side effects of cancer therapy. The prospect of partial or total infertility can significantly add to anxiety and emotional strain during disease management, and may also compromise quality of life [2]. To offset these risks, women can be offered several options for fertility preservation, including conservative cancer management, and cryopreservation of oocyte, embryo or ovarian tissue. Embryo and oocyte cryopreservation are considered established fertility preservation techniques and have been widely applied across the world [3,4]. On the other hand, ovarian tissue cryopreservation is still considered an experimental technique, despite advances in recent years [5].Studies exploring the mechanisms behind the actions of the different chemotherapy agents are providing greater information as to the specific effects of each agent on the different cell types of the ovary. The effects of antineoplastic agents on the ovaries are clinically inferred from a variety This article will review all the mechanism and clinical impact of chemotherapy on ovarian reserve. Ovarian agingThe ovary has a finite endowment of primordial follicles that is established during the second half of intrauterine life, followed by a steady decline until menopause. Each primordial follicle consists of an immature oocyte surrounded by a single layer of granulosa cells. The primordial follicles constit...

Pregnancy, delivery, and breastfeeding after total gastrectomy for gastric cancer: a case report

“…Bedschi et al [13] reported that age of the patient and the type and dose of chemotherapy are the main factors determining the magnitude of the damage in the ovary. As for gastric cancer, TS-1 (tegafur, gimeracil, oteracil potassium), which is used as the standard adjuvant chemotherapy for patient with gastric cancer in Japan [14], and CDDP (cisplatin) are classified intermediate and low gonadotoxic chemotherapy respectively.…”

Iatrogenic and non‐iatrogenic causes of female fertility loss that may indicate fertility preservation

“…One of the hypotheses for this mechanism comprises the PI3K/PTEN pathway, where the resulting lower local anti‐Müllerian hormone concentrations cause upregulation in the PI3K/PTEN/Akt signaling pathway and lead to less suppression of growth activation . This causes excessive primordial follicle selection, resulting in follicle burn‐out . Furthermore, chemotherapy damages the ovarian stroma and vascularization, and thereby impairs steroidogenesis.…”

“…Ovarian function after chemotherapy depends on the nature of the chemotherapy, the cumulative dosage, and the age when given. Alkylating agents are the most harmful, without a consistent threshold for a safe dose . Prepubertal ovaries seem less vulnerable; early menopause and POI are seen less frequently in prepubertal and adolescent girls after stem cell transplantation …”

“…[1][2][3] This causes excessive primordial follicle selection, resulting in follicle burn-out. 4 Furthermore, chemotherapy damages the ovarian stroma and vascularization, 5,6 and thereby impairs steroidogenesis. This often causes amenorrhea during treatment, followed by a period of post-treatment amenorrhea as well.…”

“…Alkylating agents are the most harmful, without a consistent threshold for a safe dose. 4 Prepubertal ovaries seem less vulnerable; early menopause and POI are seen less frequently in prepubertal and adolescent girls after stem cell transplantation. 7 The variety in results of different therapies is illustrated by the risk of POI in Hodgkin's disease: with alkylating agents the cumulative risk of POI is 60%, but with an ABVD/EBVD regimen the risk in women younger than 32 years is only 3% and after radiotherapy is 6%.…”