Premature Ovarian Insufficiency and Long-Term Health Consequences

Author(s): Sophia Tsiligiannis*, Nick Panay, John C. Stevenson

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 6 , 2019

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Graphical Abstract:


Premature ovarian insufficiency (POI) is defined as the cessation of ovarian function before the age of 40 years. The trio of amenorrhea, elevated gonadotropins and oestrogen deficiency is associated with long-term health consequences including increased cardiovascular disease (CVD), decreased bone mineral density (BMD), significantly reduced fertility, psychological distress, vulvovaginal atrophy, neurological effects and overall reduced life expectancy. There are deficits in our understanding of this condition and subsequently the long-term health consequences. The underlying aetiology of POI and the optimal management strategies are also poorly understood. Our knowledge of long-term cardiovascular consequences specifically relating to women with POI is limited as most data on the subject are derived from studies involving women who experienced menopause at the natural age (after 40 years with an average age of 51).

Keywords: Premature ovarian insufficiency, amenorrhoea, cardiovascular disease, POI registry, women's health, menopause.

National Institute for Heath and Care Excellence (NICE). Menopause: Diagnosis and management: NICE Guideline [NG23]. 2015. Available from:
Alzubaidi NH, Chapin HL, Vanderhoof VH, et al. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol 2002; 99: 720-5.
European Society of Human Reproduction and Embryology. Management of women with premature ovarian insufficiency 2015.Available from: .
Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol 2010; 45: 257-79.
Maclaran K, Panay N. Current concepts in premature ovarian insufficiency. Womens Health 2015; 11: 169-82.
Silva CA, Yamakami LYS, Aikawa NE, et al. Autoimmune primary ovarian insufficiency. Autoimmun Rev 2014; 13: 427-30.
Nelson LM. Primary ovarian insufficiency. N Engl J Med 2009; 360: 606-14.
Cramer DW, Xu H, Harlow BL. Family history as a predictor of early menopause. Fertil Steril 1995; 64: 740-5.
van Kasteren YM, Hundscheid RD, Smits AP, et al. Familial idiopathic premature ovarian failure: An overrated and underestimated genetic disease? Hum Reprod 1999; 14: 2455-9.
Maclaran K, Panay N. Premature ovarian failure. J Fam Plann Reprod Health Care 2011; 37: 35-42.
Ossewaarde ME, Bots ML, Verbeek ALM, et al. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005; 16: 556-62.
Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: The multi-ethnic study of atherosclerosis. Menopause 2012; 19: 1081-7.
Roeters van Lennep JE, Heida KY, Bots ML, et al. Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis. Eur J Prev Cardiol 2016; 23: 178-86.
Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemic heart disease: The Adventist Health Study. J Clin Epidemiol 1999; 52: 303-7.
Muka T, Oliver-Williams C, Kunutsor S, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality. JAMA Cardiol 2016; 1: 767.
Tao X-Y, Zuo A-Z, Wang J-Q. Effect of primary ovarian insufficiency and early natural menopause on mortality: A meta-analysis. Climacteric 2016; 19: 27-36.
Atsma F, Bartelink M-LEL, Grobbee DE, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: A meta-analysis. Menopause 2006; 13: 265-79.
Løkkegaard E, Jovanovic Z, Heitmann BL, et al. The association between early menopause and risk of ischaemic heart disease: Influence of hormone therapy. Maturitas 2006; 53: 226-33.
Van der Schouw YT, van der Graaf Y, Steyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347: 714-8.
Zhao Z, Wang H, Jessup JA, et al. Role of estrogen in diastolic dysfunction. Am J Physiol Heart Circ Physiol 2014; 306: 628-40.
Sturdee DW, Collins P, Genazzani AR, et al. Aging, menopause, cardiovascular disease and HRT. International menopause society consensus statement. Climacteric 2009; 12: 368-77.
Kalantaridou SN, Naka KK, Papanikolaou E, et al. Impaired endothelial function in young women with premature ovarian failure: Normalization with hormone therapy. J Clin Endocrinol Metab 2004; 89: 3907-13.
Knauff EAH, Westerveld HE, Goverde AJ, et al. Lipid profile of women with premature ovarian failure. Menopause 2008; 15: 919-23.
Corrigan EC, Nelson LM, Bakalov VK, et al. Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women. Menopause 2006; 13: 911-6.
Eshtiaghi R, Esteghamati A, Nakhjavani M, et al. Menopause is an independent predictor of metabolic syndrome in Iranian women. Maturitas 2010; 65: 262-6.
Daan NMP, Muka T, Koster MPH, et al. Cardiovascular risk in women with premature ovarian insufficiency compared to premenopausal women at middle age. J Clin Endocrinol Metab 2016; 101: 3306-15.
Rocca WA, Grossardt BR, Miller VM, et al. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012; 19: 272-7.
Jacoby VL, Grady D, Wactawski-Wende J, et al. Oophorectomy vs. ovarian conservation with hysterectomy: Cardiovascular disease, hip fracture, and cancer in the women’s health initiative observational study. Arch Intern Med 2011; 171: 760-8.
Daan NMP, Jaspers L, Koster MPH, et al. Androgen levels in women with various forms of ovarian dysfunction: Associations with cardiometabolic features. Hum Reprod 2015; 30: 2376-86.
