Reproductive Problems in Adolescent and Young Adult Gynecology Cancer Survivors: A Systematic Review

Adolescents and young adults with gynecology cancer are unique, especially in terms of their reproductive and sexual aspects. This systematic review aimed to identify reproductive problems in adolescent and young adult survivors of gynecology cancer. Articles from five databases were reviewed. PubMed, Taylor & Francis, Scopus, Science Direct


INTRODUCTION
Adolescents and young adult are the group 15-39 years old (National Cancer Institute, 2022;Smith & Olsen, 2018). More than 30 years of age, adolescents and young adults with cancer have not increased survival rates, and cancer is still the leading cause of death among the age groups of 15-24 years old and 25-39 years old (American Cancer Society, 2020). Cancer is a major problem among adolescents and young adults, prevalence worldwide of 19/100,000 population each year in adolescent and young adult (Atta et al., 2019). The prevalence of cancer in Indonesia, based on the age group of 15-24 years old is 0.47 per 1000 population and aged 25-34 years old is 1.21 per 1000 population (Badan Penelitian dan Pengembangan Kesehatan, 2019). One of the rising cancers is gynecology cancer, which occurs in 16% of women worldwide. Nearly 10% of women diagnosed with gynecology cancer are under the age of 40 or are still in the early adult development stage (NCCN, 2022). The proportion of female cancer patients who had been treated at Dr. Cipto Mangunkusumo was 63,3% and 1.73 times more than male patients, respectively. Most cancers are cervical cancer 15.80% and breast cancer (13.50 %) (Gondhowiardjo et al., 2021).
Adolescents and young adults with cancer in women are unique, especially in terms of sexual and reproductive health. This is related to the diagnostic and treatment procedures applied to gynecology cancer, which are very diverse, complex, and long. They will have problems with body image, sexual identity, and decreased reproductive ability, which will negatively affect their quality of life (Evcili & Bekar, 2020). The need for support for adolescents and young adults with cancer will be different from that for children or older adults. Because they are differentiated by disease categories, one is childhood cancer, and the other is adult cancer. Adolescence and young adulthood are a period of transition from children to adults (Ferrari et al., 2021;Smith & Olsen, 2018). Adolescents and young adults are concerned about physical appearance and self-existence, construct their identity, develop body image and positive sexual identity, separate from their parents, develop their involvement with friends of the same age, date, and begin to make decisions and life choices (Broholm-Jørgensen et al., 2022;Ham et al., 2022).
Women undergoing cancer treatments such as chemotherapy and radiation have a negative impact on fertility (Abelman & Cron, 2020). Young infertility is a major cause of distress among patients and their families (Mulder et al., 2021).
Cancer treatments in women, such as chemotherapy and radiotherapy, are often associated with their impact on reproduction. Premature ovarian insufficiency (POI), infertility (Ojo et al., 2022), and inability to produce mature eggs for ovulation (Harzif et al., 2017) are major concerns for women undergoing cancer treatment and have a long-term impact on cancer survivors. This worsens emotional conditions, relationships, and sexuality (Harzif et al., 2019;Ojo et al., 2022).
Adolescents and young adults diagnosed with cancer at an advanced stage will experience early death from cancer because there is no hope of recovery, but they do not face the threat of death immediately after diagnosis or after completing active cancer therapy (Ham et al., 2022). The poor quality of the post-care phase in adolescents and young adulthood is one of which is counseling on reproductive health . Adolescents and young adults feel uncomfortable discussing reproductive issues with health workers. Health workers also assume that adolescent and young adult cancer survivors are not interested in sexual activity during or after cancer treatment (Murphy et al., 2015;Murphy, Klosky, et al., 2013).
Adolescents and young adults may differ from other age groups related to reproduction, but their involvement in research is still very limited (American Cancer Society, 2020). Kim et al. (2016) studied 51 qualitative articles on adolescents and young adults with cancer and recommended adjustments to the type of cancer, type, and intensity of treatment. Although cancer at a young age presents similar challenges and problems, it has a different impact. Therefore, this systematic review aimed to identify reproductive problems in adolescent and young adult survivors of gynecology cancer.

