Progesterone Within Ovulatory Menstrual Cycles Needed for Cardiovascular Protection: An Evidence-Based Hypothesis
Jerilynn C Prior
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Keywords

Acute myocardial infarction
Women’s health
Progesterone
Estradiol
Ovulatory disturbances
Menstrual cycles
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Abstract

Women experience acute myocardial infarctions (AMI) 10 years later than men – evidence that estrogen is protective is not consistent. Ovulatory disturbances (low progesterone but normal estradiol levels) silently occur in >33% of all cycles. Progesterone-based (cycle-timed serum or saliva) levels or urinary metabolite excretions are necessary to diagnose silent ovulatory disturbances within regular, normal length menstrual cycles. Progesterone acts biphasically in vitro – initial proliferation changes to differentiation. It also suppresses or complements estradiol’s actions. Basic and clinical studies show that progesterone is positively related to endothelial function/blood flow, influences vascular smooth muscle cells and cardiac electrical signals. Several studies in primates document that high fat-fed subordinate females have higher stress, fewer ovulatory cycles and lower progesterone levels but similar cycle lengths as menstruating, dominant females. Subordinate females develop arterial plaque similar to high fat-fed males. In population-based prospective data, women with early pregnancy progesterone deficiency, stress and multiple miscarriages are at five-fold higher AMI risk. Also, early menopausal AMI are associated with significantly more pre-/perimenopausal anovulatory cycles. Given the multi-dimensional positive effects of progesterone on the cardiovascular system (CVS), and persuasive data from primate and human studies associating increased AMI with ovulatory disturbances, this review presents a new CVS protection hypothesis for women – ovulatory cycles with balanced progesterone-estradiol levels decrease women’s risks for AMI. Based on this new theory, it is believed that progesterone as well as estradiol is required during the premenopausal years to prevent women’s early heart disease.

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References

Tunstall-Pedoe H. Myth and paradox of coronary risk and the menopause. Lancet. 1998; 351(9113):1425–7.
Anand SS, Islam S, Rosengren A, Franzosi MG, Steyn K, Yusufali AH, et al. Risk factors for myocardial infarction in women and men: insights from the INTERHEART study. Eur Heart J. 2008; 29(7):932–40.
Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ. 2007; 176:S1–S5.
Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007; 115(11):1481–501.
Heron M. Leading Causes of Death 2009. National Vital Statistics Reports 2012; 61:1–96.
Izadnegahdar M, Singer J, Lee MK, Gao M, Thompson CR, Kopec J, et al. Do younger women fare worse? Sex differences in acute myocardial infarction hospitalization and early mortality rates over ten years. J Womens Health (Larchmt). 2014; 23(1):10–7.
Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; 1:CD004816.
Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352(13):1293–304.
Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. J Am Med Assoc. 1979; 241(19):2035–8.
Levitzky YS, Pencina MJ, D’Agostino RB, Meigs JB, Murabito JM, Vasan RS, et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008; 51(3):264–70.
Stampfer MJ, Golditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease.N Engl J Med. 1991; 325:756–62.
Baxter S, Prior JC. The Estrogen Errors: Why Progesterone is Better For Women’s Health. Westport, CT: Praeger Publishers; 2009.
Prior JC. Postmenopausal estrogen therapy and cardiovascular disease (letter). N Engl J Med. 1992; 326:705–6.
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in health postmenopausal women: principal results from the Women’s Health Initiative Randomized Control trial. J Am Med Assoc. 2002; 288:321–33.
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. J Am Med Assoc. 2004; 291(14):1701–12.
Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, et al. KEEPS: the kronos early estrogen prevention study. Climacteric. 2005; 8(1):3–12.
Barrett-Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation. 1997; 95(1):252–64.
Li D, Hitchcock CL, Barr SI, Yu T, Prior JC. Negative spinal bone mineral density changes and subclinical ovulatory disturbances–prospective data in healthy premenopausal women with regular menstrual cycles. Epidemiol Rev. 2014; 36:137–47.
Prior JC, Elliott TG, Norman E, Stajic V, Hitchock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLOS One. 2014; 9:e84698.
Prior JC, Naess M, Langhammer A, Forsmo S. The point prevalence of ovulation in a large population-based sample of spontaneously, regularly menstruating women. The HUNT Study. Norway, Endocrine Society, OR 19-1 6573. 2013 [Abstract] .
Vollman RF. The menstrual cycle. In: Friedman EA, ed. Major Problems in Obstetrics and Gynecology, Vol 7. 1st edn. Toronto: W.B. Saunders Company; 1977. pp. 11–193.
Vitzthum VJ. The ecology and evolutionary endocrinology of reproduction in the human female. Am J Phys Anthropol. 2009; 140(Suppl 49):95–136.
Hammar N, Alfredsson L, Rosen M, Spetz CL, Kahan T, Ysberg AS. A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. Int J Epidemiol. 2001; 30(Suppl 1):S30–4.
O’Donnell E, Goodman JM, Harvey PJ. Clinical review: Cardiovascular consequences of ovarian disruption: a focus on functional hypothalamic amenorrhea in physically active women. J Clin Endocrinol Metab. 2011; 96(12):3638–48.
Creinin MD, Keverline S, Meyn LA. How regular is regular? An analysis of menstrual cycle regularity. Contraception. 2004; 70(4):289–92.
Abraham GE. The normal menstrual cycle. In: Givens JR, ed. Endocrine Causes of Menstrual Disorders, 1st edn. Chicago: Year Book Medical Publishers, Inc; 1978. pp. 15–44.
Hulley S, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc. 1998; 280(7):605–13.
Coronary Drug Project Research Group. Coronary drug project: initial findings leading to modifications of its research protocol. J Am Med Assoc. 1970; 214:1303–13.
Coronary Drug Project Research Group. Coronary drug project: findings leading to the discontinuation of the 2.5 mg/day estrogen group. J Am Med Assoc. 1973; 226:652–7.
Malcolm CE, Cumming DC. Does anovulation exist in eumenorrheic women? Obstet Gynecol. 2003; 102(2):317–8.
MacDonald PC, Dombroski RA, Casey ML. Recurrent secretion of progesterone in large amounts: an endocrine/metabolic disorder unique to young women? Endocr Rev. 1991; 12:372–401.
Vitzthum VJ, Thornburg J, Spielvogel H. Seasonal modulation of reproductive effort during early pregnancy in humans. Am J Hum Biol. 2009; 21(4):548–58.
Prior JC, Vigna YM, Schechter MT, Burgess AE. Spinal bone loss and ovulatory disturbances. N Engl J Med. 1990; 323:1221–7.
Sowers M, Randolph JF, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, et al. Urinary ovarian and gonadotropin hormone levels in premenopausal women with low bone mass. J Bone Min Res. 1998; 13(7):1191–202.
Stachenfeld NS, Silva C, Keefe DL. Estrogen modifies the temperature effects of progesterone. J Appl Physiol. 2000; 88(5):1643–9.
Israel R, Mishell DR, Jr., Stone SC, Thorneycroft IH, Moyer DL. Single luteal phase serum progesterone assay as an indicator of ovulation. Am J Obstet Gynecol. 1972; 112(8):1043–6.
Vuorento T, Hovatta O, Kurunmaki H, Ratsula K, Huhtaniemi I. Measurements of salivary progesterone throughout the menstrual cycle in women suffering from unexplained infertility reveal high frequency of luteal phase defects. Fertil Steril. 1990; 54(2):211–6.
Kassam A, Overstreet JW, Snow-Harter C, De Souza MJ, Gold EB, Lasley BL. Identification of anovulation and transient luteal function using a urinary pregnanediol-3-glucuronide ratio algorithm. Environ Health Perspect. 1996; 104(4):408–13.
O’Connor KA, Brindle E, Miller RC, Shofer JB, Ferrell RJ, Klein NA, et al. Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method. Hum Reprod. 2006; 21(6):1442–52.
Prior JC, Vigna YM, Schulzer M, Hall JE, Bonen A. Determination of luteal phase length by quantitative basal temperature methods: validation against the midcycle LH peak. Clin Invest Med. 1990; 13:123–31.
