Sexual and fertility adverse effects associated with chemotherapy treatment in women

Introduction: Earlier diagnosis and novel chemotherapy strategies have resulted in a considerable improvement in cancer survival, but the quality of that survival is influenced by late effects of chemotherapy. Premature ovarian failure is a common consequence of chemotherapy in reproductive-aged women, and, as a result, fertility issues and sexual dysfunction occur frequently in women who have undergone chemotherapy.

Areas covered: This article reviews what is known about the effects of chemotherapy on fertility and sexuality. We also discuss risk factors for premature ovarian failure, fertility preservation options in patients willing to have a child after treatment, and sexual changes associated with estrogen withdrawal and psychological factors.

Expert opinion: Chemotherapy-induced ovarian failure in young women is associated with poorer quality of life, decreased sexual functioning, psychosocial distress related to fertility concerns, and infertility. Fertility preservation options should be considered in women at risk of premature ovarian failure caused by chemotherapy. Sexual dysfunction associated with estrogen withdrawal and psychological stress is common in cancer survivors. Women who suffer from sexual dysfunction may benefit from brief counseling and targeted intervention.     

Ovarian toxicity induced by chemotherapy: Research progress北大核心CSCD

For young women with tumors, one of the adverse effecs induced by chemotherapy is ovarian toxicity, which can cause ovarian premature failure, leading to a decline in fertility. In some cases, it can even cause permanent irreversible damage to the reproductive system. Commonly-used chemotherapeutical drugs such as docetaxel, irinotecan, cyclophosphamide, cisplatin and doxorubicin (adriamycin) have been found to possess obvious ovarian toxicity and their drug-related ovarian toxic mechanism is different. The influencing factors of ovarian toxicity are believed to be associated with ovarian acute vascular injury, oxidative stress induced by reactive oxygen species, abnormality of phosphatidylinositol-3-kinase serine/threonine" kinase pathway, and suppression of steroid hormone secretion pathway, respectively. Some approaches to preservation of fertility functions have been adopted in clinical use during chemotherapy, while some prevention methods for ovarian toxicity are actively explored. Fertility preservation detection parameters have been validated and research methods for ovarian toxicity in vitro have been gradually established in order to better understand and explore prevention methods. With a better understarding of chemotherapy-induced ovarian toxic mechanisms and the diversification of prevention methods, cancer therapy and ovarian fertility preservation will strike a better balance in the future.     

Medical approaches to preservation of fertility in female cancer patients

INTRODUCTION: the loss or impairment of ovarian function is an irreversible side effect that can occur in young cancer patients undergoing anticancer treatments. Its incidence varies according to the type of chemotherapy and the patient's age. AREAS COVERED: the review includes studies or data available in literature from 1987 to 2010, examining current strategies to protect ovarian function and/or fertility in patients undergoing chemotherapy, which include oocyte, embryo or ovarian tissue cryopreservation, and temporary ovarian suppression during chemotherapy obtained by the administration of gonadotropin-releasing hormone analogues (GnRHa). The reader will gain an understanding of the incidence of premature ovarian function loss associated with chemotherapy; the advantages and disadvantages of the different strategies in protecting ovarian function; and the magnitude of the effect of GnRHa strategy in preserving ovarian function during chemotherapy. EXPERT OPINION: the administration of GnRHa before and during chemotherapy is associated with an absolute reduction in the incidence of early menopause of nearly 20%. Such a strategy may be offered to young cancer patients who are candidates for chemotherapy. The capability of such an approach in inducing long-term preservation of ovarian function including fertility is still unknown.     

The value of adjuvant treatment in young women with breast cancer.

The postoperative management of breast cancer is an ever-changing field. Young patients, in particular, have attracted recent interest as it has become apparent that age alone is a poor prognostic indicator for breast cancer. Adjuvant therapies indisputably delay breast cancer recurrence and save lives, and should be considered for all young patients. Chemotherapy is increasingly being considered appropriate for all women under the age of 35 years, regardless of other risk factors, but poses the particularly difficult problem of infertility for these young women. As the additional benefits of anthracyclines and taxanes in the adjuvant setting become clear, chemotherapy regimens are also becoming increasingly intensive and the risk of myocardial damage and leukaemia should not be ignored. The benefits of chemotherapy need to be weighed against the possible dangers, and therapy should be individualised according to cancer pathology and patient circumstance. Tamoxifen should be given for 5 years to all women whose cancer is estrogen receptor positive, regardless of whether the patient has received chemotherapy. If chemotherapy is not given, the addition of luteinising hormone-releasing hormone (LHRH) agonists to tamoxifen in patients with estrogen receptor positive breast cancers appears to be beneficial. The addition of LHRH agonists to chemotherapy and tamoxifen is currently being evaluated in randomised trials. Radiotherapy should be given after breast conservation surgery, and should include the axilla if nodes are involved and the axilla has not been surgically cleared. Chest wall radiotherapy should be considered following mastectomy in young women considered at high risk of local recurrence, but the long-term morbidity and mortality of local radiation therapy, which is increased in young women, needs to be considered.     

