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Origins and Consequences of the Elongation of the Human Menstrual Cycle during the Menopausal Transition: The FREEDOM Study

Unipath Ltd. (F.M., J.C., P.W.P., J.E.E.), Bedford, United Kingdom MK44 3UP; Unilever Research Colworth (L.J.A.), Bedford, United Kingdom MK44 1LQ; and Parkwood Clinic (S.W.P.), Bournemouth, United Kingdom BH7 7DW

Address all correspondence and requests for reprints to: Dr. F. Miro, Unipath Ltd., Priory Business Park, Bedford, United Kingdom MK44 3UP. E-mail: fernando.miro{at}unipath.com.

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.

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