Bedford JL, Prior JC, Hitchcock CL, Barr SI. Detecting evidence of luteal activity by least-squares quantitative basal temperature analysis against urinary progesterone metabolites and the effect of wake-time variability. Eur J Obstet Gynecol Reprod Biol. 2009; 146(1):76–80.
Shepard MK, Senturia YD. Comparison of serum progesterone and endometrial biopsy for confirmation of ovulation and evaluation of luteal function. Fertil Steril. 1977; 28(5):541–8.
Landgren BH, Unden AL, Diczfalusy E. Hormonal profile of the cycle in 68 normally menstruating women. Acta Endocr Copenhagen. 1980; 94:89–98.
Di Carlo C, Shaham Z, MacDougall J, Patel A, Hall ML, Jacobs HS. Polcystic ovaries as a protective factor for bone mineral loss in young women with amenorrhea. Fertil Steril. 1992; 57:314–9.
Hahn S, Janssen OE, Tan S, Pleger K, Mann K, Schedlowski M, et al. Clinical and psychological correlates of quality-of-life in polycystic ovary syndrome. Eur J Endocrinol. 2005; 153(6):853–60.
Bedford JL, Prior JC, Barr SI. A prospective exploration of cognitive dietary restraint, subclinical ovulatory disturbances, cortisol and change in bone density over two years in healthy young women. J Clin Endocrinol Metab. 2010; 95(7):3291–9.
Nielsen HK, Brixen K, Bouillon R, Mosekilde L. Changes in biochemical markers of osteoblastic activity during the menstrual cycle. J Clin Endocrinol Metab. 1990; 70:1431–7.
Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev. 1990; 11:266–301.
Groshong SD, Owen GI, Grimison B, Schauer IE, Todd MC, Langan TA, et al. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Mol Endocrinol. 1997; 11(11):1593–607.
Zhang X, Jeyakumar M, Bagchi MK. Ligand-dependent cross-talk between steroid and thyroid hormone receptors. Evidence for common transcriptional coactivator(s). J Biol Chem. 1996; 271(25):14825–33.
Graham JD, Clarke CL. Physiological action of progesterone in target tissue. Endocr Rev. 1997; 18:502–19.
Rickard DJ, Waters KM, Ruesink TJ, Khosla S, Katzenellenbogen JA, Katzenellenbogen BS, et al. Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts. J Bone Miner Res. 2002; 17(4):580–92.
Hitchcock CL, Prior JC. Oral Micronized Progesterone for Vasomotor Symptoms in Healthy Postmenopausal Women – a placebo-controlled randomized trial. Menopause. 2012; 19:886–93.
Ishida Y, Killinger DW, Khalil MW, Yang K, Strutt B, Heersche JN. Expression of steroid-converting enzymes in osteoblasts derived from rat vertebrae. Osteoporos Int. 2002; 13(3):235–40.
Ishida Y, Heersche JN. Progesterone stimulates proliferation and differentiation of osteoprogenitor cells in bone cell populations derived from adult female but not from adult male rats. Bone. 1997; 20:17–25.
Dubey RK, Gillespie DG, Jackson EK, Keller PJ. 17Beta-estradiol, its metabolites, and progesterone inhibit cardiac fibroblast growth.Hypertension. 1998; 31(1 Pt 2):522–8.
Morey AK, Pedram A, Razandi M, Prins BA, Hu RM, Biesiada E, et al. Estrogen and progesterone inhibit vascular smooth muscle proliferation.Endocrinology. 1997; 138(8):3330–9.
Everaert BR, Van Craenenbroeck EM, Hoymans VY, Haine SE, Van NL, Conraads VM, et al. Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: focus on PI3K/AKT/eNOS pathway. Int J Cardiol. 2010; 144(3):350–66.
Lemieux C, Cloutier I, Tanguay JF. Menstrual cycle influences endothelial progenitor cell regulation: a link to gender differences in vascular protection? Int J Cardiol. 2009; 136(2):200–10.
