References
- Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118(Suppl 12B):14–24.
- Harlow SD, Gass M, Hall JE, et al. Executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012;19:387–395.
- Monteleone P, Mascagni G, Giannini A, et al. Symptoms of menopause - global prevalence, physiology and implications. Nat Rev Endocrinol. 2018;14:199–215.
- Thurston RC. Vasomotor symptoms: natural history, physiology, and links with cardiovascular health. Climacteric. 2018;21:96–100.
- Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology. 2009;72:1850–1857.
- Mosconi L, Berti V, Quinn C, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS One. 2017;12:e0185926.
- Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham heart study. Circulation. 2007;116:1234–1241.
- Lee CG, Carr MC, Murdoch SJ, et al. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. J Clin Endocrinol Metab. 2009;94:1104–1110.
- Nappi RE, Palacios S, Particco M, et al. The REVIVE (Real women’s views of treatment options for menopausal vaginal changes) survey in Europe: country-specific comparisons of postmenopausal women’s perceptions, experiences and needs. Maturitas. 2016;91:81–90.
- Palacios S, Nappi RE, Bruyniks N, et al. The European vulvovaginal epidemiological survey (EVES): prevalence, symptoms and impact of vulvovaginal atrophy of menopause. Climacteric. 2018;21:286–291.
- Wahab F, Atika B, Shahab M, et al. Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. Nat Rev Urol. 2016;13:21–32.
- Szeliga A, Czyzyk A, Podfigurna A, et al. The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications. Gynecol Endocrinol. 2018;34:913–919.
- Lunenfeld B, Buhler K. The neuro control of the ovarain cycle - a hypothesis. Gynecol Endocrinol. 2018;34:278–282.
- Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20:485–500.
- Young J, George JT, Tello JA, et al. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;97:193–202.
- Rance NE, Dacks PA, Mittelman-Smith MA, et al. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34:211–227.
- Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B administration induces hot flushes in women. Sci Rep. 2015;5:8466.
- Padilla SL, Johnson CW, Barker FD, et al. A neural circuit underlying the generation of hot flushes. Cell Rep. 2018;24:271–277.
- Faubion SS, Stuenkel CA. Neurokinin 3 receptor antagonists for treatment of vasomotor symptoms: a new panacea or just a flash in the pan? Menopause. 2018;25:859–861.
- Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci U S A. 2012;109:19846–19851.
- Wakabayashi Y, Nakada T, Murata K, et al. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci. 2010;30:3124–3132.
- Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:1809–1820.
- Prague JK, Dhillo WS. Neurokinin 3 receptor antagonism - the magic bullet for hot flushes? Climacteric. 2017;20:505–509.
- Oakley AE, Steiner RA, Chavkin C, et al. Kappa agonists as a novel therapy for menopausal hot flashes. Menopause. 2015;22:1328–1334.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial. JAMA. 2004;291:1701–1712.
- 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;288:321–333.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA. 2013;310:1353–1368.
- Manson JE, Kaunitz AM. Menopause management–getting clinical care back on track. N Engl J Med. 2016;374:803–806.
- Lobo RA, Pickar JH, Stevenson JC, et al. Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016;254:282–290.
- Lobo RA, Archer DF, Kagan R, et al. A 17beta-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2018;132:161–170.
- Hagen AA, Barr M, Diczfalusy E. Metabolism of 17-beta-oestradiol-4-14-C in early infancy. Acta Endocrinol (Copenh). 1965;49:207–220.
- Abot A, Fontaine C, Buscato M, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6:1328–1346.
- Arnal JF, Lenfant F, Metivier R, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017;97:1045–1087.
- Guivarc’h E, Buscato M, Guihot AL, et al. Predominant role of nuclear versus membrane estrogen receptor alpha in arterial protection: implications for estrogen receptor alpha modulation in cardiovascular prevention/safety. J Am Heart Assoc. 2018;7:e008950.
- Sassarini J, Anderson RA. New pathways in the treatment for menopausal hot flushes. Lancet. 2017;389:1775–1777.
- Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13:220–231.
- Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–78.
- Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.
- Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933–941.
- Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the women’s health initiative. Arch Intern Med. 2006;166:357–365.
- Jordan VC, Ford LG. Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis. Cancer Prev Res (Phila). 2011;4:633–637.
- Collaborative Group on Hormonal Factors in Breast C. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713–1727.
- Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. JAMA. 2017;318:927–938.
- Baber RJ, Panay N, Fenton ATIWG. IMS recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;2016(19):109–150.
- NAMS. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728–753.
- Benoit T, Valera MC, Fontaine C, et al. Estetrol, a fetal selective estrogen receptor modulator, acts on the vagina of mice through nuclear estrogen receptor alpha activation. Am J Pathol. 2017;187:2499–2507.
- Utian WH, Gaspard U, Jost M, et al. Estetrol, the next generation of hormone therapy: results of a phase 2b dose-finding study in postmenopausal women (E4 relief). San Diego, CA, USA: NAMS; 2018 October 5.
- Coelingh Bennink HJ, Heegaard AM, Visser M, et al. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric. 2008;11(Suppl 1):2–14.
- Heegaard AM, Holinka CF, Kenemans P, et al. Estrogenic uterovaginal effects of oral estetrol in the modified Allen-Doisy test. Climacteric. 2008;11(Suppl 1):22–28.
- Holinka CF, Bressler RS, Zehr DR, et al. Comparison of effects of estetrol and tamoxifen with those of estriol and estradiol on the immature rat uterus. Biol Reprod. 1980;22:913–926.
- Holinka CF, Brincat M, Coelingh Bennink HJ. Preventive effect of oral estetrol in a menopausal hot flush model. Climacteric. 2008;11(Suppl 1):15–21.
- Montt-Guevara MM, Palla G, Spina S, et al. Regulatory effects of estetrol on the endothelial plasminogen pathway and endothelial cell migration. Maturitas. 2017;99:1–9.
- Gerard C, Mestdagt M, Tskitishvili E, et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. Oncotarget. 2015;6:17621–17636.
- Giretti MS, Montt Guevara MM, Cecchi E, et al. Effects of estetrol on migration and invasion in T47-D breast cancer cells through the actin cytoskeleton. Front Endocrinol (Lausanne). 2014;5:80.
- Gerard C, Blacher S, Communal L, et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J Endocrinol. 2015;224:85–95.
- Singer CF, Bennink HJ, Natter C, et al. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014;35:2447–2451.
- Mawet M, Maillard C, Klipping C, et al. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care. 2015;20:463–475.
- Kluft C, Zimmerman Y, Mawet M, et al. Reduced haemostatic effects with drospirenone-based oral contraceptives containing estetrol versus ethinyl estradiol. Contraception. 2017;95:140–147.
- Visser M, Holinka CF, Coelingh Bennink HJ. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric. 2008;11(Suppl 1):31–40.
- Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, et al. Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric. 2017;20:285–289.
- Coelingh Bennink HJT, Zimmerman Y, Verhoeven C, et al. Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Maturitas. 2016;91:93–100.
- Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, et al. Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study. Menopause. 2017;24:677–685.
- Donesta SPRL. A multicentre dose-finding, randomised, double-blind, placebo-controlled study to select the daily oral dose of estetrol (E4) for the treatment of vasomotor symptoms in post-menopausal women (E4 relief). ClinicalTrials.gov. NCT02834312.
- Lobo RA. Estetrol: towards the development of a new generation of hormonal therapy: update on clinical development. 16th IMS congress; 2018 Jun 6–9; Vancouver, Canada.
- Ogeda SA. Pilot/phase IIa trial to investigate the effect of ESN364 in early postmenopausal women suffering from hot flashes. EudraCT 2015-002578-20.
- Fraser GL, Hoveyda HR, Clarke IJ, et al. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology. 2015;156:4214–4225.
- Prague JK, Dhillo WS. Treating hot flushes with a neurokinin 3 receptor antagonist. Oncotarget. 2017;8:106153–106154.
