Abstract
The incidence of menstrual irregularities, both primary and secondary amenorrhea, has been reported to be as high as 60%, with the highest incidence in younger athletes, suggesting possible adverse effects on bone development. It was hypothesized that in a rat model, suppressed hypothalamic activity via a gonadotropin-releasing hormone antagonist (GnRH-a) before onset of puberty would result in a relatively larger bone strength deficit compared with suppression after puberty. Hypothalamic suppression was achieved by providing GnRH injections. Animals received injections for 25 days either before puberty (pre group) (age 23–46 days) or after puberty (post group) (age 65–90 days). Body weights and uterine weights were measured. Serum estradiol was assayed. Mechanical strength of the right femora and histomorphometry of the left femur were measured. Suppression of the hypothalamic–pituitary–gonadal axis was confirmed by significant atrophy of uterine tissue and suppressed estradiol levels. The peak moment was significantly lower in the pre and post GnRH-a groups compared with control. The percentage difference of the average peak moment and stiffness values from the respective age-matched control groups yielded a greater percentage difference in the pre group. The cortical area was less in the GnRH-a-treated groups, but no significant difference between the relative deficits between pre and post groups were found. Hypothalimic–pituitary–gonadal axis suppression before puberty resulted in a significantly larger deficit in mechanical strength compared with postpubertal animals. The time before puberty may represent a time when skeletal strength is more compromised. Women experience both primary and secondary amenorrhea; however, the treatment may need to be different for each condition.
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Redman LM, Loucks AB (2005) Menstrual disorders in athletes. Sports Med 35:747–755
Warren MP, Stiehl AL (1999) Exercise and female adolescents: effects on the reproductive and skeletal systems. J Am Med Womens Assoc 54:115–120, 138
Drinkwater BL, Nilson K, Chesnut CHIII, Bremner WJ, Shainholtz S, Southworth MB (1984) Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 311:277–281
Rencken ML, Chesnut CHIII, Drinkwater BL (1996) Bone density at multiple skeletal sites in amenorrheic athletes. JAMA 276:238–240
Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP (2007) The female athlete triad. Med Sci Sports Exerc 39:1867–1882
Pettersson U, Stalnacke B, Ahlenius G, Henriksson-Larsen K, Lorentzon R (1999) Low bone mass density at multiple skeletal sites, including the appendicular skeleton in amenorrheic runners. Calcif Tissue Int 64:117–125
Warren MP, Brooks-Gunn J, Fox RP, Lancelot C, Newman D, Hamilton WG (1991) Lack of bone accretion and amenorrhea: evidence for a relative osteopenia in weight-bearing bones. J Clin Endocrinol Metab 72:847–853
Golden NH (2000) Osteoporosis prevention: a pediatric challenge. Arch Pediatr Adolesc Med 154:542–543
Bailey DA (1997) The Saskatchewan Pediatric Bone Mineral Accrual Study: bone mineral acquisition during the growing years. Int J Sports Med 18(suppl 3):S191–S194
Bailey DA, Martin AD, McKay HA, Whiting S, Mirwald R (2000) Calcium accretion in girls and boys during puberty: a longitudinal analysis. J Bone Miner Res 15:2245–2250
Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG (2002) Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study. J Clin Endocrinol Metab 87:3162–3168
Carbon R, Sambrook PN, Deakin V, Fricker P, Eisman JA, Kelly P, Maguire K, Yeates MG (1990) Bone density of elite female athletes with stress fractures. Med J Aust 153:373–376
Ferrari SL, Chevalley T, Bonjour JP, Rizzoli R (2006) Childhood fractures are associated with decreased bone mass gain during puberty: an early marker of persistent bone fragility? J Bone Miner Res 21:501–507
Rauch F, Klein K, Allolio B, Schonau E (1999) Age at menarche and cortical bone geometry in premenopausal women. Bone 25:69–73
Kalu DN, Hardin RH, Cockerham R, Yu BP (1984) Aging and dietary modulation of rat skeleton and parathyroid hormone. Endocrinology 115:1239–1247
Myerson M, Gutin B, Warren MP, Wang J, Lichtman S, Pierson RN Jr (1992) Total body bone density in amenorrheic runners. Obstet Gynecol 79:973–978
Turner RT, Wakley GK, Hannon KS (1990) Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res 8:612–617
Turner RT, Vandersteenhoven JJ, Bell NH (1987) The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 2:115–122
Jiang Y, Zhao J, Genant HK, Dequeker J, Geusens P (1997) Long-term changes in bone mineral and biomechanical properties of vertebrae and femur in aging, dietary calcium restricted, and/or estrogen-deprived/-replaced rats. J Bone Miner Res 12:820–831
Peng Z, Tuukkanen J, Vaananen HK (1994) Exercise can provide protection against bone loss and prevent the decrease in mechanical strength of femoral neck in ovariectomized rats. J Bone Miner Res 9:1559–1564
