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

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.

Relationship between follicle-stimulating hormone levels at the beginning of the human menstrual cycle, length of the follicular phase and excreted estrogens: the FREEDOM study.

Although reproductive aging has been separately related to elevated FSH and shorter follicular phase (FP), the direct association between both parameters has not been investigated. Also, the exact effects of increased FSH on estrogen production are yet to be established.A large database of daily urinary concentrations of FSH, LH, and estrone 3-glucuronide (E1G) from 37 regularly menstruating women (median 11 cycles per patient) was used. Initial FSH levels (iFSH) were estimated as the mean value of d 1-5. The day of E1G take-off (ETO) was determined by an algorithm, and accordingly, the FP was divided into early (d 1 to ETO) and late (ETO+1 to LH peak). FP maximum and integrated E1G were calculated. Subjects were distributed according to their mean iFSH into three categories (5 to 10, and >10 IU/liter). There was a gradual decrease in FP length with increasing category (15.2 +/- 3.8, 14.1 +/- 3.6, and 13 +/- 2.6 d, respectively; P < 0.0001). A similar effect occurred in early FP (7.5 +/- 4, 6.4 +/- 3.7, and 5.4 +/- 2.7; P < 0.0001); in contrast, late FP was unaffected (7.7 +/- 2.1, 7.7 +/- 2.1, and 7.6 +/- 2.4; P = 0.86). No consistent increase in E1G was found with advancing iFSH category; however, women with mean initial LH higher than 6 IU/liter had significantly elevated maximum (P < 0.0001) and integrated (P = 0.002) E1G.FP length decreases in parallel with increasing iFSH, with a selective effect on the early FP. Increased FSH does not affect E1G; however, elevated initial LH level was related to higher E1G.