- Imperial College London. New class of menopause drugs reduces number and severity of hot flushes. 2018 Mar 14 [cited 2018 Nov 26]. Available from: https://www.sciencedaily.com/releases/2018/03/180314092319.htm
- Hoveyda HR, Fraser GL, Roy MO, et al. Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I). J Med Chem. 2015;58:3060–3082.
- Hoveyda HR, Fraser GL, Dutheuil G, et al. Optimization of novel antagonists to the neurokinin-3 receptor for the treatment of sex-hormone disorders (Part II). ACS Med Chem Lett. 2015;6:736–740.
- Fraser GL, Ramael S, Hoveyda HR, et al. The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J Clin Endocrinol Metab. 2016;101:417–426.
- Fraser GL. Postmenopausal hot flashes cut by 93% with novel nonhormonal treatment. ENDO Congress; 2017 Feb 16–19; Hyderabad, India.
- Ogeda SA. A dose-ranging study of the efficacy of ESN364 in postmenopausal women suffering vasomotor symptoms (hot flashes). ClinicalTrials.gov NCT03192176.
- KaNDy therapeutics press release. 2018 Oct 4 [cited 2018 Nov 26]. Available from: https://www.kandytherapeutics.com/kandy-therapeutics-presents-new-compelling-data-with-lead-candidate-nt-814-at-the-north-american-menopause-society-2018-annual-meeting/
- Nerre Therapeutics. A Study of NT-814 in the Treatment of Troublesome Post-menopausal Symptoms (SWITCH-1). ClinicalTrials.gov NCT03596762.
- Litman RE, Smith MA, Desai DG, et al. The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: a proof-of-principle study. J Clin Psychopharmacol. 2014;34:199–204.
- Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018;25:862–869.
- Mitsubishi Tanabe Pharma America. [cited 2018 Jul 30]. Available from: https://www.mt-pharma.co.jp/e/develop/pipeline/e_pipeline1803.pdf
- Mitsubishi Tanabe Pharma America. A study to investigate the safety, tolerability and pharmacokinetics of multiple doses of MT-8554 in female subjects experiencing vasomotor symptoms. ClinicalTrial.gov NCT02803268.
- Mitsubishi tanabe pharma America. MT-8554 for reduction of vasomotor symptoms in postmenopausal women. ClinicalTrials.gov NCT03291067.
- Mitsubishi Tanabe Pharma America. Long-term safety and efficacy study of MT-8554 in postmenopausal women with vasomotor symptoms. ClinicalTrials.gov NCT03541200.
- Fervent Pharmaceuticals. [ cited 2018 Jul 30]. Available from: http://ferventpharma.com/development-pipeline/
- Fervent Pharmaceuticals. FP-101 for the treatment of hot flashes in postmenopausal women. ClinicalTrials.gov NCT03285672.
- QUE Oncology. [ cited 2018 Aug 3]. Available from: https://www.queoncology.com/
- Liang Z, Zhan W, Zhu A, et al. Development of a unique small molecule modulator of CXCR4. PLoS One. 2012;7:e34038.
- Metastatix Inc. MSX-122 administered orally in patients with refractory metastatic or locally advanced solid tumors. ClinicalTrials.gov NCT00591682.
- Painter W, Speed AL, Phillips K, et al. Results of a phase Ib study of Q-122 treatment of vasomotor symptoms in breast cancer patients. J Clin Oncol. 2015;33(Suppl.28):99.
- Que Oncology. Safety/efficacy of Q-122 in breast cancer patients taking tamoxifen or aromatase inhibitor. ClinicalTrials.gov NCT03518138
- Genazzani AR, Simoncini T. Pharmacotherapy: benefits of menopausal hormone therapy–timing is key. Nat Rev Endocrinol. 2013;9:5–6.
- LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305:1305–1314.
- Force USPST, Grossman DC, Curry SJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US preventive services task force recommendation statement. JAMA. 2017;318:2224–2233.
- Langer RD, Simon JA, Pines A, et al. Menopausal hormone therapy for primary prevention: why the USPSTF is wrong. Climacteric. 2017;20:402–413.
- Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409.
- Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221–1231.
- Renoux C, Dell’Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost. 2010;8:979–986.