Abstract
Context
Although stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors).
Objective
This work aimed to evaluate applying STRAW + 10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and to assess how cancer treatment gonadotoxicity is related to reproductive aging stage.
Design
The sample (n = 338) included AYA survivors from the Reproductive Window Study cohort. Menstrual bleeding data and dried-blood spots for antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) measurements (Ansh DBS enzyme-linked immunosorbent assays) were used for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records.
Results
Among participants, mean age 34.0 ± 4.5 years and at a mean of 6.9 ± 4.6 years since cancer treatment, the most common cancers were lymphomas (31%), breast (23%), and thyroid (17%). Twenty-nine percent were unclassifiable by STRAW + 10 criteria, occurring more frequently in the first 2 years from treatment. Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, and 7% postmenopause), endocrine biomarkers distinguished among peak, early, and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages.
Conclusions
We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit the STRAW + 10 criteria, suggesting the need for modified staging for this population.
Keywords: reproductive aging, menopausal transition, premature ovarian insufficiency, STRAW, adolescent and young adult cancer
There are nearly 400 000 reproductive age, female survivors of cancers diagnosed as adolescents and young adults in the United States (AYA survivors) (1). Due to gonadotoxic cancer treatments, many AYA survivors will experience shortened reproductive lifespans, which can negatively affect quality of life (2-5). The risk of premature reproductive senescence varies by cancer treatment, with exposure to gonadal radiation and alkylating chemotherapy and older age at treatment conferring increased risks (6,7). Although data describe the occurrence of primary ovarian insufficiency (POI) and early menopause before age 40 years (8-11), a lack of data exists characterizing the process of reproductive aging preceding ovarian insufficiency in AYA survivors.
In the general population, longitudinal cohort studies provided data on bleeding patterns, endocrine biomarkers, sonographic findings and symptoms that enabled staging the process of reproductive aging. The Stages of Reproductive Aging Workshop + 10 (STRAW + 10) generated a system that divides reproductive aging into 3 broad phases (reproductive, menopausal transition, and postmenopause) encompassing 7 stages (early, peak, late reproductive; early, late menopausal transition; early, and late postmenopause) (12). Most women are observed to progress through these stages in order with variable durations in each stage (13). STRAW + 10 staging serves as a clinical and research tool, allowing for more targeted risk-assessment screening based on reproductive stage rather than chronological age alone (14-16). For example, the menopausal transition is a critical period for both quality of life and short- and long-term metabolic, cardiovascular and bone health outcomes (17-20). Because staging criteria in the general population may not be applicable to special populations such as females undergoing chemotherapy, the present analysis was undertaken.
AYA survivors face increased risks for not only POI and early menopause, but also adverse metabolic, cardiovascular, and bone health outcomes; as such, criteria that stage reproductive aging in this population would enable research on whether risks differ by stage and, ultimately, inform how to target clinical care by stage (9-11, 21-25). Current clinical society cancer survivorship guidelines recommend monitoring ovarian function with bleeding pattern alone without endocrine biomarkers unless a problem (ie, hot flashes) arises (26, 27). If reproductive aging in AYA survivors mirrors that of the general population, this approach may be problematic because ovarian reserve measures decline in women without cancer before menstrual pattern changes. An added consideration is fluctuation of ovarian reserve measures and bleeding pattern in AYA survivors following cancer treatment (28). To date, no studies have characterized AYA survivors into reproductive aging stages by bleeding pattern and endocrine biomarkers. It is unclear whether and how endocrine biomarkers contribute to defining the reproductive aging stage of AYA survivors, as well as whether all AYA survivors can be categorized by existing stages created for the general population.
The overall objective of this study was to assess the generalizability of STRAW + 10 staging criteria to AYA survivors. First, we hypothesized that the addition of endocrine biomarkers to bleeding pattern would alter the reproductive aging stage of AYA survivors, compared to bleeding pattern alone. We further hypothesized that the STRAW + 10 staging criteria could not be applied to all AYA survivors because endocrine biomarkers and bleeding patterns have been observed to fluctuate in patterns different from the general population. Finally, we hypothesized that known gonadotoxic treatments (ie, alkylating chemotherapy and pelvic radiation) would be associated with more advanced reproductive stages secondary to accelerated reproductive aging.
Materials and Methods
Study population
This analysis was conducted using data from participants in the Reproductive Window Study, a prospective cohort study on ovarian function in reproductive-age AYA survivors. Eligibility criteria for the Reproductive Window Study included cancer diagnosis between ages 15 and 35 years, study enrollment ages 18 to 39 years, completion of primary cancer treatment, and presence of at least one ovary (28). The following types of cancer were included: breast, blood and leukemia, lymphoma, gynecologic (cervix, uterus, ovary), intestines, gall bladder, pancreas, bone, soft-tissue tumor of bone/fat, skin, and thyroid. Participants were recruited between 2015 and 2018 from the California and Texas Cancer Registries (38.1%), University of California, San Diego Health System (27.8%), cancer advocacy organizations (9.7%), physician referrals (5.5%), and other sources (18.8%).
