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Menopause Transition: Annual Changes in Serum Hormonal Patterns over the Menstrual Cycle in Women during a Nine-Year Period Prior to Menopause

Department of Clinical Science (B.-M.L., A.C., G.C.), Division of Obstetrics and Gynaecology, Karolinska Institutet, Huddinge University Hospital, SE-14186 Stockholm, Sweden; and Prince Henry’s Institute of Medical Research (H.G.B., L.B., D.M.R.), Clayton, Victoria, 3168, Australia

Address all correspondence and requests for reprints to: B.-M. Landgren, M.D., Ph.D., Department of Clinical Science, Division of Obstetrics and Gynaecology, Karolinska Institutet, Huddinge University Hospital, SE-14186 Stockholm, Sweden.

To examine the hormonal characteristics of menstrual cycles in healthy women approaching menopause, serum hormone profiles were investigated annually in this longitudinal study of 13 healthy women between 4 and 9 yr before menopause and the year of the menopause. Serum FSH, LH, estradiol, progesterone, total inhibin, inhibins A and B, and prolactin were determined in blood samples collected annually three times weekly for 4 wk beginning with the onset of menses. Menstrual bleeding diaries covering this 4- to 9-yr period were also collected allowing the prospective identification of the final menstrual period. A change in serum hormone patterns was observed in cycles approaching menopause, exemplified by an increasing number of cycles of prolonged length with a prolonged follicular phase resulting in a failure to detect a luteal phase rise in serum progesterone within the 4-wk collection period. These prolonged cycles (designated B cycles based on a previous work) were analyzed separately and compared with the remaining ovulatory (D) cycles. No B cycles were identified in any women earlier than 27 cycles from menopause. The proportion of B cycles increased as menopause approached, reaching 62% in the last 10 cycles. The proportion of D cycles decreased accordingly. The B cycles during the initial 4-wk collection period were characterized by elevated FSH, LH, FSH/inhibin A and FSH/inhibin B ratios, and longer duration, although cycle length/subject was not significantly different presumably due to the small number of B cycles. The D cycles showed no changes in hormonal profiles over the 4- to 9-yr time period.

These data indicate that there is a time-related change in the character of menstrual cycles as menopause approaches, with an increasing proportion of cycles observed with prolonged follicular phases that may either be delayed ovulatory cycles or anovulatory cycles. The increase in the proportion of B cycles with elevated early follicular phase FSH levels and low inhibin/FSH ratios toward menopause provides a basis for the apparent early increase in serum FSH and decrease in serum inhibins observed previously in studies of the menopause transition based on sampling confined to the follicular phase only. The data amplify and clarify current concepts of the endocrine basis of the menopause transition.

This work was supported by the Swedish National Banks Jubilee Foundation, grants from the Karolinska Institute and The Swedish Medical Research Council (3972, 3529, 12238), and a Program Grant (983212) from the National Health and Medical Research Council of Australia.

Abbreviations: E2, Estradiol; FMP, final menstrual period; P, progesterone; WHO, World Health Organization.

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