Date Published: July 20, 2017
Publisher: Public Library of Science
Author(s): Thomas W. Kelsey, Lauren McConville, Angela B. Edgar, Alex I. Ungurianu, Rod T. Mitchell, Richard A. Anderson, W. Hamish B. Wallace, Stefan Schlatt.
The accuracy of Follicle Stimulating Hormone as a predictor of azoospermia in adult survivors of childhood cancer is unclear, with conflicting results in the published literature. A systematic review and post hoc analysis of combined data (n = 367) were performed on all published studies containing extractable data on both serum Follicle Stimulating Hormone concentration and semen concentration in survivors of childhood cancer. PubMed and Medline databases were searched up to March 2017 by two blind investigators. Articles were included if they contained both serum FSH concentration and semen concentration, used World Health Organisation certified methods for semen analysis, and the study participants were all childhood cancer survivors. There was no evidence for either publication bias or heterogeneity for the five studies. For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%–86%) and sensitivity 83% (95% CI 76%–89%). The AUC was 0.89 (95%CI 0.86–0.93). A range of threshold FSH values for the diagnosis of azoospermia with their associated sensitivities and specificities were calculated. This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer.
The potential impact of childhood cancer treatment on male fertility is a significant issue for both families at the time of diagnosis, and the young adult survivor [1, 2]. Treatment at any age, with chemotherapy agents, particularly high doses of alkylating agents, and pelvic radiotherapy, may damage the testes resulting in impaired sperm production[2–7]. While semen analysis remains the gold standard, a serum biomarker of sufficient accuracy, for example Follicle Stimulating Hormone (FSH) would provide a useful indirect assessment of fertility.
Using an established methodology [16–18], a scoping search was carried out using relevant MeSH headings which generated 680 results on PubMed and 973 on Scopus. The Medline search strategy used was 1. ‘Follicle Stimulating Hormone/b 2. FSH.ti,ab. 3. Inhibin/bl 4. Inhibin В/Ы 5. Follicle stimulating hormone.ti,ab. 6. exp Sperm Count/ 7. spermato$.ti,ab. 8. semen/су 9. (male adj3 fertil$).ti,ab. 10. azoospermia.ti,ab. 11. semen analysis.ti,ab. 12. sperm concentration.ti, ab. 13. oligospermia.ti,ab. 14. semen.ti,ab. 15. 1 or 2 or 3 or 4 or 5 16. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 orm14 17. 15 and 16 18. (HUMANS not ANIMALS).sh. 19. 17 and 18. Only publications in written in English were screened.
The application of inclusion and exclusion criteria to the studies found in the literature yielded four sources of FSH and semen concentration in CCS (Table 1, S2 Table, Fig 1) [5, 14, 32, 33]. Studies identified for full-text analysis, but excluded are listed in S1 References together with reasons for exclusion. The Chi-squared statistical test for funnel plot asymmetry (Fig 2) did not reach statistical significance (p = 0.32 for sensitivity; p = 0.17 for specificity), suggesting that neither studies with small sample size nor studies with results lacking statistical significance are missing from the literature. As all the included studies used WHO protocols, we conclude that they are at low risk of bias and have low concern about applicability, as specified by the QUODAS-2 and STARD frameworks for reporting diagnostic accuracy [34, 35].
We have shown that FSH has strong diagnostic power, with 89% probability that FSH levels will correctly classify as azoospermic, not azoospermic a randomly chosen survivor of childhood cancer (i.e. positive predictive value) , with 95% confidence that this probability is within 85% and 92% (Fig 4). For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%–86%) and sensitivity 83% (95% CI 76%–89%). The AUC was 0.89 (95%CI 0.86–0.93). This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer. We have also calculated clinically-useful diagnostic levels for a range of FSH thresholds (Table 2).