We performed a cross-sectional analysis using data collected at baseline. The analytic cohort was restricted to participants with a uterus and available data on antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels at baseline. Additionally, included participants were not pregnant or breastfeeding, on hormonal contraception (combined hormonal contraception, depot medroxyprogesterone acetate, progestin implants, progestin intrauterine devices), menopausal hormone therapy, or endocrine therapy (gonadotropin-releasing hormone agonists, tamoxifen, aromatase inhibitors) within the prior 12 months. The State of California Committee for the Protection of Human Subjects and the institutional review boards at the University of California, San Diego, and the Texas Department of State Health Services approved this study.
Data collection
At baseline, participants provided informed consent and completed an online questionnaire on demographics, cancer and treatment characteristics, menstrual history, hysterectomy and/or oophorectomy, and contraceptive management using questions derived from large cancer and reproductive cohort studies (29, 30). Participants self-reported the number of periods in the past year, whether a 7-day or greater difference in length of consecutive cycles persistently occurred in the past year, whether a 60-day or greater difference in length of consecutive cycles occurred in the past year, and the reason for amenorrhea if amenorrheic for the past year (12, 29, 31).
Following consent for HIPAA (US Health Insurance Portability and Accountability Act) and medical record release, primary cancer treatment records were obtained and cancer diagnosis and treatment data were abstracted by 2 board-certified pediatric oncologists and 1 board-certified reproductive endocrinologist using the Childhood Cancer Survivor Study methods and case report forms with high agreement on re-review of 25% of abstracted data (32).
Endocrine biomarkers were measured in self-collected dried-blood spots (DBS). Menstruating participants collected DBS on cycle days 3 through 7; amenorrheic participants collected DBS on a random day. Participants were instructed to puncture their finger pad and apply up to 5 drops of whole blood to the blood-spot filter paper, following written and pictorial instructions. Telephone or video calls with study staff were deployed during each participant’s first DBS collection for quality control. Participants were then instructed to allow samples to dry at room temperature for at least 4 hours prior to placement in a gas impermeable plastic bag with desiccant and shipment back to study staff via 2-day mail. Once received, DBS samples were inspected for quality and frozen at –80°C.
Endocrine measures
DBS were assayed for AMH and FSH levels (Limit of detection 0.03 ng/mL and 0.07 mIU/mL, respectively, and interassay and intra-assay coefficient of variation < 10%) using enzyme-linked immunosorbent assays (ELISAs) designed specifically for the measurement of human DBS specimens (AL-129, AL-187, Ansh Labs). DBS AMH concentrations are traceable to the manufacturer’s recombinant human AMH standard and are corrected for the DBS dilution factor so values assigned are relative to the participant’s serum levels. DBS FSH concentrations are traceable to World Health Organization preparations 83 and 575, respectively. The FSH calibrators are corrected for the DBS dilution factor so values assigned are relative to the participant’s serum levels. Using 29 matched serum and DBS samples ranging from 0.745 to 16.326 ng/mL AMH in serum, DBS AMH levels measured in these samples have been compared to serum levels measured with the Ansh picoAMH ELISA (AL-124). Passing-Bablock analysis of the results yielded the following: DBS AMH ng/mL = –4.404 + 0.065 serum AMH ng/mL (r = 0.96). Using 14 matched serum and DBS samples ranging from 0.97 to 8.5 mIU/mL of FSH in serum, DBS FSH levels were measured and compared to serum levels measured with the Ansh FSH ELISA (AL-186). Regression analysis of the results yielded the following: DBS FSH mIU/mL = 0.92 serum FSH + 0.35 mIU/mL (r = 0.96).
Reproductive aging stage classification
STRAW + 10 criteria were used to categorize participants (Table 1) (12). First, using bleeding pattern alone, all participants were categorized into reproductive (≥ 10 periods in past 12 months, not variable in length), early menopausal transition (persistent ≥ 7-day difference in length of consecutive cycles), late menopausal transition (amenorrhea ≥ 60 days and < 12 months), or postmenopausal stages (0 periods in the past 12 months). Second, using bleeding pattern plus AMH and FSH values, participants were categorized into the following stages: peak reproductive (≥ 10 periods in the past 12 months not variable in length, AMH ≥ 1 ng/mL and FSH < 10 IU/L), late reproductive (≥ 10 periods in the past 12 months not variable in length, and either AMH < 1 ng/mL or FSH 10-25 IU/L), early menopausal transition (persistent ≥ 7-day difference in length of consecutive cycles, AMH < 1 ng/mL and FSH 10-25 IU/L), late menopausal transition (amenorrhea ≥ 60 days and < 12 months, AMH < 1 ng/mL and FSH ≥ 25 IU/L), and postmenopause (amenorrhea for ≥ 12 months, AMH < 1 ng/mL and FSH > 25 IU/L). The AMH cut point of 1 ng/mL was selected based on definitions in studies of low responders to assisted reproduction as well as fecundability (33-36). Third, participants who had discrepant bleeding pattern and endocrine biomarkers were categorized as unclassifiable within the stage assigned by their menstrual pattern. For example, an individual with amenorrhea for 60 days or more and less than 12 months in the past year (consistent with the late menopausal transition bleeding pattern) and high AMH and low FSH levels (consistent with reproductive stages) was categorized as unclassifiable.