METHODS
This systematic review aimed to identify reproductive problems in adolescent and young adult survivors of gynecology cancer. Format-based clinical questions Population, Interest, and Context (PICo). The steps in conducting a systematic review were adjusted to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist from Page et al. (2021). The inclusion criteria in the systematic review included nonexperimental research articles (cross-sectional, observational study, or articles mixed method with observational study), article full text, and in English, a study with a sample of 15-39 years old gynecology cancer survivors who had completed primary cancer treatment.
Five databases were searched: PubMed, Taylor&Francis, Scopus, Science Direct, and Proquest. An article search was carried out by collecting and exploring articles published between 2012-2022 that reported reproductive problems in gynecological cancer survivors. A comprehensive article search was conducted. A search was also carried out using a list of references identified from articles obtained from the databases. Database searches were performed according to PICo combined with AND, OR Boolean operators, namely (gynecology cancer* OR gynecology neoplasms* OR female genital neoplasms*) AND (adolescent and young adult* OR emerging adult* OR youth*) AND (reproductive problems*OR sexual problems*OR reproductive burden*OR reproductive concern). The detailed search strategy is shown in Figure 1. Process risk of bias for cross-sectional and cohort studies using the Joanna Briggs Institute (JBI) tool. The tool focused on three components: design, data collection, and analysis. There were questions to evaluate an article with yes, and no/unclear answer choices. Studies with high scores were indicated to have a low risk of methodological bias. Risk of bias is categorized as high risk of bias (1-3), medium risk of bias (4-6), and low risk of bias (7-9) (Harris et al., 2022). The rating score values of the risk of bias are displayed in Table 1. Data extraction included author's name, date of publication, country where research was conducted, research design, data source, data collection method, date of data collection, sample characteristics, findings, and quality of the article.

Characteristic of Respondents
A total of 4479 female adolescent and young adult cancer survivors and 990 female patients with gynecology cancer types (cervical, ovarian, endometrial, pelvic, and vulvar) were included. The average age at diagnosis of cancer from the 12 articles was 33.58 years. Survivors in the 12 studies included patients with cancer who had completed treatment for their primary cancer. The length of time spent as a survivor ranges from one day to 27 years. There were seven studies in which the data collection had been survivors of less than five years. The most common treatment experienced by survivors was more than two therapy/combination therapies (49.70%-69.70%), chemotherapy (50%-78%), and surgery (64%-92.50%).

Reproductive Problems in Adolescent and Young Adult Survivors
Reproductive and fertility problems occurred in 82.7% of adolescent and young adult survivors, which was significantly higher than that of adolescents and young adults who had never been diagnosed with cancer (p<0,01) (Furui et al., 2019). Gynecological cancer survivors experience moderate-to-severe reproductive problems (Young et al., 2019). Women with cervical and ovarian cancer experience ≥ 1 domain of sexual dysfunction. Problems with sexual dysfunction (interest in sexual activity) with OR 0.92; CI95% (0.59-1.43) (Wettergren et al., 2022). Sexual activity was significantly lower in middle-aged adults (p=0.0001) in sexual activity. Comparing survivors aged ≤ 45 years and >45 years, sexual satisfaction, vaginal sexual function, and body image of survivors aged ≤ 45 years were significantly higher than those of survivors aged > 45 years (p=0.001; p =0.001; p = 0.009) (Bifulco et al., 2012).
Women with reproductive cancer were significantly more dissatisfied with sexual activity than women with nonreproductive cancer (p=0.042) (Mütsch et al., 2019). Reproductive problems may be related to the characteristics of cancer survivors during adolescence and young adulthood. Reproductive problems occurred in 68% of adolescent and young adult survivors undergoing chemotherapy (Furui et al., 2019), aged 25-30 years (p=<0,001), and those who were not married (p<0.001). Adolescent and young adult cancer survivors were also at high risk of moderate and high fertility disturbances (6.74 ± 1.96; mean ± SD). Infertility can occur as a result of cancer therapy (Urech et al. 2018). Among adolescent and young adult cancer survivors, 9,6% experienced amenorrhea, 47.2% experienced oligomenorrhea, 38.4% experienced menstruation ≤ 7 days, and 20.2% experienced menstruation 60 days/year apart (Kim et al., 2021). Survivors aged ≤ 45 years were significantly more likely to experience menopausal symptoms than those aged >45 years (p = 0.0001).

