Ovarian reserve after treatment with alkylating agents during childhood

Hum Reprod. 2015 Jun;30(6):1437-46. doi: 10.1093/humrep/dev060. Epub 2015 Mar 23.


Study question: What is the effect of different alkylating agents used without pelvic radiation to treat childhood cancer in girls on the ovarian reserve in survivors?

Summary answer: Ovarian reserve seems to be particularly reduced in survivors who received procarbazine (in most cases for Hodgkin lymphoma) or high-dose chemotherapy; procarbazine but not cyclophosphamide dose is associated with diminished ovarian reserve.

What is known already: A few studies have demonstrated diminished ovarian reserve in survivors after various combination therapies, but the individual role of each treatment is difficult to assess.

Study design: Prospective cross-sectional study, involving 105 survivors and 20 controls.

Participants/materials, setting, methods: One hundred and five survivors aged 17-40 years and 20 controls investigated on Days 2-5 of a menstrual cycle or Day 7 of an oral contraceptive pill-free interval.

Main outcome measures: ovarian surface area (OS), total number of antral follicles (AFC), serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and anti-Müllerian hormone (AMH).

Main results and the role of chance: Survivors had a lower OS than controls: 3.5 versus 4.4 cm(2) per ovary (P = 0.0004), and lower AMH levels: 10.7 versus 22 pmol/l (P = 0.003). Ovarian markers (OS, AMH, AFC) were worse in patients who received high-dose compared with conventional-dose alkylating agents (P = 0.01 for OS, P = 0.002 for AMH, P < 0.0001 for AFC). Hodgkin lymphoma survivors seemed to have a greater reduction in ovarian reserve than survivors of leukaemia (P = 0.04 for AMH, P = 0.01 for AFC), sarcoma (P = 0.04 for AMH, P = 0.04 for AFC) and other lymphomas (P = 0.04 for AFC). A multiple linear regression analysis showed that procarbazine but not cyclophosphamide nor ifosfamide dose was associated with reduced OS (P = 0.0003), AFC (P = 0.0007), AMH (P < 0.0001) and higher FSH levels (P < 0.0001).

Limitations, reasons for caution: The small percentage of participating survivors (28%) from the total cohort does not allow conclusion on fertility issues because of possible response bias. The association between procarbazine and HL makes it impossible to dissociate their individual impacts on ovarian reserve. The number of controls is small, but ovarian volume and AMH levels in survivors were compared with published normal values and results were unchanged.

Wider implications of the findings: Early detection and follow-up of compromised ovarian function after cancer therapy should help physicians to counsel young survivors about their fertility window. However, longitudinal follow-up is required to determine the rate of progression from low ovarian reserve to premature ovarian failure.

Study funding/competing interests: La Ligue contre le Cancer (grant no., PRAYN7497). The authors have no competing interests to disclose.

Keywords: AMH; chemotherapy; childhood cancer survivors; hodgkin lymphoma; ovarian reserve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-Mullerian Hormone / blood
  • Antineoplastic Agents, Alkylating / adverse effects*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Cross-Sectional Studies
  • Estradiol / blood
  • Female
  • Follicle Stimulating Hormone / blood
  • Hodgkin Disease / drug therapy*
  • Humans
  • Linear Models
  • Luteinizing Hormone / blood
  • Ovarian Reserve / drug effects*
  • Ovary / diagnostic imaging
  • Ovary / drug effects
  • Procarbazine / adverse effects*
  • Procarbazine / therapeutic use
  • Prospective Studies
  • Survivors
  • Ultrasonography


  • Antineoplastic Agents, Alkylating
  • Procarbazine
  • Estradiol
  • Anti-Mullerian Hormone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone