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Article: Jagteshwar Grewal, MaryFran R. Sowers, John F. Randolph, Jr, Sioban D. Harlow, and Xihong Lin LOW BONE MINERAL DENSITY IN THE EARLY MENOPAUSAL TRANSITION: ROLE FOR OVULATORY FUNCTION J Clin Endocrinol Metab 2006; 0: jc.2006-0544v1 [Abstract]

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RE: Failure to find a Cross-Sectional Bone-Ovulation Relationship in SWAN

Shirin Kalyan, Vanadin Seifert-Klauss, Christine Hitchcock, Jerilynn C. Prior   (12 February 2007)

RE: Failure to find a Cross-Sectional Bone-Ovulation Relationship in SWAN 12 February 2007
Shirin Kalyan, research scientist Centre for Menstrual Cycle and Ovulation Research (CeMCOR), University of British Columbia, Vanadin Seifert-Klauss, Christine Hitchcock, Jerilynn C. Prior Send letter to journal: Re: RE: Failure to find a Cross-Sectional Bone-Ovulation Relationship in SWAN shirin.kalyan{at}vch.ca Shirin Kalyan, et al.	In their study of midlife women, Grewal and colleagues concluded that ovulatory status from a single cycle of urinary data did not relate to cross-sectional bone density, but rather that urinary FSH and estrogen did (1). The Study of Women Across the Nation (SWAN) has great potential to explore causes of perimenopausal bone change, but clarification about certain methodological questions is needed. How was luteal length (LL) determined in this study? The method described in the paper (Kassam interval method + 1 day) estimates a date that is 4.2 d after the serum LH peak (2), yet the authors report an average LL of 13.7 d, which corresponds to an implausible average LL of 17.9 d by serum LH peak. How were “all cycle lengths standardized to 28 d” before computing area under the curve? From our perspective, it, it would be preferable to adjust for cycle length after AUC computations (for example, by multiplying by 28/cycle length). Given the within-person variability of ovulation, despite the more than 600 women studied, we would not expect cross-sectional DXA-determined bone mineral density to relate to single-cycle hormonal characteristics. A longer sampling interval is required to estimate the important variability in ovulation between cycles. For example, 20% of change in cancellous bone density measured by quantitative computed tomography was accounted for by the mean year-one LL (which would take into account subclinical luteal phase defects across a year) (3); however, the year-five DXA was not correlated with ovulatory disturbances in a few cycles at that year’s end (4). Bone formation effects of progesterone on human bone balance are not “visible” in the face of high bone resorption. Only because estradiol levels, cycle lengths and bone resorption were all normal, could we show that progesterone related to bone change (3). A recent 6-year prospective study of perimenopausal cancellous bone change documented that bone loss occurred despite maintained estradiol levels (5). Integration of available data strongly suggests that other ovarian aging-related changes besides mean estrogen account for rapid perimenopausal bone loss. Why pit estrogen and progesterone “against” each other? Clearly, both are necessary and are synergistic for bone. References 1. Grewal J, Sowers MR, Randolph JF, Jr., Harlow SD, Lin X. 2006. Low bone mineral density in the early menopausal transition: role for ovulatory function. J Clin Endocrinol Metab 91:3780-3785 2. O'Connor KA, Brindle E, Miller RC, Shofer JB, Ferrell RJ, Klein NA, Soules MR, Holman DJ, Mansfield PK, Wood JW. 2006. Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method. Hum Reprod 21:1442-1452 3. Prior JC, Vigna YM, Schechter MT, Burgess AE. 1990. Spinal bone loss and ovulatory disturbances. N Engl J Med 323:1221-1227 4. Prior JC, Vigna YM, Barr SI, Kennedy S, Schulzer M, Li DK. 1996. Ovulatory premenopausal women lose cancellous spinal bone: a five year prospective study. Bone 18:261-267 5. Seifert-Klauss V, Link T, Heumann C, Luppa P, Haseitl M, Laakmann J, Rattenhuber J, Kiechle M. 2006. Influence of pattern of menopausal transition on the amount of trabecular bone loss: results from a 6-year prospective longitudinal study. Maturitas 55:317-324