Psychosocial Impacts Affecting Reproduction
Adolescent and young adult cancer survivors experience severe stress (Kim et al., 2021). Adolescent and young adult survivors undergoing chemotherapy or radiotherapy were more stressed than other cancer treatments (OR=5.55;95%CI 0. 37-83.19). Cancer damage to body image affects interpersonal relationships, causing stress (Duan et al., 2021). The emotional function of survivors aged ≤45 years was significantly lower than that of survivors aged >45 years (p= 0.03) (Bifulco et al., 2012). There was no significant association between the stress experienced by adolescent and young adult survivors and decreased ovarian function in 311 survivors who had completed cancer treatment for >2 years. -Survivors without prior pregnancy or live birth, either before or after cancer, were also more likely to have moderate to high reproductive concerns (P < .001) than those with prior pregnancy or live birth.
-Cancer type, age at diagnosis, radioiodine therapy, and surgery were not associated with reproductive concerns.

7
(Low risk of bias)

The Desire to Have Children
In two studies, 73.2% of adolescent and young adult cancer survivors wanted to have children in the future (Lam et al., 2020) and 82.9% stated that having children was important to them (Urech et al., 2018). A study by Young et al. (2019) found that more than half (74.8%) of the survivors did not want to give birth after a cancer diagnosis. Age, sexual identity, history of pregnancy, cancer treatment were not significantly related to voluntarily childless (OR=0.60; 95% CI 0.35-1.02). Adolescent and young adult cancer survivors ages 36-40 years were three times more voluntarily childless than those aged 25-35 years (OR=2.97; 95% CI 1.71-5.18) (Lam et al., 2020). The results of a study by Mattsson et al. (2020) showed that 59.6% of ovarian cancer survivors and 60% of uterine cancer survivors did not have children before being diagnosed with cancer. Results study of Anderson et al. (2023) found that more than half (59%) of the respondents had never given birth before being diagnosed with cancer. Only 21% of the women were pregnant for 10 years from the time of cancer diagnosis. Adolescent and young adult survivors who became pregnant after cancer treatment included live births (53%), miscarriage (22%), infertility (14%), pregnancy termination (7%), pregnancy (3%), and stillbirth or ectopic pregnancy (0.4%). Adolescent and young adult survivors aged 35-39 (PR= 0.59; 95% CI, 0.41, 0.86) at diagnosis were less likely to become pregnant from 15 to 24 years of age. Based on cancer characteristics, the type of cancer is significantly associated with pregnancy; survivors of gynecological cancer (PR=0.46; 95% CI, 0.32-0.67) are less likely to become pregnant than survivors of thyroid cancer (Anderson et al., 2023).

Need for Reproductive support
Four studies reported a need for reproductive support (Anderson et al., 2023;Mattsson et al., 2020;Urech et al., 2018;Young et al., 2019). Adolescent and young adult cancer survivors did not receive fertility preservation services (88,2%) (Young et al., 2019); only 29.9% followed fertility preservation (Urech et al., 2018). Fertility counseling was not obtained in 81.1% (Young et al., 2019)and 66.7% (Mattsson et al., 2020) of adolescent and young adult survivors, respectively, diagnosed with cancer and during treatment. Only 5% of gynecological cancer survivors receive fertility counseling compared with other types of cancer (Young et al., 2019), and 80% of ovarian cancer survivors do not receive long-term support (Mattsson et al., 2020). Based on the type of cancer, 85% of gynecological cancer survivors discussed fertility, and 25% received counseling from a fertility specialist. Fertility counseling conducted with health professionals or fertility specialists from the diagnosis of cancer to the start of treatment was significantly associated with successful pregnancy (PR=1.74; 95% CI, 1.31, 2.32) (Anderson et al., 2023).
Reproductive problems occur in adolescent and young adult survivors undergoing chemotherapy (Furui et al., 2019). Cancer treatments, such as chemotherapy, decrease ovarian follicles. Chemotherapy agents affect the growth of follicles in the ovaries due to the disruption of granulosa cell division caused by inhibition of DNA replication. Chemotherapy induces vascular damage and cortical ovarian fibrosis, resulting in local ischemia and a reduction in primordial follicles. In cancer patients, amenorrhea is a temporary effect of chemotherapy (Sodeifian et al., 2022). Cancer survivors who have completed cancer treatment experience amenorrhea, oligomenorrhea, menses ≤ 7 days, and menses 60 days/year apart (Kim et al., 2021). Survivors aged ≤ 45 years are significantly more likely to experience menopausal symptoms than those aged >45 years (Bifulco et al. 2012). A study by Wettergren et al. (2022) also showed that early menopause occurred in cervical cancer survivors because radiotherapy damaged the vaginal mucosa, causing the vagina to become fibrous, shortened, and dry (Wettergren et al., 2022).
Fertility disorders affect the possibility of pregnancy after a cancer diagnosis, even if these conditions may have occurred before a cancer diagnosis. Ovarian (59.6%) and uterine cancer survivors (60%) (Mattsson et al., 2020) did not have children before they were diagnosed with cancer. More than half (59%) of the adolescent and young adult survivors had never given birth before being diagnosed with cancer. Only 21% of the women were pregnant for 10 years from the time of cancer diagnosis. The cancer type is also significantly associated with pregnancy. Gynecological cancer survivors are less likely to become pregnant than thyroid cancer survivors are (Anderson et al. 2023).
In a study conducted by Urech et al. (2018), more than half (82.9%) of the survivors stated that having children was important. The results of this study are contrary to of those a study conducted by Young et al. (2019), which showed that more than half (74.8%) of survivors did not want to give birth after a cancer diagnosis and 98.5% did not want to adopt (Young et al., 2019). Survivors aged 36-40 years are three times more likely to be voluntarily childless than those aged 25-35 years (Lam et al., 2020). Not wanting to become pregnant can be caused by a possibly poor pregnancy outcome. Adolescent and young adult survivors who become pregnant after cancer include live births (53%), miscarriage (22%), infertility (14%), termination of pregnancy (7%), pregnancy (3%), and stillbirth or ectopic pregnancy (0.4%) (Anderson et al., 2023). Survivors are voluntarily childless because of the high risk of being passed on to children, or it is possible that children will have poor health conditions if born after suffering from cancer. Becoming a parent is not the primary goal for adolescent and young adult cancer survivors (Lam et al., 2020).
Decreasing ovarian function due to cancer treatment and having a long-term impact on women before the age of 40 will affect sexual health and function (Ayuandari et al., 2021;Hoven et al., 2021). Decreased sexual function is associated with decreased estrogen levels. Estrogen plays an important role in sexual desire, lubrication, and orgasm. Decreased estrogen levels as a result of decreased ovarian function can cause disturbances in sexual response and sexual desire (Codacci-Pisanelli et al., 2017). Cervical (61%) and ovarian cancer survivors (66%) experienced sexual dysfunction in more than one domain. Decreased desire for sexual activity and inability to orgasm (Wettergren et al., 2022). Women with reproductive cancer survivors were significantly dissatisfied with their sexual activity compared to women with non-reproductive cancers (Mütsch et al., 2019).
Female cancer survivors age range-25-30 years and not married have more severe symptoms (Young et al., 2019).
These results contradict those reported by Mütsch et al. (2019) and Bifulco et al. (2012). Older female survivors had significantly lower levels of sexual satisfaction (Mütsch et al., 2019). Sexual satisfaction and vaginal sexual function scores in survivors of gynecological cancer aged ≤ 45 years were higher than those in survivors aged >45 years (Bifulco et al., 2012). This difference can be influenced by marital status or the presence of a partner. Older women with reproductive cancer have more partners than younger women (Anderson et al., 2023;Duan et al., 2021;Kacou et al., 2021;Mütsch et al., 2019). Survivors of gynecological cancer who are >45 years of age also have a higher sexual activity score than those aged ≤45 years (Bifulco et al., 2012).
Survivors of gynecological cancer have been reported to have more psychological problems than physical problems due to cancer or cancer treatment (Brotto et al., 2008). The results of this study indicated that younger survivors of gynecological cancer have negative emotional and social impacts (Bifulco et al., 2012). The psychosocial impact on adolescent and young adult cancer survivors is related to demographic characteristics (gender, age, marital status, length of time being a survivor) and clinical characteristics (type of cancer and cancer treatment) (Bifulco et al., 2012;Duan et al., 2021). Females, younger adolescents, and young adults have a high level of stress (Duan et al., 2021). A decrease in the amount of estrogen during a decline in ovarian function causes disturbances in the sexual response and sexual desire. Sex hormones also have neurobiological functions; a decrease in the amount of these hormones causes anxiety in patients and disrupts neurovascular sexual responses (Codacci-Pisanelli et al., 2017). These results are in agreement with the results of a study (Mütsch et al., 2019) that found no difference in the psychological problems experienced by adolescent and young adult survivors with reproductive and non-reproductive cancers. There was no significant relationship between decreased ovarian function in 311 adolescent and young adult cancer survivors who had completed cancer treatment for >2 years (Kim et al., 2021). Regardless of the type of cancer, adolescent and young adult cancer survivors experience changes in body image, shape, and weight, which can reduce self-confidence (Sodeifian et al., 2022).
Adolescent and young adult cancer survivors are still not met with fertility counseling and fertility preservation (Mattsson et al., 2020;Urech et al., 2018;Young et al., 2019). There are some obstacles in providing fertility services to adolescent and young adult women with cancer from the patient's perspective, such as because fertility is not their main focus; they only focus on survival and cancer treatment. Obstacles from health workers include a lack of awareness and knowledge related to fertility (Berg et al., 2019). There is an unmet need for fertility preservation because the costs are very expensive and are not facilitated by health insurance (Anderson et al., 2023). Adolescent and young adult cancer survivors expect that every cancer patient receiving therapy that can affect fertility should receive fertility preservation (Urech et al., 2018). Survivors expect psychological services from professional health workers when treatment is finished, information regarding the long-term effects of surgery and medication, and distress due to sexuality and infertility problems that are not well understood by the team and not understood to deal with sexual problems and their impact on relationships (Mattsson et al., 2020).

