Evidence-Based Hormone Therapies

Pharmacokinetics

Serum LH and LH pulse frequency: the changes with oral progesterone LH pulse secretion in the mid-follicular phase at 09h: no significant influence of oral progesterone during 5 days (cycle days 5-9) in premenopausal women (1 reference)

1. Kim SH, Burt Solorzano CM, McCartney CR. Progesterone administration does not acutely alter LH pulse secretion in the mid-follicular phase in women. Physiol Rep. 2018 Apr;6(8):e13680.

LH pulse frequency: the reduction of LH pulse frequency during waking but not during sleep with oral progesterone for 6 days menstrual cycle days 6 to 11In late pubertal girls (1 reference)

2. Kim SH, Lundgren JA, Bhabhra R, Collins JS, Patrie JT, Burt Solorzano CM, Marshall JC, McCartney CR. Progesterone-mediated inhibition of the GnRH pulse generator: differential sensitivity as a function of sleep status. J Clin Endocrinol Metab. 2018 Mar 1;103(3):1112-1121.

LH secretory responses to progesterone administered at 06h: the amplification in mean LH and LH pulse amplitude, and mean FSH but no change in LH pulse frequency) with a single intake of oral progesterone administered at 06h in the late follicular phase (cycle days 7-11) in premenopausal women pretreated with 3 days of transdermal estradiol (0.2 mg/day). in contrast with the reduction of pulse frequency when progesterone administered at 18h:00 (1 reference)

3. Hutchens EG, Ramsey KA, Howard LC, Abshire MY, Patrie JT, McCartney CR. Progesterone has rapid positive feedback actions on LH release but fails to reduce LH pulse frequency within 12 h in estradiol-pretreated women. Physiol Rep. 2016 Aug;4(16). pii: e12891.

Serum free thyroxine: the improvement with oral progesterone

Serum free thyroxin level: the improvement (increased serum free T4) with 300 mg/day of oral progesterone for 12 weeks in postmenopausal women (1 reference)

4. Sathi P, Kalyan S, Hitchcock CL, Pudek M, Prior JC. Progesterone therapy increases free thyroxine levels–data from a randomized placebo-controlled 12-week hot flush trial. Clin Endocrinol (Oxf). 2013 Aug;79(2):282-7.

Tests

Salivary progesterone measurements: caution in the use of salivary progesterone tests to measure progesterone absorption from transdermal progesterone creams used for 2x 3 weeks in postmenopausal women. (1 reference)

5. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women. Maturitas. 2002 Jan 30;41(1):1-6.

Anxiety

Anxiety: the improvement (anxiety reduction) with different doses (30-60-200 mg/day) of oral progesterone for  4 treatment cycles through its conversion into the sleep-inducing metabolite allopregnanolone in postmenopausal women (1 reference)

6. Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T. Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone. Psychopharmacology (Berl). 2006 Aug;187(2):209-21.

Sedation: the improvement (mild sedation with  small, delayed increases in heart rate and feelings of fatigue, and impaired smooth eye pursuit) with a single 200 mg intramuscular injection of progesterone in women in their early follicular phase and in men (1 reference)

7. Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H. Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology. 2004 Apr;29(3):339-54.

Anxiety: the improvement (reduction though conversion of progesterone into allopregnanolone) with a single intake of a very high dose (1200 mg) of oral progesterone in young premenopausal women (1 reference)

8. Freeman EW, Purdy RH, Coutifaris C, Rickels K, Paul SM. Anxiolytic metabolites of progesterone: correlation with mood and performance measures following oral progesterone administration to healthy female volunteers. Neuroendocrinology. 1993 Oct;58(4):478-84.

Depression

Mood: the adverse effects (negative mood effects) with very high doses (400-800 mg/day) of vaginal progesterone suppositories for three 28-day cycles  in women without prior premenstrual syndrome (1 reference)

9. Andréen L, Bixo M, Nyberg S, Sundström-Poromaa I, Bäckström T. Progesterone effects during sequential hormone replacement therapy. Eur J Endocrinol. 2003 May;148(5):571-7.

Mood: no adverse effects with 200 mg/day of oral progesterone (and also not with 5 mg/day of medroxyprogesterone acetate) alone for 2 weeks in early postmenopausal women, which are not depressed, nor anxious  (1 reference)

10. Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause. 2002 Jul-Aug;9(4):253-63.

Mood and performance: no adverse effects with single high doses (300, 600, 1200 mg/day) with oral progesterone in young premenopausal women, but transient behavioral effects (decreased information processing and verbal memory function as well as fatigue) only at the highest doses (1 reference)

11. Freeman EW, Weinstock L, Rickels K, Sondheimer SJ, Coutifaris C. A placebo-controlled study of effects of oral progesterone on performance and mood. Br J Clin Pharmacol. 1992 Mar;33(3):293-8.

Memory improvement

Cognitive performance and smoking urges: the improvement (in cognitive performances and reduction in smoking urges) with 200 mg/day of oral progesterone for 4 days in abstinent male and female smokers (1 reference)

12. Sofuoglu M, Mouratidis M, Mooney M. Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. 2011 Jan;36(1):123-32.  

Memory impairment

Memory: the impairment by a single intake of oral progesterone through its conversion into the sleep-inducing metabolite allopregnanolone in healthy  young premenopausal women (1 reference)

13. van Wingen G, van Broekhoven F, Verkes RJ, Petersson KM, Bäckström T, Buitelaar J, Fernández G. How progesterone impairs memory for biologically salient stimuli in healthy young women. J Neurosci. 2007 Oct 17;27(42):11416-23. ¹ C.

Sleep

Sleep: the improvement (better sleep without the sleep-EEG alterations induced by GABA active compounds) with a single intake of intranasal progesterone in healthy postmenopausal women. (1 reference)

14. Schüssler P, Kluge M, Adamczyk M, Beitinger ME, Beitinger P, Bleifuss A, Cordeiro S, Mattern C, Uhr M, Wetter TC, Yassouridis A, Rupprecht R, Friess E, Steiger A. Sleep after intranasal progesterone vs. zolpidem and placebo in postmenopausal women – A randomized, double-blind cross over study. Psychoneuroendocrinology. 2018 Jun;92:81-86.   

Sleep disturbances: the improvement with oral progesterone for 3 weeks in postmenopausal women with disturbed sleep, but no effects on the sleep of postmenopausal women with undisturbed sleep (1 reference)

15. Caufriez A, Leproult R, L’Hermite-Balériaux M, Kerkhofs M, Copinschi G. Progesterone prevents sleep disturbances and modulates GH, TSH, and melatonin secretion in postmenopausal women. J Clin Endocrinol Metab. 2011 Apr;96(4):E614-23.

Premenstrual syndrome

Premenstrual syndrome: the improvement (relief of symptoms) with very high doses (2x 400 mg/day) of vaginal or rectal progesterone pessaries for 14 days before the expected onset of menstruation until the onset of vaginal bleeding, for 4 consecutive menstrual cycles in premenopausal women (1 reference)

16. Magill PJ. Investigation of the efficacy of progesterone pessaries in the relief of symptoms of premenstrual syndrome. progesterone Study Group. Br J Gen Pract. 1995 Nov;45(400):589-93.

No significant effect on premenstrual syndrome

Premenstrual syndrome: no significant beneficial effects (relief of symptoms) with very high doses 4x 300 to 4x 440 mg/day) of oral progesterone from day 18 to day 2 of the next menstrual cycle in premenopausal women (1 reference)

17. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA. 1995 Jul 5;274(1):51-7.

Premenstrual syndrome: no significant beneficial effects of very high doses (400-800 mg/day) of rectal progesterone suppositories in premenopausal women (1 reference)

18. Freeman E, Rickels K, Sondheimer SJ, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA. 1990 Jul 18;264(3):349-53.  

Premenstrual syndrome: no or poor (marginal) significant beneficial effects of high doses (2x 400 mg/day) of vaginal progesterone suppositories for a minimum of 12 days before the onset of menstruation for 3 months in premenopausal women (1 reference)

19. Maddocks S, Hahn P, Moller F, Reid RL. A double-blind placebo-controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome. Am J Obstet Gynecol. 1986 Mar;154(3):573-81.

Premenstrual syndrome: no significant beneficial effects (on relief of symptoms) with 2x 100 mg/day) of vaginal progesterone pessaries in premenopausal women with premenstrual syndrome (1 reference)

20. Andersch B, Hahn L. Progesterone treatment of premenstrual tension–a double-blind study. J Psychosom Res. 1985;29(5):489-93.