Bernini GP, Moretti A, Sgró M, et al. Influence of endogenous androgens on carotid wall in postmenopausal women. Menopause 2001; 8: 43-50.
Stevenson JC. The metabolic basis for the effects of HRT on coronary heart disease. Endocrine 2004; 24: 239-44.
Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001; 75: 898-915.
Stevenson JC, Rioux JE, Komer L, et al. 1 and 2 mg 17beta-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women. Climacteric 2005; 8: 352-9.
Stevenson JC, Chines A, Pan K, et al. A pooled analysis of the effects of conjugated estrogens/bazedoxifene on lipid parameters in postmenopausal women from the selective estrogens, menopause, and response to therapy (SMART) trials. J Clin Endocrinol Metab 2015; 100: 2329-38.
Scarabin P-Y, Oger E, Plu-Bureau G, et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003; 362: 428-32.
Paschou S, Anagnostis P, Vryonidou A, et al. Diabetes and atherosclerosis: Old players in a new field, Osteoporosis. Curr Vasc Pharmacol 2018; 16: 524-7.
van Der Voort DJM, van Der Weijer PHM, Barentsen R. Early menopause: Increased fracture risk at older age. Osteoporos Int 2003; 14: 525-30.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women’s health initiative randomized controlled trial. JAMA 2002; 288: 321-33.
Popat VB, Calis KA, Kalantaridou SN, et al. Bone mineral density in young women with primary ovarian insufficiency: Results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab 2014; 99: 3418-26.
van der Klift M, de Laet CE, McCloskey EV, et al. Risk factors for incident vertebral fractures in men and women: The rotterdam study. J Bone Miner Res 2004; 19: 1172-80.
Baber RJ, Panay N, Fenton A, et al. 2016 IMS recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016; 19: 109-50.
British Menopause Society (BMS). Premature ovarian insufficiency. British menopause society council consensus statement. 2017.Available from: .
van der Stege JG, Groen H, van Zadelhoff SJN, et al. Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause 2008; 15: 23-31.
Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: A systematic review and meta-analysis. J Steroid Biochem Mol Biol 2014; 142: 90-8.
The Daisy Network Premature Menopause Support Group. Available from
Nelson LM, Covington SN, Rebar RW. An update: Spontaneous premature ovarian failure is not an early menopause. Fertil Steril 2005; 83: 1327-32.
Bidet M, Bachelot A, Touraine P. Premature ovarian failure: Predictability of intermittent ovarian function and response to ovulation induction agents. Curr Opin Obstet Gynecol 2008; 20: 416-20.
Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of Parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008; 70: 200-9.
Soni M, Hogervorst E. Premature ovarian insufficiency and neurological function. Minerva Endocrinol 2014; 39: 189-99.
Ryan J, Scali J, Carrière I, et al. Impact of a premature menopause on cognitive function in later life. BJOG 2014; 121: 1729-39.
Mittal M, Savvas M, Narvekar N, et al. A cross-sectional national questionnaire survey assessing the clinical attitudes of members of the British menopause society to the management of women with premature ovarian insufficiency. Post Reprod Health 2014; 20: 90-7.
Lethaby A, Suckling J, Barlow D, et al. Hormone replacement therapy in postmenopausal women: Endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004; 4CD000402
Renoux C, Dell’Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: A population-based study. J Thromb Haemost 2010; 8: 979-86.
Rosano GM, Vitale C, Silvestri A, et al. Metabolic and vascular effect of progestins in post-menopausal women: Implications for cardioprotection. Maturitas 2003; 46: 17-29.
Panay N, Hamoda H, Arya R, et al. British menopause society and women’s health concern. The 2013 British menopause society & women’s health concern recommendations on hormone replacement therapy. Menopause Int 2013; 19: 59-68.
Utian WH, Archer DF, Bachmann GA, et al. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of the north American menopause society. Menopause 2008; 15: 584-602.
Wu X, Cai H, Kallianpur A, et al. Impact of premature ovarian failure on mortality and morbidity among chinese women. PLoS One 2014; 9e89597
Guttmann H, Weiner Z, Nikolski E, et al. Choosing an oestrogen replacement therapy in young adult women with Turner syndrome. Clin Endocrinol 2001; 54: 159-64.
Langrish JP, Mills NL, Bath LE, et al. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009; 53: 805-11.
Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: Effects on bone mass acquisition and turnover. Clin Endocrinol 2010; 73: 707-14.
Cartwright B, Robinson J, Seed PT, et al. Hormone replacement therapy versus the combined oral contraceptive pill in premature ovarian failure: A randomized controlled trial of the effects on bone mineral density. J Clin Endocrinol Metab 2016; 101: 3497-505.
Panay N, Fenton A. Premature ovarian insufficiency: Working towards an international database. Climacteric 2012; 15: 295-6.

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Article Details

Year: 2019
Page: [604 - 609]
Pages: 6
DOI: 10.2174/1570161117666190122101611
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