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      Gonadal Function in Female Adolescent and Young Adult Survivors of Childhood Cancer

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          Abstract

          Purpose

          Childhood cancer survivors (CCSs) are at risk for premature ovarian insufficiency (POI). The aim of this study is to evaluate ovarian function and associated health outcomes in female adolescent and young adult survivors of childhood cancer.

          Materials and Methods

          Sixty-nine female CCSs were enrolled. Medical records of CCSs were retrospectively reviewed. The subjects were categorized into three groups according to follicular stimulating hormone (FSH) levels (cutoff, 12, 40 IU/L). Anti-müllerian hormone (AMH) level less than 1 ng/mL was considered low AMH level.

          Results

          Of 69 subjects, 14 (20.3%) had POI and 14 (20.3%) had FSH levels between 12 and 40 IU/L. Forty-one of 69 (59.4%) had normal FSH levels. Pelvic irradiation and stem cell transplantation (SCT) were more frequently performed in subjects with POI (p=0.001 and p < 0.001). AMH levels were remarkably low when FSH levels were over 12 IU/L (p < 0.001). In multivariate analysis, cyclophosphamide equivalent dose and SCT were significant treatment factors for developing low AMH levels (p=0.005 and p=0.002, respectively). Total, low-density lipoprotein cholesterol and triglyceride were significantly different in three groups according to FSH levels (p=0.047, p=0.030, and p=0.045). Z-score of femur neck bone mineral density was significantly reduced when FSH levels were increased (p=0.011).

          Conclusion

          Gonadal dysfunction is common in CCSs. Gonadal function was associated with a few treatment factors known to increase the risk of POI. Regular monitoring of gonadal function is needed for better health outcomes.

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          Most cited references37

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          Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update

          Erica Wang, Alison Loren, Joyce D Reinecke … (2018)
          Purpose To provide current recommendations about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from January 2013 to March 2017 was completed using PubMed and the Cochrane Library. An Update Panel reviewed the identified publications. Results There were 61 publications identified and reviewed. None of these publications prompted a significant change in the 2013 recommendations. Recommendations Health care providers should initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible. Providers should be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, providers should advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm, oocyte, and embryo cryopreservation are considered standard practice and are widely available. There is conflicting evidence to recommend gonadotrophin-releasing hormone agonists (GnRHa) and other means of ovarian suppression for fertility preservation. The Panel recognizes that, when proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, GnRHa may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. GnRHa should not be used in place of proven fertility preservation methods. The panel notes that the field of ovarian tissue cryopreservation is advancing quickly and may evolve to become standard therapy in the future. Additional information is available at www.asco.org/survivorship-guidelines .
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            Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

            Maria Almeida, Michaël R Laurent, Vanessa Dubois … (2017)
            Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution.
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              Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study.

              M. Green, Marilyn Stovall, John Whitton … (2009)
              These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Res Treat
                Journal ID (iso-abbrev): Cancer Res Treat
                Journal ID (publisher-id): CRT
                Title: Cancer Research and Treatment : Official Journal of Korean Cancer Association
                Publisher: Korean Cancer Association
                ISSN (Print): 1598-2998
                ISSN (Electronic): 2005-9256
                Publication date (Print): July 2023
                Publication date (Electronic): 31 January 2023
                Volume: 55
                Issue: 3
                Pages: 992-1000
                Affiliations
                Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, Goyang, Korea
                Author notes
                Correspondence: Hyeon Jin Park, Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea, Tel: 82-31-920-1654 Fax: 82-31-920-1244 E-mail: hjpark@ 123456ncc.re.kr
                Author information
                https://orcid.org/0000-0003-1433-3394
                https://orcid.org/0000-0002-9557-3412
                Article
                Publisher ID: crt-2022-1518
                DOI: 10.4143/crt.2022.1518
                PMC ID: 10372588
                PubMed ID: 36731461
                SO-VID: 2faa5afb-b4b2-4db9-82e2-4a0c62ddeeee
                Copyright © Copyright © 2023 by the Korean Cancer Association
                License:

                This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 November 2022
                Date accepted : 30 January 2023
                Categories
                Subject: Original Article
                Subject: Pediatric Cancer

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: childhood cancer survivors,premature ovarian insufficiency,anti-müllerian hormone,gonadal dysfunction
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: childhood cancer survivors, premature ovarian insufficiency, anti-müllerian hormone, gonadal dysfunction

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