Breast

Breast epithelial cell proliferation: the improvement (reduction) with topical progesterone gel for 10-13 days before surgery in premenopausal women (1 reference)

21. Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Ligniéres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995 Apr;63(4):785-91.

Mastalgia: the improvement (reduced breast pain) with 100 mg/day of with vaginal progesterone cream for 6 menstrual cycles in premenopausal women with  severe cyclical mastodynia (1 reference)

22. Nappi C, Affinito P, Di Carlo C, Esposito G, Montemagno U. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endocrinol Invest. 1992 Dec;15(11):801-6.

Withdrawal bleeding

Withdrawal bleeding: the increase in frequency with 300 mg/day, and not 200 mg/day, of oral progesterone for 10 days in premenopausal women with secondary amenorrhea (1 reference)

23. Shangold MM, Tomai TP, Cook JD, Jacobs SL, Zinaman MJ, Chin SY, Simon JA. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea. Fertil Steril. 1991 Dec;56(6):1040-7. Department of Obstetrics and Gynecology, Hahnemann University, Philadelphia, Pennsylvania 19102.

Postmenopausal symptoms

Vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life: no significant beneficial effects with 32 mg/day of transdermal progesterone cream for 12 weeks in postmenopausal women (1 reference)

24. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause. 2003 Jan-Feb;10(1):13-8.

No significant effects on menopausal symptoms

Menopausal symptoms: no beneficial effect (no reduction of menopausal symptoms) with 60-40-20-5- mg/day of  transdermal progesterone cream for 3 years in postmenopausal women (1 reference)

25. Benster B, Carey A, Wadsworth F, Vashisht A, Domoney C, Studd J. A double-blind placebo-controlled study to evaluate the effect of progesterone cream on postmenopausal women. Menopause Int. 2009 Jun;15(2):63-9

Vasomotor symptoms

Vasomotor symptoms: the improvement (reduction of hot flushes and night sweats) with oral progesterone for 12 weeks in early postmenopausal women (1 reference)

26. Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms–a placebo-controlled randomized trial in healthy postmenopausal women. Menopause. 2012 Aug;19(8):886-93.

Vasomotor symptoms: the improvement with 20 mg/day of transdermal progesterone cream for 1 year in postmenopausal bone loss but beneficial effect on bone density (1 reference)

27. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999 Aug;94(2):225-8  

Substance abuse

Tobacco smoking

Smoking misuse: the improvement (more likely maintenance of abstinence, longer time to relapse, less smoking craving) with oral progesterone for 8 weeks immediately after delivery in postpartum women with a history of pre-pregnancy smoking who achieved abstinence by 32 weeks of gestation (1 reference)

28. Forray A, Gilstad-Hayden K, Suppies C, Bogen D, Sofuoglu M, Yonkers KA. Progesterone for smoking relapse prevention following delivery: A pilot, randomized, double-blind study. Psychoneuroendocrinology. 2017 Dec;86:96-103.

Postpartum smoking abstinence: the improvement (higher prevalence of abstinence at week 4) with oral progesterone for 4 weeks in postpartal women (no adverse effects in breastfeeding at 200mg/day) (1 reference)

29. Allen SS, Allen AM, Lunos S, Tosun N. Progesterone and postpartum smoking relapse: A pilot double-blind placebo-controlled randomized trial. Nicotine Tob Res. 2016 Nov;18(11):2145-2153

Cocaine use

Cocaine use in postpartum: the improvement (reduction) with oral progesterone for 12 weeks in postpartum women with a cocaine use disorder (1 reference)

30. Yonkers KA, Forray A, Nich C, Carroll KM, Hine C, Merry BC, Shaw H, Shaw J, Sofuoglu M. Progesterone reduces cocaine use in postpartum women with a cocaine use disorder: a randomized,double-blind study. Lancet Psychiatry. 2014 Oct 1;1(5):360-367.  

No significant effect in cocaine use

Cocaine use: no beneficial effects with 200-600 mg/day of oral progesterone for 10 weeks in men with cocaine user stabilized under methadone (1 reference)

31. Sofuoglu M, Poling J, Gonzalez G, Gonsai K, Oliveto A, Kosten TR. Progesterone effects on cocaine use in male cocaine users maintained on methadone: a randomized, double-blind, pilot study. Exp Clin Psychopharmacol. 2007 Oct;15(5):453-60.

Traumatic brain injury

Acute severe traumatic brain injury: the modest improvement with (100-200 mg/day of)  intramuscular progesterone for 5 days in patients with acute severe traumatic brain injury (1 reference)

32. Sinha S, Raheja A, Samson N, Goyal K, Bhoi S, Selvi A, Sharma P, Sharma BS. A randomized placebo-controlled trial of progesterone with or without hypothermia in patients with acute severe traumatic brain injury. Neurol India. 2017 Nov-Dec;65(6):1304-11.

Acute severe traumatic brain injury: the improvement (reduction mortality and neurological adverse outcome) with (100-200 mg/day of) intramuscular progesterone (initiated within 8 hours of injury)  for 5 days in patients (1 reference)

33. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61.

No significant effects on traumatic brain injury

Traumatic brain injury: no significant beneficial effects (no lower mortality, nor was any improved functional outcome) with intravenous progesterone (initiated within 4 hours of injury) for 4 days in patients with moderate to severe traumatic brain injury (1 reference)

34. Goldstein FC, Caveney AF, Hertzberg VS, Silbergleit R, Yeatts SD, Palesch YY, Levin HS, Wright DW. Very early administration of progesterone does not improve neuropsychological outcomes in subjects with moderate to severe traumatic brain J Neurotrauma. 2017; 34 (1): Apr 15.  

Traumatic brain injury: no significant beneficial effects (no lower mortality, nor was any improved functional outcome) with intravenous progesterone for 5 days starting  within 8 hours after injury in patients with acute traumatic brain injury (1 reference)

35. Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N; SYNAPSE Trial Investigators. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014 Dec 25;371(26):2467-76.  

Acute traumatic brain injury: no significant beneficial effects n outcome (no lower mortality, nor was any improved functional outcome)  with intravenous progesterone for 4 days starting  within 4 hours after injury in patients with acute traumatic brain injury (1 reference)

36. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; NETT Investigators. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014 Dec 25;371(26):2457-66

Traumatic spinal cord injury

Traumatic spinal cord injury: the improvement (better functional recovery and outcome) with intramuscular progesterone associated with vitamin D for 5 days treatment in patients (1 reference)

37. Aminmansour B, Asnaashari A, Rezvani M, Ghaffarpasand F, Amin Noorian SM, Saboori M, Abdollahzadeh P. Effects of progesterone and vitamin D on outcome of patients with acute traumatic spinal cord injury; a randomized, double-blind, placebo controlled study. J Spinal Cord Med. 2016 May;39(3):272-80.

Epilepsy

Epilepsy: the improvement (reduction of epilepsy) with cyclic progesterone treatment in women with higher levels of perimenstrual seizure exacerbation, but not in women with other types of epilepsy (1 reference)

38. Valencia-Sanchez C, Crepeau AZ, Hoerth MT, Butler KA, Almader-Douglas D, Wingerchuk DM, O’Carroll CB. Is adjunctive progesterone effective in reducing seizure frequency in patients with intractable catamenial epilepsy? A Critically appraised topic. Neurologist. 2018 May;23(3):108-112.

Epilepsy: the improvement (reduction of epilepsy) with progesterone treatment in women with higher levels of perimenstrual seizure exacerbation, but not in women with other types of intractable partial epilepsy (1 reference)

39. Herzog AG, Fowler KM, Smithson SD, Kalayjian LA, Heck CN, Sperling MR, Liporace JD, Harden CL, Dworetzky BA, Pennell PB, Massaro JM; Progesterone Trial Study Group. Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology. 2012 Jun 12;78(24):1959-66

Cardiovascular

Serum lipids

Serum total cholesterol levels: the improvement (reduction of total cholesterol) with oral progesterone for 23 days in postmenopausal women but reduction of HDL cholesterol and adiponectin levelsSerum lipids: the improvement (reduction of total and LDL cholesterol, and apolipoprotein B) with intramuscular estradiol for 23 days in postmenopausal women (1 reference)

40. Roelfsema F, Yang RJ, Veldhuis JD. Differential Effects of Estradiol and Progesterone on Cardiovascular Risk Factors in Postmenopausal Women. J Endocr Soc. 2018 Jun 14;2(7):794-805.  

No adverse effects on serum lipids

Serum lipids and lipoproteins: no adverse effects of oral bioidentical progesterone (versus placebo) for 1 year added to estrogen therapy for 12 days of each treatment cycle during 1 year on the beneficial estrogenic actions on serum lipids and lipoproteins in postmenopausal women (1 reference)

41. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol. 1987 Jan;156(1):66-71.

No significant effects on atherosclerosis and bones

Asymptomatic atherosclerosis and bone density: no beneficial effects with 2x 20 mg/day of transdermal progesterone cream for 3 years in postmenopausal women (1 reference)

42. Benster B, Carey A, Wadsworth F, Griffin M, Nicolaides A, Studd J. Double-blind placebo-controlled study to evaluate the effect of pro-juven progesterone cream on atherosclerosis and bone density. Menopause Int. 2009 Sep;15(3):100-6  

Blood pressure in men and women

Blood pressure: the improvement (reduction of blood pressure) with single intakes of increasingly greater doses of up to 200 mg to 600 mg/day of oral progesterone in men and women with mild to moderate hypertension who were not receiving any other antihypertensive drugs (1 reference)

43. Rylance PB, Brincat M, Lafferty K, De Trafford JC, Brincat S, Parsons V, Studd JW. Natural progesterone and antihypertensive action. Br Med J (Clin ResEd). 1985 Jan 5;290(6461):13-4.

Vascular function: no adverse effects

Vascular function: no adverse effects of 100 mg/day of oral progesterone for 6 weeks in postmenopausal women (1 reference)

44. Honisett SY, Pang B, Stojanovska L, Sudhir K, Komesaroff PA. Progesterone does not influence vascular function in postmenopausal women. J Hypertens. 2003 Jun;21(6):1145-9.

Vascular function: endothelium-dependent vasodilation): no adverse effects of a single application of vaginal bioidentical progesterone added to transdermal estradiol on the vascular function; improvement with estradiol in  postmenopausal women with mild hypercholesterolemia (1 reference)

45. Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998 Sep22;98(12):1158-63.

Vascular and cardiac function

Endothelial function and cardiovascular safety: no significant adverse effect of high doses (300 mg/day) of oral progesterone for 3 months in early postmenopausal women (1 reference)

46. Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLoS One. 2014 Jan 21;9(1):e84698 

Cardiac function

Heart function (drug-induced QTcI lengthening): the improvement (attenuation of drug-induced QTcI lengthening) with oral progesterone for 7 days at the end of the menstrual cycle in premenopausal women (1 reference)

47. Tisdale JE, Jaynes HA, Overholser BR, Sowinski KM, Flockhart DA, Kovacs RJ3.JACC Influence of oral progesterone administration on drug-induced qt interval lengthening: a randomized, double-blind, placebo-controlled crossover study. Clin Electrophysiol. 2016 Dec;2(7):765-774.

Myocardial ischemia: the improvement (enhancement of the beneficial myocardial effects of estrogen) with 90 mg every 2 days of natural (bioidentical) vaginal progesterone for 12 days added to transdermal estradiol therapy, but not with medroxyprogesterone acetate, in postmenopausal women with coronary artery disease or previous myocardial infarction, or both (1 reference)

48. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate,  enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000 Dec;36(7):2154-9  

Bone density

Bone density: no adverse effects by adding oral bioidentical progesterone (versus placebo) for 1 year to estrogen therapy on the beneficial estrogenic actions on bone (increase in bone density) in postmenopausal women (1 reference)

49. Riis BJ, Thomsen K, Strøm V, Christiansen C. The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. Am J Obstet Gynecol. 1987 Jan;156(1):61-5.  

Uterine electrical activity, contractility, and artery pulsatility

Uterine electrical activity

Uterine electrical activity: the improvement (reduction of the propagation velocity of electrical signals within the myometrium and a shift toward lower uterine electrical signal frequencies) with single intake of. vaginal micronized progesterone for maintenance tocolysis in pregnant women who experienced preterm labor (1 reference)

50. Lucovnik M, Trojner Bregar A, Bombac L, Gersak K, Garfield RE. Effects of vaginal progesterone for maintenance tocolysis on uterine electrical activity. J Obstet Gynaecol Res. 2018 Mar;44(3):408-416.

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Pharmacokinetics

Estrogen pharmacokinetics

Estrogen pharmacokinetics: the improvement with transdermal estradiol alone

Serum estradiol and estrone levels: the improvement (dose-dependent increases to 33.5 and 65.0 pg/mL for estradiol and 49.0 and 58.0 pg/mL for estrone) with transdermal estradiol alone for 12 weeks in symptomatic postmenopausal women (1 reference)

1. Brennan JJ, Lu Z, Whitman M, Stafiniak P, van der Hoop RG. Serum concentrations of 17beta-estradiol and estrone after multiple-dose administration of percutaneous estradiol gel in symptomatic menopausal women. Ther Drug Monit. 2001 Apr;23(2):134-8.

Estradiol pharmacokinetics/pharmacodynamics: the improvement (increase in estradiol levels) with oral estradiol with or without oral drospirenone in the treatment of postmenopausal women with moderate to severe vasomotor symptoms, with prolonged increases in serum estradiol levels after alcohol intake (1 reference)

2. Ginsburg ES, Walsh BW, Shea BF, Gao X, Gleason RE, Barbieri RL. The effects of ethanol on the clearance of estradiol in postmenopausal women. Fertil Steril. 1995 Jun;63(6):1227-30.

Estrogen pharmacokinetics: the increase with oral or transdermal estradiol

Serum estrone: much greater (40x more) increase with oral than transdermal estradiol alone for 9 months in postmenopausal women (1 reference)

3. Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women. Menopause. 2001 May-Jun;8(3):200-3.

Estrogen pharmacokinetics: the improvement with oral estradiol alone

Testosterone levels: the provement (no reduction of serum testosterone levels with physical activity as for placebo-treated women) with oral estradiol alone in postmenopausal women (1 reference)

4. Choudhury F, Bernstein L, Hodis HN, Stanczyk FZ, Mack WJ. Physical activity and sex hormone levels in estradiol- and placebo-treated postmenopausal women. Menopause. 2011 Oct;18(10):1079-86.

Serum estradiol and estrone levels (acute and long-term kinetics): the improvememnt (increase in of serum estrogen levels (-33% less estrone for example) with acute oral estradiol alone for 13 treatment cycles in postmenopausal, with negative effect (reduction of serum estradiol levels) of smoking (2 randomized trials) (1 reference)

5. Bjarnason NH, Jørgensen HL, Christiansen C. Acute and long-term estradiolki netics in smoking postmenopausal women. Climacteric. 2012 Oct;15(5):449-54

Serum estrone and 17β-estradiol, DHEA, androstenedione, testosterone levels: the improvement (increase in serum estrogen levels) with oral estradiol alone for 2 years (but no significant effect of statins on serum estrone and 17β-estradiol, DHEA, androstenedione, testosterone levels) (1 reference)

6. Peck A, Chaikittisilpa S, Mirzaei R, Wang J, Mack WJ, Hodis HN, Stanczyk FZ. Effect of statins on estrogen and androgen levels in postmenopausal women treated with estradiol. Climacteric. 2011 Feb;14(1):49-53.

Estrogen pharmacokinetics: the improvement with oral estradiol alone, and oral oral estradiol and an oral progestogen

Estradiol pharmacokinetics/pharmacodynamics: the improvement (increase in estradiol levels) with oral estradiol with or without oral drospirenone for 12 weeks in postmenopausal women with moderate to severe vasomotor symptoms, with negative effect (reduction of serum estradiol levels) of smoking (1 reference)

7. Sutter G, Schmelter T, Gude K, Schaefers M, Gerlinger C, Archer DF. Population pharmacokinetic/pharmacodynamic evaluation of low-dose drospirenone with 17β-estradiol in postmenopausal women with moderate to severe vasomotor symptoms. Menopause. 2014 Mar;21(3):236-42.

Estradiol effects on levels of estrogen receptors

Tissue estrogen receptors: no significant effects with transdermal estradiol alone

Proportion of adipose tissue estrogen receptor ERα/ERβ protein: no significant change in levels with transdermal estradiol for 1 week in early as well as late postmenopausal women (1 reference)

8. Park YM, Pereira RI, Erickson CB, Swibas TA, Cox-York KA, Van Pelt RE. Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women. PLoS One. 2017 May 4;12(5):e0176446.

