Antral Follicles Count and Anti-Müllerian Hormone Levels after Gonadotoxic Chemotherapy in Patients with Breast Cancer: Cohort Study

Abstract

Aim To assess ovarian reserve (OVR) by means of follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), and antral follicle count (AFC) measurement in eumenorrheic women with breast cancer, exposed to gonadotoxic chemotherapy.

Method Fifty-two women (35.3 ± 3.8 years old) with breast cancer and undergoing cyclophosphamide-containing chemotherapy were enrolled. The assessment was performed before chemotherapy (T1) and after 2 (T2) and 6 months (T3).

Results Six months after chemotherapy, the prevalence of regular cycles was 60%. Anti-Müllerian hormone decreased down to undetectable levels at T2 and T3 (T1: 2.53 [1.00–5.31]; T2 < 0.08; T3: < 0.08 [< 0.08–1.07] ng/mL), (p < 0.0001). Antral follicle count was 11 [8.0–13.5] follicles at T1 and lower at T2 (5.50 [3.75–8.0] and T3 (5.0 [2.5–7.0]) (p < 0.0001). In patients who remained with regular cycles during chemotherapy or resumed normal menses, FSH and estradiol levels remained unchanged.

Conclusion Anti-Müllerian hormone and AFC are useful as markers of OVR decline in women exposed to chemotherapy. Follicle-stimulating hormone is only adequate in women who become amenorrheic.

Resumo

Objetivo Avaliar a reserva ovariana (OVR) através da contagem de folículos antrais (AFC), dosagem sérica de hormônio folículo estimulante (FSH) e hormônio anti-Mülleriano (AMH) em mulheres com câncer de mama submetidas a quimioterapia gonadotóxica.

Método Foram incluídas na pesquisa 52 mulheres (35,3 ± 3,8 anos) com câncer de mama, em tratamento com quimioterapia com ciclofosfamida. As dosagens e medidas foram realizadas antes do início da quimioterapia (T1) e após 2 (T2) e 6 meses (T3).

Resultados Seis meses após quimioterapia, a prevalência de ciclos regulares foi de 60%. O AMH sérico diminuiu a níveis indetectáveis em T2 e T3 (T1: 2,53 [1,00–5,31] ]; T2 < 0,08; T3: < 0,08 [< 0,08–1,07] ng/mL) (p < 0,0001). A contagem de folículos antrais foi de 11 [8,0–13,5] folículos em T1, e ainda menor em T2 (5,50 [3,75–8,0] e T3 (5,0 [2,5–7,0]), (p < 0,0001). Em pacientes que mantiveram ciclos regulares durante a quimioterapia ou retomaram a menstruação normalmente, os níveis de FSH e estradiol permaneceram inalterados.

Conclusão O AMH e a AFC são marcadores úteis do declínio da OVR em mulheres expostas à quimioterapia. O FSH só é adequado em mulheres que se tornam amenorreicas.

Keywords

anti-Müllerian hormone - antral follicle count - ovarian reserve - chemotherapy-induced amenorrhea - anovulation

Palavras-chave

hormônio anti-Mülleriano - contagem de folículos antrais - reserva ovariana - amenorreia induzida por quimioterapia - anovulação