Preserving fertility when choosing chemotherapy regimens – the role of gonadotropin-releasing hormone agonists

Introduction: The late effects of cancer treatment have recently gained a worldwide ubiquitous interest among reproductive endocrinologists, oncologists, and all health care providers. Despite many publications on this subject, there are many equivocal issues necessitating summary. The case for and against using GnRH-agonist for fertility preservation is summarized with the rationale that preventing ovarian failure may be better than treating it.

Areas covered: We searched Medline in the last 10 years using terms: ‘fertility preservation’, ‘female chemotherapy’, ‘Gonadotropin-releasing hormone (GnRH) analogues’, ‘GnRH agonists’ ‘gonadotoxicity’, and ‘cancer treatment’. We included mainly publications from the past 7 years, but did not exclude previous, commonly referenced publications. Here, we summarize the various methods available for fertility preservation and minimizing chemotherapy induced gonadotoxicity.

Expert opinion: Until now, 20 studies (15 retrospective and 5 randomized controlled trial) have reported on 2038 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in premature ovarian failure (POF) rate in survivors versus 8 studies reporting on 509 patients, with negative results. Patients treated with GnRH-a in parallel to chemotherapy preserved their cyclic ovarian function in 91% of cases as compared to 41% of controls, with a pregnancy rate of 19 – 71% in the treated patients. Furthermore, over 10 recent meta-analyses have concluded that GnRH-a are beneficial and may decrease the risk of POF in survivors. Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and unequivocally successful, these young patients deserve to be informed with all the various modalities to minimize gonadal damage and preserve ovarian function and future fertility. Combining the various modalities for a specific patient may increase the odds of preservation of future fertility.     

Roles of growth factors in chemotherapy-induced intestinal mucosal damage repair

Chemotherapy agents induce apoptotic cell death and loss of cell proliferation in the intestinal crypt epithelium, resulting in intestinal mucosal damage called "mucositis". Small intestinal mucositis is characterized structurally by crypt loss and villus atrophy, and functionally by absorptive and barrier impairments. The increased use of chemotherapy in cancer treatment and the clinical importance of the intestinal mucositis as a common side effect have stimulated more active research into understanding the pathophysiology of intestinal mucositis and developing agents for preventing or treating this condition. Rodent studies have shown that, following the chemotherapy-induced initial apoptosis and loss of crypt cell proliferation, many different growth factors or their receptors are upregulated locally at the crypts, preceding or coinciding with the epithelial hyperproliferative repair response. Aiming to reduce crypt cell apoptotic sensitivity to cytotoxic chemotherapy and/or to enhance crypt epithelial proliferative repair, several exogenous growth factor treatments have been tested, either preclinically and/or clinically, and are showing promise for their efficacy or safety in preventing or treating chemotherapy-induced mucositis. These tested growth factors include keratinocyte growth factor, interleukin-11, transforming growth factor beta, milk-derived growth factor extract, macrophage/granulocyte colony stimulating factors, and glucagon-like peptide 2. Further research on the basic and discovery levels and subsequent translational studies are needed to understand more about chemotherapy-induced intestinal mucositis and to identify candidates of growth factors or other agents that will potentially prevent or treat chemotherapy-induced mucositis more effectively, specifically, safely, and practically in chemotherapy patients.     

Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons

The awareness of the long-term toxicities of cancer survivors after chemotherapy treatment has been gradually strengthened as the population of cancer survivors grows. Generally, chemotherapy-induced peripheral neurotoxicity (CIPN) is studied by animal models which are not only expensive and time-consuming, but also species-specific differences. The generation of human induced pluripotent stem cells (hiPSCs) and differentiation of peripheral neurons have provided an in vitro model to elucidate the risk of CIPN. Here, we developed a drug-induced peripheral neurotoxicity model using hiPSC-derived peripheral neurons (hiPSC-PNs) to study the mechanisms of different chemotherapeutic agents on neuronal viability using LDH assay, a cell apoptosis assay determined by caspase 3/7 activation, neurite outgrowth, ion channel expression and neurotransmitter release following treatment of cisplatin, bortezomib, ixabepilone, or pomalidomide. Our data showed that the multiple endpoints of the hiPSC-PNs model had different sensitivity to various chemotherapeutic agents. Furthermore, the chemotherapeutics separated cell viability from the decrease in neurite lengthand changed levels of ion channels and neurotransmitters to a certain extent. Thus, we study the mechanisms of peripheral neurotoxicity induced by chemotherapeutic agents through changes in these indicators.     

Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management

Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents.The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.     

Treatment of hot flushes in breast and prostate cancer

Hot flushes, the most common health problem reported by menopausal-age women, can lead to significant morbidity and affect the social life, ability to work and sleep pattern of the sufferer. Women treated for breast cancer and men receiving androgen ablation for prostate cancer experience hot flushes that are more frequent, severe and longer lasting than those experienced by the general menopausal population. In women with breast cancer, hot flushes can result from chemotherapy-induced menopause, hormonal therapy, or ovarian suppression. In men with prostate cancer, hot flushes occur after surgical or medical castration. Hormone replacement therapy with oestrogen-based compounds has been a mainstay of treatment for hot flushes during the perimenopausal period. However, recent studies have shown that, in healthy menopausal women, hormone replacement therapy is associated with an increased risk of breast cancer, myocardial infarction, thrombo-embolic events and stroke. Thus, identifying nonhormonal agents that can control hot-flush symptoms is essential to the quality of life of a growing population of cancer survivors. The most promising agents act on the CNS and include selective serotonin reuptake inhibitors, as well as venlafaxine and gabapentin.     

The impact of chemotherapy on male fertility: a survey of the biologic basis and clinical aspects

The introduction of cisplatin-based polychemotherapy has led to cure rates of up to 90% for the most frequent malignant diseases seen in young men. In view of these high cure rates, increasing clinical importance is now being attached to chemotherapy-induced fertility disorders. Comparative studies examining the impact of cytotoxic chemotherapy on gametogenesis demonstrate significant cytostatic- and dose-specific differences. The extensive literature on possible teratogenic effects of chemotherapy provides no evidence suggesting that offspring of patients with a history of chemotherapy have an increased risk of malformations. However, these studies, the scope and follow-up of which may still be inadequate, have failed to eliminate the fear of such risk. Hormonal protection from chemotherapy-induced testicular damage has thus far succeeded only in animal models pretreated by application of gonadotropin-releasing hormone agonists combined with nonsteroidal antiandrogens or testosterone plus 17β-estradiol. The same holds true for hormone therapy aimed at stimulating the recovery of spermatogenesis after chemotherapy-induced testicular damage. Cryopreservation of germ cells can be suggested to patients undergoing cytostatic therapy. In some cases, testicular extraction of spermatozoa can also be offered as a novel approach.     

Treatment of premenopausal women with early breast cancer: old challenges and new opportunities

Breast cancer occurring in women before the age of menopause continues to be a major medical and psychological challenge. Endocrine therapy has emerged as the mainstay of adjuvant treatment for women with estrogen receptor-positive tumours. Although the suppression of ovarian function (by oophorectomy, irradiation of the ovaries or gonadotropin releasing factor analogues) is effective as adjuvant therapy if used alone, its value has not been proven after chemotherapy. This is presumably because of the frequent occurrence of chemotherapy-induced amenorrhoea. Tamoxifen reduces the risk of recurrence by approximately 40%, irrespective of age and the ovarian production of estrogens. The worth of ovarian function suppression in combination with tamoxifen is unproven and is being investigated in an intergroup randomised clinical trial (SOFT [Suppression of Ovarian Function Trial]). Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are only being investigated in younger patients. The use of chemotherapies is identical in younger and older patients; however, at present the efficacy of chemotherapy in addition to ovarian function suppression plus tamoxifen is unknown in premenopausal patients with endocrine responsive disease. 'Targeted' therapies such as monoclonal antibodies to human epidermal growth factor receptor (HER)-2, HER1 and vascular endothelial growth factor, 'small molecule' inhibitors of tyrosine kinases and breast cancer vaccines are rapidly emerging. Their use depends on the function of the targeted pathways and is presently limited to clinical trials. Premenopausal patients are best treated in the framework of a clinical trial.     