Estradiol effects on levels or activity of other hormones

Serum LH and FSH levels: the reduction with transdermal estradiol

Plasma LH and FSH: the reduction with transdermal estradiol for 4 weeks in ovariectomized women (1 reference)

9. Nappi C, Petraglia F, de Chiara BM, Genazzani AD, Montemagno R, Genazzani AR, Montemagno U. The effect of various drugs with neuroendocrine activity and transdermal estradiol on plasma gonadotropin concentrations after ovariectomy in reproductive-aged women. Acta Obstet Gynecol Scand. 1991;70(6):435-9.

Serum ACTH levels: the reduction with oral estradiol

Serum ACTH: the reduction with a single intake of oral estradiol treatment in older women aged 58 years on average (1 reference)

10. Sharma AN, Aoun P, Wigham JR, Weist SM, Veldhuis JD. Estradiol, but not testosterone, heightens cortisol-mediated negative feedback on pulsatile ACTH secretion and ACTH approximate entropy in unstressed older men and women. Am J Physiol Regul Integr Comp Physiol. 2014 May;306(9):R627-35.

Serum cortisol levels after CRH: the reduction with transdermal estradiol

Endocrine responses to dexamethasone/CRH hormone: the blunting of the total plasma cortisol response in the Dex-CRH test) with transdermal estradiol patches for 2 weeks in older postmenopausal women (1 reference)

11. Kudielka BM, Schmidt-Reinwald AK, Hellhammer DH, Kirschbaum C. Psychological and endocrine responses to psychosocial stress and dexamethasone/corticotropin-releasing hormone in healthy postmenopausal women and young controls: the impact of age and a two-week estradiol treatment. Neuroendocrinology. 1999 Dec;70(6):422-30. Neuroendocrinology. 1999 Dec;70(6):422-30.

Ghrelin potency: the increase with intravenous estradiol

Ghrelin: the increase in ghrelin potency (reduction of the effective dose ED50 of ghrelin) when GHRH is present with a single intravenous estradiol alone treatment in postmenopausal women (1 reference)

12. Norman C, Rollene N, Weist SM, Wigham JR, Erickson D, Miles JM, Bowers CY, Veldhuis JD. Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women. J Clin Endocrinol Metab. 2014 Jan;99(1):E73-80

Serum GH and GH secretion: the increase with transdermal estradiol

Growth hormone; the improvement (increase of growth hormone secretion) with a single transdermal estradiol treatment in postmenopausal women (1 reference)

13. Norman C, Rollene NL, Erickson D, Miles JM, Bowers CY, Veldhuis JD. Estradiol regulates GH-releasing peptide’s interactions with GH-releasing hormone and somatostatin in postmenopausal women. Eur J Endocrinol. 2013 Nov 29;170(1):121-9.

Growth hormone secretion: the increase with estradiol treatment (graded transdermal addback of estradiol) in premenopausal women (1 reference)

14. Erickson D, Keenan DM, Farhy L, Mielke K, Bowers CY, Veldhuis JD. Determinants of dual secretagogue drive of burst-like growth hormone secretion in premenopausal women studied under a selective estradiol clamp. J Clin Endocrinol Metab. 2005 Mar;90(3):1741-51

Serum GH and GH secretion: the increase with oral estradiol

Growth hormone secretion kinetics: the effect (amplifying GH secretory-burst mass, initiating rapid onset of GHRH-stimulated GH release, and potentiating IGF-I-dependent suppression of unstimulated GH concentrations) withe oral estradiol alone for 10 days in postmenopausal women (1 reference)

15. Veldhuis JD, Anderson SM, Kok P, Iranmanesh A, Frystyk J, Ørskov H, Keenan DM. Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women. J Clin Endocrinol Metab. 2004 Mar;89(3):1312-8.

Growth hormone secretion kinetics: the effect (doubles GH secretion, amplifying GH pulsatile secretion, secretory-burst mass) withe oral estradiol in postmenopausal women (1 reference)

16. Veldhuis JD, Anderson SM, Patri JT, Bowers CY. Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. J Clin Endocrinol Metab. 2004 Jan;89(1):121-7.

Growth hormone and metabolism: the greater improvement (higher increase of the serum IGF-1/IGFBP-3 ratio and lower serum insulin but no significant change of serum levels of GH and IGF-1) with evening administrations of oral estradiol and subcutaneous growth hormone in girls wth hormone and metabolism: the greater improvement (increase) with evening administrations of oral estradiol and suncutaneous growth hormone in girls with Turner syndrome receiving growth hormone versus morning treatments (1 reference)

17. Naeraa RW, Gravholt CH, Kastrup KW, Svenstrup B, Christiansen JS. Morning versus evening administration of estradiol to girls with turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study. Acta Paediatr. 2001 May;90(5):526-31.

Growth hormone secretion (GH secretory bursts mass, basal and under stimulation by GHRP-2): the improvement (further strong increase of the enhancement of GH secretion stimulated by GHRP-2, increase of vasodilation) with shor –term oral estradiol alone for 7-12 days in postmenopausal women (single-blind study (patient-blinded)) (1 reference)

18. Anderson SM, Shah N, Evans WS, Patrie JT, Bowers CY, Veldhuis JD. Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women. J Clin Endocrinol Metab. 2001 Feb;86(2):551-60.

GH secretion stimulated by continuous IV GHRP-2: the improvement (further increase) with oral estradiol alone for 7-12 days in postmenopausal women (1 reference)

19. J Shah N, Evans WS, Bowers CY, Veldhuis JD. Oral estradiol administration modulates continuous intravenous growth hormone (GH)-releasing peptide-2-driven GH secretion in postmenopausal women. J Clin Endocrinol Metab. 2000 Aug;85(8):2649-59.

Serum IGF-1/IGF-BP-3: the increase with evening administration of oral estradiol in patients treated with growth hormone vesus morning administration

Growth hormone and metabolism: the greater improvement (higher increase of the serum IGF-1/IGFBP-3 ratio and lower serum insulin but no significant change of serum levels of GH and IGF-1) with evening administrations of oral estradiol and subcutaneous growth hormone in girls wth hormone and metabolism: the greater improvement (increase) with evening administrations of oral estradiol and suncutaneous growth hormone in girls with Turner syndrome receiving growth hormone versus morning treatments (1 reference)

20. Naeraa RW, Gravholt CH, Kastrup KW, Svenstrup B, Christiansen JS. Morning versus evening administration of estradiol to girls with turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study. Acta Paediatr. 2001 May;90(5):526-31.

Serum IGF-1 and IGF_1/IGFBP-3: the reduction with oral estradiol

Serum IGF-1 and serum IGF-1/IGFBP1 ratio: the reduction with oral estradiol in postmenopausal women (1 reference)

21. Veldhuis JD, Frystyk J, Iranmanesh A, Ørskov H. Testosterone and estradiol regulate free insulin-like growth factor I (IGF-I), IGF binding protein 1 (IGFBP-1), and dimeric IGF-I/IGFBP-1 concentrations. J Clin Endocrinol Metab. 2005 May;90(5):2941-7.

Serum IGF-1 and GH secretion: the reduction of serum IGF-1 and increase in GH secretion  with oral estradiol

Serum IGF-1 and growth hormone secretion and under combined stimulation of 2 growth hormone secretagogues GHRH and GHRP-2: the -44% reduction with oral estradiol alone in postmenopausal women but oral estradiol potentiates GH secretion and has no significant effect on the GH secretion induced by growth hormone secretagogues (1 reference)

22. J Veldhuis JD, Evans WS, Bowers CY. Impact of estradiol supplementation on dual peptidyl drive of GH secretion in postmenopausal women. J Clin Endocrinol Metab. 2002 Feb;87(2):859-66.

Serum IGF-1: the reduction with oral estradiol but attenuation of IGF-1’s inhibition of pulsatile GH secretion

IGF-I’s inhibition of pulsatile GH secretion: the attenuation by oral estradiol treatment in postmenopausal women, and lowering of endogenous secretion (1 reference)

23. Veldhuis JD, Keenan DM, Bailey JN, Adeniji A, Miles JM, Paulo R, Cosma M, Soares-Welch C. Estradiol supplementation in postmenopausal women attenuates suppression of pulsatile growth hormone secretion by recombinant human insulin-like growth factor type I. J Clin Endocrinol Metab. 2008 Nov;93(11):4471-8.

Serum IGF-1 and growth hormone secretion: the reduction of serum IGF-1 and attenuation of somastatin’s inhibition of growth hormone secretion with oral estradiol alone in postmenopausal women but oral estradiol potentiates GH secretion (1 reference)

24. Veldhuis JD, Evans WS, Bowers CY. Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu. J Clin Endocrinol Metab. 2003 Nov;88(11):5484-9.

