Self-collected dried blood spots as a tool for measuring ovarian reserve in young female cancer survivors.

STUDY QUESTION: Are female young cancer survivors (YCS) able to self-collect high-quality dried blood spots (DBSs) at home to provide biospecimens for studying ovarian reserve? SUMMARY ANSWER: YCS can self-collect high-quality DBS specimens in non-clinical settings, and anti-Mullerian hormone (AMH) levels can be assayed in such specimens. WHAT IS KNOWN ALREADY: Large-scale biosample collection is a barrier to studying ovarian reserve in YCS. DBS collected by research personnel has high acceptability. AMH levels measured in DBS are highly correlated with those measured by serum-based methods. STUDY DESIGN, SIZE, DURATION: In a prospective cohort study, YCS were recruited to self-collect DBS samples. AMH levels were assayed in 112 samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: YCS participants, ages 18-44, were recruited from a nationwide longitudinal cohort and DBS collection materials were posted to them. AMH levels were assayed by the Ansh DBS AMH ELISA and compared according to participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Among 163 potential participants, 123 (75%) were enrolled. Of those enrolled, 112 (91%) were able to complete DBS self-collection and submit mailed samples adequate for measuring AMH. Participants (mean age 31.6 [SD 5.5]) were 85% white, 87% college graduates and 46% reported higher income. Common cancer types were lymphoma and leukemia (34%), breast cancer (30%) and thyroid or skin cancer (8%). The geometric mean (95% confidence interval) AMH level in DBS samples was 0.24 ng/ml (0.16-0.36). In adjusted analysis, AMH levels for survivors of breast cancer (0.02 ng/ml [0.01-0.07]) or leukemia/lymphoma (0.03 ng/ml [0.01-0.08]) were lower than the levels in thyroid or skin cancer survivors (0.12 ng/ml [0.03-0.44]). Pelvic radiation remained associated with lower AMH levels (0.20 ng/ml [0.10-0.40] in unexposed versus 0.02 ng/ml [0.01-0.06] in exposed). Amenorrheic survivors had AMH levels (0.02 ng/ml [0.01-0.06]) that were lower than those of YCS with 7-9 (0.09 ng/ml [0.03-0.32]) or ≥10 (0.17 ng/ml [0.08-0.37]) menstrual periods in the past year. LIMITATIONS, REASONS FOR CAUTION: The results are generalizable to a population of highly educated, higher income YCS. It is unclear how generalizable the results are to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Self-collected DBS is a patient-friendly and minimally invasive tool for studying ovarian reserve in geographically diverse populations. STUDY FUNDING/COMPETING INTERESTS: Research related to the development of this paper was supported by the National Institutes of Health, grants UL1 RR024926 pilot and HD080952-02, and by the American Cancer Society MRSG-08-110-01-CCE. The authors report no competing interests.

Impact of breast cancer on anti-mullerian hormone levels in young women.

Young women with breast cancer face treatments that impair ovarian function, but it is not known if malignancy itself impacts ovarian reserve. As more breast cancer patients consider future fertility, it is important to determine if ovarian reserve is impacted by cancer, prior to any therapeutic intervention. A cross-sectional study was conducted comparing if ovarian reserve, as measured by anti-mullerian hormone (AMH), follicle stimulating hormone (FSH), and inhibin B (inhB), differed between 108 women with newly diagnosed breast cancer and 99 healthy women without breast cancer. Breast cancer participants were ages 28-44 and were recruited from two clinical breast programs. Healthy women ages 30-44 without a history of infertility were recruited from gynecology clinics and the community. The median age (interquartile range) was 40.2(5.5) years for breast cancer participants and 33.0(4.6) years for healthy controls. The unadjusted geometric mean AMH levels (SD) for breast cancer participants and controls were 0.66(3.6) and 1.1(2.9) ng/mL, respectively. Adjusting for age, body mass index, gravidity, race, menstrual pattern, and smoking, mean AMH levels were not significantly different between breast cancer participants and healthy controls (0.85 vs. 0.76 ng/mL, p = 0.60). FSH and inhB levels did not differ by breast cancer status. In exploratory analysis, the association between AMH and breast cancer status differed by age (p-interaction = 0.02). AMH may be lower with breast cancer status in women older than 37. In younger women, AMH levels did not differ significantly by breast cancer status. Among the youngest of breast cancer patients, ovarian reserve as measured by AMH, FSH, and inhibin B did not differ significantly from healthy women of similar age. In older breast cancer patients, ovarian reserve may be adversely impacted by cancer status. These findings support the potential success and need for fertility preservation strategies prior to institution of cancer treatment.

Measuring ovarian function in young cancer survivors.

It is known that young female cancer survivors are at higher risk for decreased fertility and early menopause. Because the risk of these outcomes varies by age, cancer type, treatment regimen and other patient-specific characteristics, there is a need for valid tools for measuring and predicting reproductive function in this population. Ovarian reserve tests (ORT) include serum and ultrasound biomarkers used in characterizing healthy ovarian aging and predicting ovarian reserve prior to fertility treatment. This review summarizes efforts to translate ORT to use in female cancer patients. To date, small longitudinal and cross-sectional studies of young cancer patients demonstrate that gonadotoxic chemotherapy impact ORT. While follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume have all been demonstrated to change with exposure to gonadotoxic therapy, FSH, AMH and AFC appear to be the most sensitive. More data are needed to determine the long-term effect of hormonal agents from tamoxifen to GnRH agonists on ORT. The effect of unilateral oophorectomy acutely or in the long-term on ORT is not known. There are some early data postulating that cancer itself may impair ovarian reserve. Among cancer survivors, ORT correlate with amenorrhea. Even in young survivors with normal menstrual cycles, hormone and ultrasound measures of ovarian reserve suggest decreased underlying ovarian reserve than age-matched healthy women. More studies are needed to determine the optimal time to test ORT in the large number of young survivors on combined estrogen and progesterone contraceptives. A significant utility of ORT would be to be able to predict fertility for young survivors, and there are no data on this outcome to date. The goal of future studies of ORT in young girls and women with cancer is to determine their utility as surrogate measures of ovarian function or predictors of infertility or ovarian failure. To do so, large-scale data need to be collected through cooperative group mechanisms. Epidemiologically, studies need to move from association studies to develop ORT into appropriate screening and predictive tests.

Hormone changes associated with the menopausal transition.

The menopausal transition (MT) is the time in each woman's reproductive life that precedes the final menstrual period (FMP). MT is associated with changes in bleeding pattern and hormone profiles. In recent years, research efforts have characterized changes in reproductive hormones over MT in order to elucidate the process of late reproductive aging and potentially identify predictors of time to menopause. Follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B and estradiol represent the four primary hormone measures of these investigations. Current data show an increase in FSH and decreases in AMH, inhibin B and estradiol over MT. AMH appears to be the first marker to change, followed by FSH and inhibin B. Estradiol declines in late MT. To date, there are no validated hormone cutpoints that predict the length of MT or FMP. There are very preliminary data on AMH as a predictor of menopause. Until further evidence identifies clinically useful hormone levels for predicting MT or FMP, diagnosis of MT and FMP should be based on clinical signs and symptoms only.