Hoetzer GL, MacEneaney OJ, Irmiger HM, Keith R, Van Guilder GP, Stauffer BL, et al. Gender differences in circulating endothelial progenitor cell colony-forming capacity and migratory activity in middle-aged adults. Am J Cardiol. 2007; 99(1):46–8.
Tanaka S, Ueno T, Sato F, Chigusa Y, Kawaguchi-Sakita N, Kawashima M, et al. Alterations of circulating endothelial cell and endothelial progenitor cell counts around the ovulation. J Clin Endocrinol Metab. 2012; 97(11):4182–92.
Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, et al. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology. 2004; 145(12):5745–56.
Barbagallo M, Dominguez LJ, Licata G, Shan J, Bing L, Karpinski E, et al. Vascular effects of progesterone: role of cellular calcium regulation.Hypertension. 2001; 37(1):142–7.
Moldovanova I, Schroeder C, Jacob G, Hiemke C, Diedrich A, Luft FC, et al. Hormonal influences on cardiovascular norepinephrine transporter responses in healthy women. Hypertension. 2008; 51(4):1203–9.
Odening KE, Choi BR, Liu GX, Hartmann K, Ziv O, Chaves L, et al. Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm. 2012; 9(5):823–32.
Landau RL, Bergenstal DM, Lugibihl K, Kascht ME. The metabolic effects of progesterone in man. J Clin Endocrinol Metab. 1955; 15(10):1194–215.
Barr SI, Janelle KC, Prior JC. Energy intakes are higher during the luteal-phase of ovulatory menstrual cycles. Am J Clin Nutr. 1995; 61(1):39–43.
Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset.Science. 1974; 185:949–50.
Jasienska G, Ellison PT. Energetic factors and seasonal changes in ovarian function in women from rural Poland. Am J Hum Biol. 2004; 16(5):563–80.
Yeung EH, Zhang C, Mumford SL, Ye A, Trevisan M, Chen L, et al. Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle Study. J Clin Endocrinol Metab. 2010; 95(12):5435–42.
Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B. The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. J Clin Endocrinol Metab. 2002; 87(10):4536–40.
Shaikh AA, Naqvi RH, Shaikh SA. Concentrations of oestradiol-17-beta and progesterone in peripheral plasma of cynomolgus monkey (Macaca fascicularis) in relation to length of menstrual cycle and its component phases. J Endocrinol. 1978; 79(1):1–7.
Kaplan JR, Adams MR, Clarkson TB, Koritnik DR. Psychological influences on female ‘protection’ among cynomolgus macaques.Atherosclerosis. 1984; 53:283–95.
Adams MR, Kaplan JF, Koritnik DR. Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis. 1985; 5:192–200.
Kaplan JR, Adams MR, Koritnik DR, Rose JC, Manuck SB. Adrenal responsiveness and social status in intact and ovariectomized Macaca fascicularis. Am J Primatol. 1986; 11:181–93.
Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy M, et al. Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab. 1998; 83(2):649–59.
Mangos GJ, Walker BR, Kelly JJ, Lawson JA, Webb DJ, Whitworth JA. Cortisol inhibits cholinergic vasodilation in the human forearm. Am J Hypertens. 2000; 13(11):1155–60.
Prior JC, Ho Yeun B, Clement P, Bowie L, Thomas J. Reversible luteal phase changes and infertility associated with marathon training. Lancet. 1982; 1:269–70.
Selye H. The effect of adaptation to various damaging agents on the female sex organs in the rat. Endocrinology. 1939; 25:615–24.
Prior JC. Endocrine “conditioning” with endurance training: a preliminary review. Can J Appl Sport Sci. 1982; 7:149–57.
Prior JC. Exercise-associated menstrual disturbances. In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive Endocrinology, Surgery and Technology. New York: Raven Press; 1996. pp. 1077–91.
Barr SI, Janelle KC, Prior JC. Vegetarian versus nonvegetarian diets, dietary restraint, and subclinical ovulatory disturbances: prospective six month study. Am J Clin Nutr. 1994; 60:887–94.
