Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study

J Clin Endocrinol Metab. 2004 Oct;89(10):4910-5. doi: 10.1210/jc.2003-031731.


The menopausal transition is characterized by the appearance of elongated cycles, which become longer and more frequent as menopause approaches. Several endocrine abnormalities have been attributed to these cycles; however, no quantitative studies of their causes and consequences exist to date. This study is based on sequential daily urinary concentrations of FSH, LH, estrone 3-glucuronide (E1G), and pregnanediol 3-glucuronide (PdG) from 34 women with perimenopausal menstrual irregularity (total of 289 cycles). The timing of ovarian response was determined as the day of E1G take-off (ETO). Other parameters measured were the mean FSH concentration before ETO (FSH(ETO)) and the midluteal levels of PdG, E1G, and LH. There was a strong parallelism between ETO and cycle length variability. FSH(ETO) levels increased gradually with ETO. Both ETO and FSH(ETO) were inversely related to luteal PdG and directly related to E1G. PdG and LH levels were inversely related. All comparisons were highly significant (P < 0.0001). We conclude that delayed ovarian response underlies the elongation of the menstrual cycle in the menopausal transition, which is likely to be caused by a temporary lack of ovarian responsiveness to FSH. A progressive decline in luteal PdG with increased E1G occurs in association with these trends.

MeSH terms

  • Adult
  • Estrone / analogs & derivatives*
  • Estrone / blood
  • Female
  • Follicle Stimulating Hormone / blood
  • Follicular Phase / physiology*
  • Humans
  • Luteinizing Hormone / blood
  • Middle Aged
  • Ovary / physiology
  • Pregnanediol / analogs & derivatives*
  • Pregnanediol / blood
  • Premenopause / physiology*


  • pregnanediol-3 alpha-glucuronide
  • estrone-3-glucuronide
  • Estrone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • Pregnanediol