Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle

Hum Reprod. 2013 Jul;28(7):1846-52. doi: 10.1093/humrep/det092. Epub 2013 Apr 16.


Study question: Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle?

Summary answer: Total thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle.

What is known already: The coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results.

Study design, size, duration: Thrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication.

Participants/materials, setting, methods: The study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods.

Main results and the role of chance: It was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P = 0.027). Factor X was significantly higher during the follicular phase (P = 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P = 0.043 and P = 0.033, respectively) and with factors II and VII during the luteal phase (P = 0.034 and P = 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level >0.8).

Limitations, reasons for caution: The wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified.

Wider implications of the findings: The associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use.

Keywords: coagulation factors; menstrual cycle; progesterone; thrombin generation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Coagulation / physiology
  • Female
  • Fibrinogen / metabolism
  • Follicular Phase / metabolism*
  • Humans
  • Luteal Phase / metabolism*
  • Progesterone / metabolism
  • Regression Analysis
  • Sex Hormone-Binding Globulin / metabolism
  • Thrombin / metabolism*


  • Sex Hormone-Binding Globulin
  • Progesterone
  • Fibrinogen
  • Thrombin