Table 1.
Classification of adolescent and young adult cancer survivors (n = 338) into STRAW + 10 stages by bleeding and endocrine biomarker criteria
| Menses prior 12 mo | Reproductive | Menopausal transition | Postmenopause | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ≥ 10 past y, not variable in length, N = 187 | Persistent ≥ 7-d difference in length, N = 68 | Amenorrhea ≥ 60 and < 365 d, N = 61 | 0 menses N = 22 |
||||||
| Peak | Late | Unclassifiable | Early | Unclassifiable | Late | Unclassifiable | Postmenopause | Unclassifiable | |
| Mean age, y (SD) | 33.7 (4.7) | 35.7 (3.6) | 37.9 | 35.0 (5.3) | 33.3 (4.3) | 36.7 (2.3) | 33.3 (4.6) | 32.8 (4.1) | 31.0 (6.9) |
| AMH ≥ 1 ng/mL and FSH < 10 IU/L | 115 (61%) | – | – | – | 40 (58%) | – | 27 (44%) | – | 1 (4%) |
| AMH < 1.0 ng/mL or FSH 10-25 IU/L | – | 71 (38%) | – | 28 (42%) | – | – | 27 (44%) | – | 2 (9%) |
| AMH < 1.0 ng/mL and FSH > 25 IU/L | – | – | 0 (0%) | – | 0 (0%) | 7 (12%) | – | 18 (82%) | – |
| AMH < 1.0 ng/mL or FSH > 25 IU/L | – | – | 1 (1%) | – | 0 (0%) | – | 0 (0%) | – | 1 (4%) |
Abbreviations: AMH, antimüllerian hormone; FSH, follicle-stimulating hormone; STRAW + 10, Stages of Reproductive Aging Workshop.
Cancer treatment classification
Based on abstracted treatment data, we derived the following exposure variables: alkylating chemotherapy and cyclophosphamide equivalent dosing (CED), abdominopelvic, total body or brain/head radiation, and allogenic or autologous stem cell transplant (37). Participants were also classified by exposure to high, moderate, and low gonadotoxicity treatments based on existing literature (3, 38-40). High gonadotoxicity treatments included any exposure to pelvic radiation, stem cell or bone marrow transplants (autologous or allogeneic), or CED of 7 g/m2 or greater. Low gonadotoxicity treatments included surgery only (excluding hysterectomy and/or oophorectomy), endocrine therapy only, radioiodine treatment, and cervical trachelectomy (41). All remaining treatment exposures, for example, CED of less than 7 g/m2, any alkylating chemotherapy exposure, other chemotherapy and targeted therapy, and unilateral oophorectomy, were grouped as moderate gonadotoxicity.
Statistical analysis
Descriptive characteristics were calculated using frequency and percentages. Distributions of continuous variables were assessed for normality and reported as mean (SD) or median (range). Percentage agreement was used to describe the proportions of participants who were similarly categorized by bleeding pattern alone vs combined bleeding pattern and endocrine measures. Bivariable analyses using the chi-square test of proportions, Fisher exact, Wilcoxon rank sum, analysis of variance, or t tests, as appropriate, compared participant and cancer characteristics, first by the ability to classify participants into the STRAW + 10 reproductive aging stages and second among stages.
Multivariable analyses using multinomial logistic regression then estimated associations between CED (37) with reproductive aging stage, while adjusting for confounding (42, 43). In these analyses, stages were collapsed into the 3 broad phases (ie, reproductive, menopausal transition, postmenopause) for simplicity and statistical efficiency. Variables associated with advanced reproductive aging stages at P less than or equal to .05 were included in multivariable models. Statistical significance was set at P less than or equal to .05. All analyses were conducted using Stata 15.1.
Results
A total of 338 AYA survivors met the inclusion criteria after excluding 384 participants who were ineligible because of prior hysterectomy (n = 35), current endocrine therapy (n = 54), or hormonal contraception or menopausal hormone therapy (n = 314). Eligible patients were older (P < .001), further from cancer treatment completion (P < .01), more likely to have leukemia/lymphoma and less likely to have breast or gynecologic cancers (P = .01), and less likely to receive CED of 7 g/m2 or greater (P = .02).
Among the 338 eligible participants, mean age (SD) at enrollment was 34.0 (4.5) years, and the mean number of years since cancer treatment ended was 6.9 (4.6) years (Table 2). The majority of participants were White (72%), and 21% were Hispanic. The most common cancers were leukemia/lymphoma (36%), thyroid (23%), and breast (23%). In this cohort, 50% received alkylating chemotherapy, 7% had a cancer recurrence, 6% received stem cell transplant, 6% underwent unilateral oophorectomy, 4% received abdominopelvic radiation, and 4% received total body irradiation.
Table 2.
Participant characteristics and whether classifiable by STRAW + 10 reproductive stages using bleeding pattern and follicle-stimulating hormone and antimüllerian hormone levels (n = 338)
| Participant characteristicsa | Overall (N = 338) | Classifiable (N = 239) | Unclassifiable (N = 99) | P |
|---|---|---|---|---|
| Demographics | ||||
| Age at enrollment, mean, y (SD) | 34.0 (4.5) | 34.4 (4.5) | 33.2 (4.6) | .03 |
| 18-24 | 19 (5.6) | 12 (5.0) | 7 (7.1) | .11 |
| 25-30 | 59 (17.5) | 37 (15.5) | 22 (22.2) | |
| 31-35 | 124 (36.7) | 84 (35.1) | 40 (40.4) | |
| 36-40 | 135 (40.0) | 105 (43.9) | 30 (30.3) | |
| Race | ||||
| White | 244 (72.2) | 175 (73.2) | 69 (69.7) | .74 |
| Asian | 26 (7.6) | 17 (7.1) | 9 (9.1) | |
| Black | 10 (3.0) | 6 (2.5) | 4 (4.0) | |
| Mixed race | 58 (17.2) | 41 (17.2) | 17 (17.2) | |
| Hispanic | 70 (20.7) | 51 (21.3) | 19 (19.2) | .92 |
| BMI, kg/m² | ||||
| < 18.5 | 9 (2.7) | 6 (2.5) | 3 (3.1) | .52 |
| 18.5-24.9 | 155 (47.2) | 115 (48.1) | 40 (41.2) | |
| 25-29.9 | 80 (24.4) | 54 (22.6) | 26 (26.8) | |
| ≥ 30 | 84 (25.6) | 56 (23.4) | 28 (28.9) | |
| Smoking | 12 (3.6) | 5 (2.1) | 7 (7.1) | .02 |
| Cancer characteristics | ||||
| Age at diagnosis, y | ||||
| < 18 | 111 (32.8) | 79 (33.0) | 32 (32.3) | .96 |
| 18-24 | 30 (8.9) | 22 (9.2) | 8 (8.1) | |
| 25-30 | 119 (35.2) | 82 (34.3) | 37 (37.4) | |
| 31-35 | 77 (22.8) | 55 (23.0) | 22 (22.2) | |
| Cancer type | ||||
| Breast | 77 (22.8) | 54 (22.6) | 23 (23.2) | .67 |
| Leukemia, lymphoma | 123 (36.4) | 90 (37.7) | 33 (33.3) | |
| Cervix, uterus, ovary | 23 (6.8) | 18 (7.5) | 5 (5.1) | |
| Intestines, stomach, gallbalder | 13 (3.8) | 7 (2.9) | 6 (6.1) | |
| Bone/soft tissue | 25 (7.4) | 18 (7.5) | 7 (7.1) | |
| Thyroid | 77 (22.8) | 52 (21.8) | 25 (25.3) | |
| Years since cancer treatment end, mean (SD) | 6.9 (4.6) | 7.2 (4.4) | 6.1 (4.5) | .04 |
| < 2 | 39 (11.5) | 20 (8.4) | 19 (19.2) | .04 |
| 2 to < 5 | 84 (24.9) | 61 (25.5) | 23 (23.2) | |
| 5 to < 10 | 150 (44.4) | 109 (45.6) | 41 (41.4) | |
| ≥ 10 | 65 (19.2) | 49 (20.5) | 16 (16.1) | |
| Cancer recurrence | 25 (7.4) | 25 (10.5) | 0 (0) | < .01 |
| Cancer treatments | ||||
| Radiation abdomen/pelvis | 12 (3.6) | 10 (4.2) | 2 (2.0) | .52 |
| Radiation brain | 4 (1.2) | 2 (0.8) | 2 (2.0) | .58 |
| Total body irradiation | 13 (3.8) | 9 (3.7) | 4 (4.0) | .56 |
| Alkylating chemotherapy | 170 (50.3) | 122 (51.1) | 48 (48.5) | .67 |
| Cyclophosphamide equivalent dose, g/m2 | ||||
| None | 221 (65.4) | 156 (65.3) | 65 (65.7) | .80 |
| < 7 | 88 (26.0) | 61 (25.5) | 27 (27.3) | |
| ≥ 7 | 29 (8.6) | 22 (9.2) | 7 (7.0) | |
| Stem cell transplant | 21 (6.2) | 19 (7.9) | 2 (2.0) | .05 |
| Oophorectomy unilateral | 21 (6.2) | 18 (7.5) | 3 (3.0) | .14 |
| Gonadotoxicity risk group | .39 | |||
| Low | 106 (31.4) | 72 (30.1) | 34 (34.3) | |
| Moderate | 193 (57.1) | 136 (56.9) | 57 (57.6) | |
| High | 39 (11.5) | 31 (13.0) | 8 (8.1) |
Abbreviations: BMI, body mass index; STRAW + 10, Stages of Reproductive Aging Workshop.
a Data expressed as n (%) unless otherwise noted; not all percentages add up to 100 because of missing data.
