A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.

Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown. Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS). Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways. Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

Symptoms: Menopause, Infertility, and Sexual Health.

By 2022, the number of survivors is expected to grow to nearly 18 million. Therefore, addressing acute and chronic negative sequelae of a cancer diagnosis and its treatments becomes a health imperative. For women with a history of breast cancer, one of the common goals of treatment and prevention of recurrence is to reduce circulating concentrations of estradiol, especially in women with hormone receptor positive breast cancer. Hormone deprivation after a diagnosis of breast cancer impacts physiological targets other than in the breast tissue and can result in unwanted side effects, all of which can negatively impact quality of life and function and cause distress. Symptoms that are most strongly linked by evidence to hormone changes after cancer diagnosis and treatment include hot flashes, night sweats, sleep changes, fatigue, mood changes, and diminishing sexual function, including vaginal atrophy (decreased arousal, dryness and dyspareunia), infertility, decreased desire and negative self-image. Weight gain and resulting body image changes are often concomitants of the abrupt onset of treatment-induced menopause. The purpose of this chapter is to briefly review what is known about the advent of premature menopause in women treated for breast cancer, menopausal symptoms that are exacerbated by endocrine treatments for breast cancer, and the associated concerns of hot flashes and related menopausal symptoms, sexual health and fertility issues. We will discuss limitations in the current research and propose strategies that address current limitations in order to move the science forward.

A pilot study about female adolescent/young childhood cancer survivors' knowledge about reproductive health and their views about consultation with a fertility specialist.

OBJECTIVE: Impaired fertility and reproductive health after cancer treatment is an important quality-of-life issue among female childhood cancer survivors (CCSs). This study aims to measure female CCSs' knowledge about their reproductive health and their exposure to and views about reproductive counseling (RC). METHOD: This is a cross-sectional, web-survey study of female CCSs aged 18 to 45 years who were diagnosed with cancer before age 21 years and currently had no evidence of disease. RESULTS: Fifty-six CCSs participated (response rate = 48%; mean current age = 26). Knowledge about reproductive health after cancer treatment was severely limited within this sample of highly educated survivors (91% educated beyond high school), who provided correct answers only 32% of the time. Only 9 and 5% of the women had pursued RC with a fertility specialist before and after cancer treatment, respectively. The majority thought they had not been provided enough information about reproductive health. White ethnicity (p < 0.001), higher annual income (p = 0.007), and higher education level (p = 0.02) were significantly associated with a positive opinion about RC. SIGNIFICANCE OF RESULTS: A limited number of CCSs took advantage of RC in spite of their high interest in and limited knowledge about reproductive issues. Targeted referrals for RC may allow for improved decision making about reproductive options.

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges.

BACKGROUND: Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study. METHODS: The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements. DISCUSSION: The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators. TRIAL REGISTRATION: NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922

Effect of radiation on age at menopause among atomic bomb survivors.

Exposure to ionizing radiation has been thought to induce ovarian failure and premature menopause. Proximally exposed female atomic bomb survivors were reported to experience menopause immediately after the exposure more often than those who were distally exposed. However, it remains unclear whether such effects were caused by physical injury and psychological trauma or by direct effects of radiation on the ovaries. The objective of this study was to see if there are any late health effects associated with the exposure to atomic bomb radiation in terms of age at menopause in a cohort of 21,259 Life Span Study female A-bomb survivors. Excess absolute rates (EAR) of natural and artificial menopause were estimated using Poisson regression. A linear threshold model with a knot at 0.40 Gy [95% confidence interval (CI): 0.13, 0.62] was the best fit for a dose response of natural menopause (EAR at 1 Gy at age of 50 years = 19.4/1,000 person-years, 95% CI: 10.4, 30.8) and a linear threshold model with a knot at 0.22 Gy (95% CI: 0.14, 0.34) was the best fit for artificial menopause (EAR at 1 Gy at age of 50 years for females who were exposed at age of 20 years = 14.5/1,000 person-years, 95% CI: 10.2, 20.1). Effect modification by attained age indicated that EARs peaked around 50 years of age for both natural and artificial menopause. Although effect modification by age at exposure was not significant for natural menopause, the EAR for artificial menopause tended to be larger in females exposed at young ages. On the cumulative incidence curve of natural menopause, the median age at menopause was 0.3 years younger in females exposed to radiation of 1 Gy compared with unexposed females. The median age was 1 year younger for combined natural and artificial menopause in the same comparison. In conclusion, age at menopause was thought to decrease with increasing radiation dose for both natural and artificial menopause occurring at least 5 years after the exposure.