Katsumata T, Nakamura T, Ohnishi H, Sakurama T (1995) Intermittent cyclical etidronate treatment maintains the mass, structure and the mechanical property of bone in ovariectomized rats. J Bone Miner Res 10:921–931
Yingling VR, Khaneja A (2006) Short-term delay of puberty causes a transient reduction in bone strength in growing female rats. Bone 38:67–73
Turner RT, Maran A, Lotinun S, Hefferan T, Evans GL, Zhang M, Sibonga JD (2001) Animal models for osteoporosis. Rev Endocr Metab Disord 2:117–127
Li XQ, Klein L (1990) Age-related inequality between rates of formation and resorption in various whole bones of rats. Proc Soc Exp Biol Med 195:350–355
Roth CL, Neu C, Jarry H, Schoenau E (2005) Different effects of agonistic vs. antagonistic gnrh-analogues (triptorelin vs. cetrorelix) on bone modeling and remodeling in peripubertal female rats. Exp Clin Endocrinol Diabetes 113:451–456
Roth C, Leonhardt S, Seidel C, Luft H, Wuttke W, Jarry H (2000) Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model. Pediatr Res 48:468–474
Yingling VR, Taylor G (2008) Delayed pubertal development by hypothalamic suppression causes an increase in periosteal modeling but a reduction in bone strength in growing female rats. Bone 42:1137–11343
Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610
Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: a tutorial. Bone 14:595–608
Brodt MD, Ellis CB, Silva MJ (1999) Growing C57Bl/6 mice increase whole bone mechanical properties by increasing geometric and material properties. J Bone Miner Res 14:2159–2166
Di Masso RJ, Font MT, Capozza RF, Detarsio G, Sosa F, Ferretti JL (1997) Long-bone biomechanics in mice selected for body conformation. Bone 20:539–545
Chevalley T, Bonjour JP, Ferrari S, Rizzoli R (2008) Influence of age at menarche on forearm bone microstructure in healthy young women. J Clin Endocrinol Metab 3:2594–2601
Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK (2003) Bone loss and bone size after menopause. N Engl J Med 349:327–334
Riggs BL, O’Fallon WM, Muhs J, O’Connor MK, Kumar R, Melton LJ 3rd (1998) Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res 13:168–174
Szulc P, Seeman E, Duboeuf F, Sornay-Rendu E, Delmas PD (2006) Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res 21:1856–1863
Kim BT, Mosekilde L, Duan Y, Zhang XZ, Tornvig L, Thomsen JS, Seeman E (2003) The structural and hormonal basis of sex differences in peak appendicular bone strength in rats. J Bone Miner Res 18:150–155
Bagi CM, Ammann P, Rizzoli R, Miller SC (1997) Effect of estrogen deficiency on cancellous and cortical bone structure and strength of the femoral neck in rats. Calcif Tissue Int 61:336–344
Rauch F, Travers R, Glorieux FH (2006) Cellular activity on the seven surfaces of iliac bone: a histomorphometric study in children and adolescents. J Bone Miner Res 21:513–519
Rauch F, Travers R, Glorieux FH (2007) Intracortical remodeling during human bone development—a histomorphometric study. Bone 40:274–280
Warden SJ, Fuchs RK, Castillo AB, Nelson IR, Turner CH (2007) Exercise when young provides lifelong benefits to bone structure and strength. J Bone Miner Res 22:251–259
Bagi C, van der Meulen M, Brommage R, Rosen D, Sommer A (1995) The effect of systemically administered rhIGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats. Bone 16:559–565
Gafni RI, McCarthy EF, Hatcher T, Meyers JL, Inoue N, Reddy C, Weise M, Barnes KM, Abad V, Baron J (2002) Recovery from osteoporosis through skeletal growth: early bone mass acquisition has little effect on adult bone density. FASEB J 16:736–738
Gafni RI, Baron J (2000) Catch-up growth: possible mechanisms. Pediatr Nephrol 14:616–619
Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG, Hamilton L (2003) Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil Steril 80:398–404
Yingling VR, Xiang Y, Raphan T, Schaffler MB, Koser K, Malique R (2007) The effect of a short-term delay of puberty on trabecular bone mass and structure in female rats: a texture-based and histomorphometric analysis. Bone 40:419–424
Roth C, Leonhardt S, Seidel C, Lakomek M, Wuttke W, Jarry H (2000) GnRH antagonist cetrorelix prevents sexual maturation of peripubertal male rats. Exp Clin Endocrinol Diabetes 108:358–363
Fyhrie DP, Fazzalari NL, Goulet R, Goldstein SA (1993) Direct calculation of the surface-to-volume ratio for human cancellous bone. J Biomech 26:955–967
Schaffler MB, Reimann DA, Parfitt AM, Fyhrie DP (1997) Which stereological methods offer the greatest help in quantifying trabecular structure from biological and mechanical perspectives? Forma 12:197–207
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Yingling, V., Elle Saine, M. & Joshi, R. Hypothalamic Suppression Decreases Bone Strength Before and After Puberty in a Rat Model. Calcif Tissue Int 84, 485–493 (2009). https://doi.org/10.1007/s00223-009-9241-y
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DOI: https://doi.org/10.1007/s00223-009-9241-y