First, we characterized all 338 eligible participants into reproductive aging stages by bleeding pattern alone; without AMH and FSH measures, bleeding pattern could not distinguish between peak and late reproductive stage. Fifty-five percent (n = 187) were in the reproductive stage, 20% (n = 68) were in early menopausal transition, 18% (n = 61) were in late menopausal transition, and 7% (n = 22) were in postmenopausal stage.
Including AMH and FSH measures, 71% of the 338 participants (n = 239) could be classified into a STRAW + 10 stage, whereas 29% could not be classified (see Table 1). Among classifiable participants, 48% (n = 115) were in peak reproductive stage, 30% (n = 71) were in late reproductive stage, 11% (n = 28) were in early menopausal transition, 3% (n = 7) were in late menopausal transition, and 8% (n = 18) were in the postmenopausal stage. Within the reproductive phase, the addition of endocrine biomarkers distinguished between peak and late reproductive stages.
The percentage agreement between classification by bleeding pattern alone vs bleeding pattern with ovarian reserve testing was high for the reproductive (99%, n = 186/187) and postmenopausal stages (82%, n = 18/22) (see Table 1). However, the early menopausal transition (41%, n = 28/68) and late menopausal transition (12%, n = 7/61) were highly discrepant between the 2 classification approaches. This discrepancy arose from participants with bleeding patterns consistent with the menopausal transition, but were unclassifiable when incorporating endocrine measures with bleeding pattern because their AMH and/or FSH levels were consistent with the reproductive stage (Fig. 1).
Figure 1.
Biomarker profiles within each STRAW + 10, Stages of Reproductive Aging Workshop (STRAW + 10) stage classified by bleeding pattern: reproductive phase (n = 187), early menopausal transition stage (early MT) (n = 68), late menopausal transition stage (late MT) (n = 61), and postmenopause (PM) (n = 22). Antimüllerian hormone (AMH) ≥ 1 ng/mL and follicle-stimulating hormone (FSH) < 10 IU/L, AMH < 1.0 ng/mL or FSH 10 to 25 IU/L, AMH < 1.0 ng/mL and FSH > 25 IU/L, AMH < 1.0 ng/mL or FSH > 25 IU/L.
Compared with classifiable participants, unclassifiable survivors were younger, more likely to smoke and undergo stem cell transplant, less likely to have a cancer recurrence, and had shorter time since cancer treatment completion (all P < .05) (see Table 2). Specifically, 49% of participants who were less than 2 years from treatment could not be classified, compared with 27% of those at least 2 years from treatment (P = .005).
We next compared classifiable (see Table 1) participants’ characteristics by stage (Table 3). Age at enrollment, age at cancer diagnosis, years since cancer treatment, and recurrence were different by stage, but not in an ordered pattern (all P < .05). When looking at the impact of cancer treatments on reproductive aging, gonadotoxic treatment exposures except total body irradiation (abdominopelvic radiation, alkylating chemotherapy, CED, stem cell transplant) were each significantly associated with more advanced reproductive stages (all P < .05). Brain radiation was not related to stage.
Table 3.
Classifiable participants’ characteristics by STRAW + 10 reproductive aging stage using bleeding pattern and follicle-stimulating hormone and antimüllerian hormone levels (n = 239)
| Participant characteristicsa | Peak reproductive N = 115 | Late reproductive N = 71 | Early transition N = 28 | Late transition N = 7 | Postmenopause N = 18 | P |
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Age at enrollment, mean, y (SD) | 33.7 (4.7) | 35.7 (3.6) | 35.0 (5.3) | 36.7 (2.3) | 32.8 (4.1) | < .01 |
| Race | ||||||
| Black | 1 (0.9) | 3 (4.2) | 2 (7.1) | 0 (0) | 0 (0) | .76 |
| White | 87 (75.7) | 48 (67.6) | 20 (71.4) | 6 (85.7) | 14 (77.8) | |
| Asian | 10 (8.7) | 4 (5.6) | 2 (7.1) | 0 (0) | 1 (5.6) | |
| Mixed race | 17 (14.8) | 16 (22.5) | 4 (14.3) | 1 (14.3) | 3 (16.7) | |
| Hispanic | 19 (16.5) | 15 (21.1) | 9 (32.1) | 3 (42.9) | 5 (27.8) | .46 |
| BMI, kg/m² | ||||||
| < 18.5 | 3 (2.6) | 2 (2.2) | 0 (0) | 0 (0) | 1 (5.6) | .43 |
| 18.5-24.9 | 60 (52.2) | 30 (42.3) | 14 (50.0) | 3 (42.9) | 8 (44.4) | |
| 25-29.9 | 23 (20.0) | 17 (23.9) | 10 (35.7) | 3 (42.9) | 1 (5.6) | |
| ≥ 30 | 25 (21.6) | 19 (26.8) | 4 (14.3) | 1 (14.3) | 7 (38.9) | |
| Smoking | 2 (1.7) | 1 (1.4) | 1 (3.6) | 0 (0) | 1 (5.6) | .51 |
| Cancer characteristics | ||||||
| Age at diagnosis, y | ||||||
| < 18 | 46 (40.4) | 18 (25.4) | 6 (21.4) | 1 (14.3) | 8 (44.4) | .01 |
| 18-24 | 9 (7.9) | 4 (5.6) | 7 (25.0) | 0 (0) | 2 (11.1) | |
| 25-30 | 37 (32.5) | 30 (42.3) | 8 (28.6) | 1 (14.3) | 6 (33.3) | |
| 31-35 | 22 (19.3) | 19 (26.8) | 7 (25.0) | 5 (71.4) | 2 (11.1) | |
| Cancer type | ||||||
| Breast | 24 (20.9) | 19 (26.8) | 6 (21.4) | 4 (57.1) | 1 (5.6) | .13 |
| Leukemia/ lymphoma | 43 (37.4) | 22 (40.0) | 10 (35.7) | 3 (42.9) | 12 (66.7) | |
| Cervix, uterus, ovary | 6 (5.2) | 6 (8.5) | 4 (14.3) | 0 (0) | 2 (11.1) | |
| Intestines, gallbladder, stomach | 3 (2.6) | 2 (2.8) | 0 (0) | 0 (0) | 2 (11.1) | |
| Bone/soft tissue | 10 (8.7) | 5 (7.0) | 2 (7.1) | 0 (0) | 1 (5.6) | |
| Thyroid | 29 (25.2) | 17 (23.9) | 6 (21.4) | 0 (0) | 0 (0) | |
| Years since cancer treatment, mean (SD) | 7.1 (4.4) | 7.1 (3.9) | 9.2 (5.6) | 5.8 (4.8) | 4.9 (3.4) | .03 |
| Cancer recurrence | 6 (5.2) | 7 (9.9) | 1 (3.6) | 0 (0) | 11 (61.1) | < .01 |
| Cancer treatments | ||||||
| Radiation abdomen/pelvis | 0 (0) | 2 (2.8) | 0 (0) | 1 (14.3) | 7 (38.9) | < .01 |
| Radiation brain | 1 (0.9) | 0 (0) | 0 (0) | 0 (0) | 1 (5.6) | .28 |
| Total body irradiation | 4 (3.5) | 2 (2.8) | 3 (10.7) | 0 (0) | 0 (0) | .39 |
| Alkylating chemotherapy | 53 (46.1) | 34 (47.9) | 15 (53.6) | 6 (85.7) | 14 (77.8) | .04 |
| CED, g/m2 | ||||||
| None | 90 (78.3) | 46 (64.8) | 16 (57.1) | 0 (0) | 4 (22.2) | < .01 |
| < 7 | 21 (18.3) | 20 (28.2) | 9 (32.1) | 6 (85.7) | 5 (27.8) | |
| ≥ 7 | 4 (3.5) | 5 (7.0) | 3 (10.7) | 1 (14.3) | 9 (50.0) | |
| Stem cell transplant | 0 (0) | 4 (5.6) | 0 (0) | 2 (28.6) | 13 (72.2) | < .01 |
| Oophorectomy unilateral | 4 (3.5) | 9 (12.7) | 4 (14.3) | 1 (14.3) | 0 (0) | .03 |
| Gonadotoxicity risk group | < .01 | |||||
| Low | 43 (37.4) | 23 (32.4) | 6 (21.4) | 0 (0) | 0 (0) | |
| Moderate | 69 (60.0) | 41 (57.8) | 20 (71.4) | 5 (71.4) | 1 (5.6) | |
| High | 3 (2.6) | 7 (9.9) | 2 (7.1) | 2 (28.6) | 17 (94.4) |
Abbreviations: BMI, body mass index; CED, Cyclophosphamide equivalent dose; STRAW + 10, Stages of Reproductive Aging Workshop.
a Data expressed as n (%) unless otherwise noted; not all percentages add up to 100 because of missing data.
In multivariable analysis, we collapsed classifiable participants into the 3 broad phases of reproductive stage, menopausal transition, and postmenopause for simplicity and statistical efficiency. Because enrollment age, age at diagnosis, and time since treatment were highly correlated, only enrollment age was included in these models. After adjusting for enrollment age and cancer recurrence, CED remained significantly associated with dose-dependent, increased risks of menopausal transition and postmenopause (see Table 4). For example, participants receiving a CED of 7 g/m2 or greater had a 4.3-fold higher relative risk of being in the menopausal transition vs reproductive phase, compared to participants not exposed to these drugs. Owing to low number of exposures by bleeding pattern group, multivariable models for the other gonadotoxic treatment exposures (ie, abdominal-pelvic radiation, stem cell transplant, gonadotoxicity risk group and unilateral oophorectomy) were not undertaken.