IGF-1’s inhibition of pulsatile GH secretion: the attenuation with oral estradiol alone

Somatostatin’s dose-dependent inhibition of fasting growth hormone secretion: the opposing effects (significant elevation of the half-maximally inhibitory dose of infused somatostatin by 13.5-fold but no effect on the maximally effective dose of somatostatin to reduce serum growth hormone by 89%) with short-term oral micronized estradiol alone for 7-12 days in postmenopausal women, suggesting that estradiol can facilitate pulsatile GH secretion, possibly in part, by opposing the repressive actions of somatostatin) (1 reference)

25. Bray MJ, Vick TM, Shah N, Anderson SM, Rice LW, Iranmanesh A, Evans WS, Veldhuis JD. Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin’s dose-dependent inhibition of fasting growth hormone secretion. J Clin Endocrinol Metab. 2001 Jul;86(7):3143-9.

Serum GH and IGF-1:  no effect of transdermal estradiol alone

Growth hormone/insulin-like growth factor-1 axis: little difference (lower serum IGFBP-3, but no effect on serum GH and IGF-1) with 6 days of transdermal estradiol effects in amenorrheic premenopausal athletes (1 reference)

26. Waters DL, Dorin RI, Qualls CR, Ruby BC, Baumgartner RN, Robergs RA. Estradiol effects on the growth hormone/insulin-like growth factor-1 axis in amenorrheic athletes. Can J Appl Physiol. 2003 Feb;28(1):64-78

Serum leptin: no significant effect of transdermal estradiol alone

Serum leptin levels: no significant effect of low-dose (50 mcg/day) transdermal estradiol patch in postmenopausal women but +20% increased intracellular water and -10% decreased extracellular water (1 reference)

27. Cagnacci A, Malmusi S, Arangino S, Zanni A, Rovati L, Cagnacci P, Volpe A. Influence of transdermal estradiol in the regulation of leptin levels of postmenopausal women: a double-blind, placebo-controlled study. Menopause. 2002 Jan-Feb;9(1):65-71.

Neurosteroids (sensitivity to): the increase with oral estradiol alone, and oral estradiol and vaginal progesterone

Sensitivity (saccadic eye movement velocity and acceleration, and self-rated sedation) to a neurosteroid (intravenous pregnanolone): the increase with oral estradiol alone or with (sequential) vaginal progesterone in postmenopausal women (1 reference)

28. Wihlbäck AC, Nyberg S, Bäckström T, Bixo M, Sundström-Poromaa I. Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women. Psychoneuroendocrinology. 2005 Jan;30(1):38-50

Estradiol effects on drugs

Antidepressant selegiline: the reduction of the serum level of selegiline with oral estradiol and a progestogen

Selegiline pharmacokinetics: only smalle interference (reductions) oral combined estradiol and levonorgestrel in healthy premenopausal women, unlike oral contraceptives (with ethinylestradiol) (1 reference)

29. Palovaara S, Anttila M, Nyman L, Laine K. Effect of concomitant hormone replacement therapy containing estradiol and levonorgestrel on the pharmacokinetics of selegiline. Eur J Clin Pharmacol. 2002 Jul;58(4):259-63

D-amphetamine: the increase in effects with transdermal oestradiol

Response to d-amphetamine: the acute effects (increased the magnitude of the effects of d-amphetamine on subjective ratings of ‘pleasant stimulation’ and decreased ratings of ‘want more’) with transdermal estradiol pretreatment in premenopausal women (1 reference)

30. Justice AJ, de Wit H. Acute effects of estradiol pretreatment on the response to d-amphetamine in women. Neuroendocrinology. 2000 Jan;71(1):51-9.

Endometrial safety

Endometrial safety of transdermal estradiol alone

Endometrial hyperplasia, endometrial proliferation, and vaginal bleeding: no signifcant effect (little or no endometrial stimulation) with 2 years of ultralow-dose (14 µg/day) unopposed transdermal estradiol alone in postmenopausal women (1 reference)

31. Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J, Grady D. Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol. 2005 Apr;105(4):779-87.

Endometrial safety of ultra-low-dose (10 µg) estradiol vaginal tablets in postmenopausal women with vaginal atrophy. (1 reference)

32. Simon J, Nachtigall L, Ulrich LG, Eugster-Hausmann M, Gut R. Endometrial safety of ultra-low-dose estradiol vaginal tablets. Obstet Gynecol. 2010 Oct;116(4):876-83.

Endometrial safety of transdermal estradiol with an oral progestogen

Endometrial proliferation: no significant effect of 1 year of continuous low-dose (25 mcg/day) transdermal combined estradiol/norethisterone acetate patch in postmenopausal women (1 reference)

33. Brynhildsen J, Hammar M. Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women. Menopause. 2002 Mar-Apr;9(2):137-44  

Endometrial safety of oral estradiol with an oral progestogen

Endometrial safety of an oral contraceptive containing estradiol valerate and dienogest in premenopausal women (1 reference)

34. Bitzer J, Parke S, Roemer T, Serrani M. Endometrial safety of an oral contraceptive containing estradiol valerate and dienogest. Int J Womens Health. 2011 Apr 18;3:127-32.

Endometrial safety: very good with sequential combinations of 1 mg 17 beta-estradiol with 5 or 10 mg dydrogesterone (less bleeding) and 2 mg 17 beta-estradiol with 10 or 20 mg dydrogesterone in postmenopausal women. (1 reference)

35. Ferenczy A, Gelfand MM, van de Weijer PH, Rioux JE. Endometrial safety bleeding patterns during a 2-year study of 1 or 2 mg 17 beta-estradiol combined with sequential 5-20 mg dydrogesterone. Climacteric. 2002 Mar;5(1):26-35

Good tolerability of ultra-low-dose of oral combined 17beta-estradiol and norethisterone acetate: laboratory and safety results in postmenopausal women (1 reference)

36. Samsioe G, Hruska J; CHOICE Study Investigators. Optimal tolerability of ultra-low-dose continuous combined 17beta-estradiol and norethisterone acetate: laboratory and safety results. Climacteric. 2010 Feb;13(1):34-44.

Endometrial safety of transdermal estradiol associated to raloxifene

Endometrium thickness and vaginal bleeding: no proliferation of endometrium and no vaginal bleeding with low-dose (0.5 mg) transdermal estradiol associated to raloxifene in postmenopausal women (1 reference)

37. Valiati B, Capp E, Edelweiss MI, de Freitas FM, Wender MC. Effect of raloxifene and low-dose percutaneous 17beta-estradiol on menopause symptoms and endometrium–a randomized controlled trial. Maturitas. 2009 Jan 20;62(1):81-4.

Safety of estradiol in breast feeding women

Breastfeeding child: no significant adverse effect with transdermal estradiol alone in breastfeeding mother

Serum estradiol and estrone, infant growth; no significant effect on breast-feeded child of transdermal estradiol treatment alone in breastfeeding women-with postpartum depression (1 reference)

38. Arch Womens Ment Health. 2016 Apr;19(2):409-13. doi: 10.1007/s00737-015-0532-1. Epub 2015 Pinheiro E, Bogen DL, Hoxha D, Wisner KL. Transdermal estradiol treatment during breastfeeding: maternal and infant serum concentrations. Arch Womens Ment Health. 2016 Apr;19(2):409-13.

Breast feeding: no transfer of transdermal estradiol into breast milk (1 reference)

39. Perheentupa A, Ruokonen A, Tapanainen JS. Transdermal estradiol treatment suppresses serum gonadotropins during lactation without transfer into breast milk. Fertil Steril. 2004 Oct;82(4):903-7.

Sensitivity to steroid-negative feedback: the enhancement of the suppression of gonadotropins, inhibin B, and ovarian activity with low-dose transdermal (50 mcg) estradiol patch in premenopausal women during breastfeeding despite no increase of serum estradiol levels (1 reference)

40. Perheentupa A, Critchley HO, Illingworth PJ, McNeilly AS. Enhanced sensitivity to steroid-negative feedback during breast-feeding: low-dose estradiol (transdermal estradiol supplementation) suppresses gonadotropins and ovarian activity assessed by inhibin B. J Clin Endocrinol Metab. 2000 Nov;85(11):4280-6.

Work productivity

Work productivity: the improvement with oral estradiol and an oral progestogen

Work productivity and activities of daily living: the improvement with oral estradiol valerate and oral ¨diongenest (Qlaira) for 7 menstrual cycles (196 days) in premenopausal women with heavy menstrual bleeding. (2 references)

41. Wasiak R, Filonenko A, Vanness DJ, Law A, Jeddi M, Wittrup-Jensen KU, Stull DE, Siak S, Jensen JT. Impact of estradiol valerate/dienogest on work productivity and activities of daily living in women with heavy menstrual bleeding. J Womens Health (Larchmt). 2013 Apr;22(4):378-84.

