Serum Soluble Interleukin-6 Receptor and Biochemical Markers of Bone Metabolism Show Significant Variations During the Menstrual Cycle

Abstract

We examined sequential changes of bone-resorbing cytokines and bone metabolic markers and the effect of ovarian hormones on bone metabolism during the menstrual cycle in 10 healthy Japanese women, aged 22-43 yr, with normal ovarian function. Serum soluble interleukin-6 receptor (sIL-6R) showed a significant variation; a rise during the early and late follicular periods followed by a fall during the early luteal period (P = 0.0423, P = 0.0334) and an increase during the mid and late luteal periods. There were significant changes in the levels of markers of bone formation: a rise in serum bone-specific alkaline phosphatase (ALP) during the mid and late follicular (P = 0.0265) periods and a fall in serum carboxyl-terminal propeptide of type I procollagen (PICP) during the midluteal period (P = 0.0161). As for the levels of bone resorption markers, urinary type I collagen C-telopeptide breakdown products (CTx) and free deoxypyridinoline (D-Pyr) decreased significantly during the early and midfollicular periods, urinary free D-Pyr and serum pyridinoline cross-linked carboxyl-terminal telopeptide of type I collagen (ICTP) (P = 0.0440) increased significantly during the early luteal period, and urinary CTx, free D-Pyr, and serum ICTP decreased significantly during the late luteal period (P = 0.0170-0.0008). The serum PTH level was significantly higher during the follicular than the luteal period (P = 0.0132). Serum sIL-6R significantly correlated with urinary CTx (r = 0.190, P < 0.05) and serum ALP (r = 0.209, P < 0.05) and serum estradiol with intact osteocalcin (r = 0.309, P < 0.0005) and serum ALP (r = 0.181, P < 0.05). These observations strongly suggest that cyclic variations in the levels of bone formation and resorption markers and of a bone-resorbing cytokine may be modulated by cyclic changes in serum steroid hormones during the menstrual period. In addition, the specific days of biochemical events in the menstrual cycle are crucial for evaluating osteoclastic and osteoblastic activities in pre- and perimenopausal women or in women starting GnRH agonist therapy.

Changes in Bone Resorption During the Menstrual Cycle

“…It is possible however, that serum Dpyr better reflects the bone resorption process and is therefore more biologically meaningful. Our results regarding urine Dpyr are similar to Schlemmer et al (6) but different from those of Gorai et al (7,8) The latter reported differences in urine Dpyr between subphases of the cycle, but the patterns of change differ between their two publications. Taken together, the two studies therefore appear to be compatible with our results.…”

“…For purposes of graphing or examining summary values by day, the visits were assigned to 2-day bins, so that a visit on day −14 or −13 was counted as day −14, a visit on day −12 or −11 was counted as day −12, etc. Cycles were divided into FP (day −14 to day −1) and LP (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Subphases were defined following Gorai et al (7,8) as early (the first 4 days), mid-(the middle 6 days), or late (the last 4 days).…”

“…Cycles were divided into FP (day −14 to day −1) and LP (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Subphases were defined following Gorai et al (7,8) as early (the first 4 days), mid-(the middle 6 days), or late (the last 4 days). The significance of pairwise differences of variables between menstrual phases (FP vs. LP) or subphases were assessed by the Wilcoxon signed-rank test, because most measurements at most times showed evidence of non-normality.…”

“…This is in agreement with the findings of Schlemmer et al (6) and Tjellesen et al (5) but different from those of Nielsen et al (4) who reported an increase in serum OC and BAP during the LP in eight premenopausal women. Gorai et al (8) found differences in serum BAP between subphases of the menstrual cycle, but these did not show an overall FP-LP difference and did not seem to form a consistent pattern because values were generally higher nearer to day 0 but low at day 0 itself.…”

“…(2,3) However, the influence of the naturally occurring cyclic changes of estrogen and P levels on bone turnover in premenopausal women has received limited attention and the results of the few available studies are variable and inconclusive. (4)(5)(6)(7)(8) One study of eight women reported that the circulating osteocalcin (OC) concentration is increased during the luteal phase (LP) of the menstrual cycle in normal premenopausal women. (4) Gorai et al (7) reported that bone resorption markers such as urinary hydroxylysylpyridinoline, lysylpyridinoline, and type I collagen cross-linked N-telopeptide varied during the menstrual cycle in nine women.…”