Table 4.
Multivariable multinomial logistic model for the association between cyclophosphamide equivalent dose and STRAW + 10 stage (menopausal transition or postmenopause vs reproductive), adjusting for age and cancer recurrence
| Unadjusted RR (95% CI) | Adjusted RR (95% CI) | |
|---|---|---|
| Reproductive stage | (Reference) | (Reference) |
| Menopausal transition | ||
| CED none | (Reference) | (Reference) |
| CED < 7 g/m2 | 3.1 (1.4-6.8) | 3.0 (1.4-6.6) |
| CED ≥ 7 g/m2 | 3.8 (1.0-13.7) | 4.3 (1.2-16.1) |
| Recurrence | 0.39 (0.05-3.1) | 0.34 (0.04-2.8) |
| Enrollment age, per y | 1.1 (1.0-1.2) | 1.1 (0.96-1.1) |
| Postmenopause | ||
| CED none | (Reference) | (Reference) |
| CED < 7 g/m2 | 4.1 (1.1-16.2) | 4.1 (1.0-17.4) |
| CED ≥ 7 g/m2 | 34 (8.8-132.1) | 15.8 (3.4-73.6) |
| Recurrence | 20.9 (6.9-63.0) | 13.0 (3.7-45.5) |
| Enrollment age, per y | 0.9 (0.9-1.0) | 1.0 (0.8-1.1) |
Abbreviations: CED, cyclophosphamide equivalent dose; RR, relative risk; STRAW + 10, Stages of Reproductive Aging Workshop.
Discussion
For female AYA survivors, there has been a lack of data characterizing the process of reproductive aging leading to postmenopause, and accurate measurements and nomenclature on this process may be clinically important for fertility and family planning, cancer treatment decisions, and screening for additional cardiovascular, metabolic, and bone late effects (27, 44-46). The present study applied the STRAW + 10 criteria, the standard for describing reproductive aging in general population, to a young cancer survivor population (12). The analysis demonstrated that gonadotoxic cancer treatments are related to advanced reproductive stages, as hypothesized. However, a significant proportion of AYA survivors could not be categorized by existing stages, highlighting the limitation of current criteria. Moreover, combining FSH and AMH levels with bleeding patterns showed that classifying by bleeding pattern alone frequently categorized AYA survivors into either more or less advanced stages of reproductive aging. The clinical consequence of this misclassification may be either false concern or false reassurance.
We hypothesized that gonadotoxic treatments would be associated with advanced reproductive aging stages based on prior studies demonstrating destruction of the resting ovarian follicle pool and association with premature ovarian insufficiency (2, 3, 9,39, 47-49) Accordingly, we observed that exposure to alkylating chemotherapy, radiation to the pelvis, and/or stem cell transplant was associated with distributions of reproductive aging stages skewed toward the menopausal transition and postmenopause. We were also able to observe dose-dependent effects with CED and gonadotoxicity risk group. These findings support the validity of reproductive staging criteria based on oocyte depletion (such as the STRAW + 10 system) in a significant portion of the AYA survivor population.
Across stages, AYA survivors were younger than expected of the general population, consistent with accelerated ovarian aging. For example, in the longitudinal TREMIN cohort, median ages at entering the early and late transition stages were in the early and late 40s, respectively (50). Despite young chronologic age (mean age of classifiable survivors was 34.4 years), more than half of the participants were categorized as beyond the peak reproductive stage. In the general population, the late reproductive stage marks a time when fecundability begins to decline, and menopausal transition stages are related to worsening metabolic, cardiovascular, and bone health outcomes (51). Specifically, the menopausal transition is associated with an acceleration in bone loss, which increases the risk for hip fractures (52, 53), and deleterious metabolic changes including elevations in body fat composition, lipids and lipoproteins, and vascular remodeling (53-55). In addition, initiation of the late menopausal transition has some predictive value for time to postmenopause (56). The relationships between reproductive aging stage and clinical outcomes is salient in AYA survivors because cancer treatments also adversely affect each of these outcomes (21-25). Developing nomenclature to stage ovarian senescence will enable studies on their association with fecundity, metabolic, cardiovascular, and bone health outcomes in this population and targeting counseling and clinical screening based on cancer treatment exposures and reproductive aging.