McLean JA, Barr SI, Prior JC. Cognitive dietary restraint is associated with higher urinary cortisol excretion in healthy premenopausal women.Am J Clin Nutr. 2001; 73:7–12.
Prior JC, Seifert-Klauss VR, Hale G. The endocrinology of perimenopause – new definitions and understandings of hormonal and bone changes. In: Dvornyk V, ed. Current Topics in Menopause. Hong Kong: Benthan Science Publishers; 2013. pp. 54–83.
Prior JC. The ageing female reproductive axis II: ovulatory changes with perimenopause. In: Chadwick DJ, Goode JA, eds. Endocrine Facets of Ageing, 242th edn. Chichester, UK: John Wiley and Sons Ltd; 2002. pp. 172–86.
Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and hypothalamic-pituitary sensitivity to estrogen. J Am Med Assoc. 2004; 292(24):2991–6.
La Vecchia C, Decarli A, Franceschi S, Gentile A, Negri E, Parazzini F. Menstrual and reproductive factors and the risk of myocardial infarction in women under fifty-five years of age. Am J Obstet Gynecol. 1987; 157(5):1108–12.
Palmer JR, Rosenberg L, Shapiro S. Reproductive factors and risk of myocardial infarction. Am J Epidemiol. 1992; 136(4):408–416.
Bertuccio P, Tavani A, Gallus S, Negri E, La Vecchia C. Menstrual and reproductive factors and risk of non-fatal acute myocardial infarction in Italy. Eur J Obstet Gynecol Reprod Biol. 2007; 134(1):67–72.
Harris MA, Prior JC, Koehoorn M. Age at menarche in the Canadian population: secular trends and relationship to adulthood BMI. J Adolesc Health. 2008; 43(6):548–54.
Jacobsen BK, Heuch I, Kvale G. Association of low age at menarche with increased all-cause mortality: a 37-year follow-up of 61,319 Norwegian women. Am J Epidemiol. 2007; 166(12):1431–7.
Jacobsen BK, Nilssen S, Heuch I, Kvale G. Does age at natural menopause affect mortality from ischemic heart disease? J Clin Epidemiol. 1997; 50(4):475–79.
Kalyan S, Hitchcock CL, Sirrs S, Pudek M, Prior JC. Cardiovascular and metabolic effects of medroxyprogesterone acetate versus conjugated equine estrogen after premenopausal hysterectomy with bilateral ovariectomy. Pharmacotherapy. 2010; 30(5):442–52.
Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002; 87:2013–7.
Talbott EO, Kuller LH, Detre K, Matthews K, Norman S, Kelsey SF, et al. Reproductive history of women dying of sudden cardiac death: a case-controlled study. Int J Epidemiol. 1989; 18:589–94.
Lawlor DA, Emberson JR, Ebrahim S, Whincup PH, Wannamethee SG, Walker M, et al. Is the association between parity and coronary heart disease due to biological effects of pregnancy or adverse lifestyle risk factors associated with child-rearing? Findings from the British Women’s Heart and Health Study and the British Regional Heart Study. Circulation. 2003; 107(9):1260–4.
Catov JM, Newman AB, Sutton-Tyrrell K, Harris TB, Tylavsky F, Visser M, et al. Parity and cardiovascular disease risk among older women: how do pregnancy complications mediate the association? Ann Epidemiol. 2008; 18(12):873–9.
Parikh NI, Cnattingius S, Dickman PW, Mittleman MA, Ludvigsson JF, Ingelsson E. Parity and risk of later-life maternal cardiovascular disease.Am Heart J. 2010; 159(2):215–21.
Hitchcock CL, Elliott TG, Norman EG, Stajic V, Teede H, Prior JC. Hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women. Menopause. 2012; 19(11):1208–14.
Mather KJ, Norman EG, Prior JC, Elliott TG. Preserved forearm endothelial responses with acute exposure to progesterone: a randomized cross-over trial of 17-b estradiol, progesterone, and 17-b estradiol with progesterone in healthy menopausal women. J Clin Endocrinol Metab. 2000; 85:4644–9.