• References

• 1 Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2012; 98 (06) 1407-1415
• 2 Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12 (06) 685-718
• 3 Bancsi LF, Broekmans FJ, Eijkemans MJ, de Jong FH, Habbema JD, te Velde ER. Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77 (02) 328-336
• 4 Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian reserve to predict age at menopause. Maturitas 2009; 63 (04) 280-291
• 5 Domingues TS, Rocha AM, Serafini PC. Tests for ovarian reserve: reliability and utility. Curr Opin Obstet Gynecol 2010; 22 (04) 271-276
• 6 La Marca A, Pati M, Orvieto R, Stabile G, Carducci Artenisio A, Volpe A. Serum anti-müllerian hormone levels in women with secondary amenorrhea. Fertil Steril 2006; 85 (05) 1547-1549
• 7 La Marca A, Volpe A. Anti-Müllerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool?. Clin Endocrinol (Oxf) 2006; 64 (06) 603-610
• 8 D'Avila AM, Fracasso GL, Capp E, Brum IS, Corleta HE. Hormônio anti-mülleriano: um marcador mais fidedigno da reserva ovariana?. Reprod Clim 2008; 23: 14-19
• 9 van Rooij IA, Tonkelaar Id, Broekmans FJ. , et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004; 11 (6 Pt 1): 601-606
• 10 van Rooij IAJ, Broekmans FJM, te Velde ER. , et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17 (12) 3065-3071
• 11 Durlinger AL, Gruijters MJ, Kramer P. , et al. Anti-Müllerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology 2001; 142 (11) 4891-4899
• 12 Durlinger AL, Kramer P, Karels B. , et al. Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Endocrinology 1999; 140 (12) 5789-5796
• 13 La Marca A, De Leo V, Giulini S. , et al. Anti-Mullerian hormone in premenopausal women and after spontaneous or surgically induced menopause. J Soc Gynecol Investig 2005; 12 (07) 545-548
• 14 Louis J, Limarzi LR, Best WR. Treatment of chronic granulocytic leukemia with myleran. AMA Arch Intern Med 1956; 97 (03) 299-308
• 15 Apperley JF, Reddy N. Mechanism and management of treatment-related gonadal failure in recipients of high dose chemoradiotherapy. Blood Rev 1995; 9 (02) 93-116
• 16 Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 2010; 116 (05) 1171-1183
• 17 Blumenfeld Z. Ovarian rescue/protection from chemotherapeutic agents. J Soc Gynecol Investig 2001; 8 (1, Suppl Proceedings) S60-S64
• 18 Long WQ, Ranchin V, Pautier P. , et al. Detection of minimal levels of serum anti-Müllerian hormone during follow-up of patients with ovarian granulosa cell tumor by means of a highly sensitive enzyme-linked immunosorbent assay. J Clin Endocrinol Metab 2000; 85 (02) 540-544
• 19 Frattarelli JL, Levi AJ, Miller BT, Segars JH. A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles. Fertil Steril 2003; 80 (02) 350-355
• 20 Fanchin R, Schonäuer LM, Righini C, Guibourdenche J, Frydman R, Taieb J. Serum anti-Müllerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003; 18 (02) 323-327
• 21 Broekmans FJ, de Ziegler D, Howles CM, Gougeon A, Trew G, Olivennes F. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010; 94 (03) 1044-1051
• 22 Stearns V, Schneider B, Henry NL, Hayes DF, Flockhart DA. Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants. Nat Rev Cancer 2006; 6 (11) 886-893
• 23 Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999; 17 (08) 2365-2370
• 24 Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344 (26) 1997-2008
• 25 Su HI, Sammel MD, Green J. , et al. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer 2010; 116 (03) 592-599
• 26 D'Avila AM, Biolchi V, Capp E, Corleta Hv. Age, anti-müllerian hormone, antral follicles count to predict amenorrhea or oligomenorrhea after chemotherapy with cyclophosphamide. J Ovarian Res 2015; 8: 82
• 27 Partridge A, Gelber S, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Winer E. Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer 2007; 43 (11) 1646-1653
• 28 Petrek JA, Naughton MJ, Case LD. , et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006; 24 (07) 1045-1051
• 29 Dunlop CE, Anderson RA. Uses of anti-Müllerian hormone (AMH) measurement before and after cancer treatment in women. Maturitas 2015; 80 (03) 245-250
• 30 Bozza C, Puglisi F, Lambertini M, Osa EO, Manno M, Del Mastro L. Anti-Mullerian hormone: determination of ovarian reserve in early breast cancer patients. Endocr Relat Cancer 2014; 21 (01) R51-R65
• 31 Ruddy KJ, O'Neill A, Miller KD. , et al. Biomarker prediction of chemotherapy-related amenorrhea in premenopausal women with breast cancer participating in E5103. Breast Cancer Res Treat 2014; 144 (03) 591-597
• 32 Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 2006; 21 (10) 2583-2592
• 33 Lie Fong S, Laven JS, Hakvoort-Cammel FG. , et al. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone. Hum Reprod 2009; 24 (04) 982-990
• 34 Ben-Aharon I, Shalgi R. What lies behind chemotherapy-induced ovarian toxicity?. Reproduction 2012; 144 (02) 153-163
• 35 de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 2002; 77 (02) 357-362
• 36 van Rooij IAJ, Broekmans FJM, Scheffer GJ. , et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83 (04) 979-987
• 37 Di Cosimo S, Alimonti A, Ferretti G. , et al. Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer. Ann Oncol 2004; 15 (07) 1065-1071
• 38 Barnabei A, Strigari L, Marchetti P. , et al. Predicting ovarian activity in women affected by early breast cancer: a meta-analysis-based nomogram. Oncologist 2015; 20 (10) 1111-1118
• 39 Iwase A, Nakamura T, Nakahara T, Goto M, Kikkawa F. Anti-Müllerian hormone and assessment of ovarian reserve after ovarian toxic treatment: a systematic narrative review. Reprod Sci 2015; 22 (05) 519-526