42. Wasiak R, Filonenko A, Vanness DJ, Wittrup-Jensen KU, Stull DE, Siak S,Fraser I. Impact of estradiol-valerate/dienogest on work productivity and activities of daily living in European and Australian women with heavy menstrual bleeding. Int J Womens Health. 2012;4:271-8.

Mental stress

Mental stress: the improvement with transdermal estradiol

Mental stress: the improvement (blunting of the epinenphrine and diastolic BP increases, and electrocardiographic findings) with transdermal estradiol alone for 3 weeks in postmenopausal women (1 reference)

43. Del Rio G, Velardo A, Menozzi R, Zizzo G, Tavernari V, Venneri MG, Marrama P, Petraglia F. Acute estradiol and progesterone administration reduced cardiovascular and catecholamine responses to mental stress in menopausal women. Neuroendocrinology. 1998 Apr;67(4):269-74.

Mental stress: the improvement with oral estradiol and an oral progestogen

Mental stress: the improvement (blunting of the epinenphrine and diastolic BP increases, and electrocardiographic findings) with transdermal estradiol alone for 3 weeks in postmenopausal women (1 reference)

44. Ceresini G, Freddi M, Morganti S, Rebecchi I, Modena AB, Rinaldi M, Manca C, Amaducci A, Del Rio G, Valenti G. The effects of transdermal estradiol on the response to mental stress in postmenopausal women: a randomized trial. Am J Med. 2000 Oct 15;109(6):463-8.

Depression (women)

Depressive symptoms: the improvement with transdermal estradiol

Depression and depressive symptoms: the improvement with transdermal estradiol patches alone for 3 weeks in perimenopausal women (1 reference)

45. Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015 Jul;72(7):714-26.

Mood: the improvement with transdermal estradiol patches alone for 8 weeks in perimenopausal but not postmenopausal women with depressive disorders, hot flashes, and sleep disturbance (1 reference)

46. Joffe H, Petrillo LF, Koukopoulos A, Viguera AC, Hirschberg A, Nonacs R, Somley B, Pasciullo E, White DP, Hall JE, Cohen LS. Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. J Clin Endocrinol Metab. 2011 Jul;96(7):E1044-54.

Depressive symptoms and cognition: reduction of depressive symptoms but no improvement of cognition with transdermal estradiol patches for 12 weeks in older cognitively normal postmenopausal hysterectomized women over 60 years of age, without clinical depression (1 reference)

47. Schiff R, Bulpitt CJ, Wesnes KA, Rajkumar C. Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo-controlled pilot cross-over study. Psychoneuroendocrinology 2005 May;30(4):309-15.

Depression: the improvement (reduction) with (100 µg/day of) transdermal estradiol patches for 12 weeks in perimenopausal women (1 reference)

48. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001 Jun;58(6):529-34.

Depressive symptoms: the improvement with transdermal estradiol and oral progesterone

Depressive symptoms: the improvement (better mood in perimenopausal and early postmenopausal women with transdermal estradiol and intermittent progesterone treatments for 1 year in peri– and early postmenopausal women (with 12 days every 3 months of oral progesterone) for 12 months but not in late menopausal women (1 reference)

49. Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018 Feb 1;75(2):149-157.

Depressive symptoms: the improvement with oral estradiol and an oral progestogen

Depression: the improvement (reduction) with oral continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) for 24 weeks in postmenopausal women (1 reference)

50. Rudolph I, Palombo-Kinne E, Kirsch B, Mellinger U, Breitbarth H, Gräser T. Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression. Climacteric. 2004 Sep;7(3):301-11.

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Pharmacokinetics

Pharmacokinetics of rectal estriol

Serum estriol and progesterone: the changes in serum hormone levels (quick increase of serum estriol levels, 20% reduction of progesterone levels, and no change of estradiol levels) with high-dosed (100 mg) rectal estriol alone in pregnant women at term (1 reference)

1. Moran DJ, McGarrigle HH, Lachelin GC. Maternal plasma progesterone levels fall after rectal administration of estriol. J Clin Endocrinol Metab. 1994 Jan;78(1):70-2. GC.

Multiple sclerosis

Multiple sclerosis: the improvement with oral estriol

Multiple sclerosis: the improvement (areas of gray matter sparing in frontal and parietal brain cortices) with oral estriol for 2 years in women with multiple sclerosis (1 reference)

2. MacKenzie-Graham A, Brook J, Kurth F, Itoh Y, Meyer C, Montag MJ, Wang HJ, Elashoff R, Voskuhl RR. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav. 2018 Aug 24:e01086.

Multiple sclerosis: the improvement (-37% less annual relapses and less vaginal infections but more irregular menses) with oral estriol alone for 2 years in patients (1 reference)

3. Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35-46

Urinary tract

Urinary infections: the improvement with vaginal estriol

Recurrent urinary tract infections: the improvement (-92% reduction of urinary tract infections compared to placebo, recolonization with lactobacilli, initially absent and regression of enterobacteriaceae positive cultures) with vaginal estriol cream for 8 months in women (1 reference)

4. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993 Sep 9;329(11):753-6

Urinary incontinence and related symptoms (pollakiuria, nycturia): the improvement with vaginal estriol

Urogenital aging: the improvement (reduction in urinary incontinence, increases in mean maximum urethral pressure, in mean urethral closure pressure as well as in the abdominal pressure transmission ratio to the proximal urethra) with 1 mg vaginal estriol ovules alone for 6 months in postmenopausal women (1 reference)

5. Dessole S, Rubattu G, Ambrosini G, Gallo O, Capobianco G, Cherchi PL, Marci R, Cosmi E. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause, 2004 Jan-Feb;11(1):49-56

Stress incontinence: the improvement (reductions in imperative micturition and number of micturitions per day, increase in bladder capacity and maximum urethral closure pressure) with intravesical estriol for 3 weeks in women with sensory urge incontinence (1 reference)

6. Kurz C, Nagele F, Sevelda P, Enzelsberger H. [Intravesical administration of estriol in sensory urge incontinence–a prospective study]. Geburtshilfe Frauenheilkd. 1993 Aug;53(8):535-8.

Stress incontinence: the improvement (reductions in strong desire to void, pollakiuria, and nycturia) with intravaginal estriol for 3 weeks in women with urge incontinence (1 reference)

7. Enzelsberger H, Kurz C, Schatten C, Huber J. The effectiveness of intravaginal estriol tablet administration in women with urge incontinence. Geburtshilfe Frauenheilkd. 1991 Oct;51(10):834-8.

Vaginal and urethral epitheliums

Vaginal and urethral epitheliums: the improvement with oral estriol

Genito-urinary symptoms: the improvement (remarkable beneficial effect on vaginal epitheliums, less pronounced beneficial effect on urethral epithelium) with oral estriol tablets for 4 weeks in postmenopausal women with genito-urinary symptoms (1 reference)

8. Van der Linden MC, Gerretsen G, Brandhorst MS, Ooms EC, Kremer CM, Doesburg WH. The effect of estriol on the cytology of urethra and vagina in postmenopausal women with genito-urinary symptoms. Eur J Obstet Gynecol Reprod Biol. 1993 Sep;51(1):29-33.

Vulvovaginal atrophy

Vulvovaginal atrophy and related symptoms: the improvement with vaginal estriol

Vulvovaginal atrophy symptoms and vaginal dryness: the improvement (improved vaginal health index and vaginal dryness) with vaginal estriol alone and even more with vaginal estriol + laser therapy (improved vaginal health index, dyspareunia, burning and dryness) for 20 weeks in postmenopausal women (1 reference)

9. Cruz VL, Steiner ML, Pompei LM, Strufaldi R, Fonseca FLA, Santiago LHS, Wajsfeld T, Fernandes CE. Randomized, double-blind, placebo-controlled clinical trial for evaluating the efficacy of fractional CO2 laser compared with topical estriol in the treatment of vaginal atrophy in postmenopausal women. Menopause. 2018 Jan;25(1):21-8

Vaginal atrophy: the improvement (increased vaginal maturation value) with ultralow dosed and normal dosed vaginal estriol gel for 3 weeks in postmenopausal women, with very low systemic estriol absorption in the ultralow dosed (20 and 50 μg/g) vaginal gels compared to the normal-dosed (500 µg/0.5 g) estriol gel (1 reference)

10. Delgado JL, Estevez J, Radicioni M, Loprete L, Moscoso Del Prado J, Nieto Magro C. Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women. Climacteric. 2016 Apr;19(2):172-80

Vaginal atrophy: the improvement (higher maturation value and lower vaginal pH, less vaginal dryness, improvement of most outstanding vaginal signs of vaginal atrophy) with ultralow dose vaginal estriol gel for 12 weeks in postmenopausal women with vaginal atrophy (1 reference)

11. Cano A, Estévez J, Usandizaga R, Gallo JL, Guinot M, Delgado JL, Castellanos E, Moral E, Nieto C, del Prado JM, Ferrer J. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause. 2012 Oct;19(10):1130-9.

