Trabecular Bone is Increased in a Rat Model of Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) in an intricate disorder characterized by reproductive and metabolic abnormalities that may affect bone quality and strength along with the lifespan. The present study analysed the impact of postnatal androgenization (of a single dose of testosterone propionate 1.25 mg subcutaneously at day 5 of life) on bone development and markers of bone metabolism in adult female Wistar rats. Compared with healthy controls, the results of measurements of micro-computed tomography (microCT) of the distal femur of androgenized rats indicated an increased cortical bone volume voxel bone volume to total volume (VOX BV/TV) and higher trabecular number (Tb.n) with reduced trabecular separation (Tb.sp). A large magnitude effect size was observed in the levels of circulating bone formation Procollagen I N-terminal propeptide (P1NP) at day 60 of life; reabsorption cross-linked C-telopeptide of type I collagen (CTX) markers were similar between the androgenized and control rats at days 60 and 110 of life. The analysis of gene expression in bone indicated elements for an increased bone mass such as the reduction of the Dickkopf-1 factor (Dkk1) a negative regulator of osteoblast differentiation (bone formation) and the reduction of Interleukin 1-b (Il1b), an activator of osteoclast differentiation (bone reabsorption). Results from this study highlight the possible role of the developmental programming on bone microarchitecture with reference to young women with PCOS.

Key words

micro CT - developmental programming - animal models of PCOS - bone - androgens

Publication History

Received: 22 May 2020
Received: 03 October 2020

Accepted: 06 October 2020

Article published online:
28 October 2020

• References

• 1 March WA, Moore VM, Willson KJ. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25: 544-551
• 2 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853-861
• 3 Adami S, Bianchi G, Brandi ML. et al. Determinants of bone turnover markers in healthy premenopausal women. Calcif Tissue Int 2008; 82: 341-347
• 4 DagogoJack S, AlAli N, Qurttom M. Augmentation of bone mineral density in hirsute women. J Clin Endocr Metab 1997; 82: 2821-2825
• 5 Zborowski JV, Cauley JA, Talbott EO. et al. Bone mineral density, androgens, and the polycystic ovary: The complex and controversial issue of androgenic influence in female bone. J Clin Endocr Metab 2000; 85: 3496-3506
• 6 Chew CK, Clarke BL. Causes of low peak bone mass in women. Maturitas 2018; 111: 61-68
• 7 Kassanos D, Trakakis E, Baltas CS. et al. Augmentation of cortical bone mineral density in women with polycystic ovary syndrome: A peripheral quantitative computed tomography (pQCT) study. Human Reproduction 2010; 25: 2107-2114
• 8 Piovezan JM, Premaor MO, Comim FV. Negative impact of polycystic ovary syndrome on bone health: A systematic review and meta-analysis. Human reproduction update 2019; 25: 633-645
• 9 Tamura N, Kurabayashi T, Nagata H. et al. Effects of testosterone on cancellous bone, marrow adipocytes, and ovarian phenotype in a young female rat model of polycystic ovary syndrome. Fertility and Sterility 2005; 84: 1277-1284
• 10 Serrano Mujica LK, Bertolin K, Bridi A. et al. The impact of postnatal leuprolide acetate treatment on reproductive characteristics in a rodent model of polycystic ovary syndrome. Mol Cell Endocrinol 2017; 442: 125-133
• 11 Serrano Mujica L, Bridi A, Della Mea R. et al. Oxidative stress and metabolic markers in pre- and postnatal polycystic ovary syndrome rat protocols. J Inflamm Res 2018; 11: 193-202
• 12 Padmanabhan V, Veiga-Lopez A, Herkimer C. et al. Developmental programming: Prenatal and postnatal androgen antagonist and insulin sensitizer interventions prevent advancement of puberty and improve lh surge dynamics in prenatal testosterone-treated sheep. Endocrinology 2015; 156: 2678-2692
• 13 Cohen J. A power primer. Psychol Bull 1992; 112: 155-159
• 14 Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature 2019; 567: 305-307
• 15 Abu EO, Horner A, Kusec V. et al. The localization of androgen receptors in human bone. J Clin Endocr Metab 1997; 82: 3493-3497
• 16 Barraclough C. Production of anovulatory, sterile rats by single injections of testosterone propionate. Endocrinology 1961; 68: 62
• 17 Prakasam G, Yeh JK, Chen MM. et al. Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats. Bone 1999; 24: 491-497
• 18 Turner RT, Wakley GK, Hannon KS. Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res 1990; 8: 612-617
• 19 Goetz LG, Mamillapalli R, Devlin MJ. et al. Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture. Am J Physiol Endocrinol Metab 2017; 313: E540-E551
• 20 Prior JC, Seifert-Klauss VR, Giustini D. et al. Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy - a systematic review and meta-analysis of controlled trials with direct randomization. J Musculoskelet Neuronal Interact 2017; 17: 146-154
• 21 Bechtold S, Dalla Pozza R, Putzker S. et al. Effect of antiandrogen treatment on bone density and bone geometry in adolescents with polycystic ovary syndrome. J Pediatr Adolesc Gynecol 2012; 25: 175-180
• 22 Diamanti-Kandarakis E, Livadas S, Katsikis I. et al. Serum concentrations of carboxylated osteocalcin are increased and associated with several components of the polycystic ovarian syndrome. Journal of Bone and Mineral Metabolism 2011; 29: 201-206
• 23 Lingaiah S, Morin-Papunen L, Piltonen T. et al. Bone markers in polycystic ovary syndrome: A multicentre study. Clinical Endocrinology 2017; 87: 673-679
• 24 Adami S, Zamberlan N, Castello R. et al. Effect of hyperandrogenism and menstrual cycle abnormalities on bone mass and bone turnover in young women. Clin Endocrinol (Oxf) 1998; 48: 169-173
• 25 Berberoglu Z, Aktas A, Fidan Y. et al. Association of plasma GDF-9 or GDF-15 levels with bone parameters in polycystic ovary syndrome. Journal of Bone and Mineral Metabolism 2015; 33: 101-108