Although advanced reproductive aging stages were related to gonadotoxic treatments as hypothesized, nearly 30% of AYA survivors could not be categorized by current bleeding and endocrine biomarker criteria. These were largely participants who were less than 2 years from the end of their cancer treatments. This observation is consistent with the timing of ovarian recovery post treatment. From prior studies, AMH levels nadir during gonadotoxic treatments and the immediate ensuing time period (57-59). When there are residual primordial ovarian follicles after cancer treatment, growth of these follicles into the primary, secondary, preantral, and antral follicle stages will result in the increase of AMH in the first 1.5 to 3 years post treatment (28, 57, 60-63). Clinically, the oligo-ovulation that occurs during ovarian recovery would manifest in irregular bleeding patterns also seen during menopausal transition stages, but ovarian reserve markers would appear more akin to reproductive stages. Hence, without AMH and FSH measurements, these AYA survivors would be categorized into menopausal transition stages based on bleeding pattern alone. Interestingly, with the exception of stem cell transplant, no other specific gonadotoxic treatments were related to the ability to be classified, and this is also consistent with our longitudinal study of AMH trajectories that showed no divergence by low, moderate or high gonadotoxicity group until after the first 2.5 years (28).
The data highlight the relevance of adding endocrine biomarkers to bleeding data in characterizing the ovarian function of AYA survivors. While clinical experts in the field are proponents (64), current childhood and AYA survivorship clinical society guidelines have yet to adopt this recommendation (26,27). Among classifiable AYA survivors, endocrine biomarkers helped to distinguish between early and late reproductive, as well as early and late menopausal transition stages, consistent with the general population. However, AYA survivors may benefit from additional modification to the current STRAW + 10 criteria. There appears to be an additional subgroup between reproductive stage and menopausal transition for individuals with normal or near normal ovarian reserve markers and irregular bleeding patterns. Longitudinal data are needed to observe if this group returns to the reproductive stages or progresses to the menopausal transition stages. Caution should be applied to using STRAW + 10 criteria to characterize AYA survivors, particularly in their first 2 years post treatment.
Beyond AYA survivors, STRAW + 10 criteria are not generalizable to several female populations, that is, women with POI (1%), hysterectomy and endometrial ablation (up to 35%), polycystic ovary syndrome (6%), and other chronic illnesses such as HIV (< 1%), and hypothalamic amenorrhea (< 1%) (12). In our study we excluded 384 AYA survivors for pregnancy, breastfeeding, hormonal contraception, menopausal hormone therapy, or endocrine therapy because of the impact of these exposures on bleeding pattern or biomarker levels. Fifty-two percent of these survivors had AMH levels of 1 ng/mL or greater, demonstrating that in some populations, ovarian function can be assessed only through endocrine biomarkers, specifically AMH. We advocate modifying the staging approach for special populations, including AYA survivors. Valid staging with endocrine biomarkers and/or bleeding pattern will enable the study of their long-term metabolic, cardiovascular, and bone health risks.
Strengths of this study include recruitment of reproductive-age AYA survivors from 2 large state cancer registries and collection of bleeding pattern and ovarian reserve markers. Primary abstraction of medical records by physicians minimizes misclassification by cancer treatment, especially given poor recall of received cancer therapies by AYA survivors (65). Several limitations should be discussed. The cross-sectional nature of this analysis precludes assessment of the amount of time spent in each stage or fluidity between reproductive aging stages in this population. AMH assays remain without standardization, thus selection of the 1.0 ng/mL cut point may not be generalizable across assays (66); varying the cut points for AMH would result in different distributions by stage and classification. Although the total sample size is sizable for an AYA survivor study, the absolute numbers both after excluding women on hormonal therapy and when looking at specific cancer treatments were small, limiting power. Some caution regarding generalizability of findings is to be noted for a population recruited for a reproductive health study.
In summary, this study shows a novel association between gonadotoxic cancer treatments and stages of reproductive aging. The combination of ovarian reserve biomarkers and bleeding pattern suggests the need for an additional stage, that is, normal ovarian reserve with irregular menstrual pattern, in the STRAW + 10 criteria for this AYA cancer population. The progression through reproductive aging stages and the association between stage and cancer-related late effects remain to be investigated.
Acknowledgments
We wish to thank the Reproductive Window Study participants, Stupid Cancer!, Fertile Action, and the Texas and California Cancer Registries for their partnership on this project. We also wish to acknowledge Ajay Kumar, PhD, and Bahnu Kalra, PhD, for development of the DBS AMH assay.
Financial Support: This work was supported by the National Institute of Child Health and Human Development (Grant No. NIH HD080952).
Glossary
Abbreviations
- AMH
antimüllerian hormone
- AYA
adolescents and young adults
- CED
cyclophosphamide equivalent dosing
- DBS
dried-blood spots
- ELISA
enzyme-linked immunosorbent assay
- FSH
follicle-stimulating hormone
- POI
primary ovarian insufficiency
- STRAW + 10
Stages of Reproductive Aging Workshop + 10.
Additional Information
Disclosure Summary: Dr Sluss works for Ansh Labs, and Dr Dietz works for bluebird bio, Inc. These companies did not sponsor, support, or have oversight of this research.
Data Availability
The data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