Combination antiemetic therapy in the control of chemotherapy-induced emesis

Severe nausea and vomiting are frequent complications of cancer chemotherapy. Historically, single-agent antiemetic therapy frequently has been less than optimal. Because multiple sites of emetogenic activity may be involved in chemotherapy-induced nausea and vomiting, many investigators are now using combinations of antiemetics in an effort to block multiple receptor sites. Several preliminary studies using combinations of antiemetic agents that have shown encouraging results are summarized.     

Risk factors for ovarian cancer: an overview with emphasis on hormonal factors

Ovarian cancer is the fifth most frequently occurring cancer among women and leading cause of gynecological cancer deaths in North America. Although the etiology of ovarian cancer is not clear, certain factors are implicated in the etiology of this disease, such as ovulation, gonadotropic and steroid hormones, germ cell depletion, oncogenes and tumor suppressor genes, growth factors, cytokines, and environmental agents. Family history of breast or ovarian cancer is a prominent risk factor for ovarian cancer, with 5-10% of ovarian cancers due to heritable risk. Reproductive factors such as age at menopause and infertility contribute to greater risk of ovarian cancer, whereas pregnancy, tubal ligation, and hysterectomy reduce risk. Oral contraceptive (OC) use has clearly been shown to be protective against ovarian cancer. In contrast, large epidemiologic studies found hormone replacement therapy (HRT) to be a greater risk factor for ovarian cancer. The marked influence of hormones and reproductive factors on ovarian cancer suggests that endocrine disrupters may impact risk; however, there is a notable lack of research in this area. Lifestyle factors such as cigarette smoking, obesity, and diet may affect ovarian cancer risk. Exposure to certain environmental agents such as talc, pesticides, and herbicides may increase risk of ovarian cancer; however, these studies are limited. Further research is needed to strengthen the database of information from which an assessment of environmental and toxicological risk factors for ovarian cancer can be made.     

72例不孕症妇女血清生殖激素异常结果分析

目的 :探讨不孕症妇女血清生殖激素异常的特点。方法 :回顾性分析 72例不孕症患者及 5 0例正常妇女的血清生殖激素水平。结果 :不孕症中生殖激素水平异常主要表现为 PCOS,占 5 9.72 % ;低 E2 水平 ,占 16.67% ;促性腺激素低水平 ,占 11.11% ;高泌乳素血症和卵巢早衰或卵巢发育不良。结论 :不孕症妇女生殖激素异常以促性腺激素水平异常最多见     

An expert opinion on pharmacologic approaches to reducing the cardiotoxicity of childhood acute lymphoblastic leukemia therapies

Introduction: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. Treatment-related cardiac damage is progressive and often difficult to reverse. Strategies to minimize cardiotoxicity during treatment are crucial to prevent severe lasting effects on health and quality of life.

Areas covered: This comprehensive review covers the pathophysiology and various presentations, both clinical and subclinical, of treatment-induced cardiotoxicity and characteristics associated with increased risk of cardiac dysfunction in childhood ALL survivors. Additionally, contemporary prevention strategies such as limiting cumulative anthracycline dose, altering drug administration schedule, the use of anthracycline structural analogs, liposomal encapsulated anthracyclines, cardioprotective agents and nutritional supplements are critically analyzed. Finally, this review covers the management options of chemotherapy-induced damage and other treatment-related cardiotoxicity.

Expert opinion: Higher lifetime cumulative doses of anthracyclines, younger age at diagnosis, longer follow-up, female sex, higher dose rates and cranial irradiation are associated with more severe cardiotoxic effects. Long-term adverse effects of both anthracycline and non-anthracycline chemotherapeutic agents are becoming an increasing focus during treatment of childhood malignancies. There must be a careful balance between achieving remission of childhood ALL while avoiding the development of another often-fatal illness, heart failure.     

Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management

Although effective anti-neoplastic agents, anthracyclines are limited by their well recognized and pervasive cardiotoxic effects. The incidence of late progressive cardiovascular disease in long-term survivors of cancer is established and may contribute to heart failure and death. To maximize the benefits of these drugs, a high-risk population has been identified and new strategies have been investigated to minimize toxic effects, including limiting the cumulative dose, controlling the rate of administration and using liposomal preparations and novel anthracycline analogues. Dexrazoxane also shows promise as a cardioprotectant during treatment. This paper reviews these strategies, as well as medications used to manage anthracycline-induced cardiotoxicity, and functional and biochemical means of monitoring cardiotoxicity, including echocardiography, radionuclide scans and biomarker analysis. The treatment of adult cancer survivors who have had anthracycline-related cardiotoxicity has not been systematically studied. Empirically, anthracycline-associated cardiac dysfunction is treated very similarly to other forms of heart failure. These treatments include avoiding additional cardiotoxic regimens, controlling hypertension, lifestyle changes, medications and heart transplantation.     