[Normal tissue tolerance to external beam radiation therapy: ovaries]. / Tolérance à l'irradiation des tissus sains: les ovaires.

Clinical situations requiring protections of ovaries are mainly paediatric irradiations and pre-menopausal pelvic irradiations. The main complication of ovarian irradiation is the induced castration. Ovaries are extremely radiosensitive organs with strong interpersonal variations. The castrative effect of irradiation depends mainly on two factors: patient's age and the dose delivered to ovaries. The surgical technique of ovarian transposition allows to minimize the dose received by ovaries by taking them away, out of irradiation fields; the aim is to exclude them from the volume receiving 5 Gy or more, and if possible from those receiving 2 Gy. This technique becomes integrated into a multidisciplinary approach of conservation of fertility for patients exposed to other cytotoxic treatments.

Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study.

BACKGROUND: Childhood cancer survivors who retain ovarian function after completing cancer treatment are at increased risk of developing premature menopause, defined as cessation of menses before age 40 years. However, published data pertaining to the risk and frequency of premature menopause are limited. METHODS: We assessed the incidence of and risk factors for premature menopause in 2819 survivors of childhood cancer who were older than 18 years and were participants in the multicenter Childhood Cancer Survivor Study (CCSS). The comparison group was 1065 female siblings of participants in the CCSS. A multiple Poisson regression model was constructed to determine risk factors for nonsurgical premature menopause. All statistical tests were two-sided. RESULTS: A total of 126 childhood cancer survivors and 33 control siblings developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically induced menopause (rate ratio [RR] = 0.8, 95% confidence interval [CI] = 0.52 to 1.23). However, the cumulative incidence of nonsurgical premature menopause was higher for survivors than for siblings (8% versus 0.8%; RR = 13.21, 95% CI = 3.26 to 53.51; P<.001). A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score (based on number of alkylating agents and cumulative dose), and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominopelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%. CONCLUSIONS: The results of this study will facilitate counseling current survivors about their future risk of premature menopause and aid in designing new regimens that seek to diminish late ovarian toxicity.

Human oocyte radiosensitivity.

The teratogenic effects of ionizing radiation are well documented, but less is known about the radiosensitivity of the human oocyte. Women of childbearing age are understandably concerned about diagnostic radiology examinations--their risk/benefit ratio and their impact on the ability to conceive. Current research and evidence gathered from studies of the long-term effects of intra-abdominal therapeutic radiation shed light on this subject. With respect to this issue, radiographers can now give more practical advice to their nongravid female patients.

Ovarian function following radiation and chemotherapy for cancer.

High-dose chemotherapy and radiotherapy have increased the long-term survival of young patients with cancer; nevertheless, the toxic effects on ovarian function causing amenorrhoea, premature menopause and infertility, are still severe.

Premature menopause after cancer treatment.

PURPOSE: The purpose of this report is to examine the impact that cancer therapies have on ovarian function. OVERVIEW: Symptoms of and conditions due to estrogen deficiency after cancer therapy are described, and interventions are proposed. The consequences of short-term as well as prolonged estrogen deficiency-including vasomotor instability, infertility, genitourinary atrophy, coronary artery disease, and osteoporosis-are discussed. CLINICAL IMPLICATIONS: Symptoms and conditions associated with premature menopause may cause additional stress for women who undergo cancer therapy. Knowledge about what happens to these women can enable healthcare providers to help them make decisions about cancer treatment, engage in self-care activities, and explore options for preserving fertility.

Feasibility of transposition of the ovaries in the surgical and radiotherapeutical treatment of cervical cancer.

Ovaries are seldom subject to metastases and therefore their preservation is possible in radical cervical cancer surgery. However, with postoperative radiotherapy they cannot be preserved unless they are placed outside the radiation field. The practicality of this transposition was analysed in a series of 126 patients with cervical cancer. The ovaries were transposed intraperitoneally in a lateral and cranial direction in 44 of the 64 women under the age of 50 years. In 16 of these 44 women, only one ovary could be preserved and transposed. A critical analysis was performed of the ovaries' new location by plotting their position, marked by 2 clips each, in a single pelvis. In 68% of the women at least one ovary was placed outside the radiation field. However, because of scattered radiation, i.e. 5% of the total radiation dose at a distance of 4 cm outside the radiation field, a substantial loss of ovarian function may occur. In 32% of the women at least one ovary received less than this 5%. Optimal transposition may be achieved after extension of the abdominal incision. However, this will be unnecessary in most cases, since postoperative radiotherapy will be indicated in only approximately 15% of the women.