Simon JA, Shangold MM, Andrews MC, Buster JC, Hodgen GD. Micronized progesterone therapy: the importance of route of administration and pharmacokinetics on clinical outcome. J Contracept Fertil Sex. 1992; 20:13–8.
Berga SL, Daniels TL, Giles DE. Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations. Fertil Steril. 1997; 67(6):1024–30.
Williams WP, III, Kriegsfeld LJ. Circadian control of neuroendocrine circuits regulating female reproductive function. Front Endocrinol (Lausanne). 2012; 3:60.
D’Agostino RB, Sr., Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008; 117(6):743–53.
Perez MV, Wang PJ, Larson JC, Virnig BA, Cochrane B, Curb JD, et al. Effects of postmenopausal hormone therapy on incident atrial fibrillation: the Women’s Health Initiative randomized controlled trials. Circ Arrhythm Electrophysiol. 2012; 5(6):1108–16.
Santoro N, Rosenberg J, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996; 81:4, 1495–501.
Prior JC. Perimenopause: the complex endocrinology of the menopausal transition. Endocr Rev. 1998; 19:397–428.
Arck P, Hansen PJ, Mulac JB, Piccinni MP, Szekeres-Bartho J. Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol. 2007; 58(3):268–79.
Arck PC, Rucke M, Rose M, Szekeres-Bartho J, Douglas AJ, Pritsch M, et al. Early risk factors for miscarriage: a prospective cohort study in pregnant women. Reprod Biomed Online. 2008; 17(1):101–13.
Kharazmi E, Fallah M, Luoto R. Miscarriage and risk of cardiovascular disease. Acta Obstet Gynecol Scand. 2010; 89(2):284–8.
Kharazmi E, Dossus L, Rohrmann S, Kaaks R. Pregnancy loss and risk of cardiovascular disease: a prospective population-based cohort study (EPIC-Heidelberg). Heart. 2011; 97(1):49–54.
Gorgels WJ, Graaf Y, Blankenstein MA, Collette HJ, Erkelens DW, Banga JD. Urinary sex hormone excretions in premenopausal women and coronary heart disease risk: a nested case-referent study in the DOM-cohort. J Clin Epidemiol. 1997; 50(3):275–81.
Prior JC, Vigna YM, Barr SI, Rexworthy C, Lentle BC. Cyclic medroxyprogesterone treatment increases bone density: a controlled trial in active women with menstrual cycle disturbances. Am J Med. 1994; 96:521–30.
Canonico M, Oger E, Plu-Bureau, Conard J, Meyer G, Levesque H, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007; 115(7):840–5.
Schussler P, Kluge M, Yassouridis A, Dresler M, Held K, Zihl J, et al. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. Psychoneuroendocrinology. 2008; 33(8):1124–31.
Prior JC, Hitchcock CL. Progesterone for hot flush and night sweat treatment – effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Gynecol Endocrinol. 2012; 28(Suppl 2):7–11.
Le Mellédo JM, Baker G. Role of progesterone and other neuroactive steroids in anxiety disorders. Expert Rev Neurother. 2004; 4(5):851–60.
Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA. Progesterone and the premenstrual syndrome: a double blind crossover trial.Br Med J. 1985; 290:1617–21.
Waugh EJ, Polivy J, Ridout R, Hawker GA. A prospective investigation of the relations among cognitive dietary restraint, subclinical ovulatory disturbances, physical activity, and bone mass in healthy young women. Am J Clin Nutr. 2007; 86(6):1791–801.
Morris FL, Payne WR, Wark JD. The impact of intense training on endogenous estrogen and progesterone concentrations and bone mineral acquisition in adolescent rowers. Osteoporos Int. 1999; 10(5):361–8.
Waller K, Reim J, Fensler L, Swan SH, Brumback B, Windham GC, et al. Bone mass and subtle abnormalities in ovulatory function in healthy women. J Clin Endocrinol Metab. 1996; 81:663–8.
Prior JC, Vigna YM, Barr SI, Kennedy S, Schulzer M, Li DK. Ovulatory premenopausal women lose cancellous spinal bone: a five year prospective study. Bone. 1996; 18:261–7.

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