STRENGTHS AND LIMITATIONS
This study is the first to address reproductive problems in adolescent and young adult women diagnosed with gynecological cancer. Different types of cancer cause different reproductive problems. This study has limitations due to the limited literature regarding adolescents and young adults with gynecological cancer. The number of samples with a diagnosis of gynecological cancer in the article is still very small, which can allow the impact not to be pathophysiological in gynecological cancer. Research places are still limited to America, Europe, Africa, and Asia (Japan and China), and the selected articles are only in English, so there is a risk of language bias (biased language).

CONCLUSIONS AND SUGGESTIONS
Cancer survivors in adolescence and young adulthood experience various reproductive problems. They are influenced by the characteristics of cancer survivors themselves. Differences in age range, marital status, and obstetric status affect various reproductive problems. Adolescent and young adult gynecological cancer survivors mostly require reproductive and fertility counselling. Younger survivors of gynecological cancer face the risks of infertility or subfertility, early menopause, and emotional disturbances.
Survivors need support regarding reproduction, sexuality, fertility, and information about the late effects on cancer.

ACKNOWLEDGMENTS
We like to express sincere gratitude to University of Indonesia for providing a database of articles.

ETHICAL CONSIDERATIONS
Ethics approval and consent to participate Not applicable Consent for publication Not applicable

Availability of Data and Material (ADM)
The dataset used in this study is available from the corresponding author on reasonable request.