河车大造胶囊治疗卵巢早衰闭经35例临床观察

目的：观察河车大造胶囊治疗卵巢早衰闭经的疗效及对激素水平的影响。方法：收集35例2005年8月至2007年1月在江苏省中医院妇科门诊就诊的卵巢早衰闭经患者，予河车大造胶囊口服3个月，分析其疗效并比较治疗前后激素水平的变化。结果：治愈率为37．14％，有效率为34．29％，总有效率为71．43％，无1例妊娠。治疗后有效患者雌激素水平较服药前明显上升，经统计学分析，差异有显著性（P〈0．05）。结论：河车大造胶囊能升高卵巢早衰闭经患者血清雌激素水平，有效治疗卵巢早衰闭经。     

坤泰胶囊对实验性卵巢早衰大鼠卵巢功能和生殖功能

目的 探讨坤泰胶囊对不同治疗方法下卵巢早衰大鼠卵巢功能和生殖功能的影响。方法 将84只SD雌性大鼠随机分为卵巢功能组和生殖功能组两个大组,分别观察卵巢功能和生殖功能,每个大组分为空白组、模型组和坤泰胶囊高、中、低剂量组及结合雌激素片组,采用ig雷公藤多苷片（75 mg/kg,14 d）建立卵巢早衰模型,造模结束后,分别用坤泰胶囊高、中、低剂量（1.2、0.6、0.3 g/kg,36 d）及结合雌激素片（0.075 mg/kg,36 d）进行治疗。治疗结束后,卵巢功能组所有大鼠用酶联免疫吸附试验（ELISA）法检测大鼠血清性激素水平的变化,用实时荧光定量PCR（qRT-PCR）法检测大鼠卵巢组织相关因子Fas、FasL mRNA的表达水平的变化。将生殖功能组所有雌性大鼠与12只SD雄性大鼠进行合笼,观察记录孕鼠一般情况及子鼠的生长发育情况,观察各组雌性大鼠的生殖能力。结果 治疗组与模型组比较,随着治疗天数的增加,大鼠的卵巢功能和生殖功能均明显改善,血清卵泡生成激素（FSH）、黄体生成激素（LH）水平明显降低,雌二醇（E2）、抗穆勒管激素（AMH）水平明显升高,FasmRNA表达明显升高、FasLmRNA表达明显降低,差异均有统计学意义（P<0.05）;孕鼠摄食量及体质量均增长较快,差异有统计学意义（P<0.05）。大鼠产仔总数多,受孕率、妊娠率均较高,无明显子代小鼠畸形率,差异有统计学意义（P<0.05）。结论 坤泰胶囊能够改善卵巢早衰大鼠的卵巢功能和生殖功能,可修复育龄期大鼠卵巢功能病理性损伤,有效调节卵巢早衰大鼠血清性激素水平,上调FasmRNA表达,下调FasLmRNA表达,提高卵巢早衰大鼠受孕率及妊娠率,对子代小鼠无明显的致畸性。     

The association between chemotherapy-induced febrile neutropenia and breast cancer subtype in Japanese patients

Background Chemotherapy-induced febrile neutropenia is a common and potentially lethal side effect; therefore, predicting febrile neutropenia development is important. Objective This study examined the risk factors for febrile neutropenia development according to breast cancer subtype among Japanese patients receiving chemotherapy. Methods This single-center retrospective study evaluated 60 outpatients who received chemotherapy for breast cancer (epirubicin plus cyclophosphamide or docetaxel plus cyclophosphamide). Their characteristics were evaluated to identify factors associated with febrile neutropenia development. Results Thirty-three patients developed febrile neutropenia and 27 patients did not. The risk of developing febrile neutropenia was significantly associated with estrogen receptor negativity (p?<?0.05). Logistic regression analysis further confirmed that estrogen receptor negativity was an independent risk factor for febrile neutropenia development (odds ratio: 4.35, 95% confidence interval: 1.05–18.0). Moreover, the highest rate of febrile neutropenia was observed in patients with hormone receptor (estrogen and/or progesterone receptor)-negative/human epidermal growth factor receptor 2-positive breast cancer. Conclusion In addition to the known risk factors for febrile neutropenia, our findings revealed that the risk of developing chemotherapy-induced febrile neutropenia is associated with the hormone receptor-negative/human epidermal growth factor receptor 2-positive subtype in Japanese patients with breast cancer.