Ovarian failure following abdominal irradiation in childhood: natural history and prognosis.

Ovarian function has been reviewed sequentially since 1975 in 53 patients treated in childhood between 1942 and 1985 for an intraabdominal tumour with surgery and external abdominal radiotherapy (XRT). Of 38 patients who received whole abdominal XRT (20-30 Gy), 27 failed to undergo or complete pubertal development (pubertal failure) and a premature menopause (median age 23.5 years) occurred in a further ten. Of 15 patients who received flank XRT (20-30 Gy), ovarian function (median age at last assessment 15.2 years) was normal in all but one in whom pubertal failure occurred. In only one patient, who developed pubertal failure after whole abdominal XRT and required sex steroid replacement therapy (HRT) to achieve normal secondary sexual characteristics, has there been evidence of reversibility of ovarian function with a documented conception at the age of 22.7 years. Five patients who developed pubertal failure required bilateral augmentation mammoplasties despite sex steroid replacement therapy. Four patients have had documented conceptions, all received whole abdominal XRT (20-26.5 Gy) and subsequently developed a premature menopause. There have been no live births, with all miscarriages occurring in the second trimester. The outlook for normal ovarian function following whole abdominal XRT is poor, flank XRT introduced intermittently from 1972, has resulted in less pubertal failure but the possibility of a premature menopause may with time become a reality.

Ovarian failure and cancer treatment: incidence and interventions for premenopausal women.

Ovarian failure may be a long-term consequence of cancer treatment for premenopausal women. Caused by several treatments, including radiation therapy and the alkylating agents, it produces signs and symptoms associated with menopause: hot flashes, amenorrhea, dyspareunia, loss of libido, and irritability. Critical factors that determine ovarian functioning after treatment for cancer are the patient's age at the time of therapy, the amount of radiation that the ovaries received, and the dose of the antineoplastic agent(s). Medical interventions, such as hormonal therapy and surgical repositioning of the ovaries, may maintain ovarian function for some women. Nursing intervention includes assessment, education, and counseling. Counseling focuses on how the prematurely menopausal patient feels about herself as indicated by self-esteem, body image, and sexuality.

Effect of low dose endometrial after-loading irradiation upon the hypophysis-ovarian axis.

Endometrial inactivation by irradiation, while simultaneously preserving the ovarian function is sometimes clinically indicated. We have found that after 1100 cGy (rad) the ovarian function remains intact, yet endometrial inactivation is unsatisfactory. Therefore, four premenopausal subjects, with clinical indications for eliminating disturbing uterine bleedings, received each an endometrial dose of 1600 cGy by using a Cathetron afterloading unit. When pre- and post-treatment cycles were compared, the circulating gonadotrophin and estrogen levels were unchanged in three subjects. Nine to 12 weeks after the treatments there were no signs of ovulation and the gonadotrophin levels were generally increased. None of the subjects had experienced any bleedings. We conclude that an endometrial dose of 1600 cGy is effective in inactivating endometrium, but may also lead to an impaired ovarian function and to a premature menopause.

Leukemia and other cancers following radiation treatment of pelvic disease.

Follow-up studies of patients treated for cancer of the cervix with radiotherapy have shown such women to be at little or no increased risk of leukemia subsequent to the radiation exposure. However, women exposed to lower doses of radiation in the pelvic area, in the induction of an artificial menopause, appear to show increased risks of both leukemia and cancers of those sites directly in the radiation field. The studies of these two types of radiation exposure are reviewed. The findings may possibly be reconciled with each other on the basis of the distribution of radiation dose to the bone marrow. Irradiation for cancer of the cervix delivers radiation doses to a small portion of the marrow which are probably lethal for most marrow cells. The mean dose to cells distant from the cervix may be too small to produce a detectable increase in leukaemia incidence. The lower and more uniformly distributed radiation dose used to induce an artificial menopause will be less lethal for marrow cells and may consequently deliver a higher "effective" marrow dose to surviving--cells, resulting in an increased leukemia risk.