Vaginal atrophy: the improvement (higher maturation value and lower vaginal pH, reduction of most bothersome symptom intensity) with ultralow dose vaginal estriol pessaries for 12 weeks in postmenopausal women with vaginal atrophy (1 reference)

12. Griesser H, Skonietzki S, Fischer T, Fielder K, Suesskind M. Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2mg and 0.03mg estriol. Maturitas. 2012 Apr;71(4):360-8.

Vaginal atrophy: the improvement with vaginal estriol associated to lactobacilli acidophili

Vaginal atrophy: the improvement (increased vaginal maturation value as well as improvement of clinical symptoms and normalization of the vaginal ecosystem) with ultralow dose vaginal estriol tablets associated to lactobacilli acidophili for 13-14 weeks (96 days) in postmenopausal women with vaginal atrophy symptoms and Vaginal Maturation Index of ≤ 40% (1 reference)

13. Jaisamrarn U, Triratanachat S, Chaikittisilpa S, Grob P, Prasauskas V, Taechakraichana N. Ultra-low-dose estriol and lactobacilli in the local treatment of postmenopausal vaginal atrophy. Climacteric. 2013 Jun;16(3):347-55.

Vaginal infections: the improvement with vaginal estriol associated to lactobacilli acidophili

Bacterial vaginosis: the improvement (cure within 2-4 weeks) with vaginal ultralow dosed estriol tablets associated to lactobacilli acidophili for 6 days in female patients (1 reference)

14. Parent D, Bossens M, Bayot D, Kirkpatrick C, Graf F, Wilkinson FE, Kaiser RR. Therapy of bacterial vaginosis using exogenously-applied Lactobacilli acidophili and a low dose of estriol: a placebo-controlled multicentric clinical trial. Arzneimittelforschung. 1996 Jan;46(1):68-73

Breast fibroadenomas

Fibroadenomas: no beneficial effects of oral estriol 

Fibroadenomas: no beneficial effects (no significant difference in indices of proliferative activity of mammary fibroadenoma = expression of Ki-67 and c-myc antigens, however a trend to worsening with increased expression) by adding oral estriol to a contraceptive pill with levonorgestrel and ethinylestradiol for 4 consecutive menstrual cycles in premenopausal women with fibroadenoma (1 reference)

15. Estevão RA, Baracat EC, Logullo AF, Oshima CT, Nazário AC. Efficacy of estriol in inhibiting epithelial proliferation in mammary fibroadenoma:randomized clinical trial. Sao Paulo Med J. 2007 Nov 1;125(6):343-50.

Fibroadenomas: no beneficial effects (maintenance of fibroadenoma at ultrasound, blocking the protection and reduction of fibroadenomas by birth-control pill) by adding oral estriol to a contraceptive pill with levonorgestrel and ethinylestradiol for 4 consecutive menstrual cycles in premenopausal women with fibroadenoma (estriol may block the protective effect of oral contraceptives on fibroadenomas) (1 reference)

16. Estevão RA, Nazário AC, Baracat EC. Effect of oral contraceptive with and without associated estriol on ultrasound measurements of breast fibroadenoma: randomized clinical trial. Sao Paulo Med J. 2007 Sep 6;125(5):275-80.

Serum lipids

Serum lipids: the improvement with oral estrone

Serum lipids: the improvement (slight but significant reduction of total cholesterol, slight increase in HDL cholesterol, but slight increase in triglycerides and VLDL) with oral estrone sulfate alone, greater improvement (greater reduction in total cholesterol and lesser increase in triglycerides) with oral estrone combined to medroxyprogesterone acetate for 2 years in postmenopausal women (1 reference)

1. Luciano AA, Miller BE, Schoenenfeld MJ, Schaser RJ; Ogen/Provera Study Group. Effects of estrone sulfate alone or with medroxyprogesterone acetate on serum lipoprotein levels in postmenopausal women. Obstet Gynecol. 2001 Jan;97(1):101-8.

Serum lipids: the improvement (increase in HDL and HDL/LDL, and reduction of LDL)) with 0.625 and 1.25 mg/day of oral estrone sulfate alone for 1 year in postmenopausal women (1 reference)

2. Notelovitz M, Katz-Karp S, Jennings D, Lancaster J, Green EM, Stoll RW. Effect of cyclic estrone sulfate treatment on lipid profiles of postmenopausal women with elevated cholesterol levels. Obstet Gynecol. 1990 Jul;76(1):65-70.

Bone density

Bone density: the improvement with oral estrone

Bone density: the improvement (increase in spinal bone density) with 0.625 and 1.25 mg/day of oral estrone sulfate for 2 years in postmenopausal women (1 reference)

3. Harris ST, Genant HK, Baylink DJ, Gallagher JC, Karp SK, McConnell MA, Green EM, Stoll RW. The effects of estrone (Ogen) on spinal bone density of postmenopausal women. Arch Intern Med. 1991 Oct;151(10):1980-4

Bone density: the improvement (increase in spinal bone density) with 0.625 and 1.25 estrone sulfate for 1 year in postmenopausal women (1 reference)

4. Genant HK, Baylink DJ, Gallagher JC, Harris ST, Steiger P, Herber M. Effect of estrone sulfate on postmenopausal bone loss. Obstet Gynecol. 1990 Oct;76(4):579-84

Quality of life and energy: the association with higher estrogen levels (3 references)

1. Studer DW. Clinical symptoms of estrogen deficiency in Estrogen Deficiency: Causes and consequence, 1996, Ed. RW Staw, The Parthenon Publishing Group, New-York, USA
2. Freedman MA. Quality of life and menopause: the role of estrogen. J Womens Health (Larchmt). 2002 Oct;11(8):703-18
3. Carette S, Dessureault M, Belanger A. Fibromyalgia and sex hormones. J Rheumatol. 1992 May;19(5):831

Lower quality of life and fatigue: the improvement with estrogen treatment alone (11 references)

1. Diem SJ, Guthrie KA, Mitchell CM, Reed SD, Larson JC, Ensrud KE, LaCroix AZ. Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized clinical trial. 2018 Oct;25(10):1086-1093.
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Lower quality of life and fatigue: the improvement with estrogen and progesterone/progestogen treatments (25 references)

1. Mirkin S, Graham S, Revicki DA, Bender RH, Bernick B, Constantine GD. Relationship between vasomotor symptom improvements and quality of life and sleep outcomes in menopausal women treated with oral, combined 17β-estradiol/progesterone. Menopause. 2019 Jan 9;26(6):637-642.
2. Simon JA, Kaunitz AM, Kroll R, Graham S, Bernick B, Mirkin S. Oral 17β-estradiol/progesterone (tx-001hr) and quality of life in postmenopausal women with vasomotor symptoms. Menopause. 2019 May;26(5):506-512.
3. Cortés-Bonilla M, Alonso-Campero R, Bernardo-Escudero R, Francisco-Doce MT, Chavarín-González J, Pérez-Cuevas R, Chedraui P. Improvement of quality of life and menopausal symptoms in climacteric women treated with low-dose monthly parenteral formulations of non-polymeric microspheres of 17β-estradiol/progesterone. Gynecol Endocrinol. 2016 Oct;32(10):831-834.
4. Caruso S, Iraci M, Cianci S, Fava V, Casella E, Cianci A. Comparative, open-label prospective study on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain on 2 mg dienogest/30 µg ethinyl estradiol continuous or 21/7 regimen oral contraceptive. J Endocrinol Invest. 2016 Aug;39(8):923-31.
5. Paoletti AM, Cagnacci A, Di Carlo C, Orrù MM, Neri M, D’Alterio MN, Melis GB. Clinical effect of hormonal replacement therapy with estradiol associated with noretisterone or drospirenone. A prospective randomized placebo controlled study. Gynecol Endocrinol. 2015 May;31(5):384-7.

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Lower quality of life and fatigue: the improvement with estrogen and testosterone treatments (3 references)

1. Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas. 1984 Dec;6(4):351-8
2. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med. 1999 Dec;44(12):1012-20
3. Adamson DL, Webb CM, Collins P. Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms. Menopause. 2001 Jul-Aug;8(4):233-8

Vasomotor symptoms (hot flushes): the Improvement with estradiol treatment alone (28 references)

1. Joffe H, Guthrie KA, LaCroix AZ, Reed SD, Ensrud KE, Manson JE, Newton KM, Freeman EW, Anderson GL, Larson JC, Hunt J, Shifren J, Rexrode KM, Caan B, Sternfeld B, Carpenter JS, Cohen L. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med. 2014 Jul;174(7):1058-66.
2. Mizunuma H. Clinical usefulness of a low-dose maintenance therapy with transdermal estradiol gel in Japanese women with estrogen deficiency symptoms. 2011 Oct;14(5):581-9.
3. Hedrick RE, Ackerman RT, Koltun WD, Halvorsen MB. Estradiol gel 0.1% relieves vasomotor symptoms independent of age, ovarian status, or uterine status. 2010 Nov-Dec;17(6):1167-73.
4. Buster JE. Low-dose estradiol spray: a novel treatment for vasomotor instability in postmenopausal women. Womens Health (Lond). 2009 Jan;5(1):23-8.
5. Haines C, Yu SL, Hiemeyer F, Schaefers M. Micro-dose transdermal estradiol for relief of hot flushes in postmenopausal Asian women: a randomized controlled trial. Climacteric. 2009 Oct;12(5):419-26.

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Vasomotor symptoms (hot flushes): the Improvement with progesterone treatment (1 reference)

1. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999 Aug;94(2):225-8

Vasomotor symptoms (hot flushes): the Improvement with estrogen and progesterone/progestogen treatments (9 references)

1. Lobo RA, Archer DF, Kagan R, Kaunitz AM, Constantine GD, Pickar JH, Graham S, Bernick B, Mirkin S. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2018 Jul;132(1):161-170
2. Zhou YZ, Sun LZ, Lin JF, Yang X, Zhang LJ, Qiao J, Wang ZH, Xu YX, Xiong ZA, Lin SQ. Evaluation of the efficacy and safety of estradiol and drospirenone tablets in the treatment of menopausal symptoms among postmenopausal Chinese healthy women:a randomized, multi-center, double-blind, placebo-controlled clinical study]. Zhonghua Fu Chan Ke Za Zhi. 2011 May;46(5):345-9.
3. Lin SQ, Sun LZ, Lin JF, Yang X, Zhang LJ, Qiao J, Wang ZH, Xu YX, Xiong ZA, Zhou YZ, Wang ML, Zhu J, Chen SR, Su H, Yang CS, Wang SH, Zhang YZ, Dong XJ. Estradiol 1 mg and drospirenone 2 mg as hormone replacement therapy in postmenopausal Chinese women. 2011 Aug;14(4):472-81.
4. Hachul H, Bittencourt LR, Andersen ML, Haidar MA, Baracat EC, Tufik S. Effects of hormone therapy with estrogen and/or progesterone on sleep pattern in postmenopausal women. Int J Gynaecol Obstet. 2008 Dec;103(3):207-12
5. Soares CN, Arsenio H, Joffe H, Bankier B, Cassano P, Petrillo LF, Cohen LS. Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life. 2006 Sep-Oct;13(5):780-6

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Mood, happiness: the association with high estradiol levels (7 references)

1. Marsh WK, Bromberger JT, Crawford SL, Leung K, Kravitz HM, Randolph JF, Joffe H, Soares CN. Life-long estradiol exposure and risk of depressive symptoms during the transition to menopause and postmenopause. Menopause. 2017 Dec;24(12):1351-1359.
2. Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015 Jul;72(7):714-26.
3. Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015 Jul;72(7):714-26.
4. Schiller CE, O’Hara MW, Rubinow DR, Johnson AK. Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression. Physiol Behav. 2013 Jul 2;119:137-44
5. Joffe H, Petrillo LF, Koukopoulos A, Viguera AC, Hirschberg A, Nonacs R, Somley B, Pasciullo E, White DP, Hall JE, Cohen LS. (Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. J Clin Endocrinol Metab. 2011 Jul;96(7):E1044-54.

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Depression: the improvement with estrogen treatment alone (11 references)

1. Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015 Jul;72(7):714-26.
2. Demetrio FN, Rennó J Jr, Gianfaldoni A, Gonçalves M, Halbe HW, Filho AH, Gorenstein C. Effect of estrogen replacement therapy on symptoms of depression and anxiety in non-depressive menopausal women: a randomized double-blind, controlled study. Arch Womens Ment Health. 2011 Dec;14(6):479-86.
3. Valen-Sendstad A, Engedal K, Stray-Pedersen B; ADACT Study Group, Strobel C, Barnett L, Meyer N, Nurminemi M. Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Am J Geriatr Psychiatry. 2010 Jan;18(1):11-20.
4. Joffe H, Petrillo LF, Koukopoulos A, Viguera AC, Hirschberg A, Nonacs R, Somley B, Pasciullo E, White DP, Hall JE, Cohen LS. Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. J Clin Endocrinol Metab. 2011 Jul;96(7):E1044-54.
5. Schiff R, Bulpitt CJ, Wesnes KA, Rajkumar C. Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo-controlled pilot cross-over study. Psychoneuroendocrinology 2005 May;30(4):309-15.

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Depression: the improvement with estrogen and progesterone/progestogen treatments (8 references)

1. Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018 Feb 1;75(2):149-157.
2. Rudolph I, Palombo-Kinne E, Kirsch B, Mellinger U, Breitbarth H, Gräser T. Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression. Climacteric. 2004 Sep;7(3):301-11
3. Soares CN, Arsenio H, Joffe H, Bankier B, Cassano P, Petrillo LF, Cohen LS. Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life. Menopause. 2006 Sep-Oct;13(5):780-6
4. Rudolph I, Palombo-Kinne E, Kirsch B, Mellinger U, Breitbarth H, Graser T. Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression. Climacteric. 2004 Sep;7(3):301-11
5. Lawrie TA, Herxheimer A, Dalton K. Oestrogens and progestogens for preventing and treating postnatal depression. Cochrane Database Syst Rev. 2000;(2):CD001690

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Postpartum depression: the association with lower estradiol levels (1 reference)

1. Luo Y, Zheng LZ, Zhou JW, Pi PX. Relationship between the levels of estradiol and monoamine neurotransmitters and postpartum depression. Zhonghua Fu Chan Ke Za Zhi. 2007 Nov;42(11):745-8.  

Postpartum depression: the improvement with estrogen treatment alone (2 references)

1. Ahokas A, Kaukoranta J, Wahlbeck K, Aito M. Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study. J Clin Psychiatry. 2001 May;62(5):332-6
2. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996 Apr 6;347(9006):930-3

Anxiety: the association with low estradiol levels in women (7 references)

1. de Rezende MG, Garcia-Leal C, Silva de Sá MF, Cavalli RC, Del-Ben CM. Withdrawal of plasma estradiol is associated with increased anxiety reported by women in the first 12 hours after delivery. Psychoneuroendocrinology. 2018 Nov 2;101:67-71.
2. Graham BM, Shin G. Estradiol moderates the relationship between state-trait anxiety and attentional bias to threat in women. Psychoneuroendocrinology. 2018 Jul;93:82-89.
3. Graham BM, Li SH, Black MJ, Öst LG. The association between estradiol levels, hormonal contraceptive use, and responsiveness to one-session-treatment for spider phobia in women. 2018 Apr;90:134-140.
4. Graham BM, Ash C, Den ML. High endogenous estradiol is associated with enhanced cognitive emotion regulation of physiological conditioned fear responses in women. Psychoneuroendocrinology. 2017 Jun;80:7-14.
5. Li S, Graham BM. Estradiol is associated with altered cognitive and physiological responses during fear conditioning and extinction in healthy and spider phobic women. Behav Neurosci. 2016 Dec;130(6):614-23.

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Anxiety: the improvement with estrogen treatment alone (6 references)

1. Walf AA, Paris JJ, Frye CA. Chronic estradiol replacement to aged female rats reduces anxiety-like and depression-like behavior and enhances cognitive performance. Psychoneuroendocrinology. 2009 Jul;34(6):909-16
2. Walf AA, Frye CA. Estradiol decreases anxiety behavior and enhances inhibitory avoidance and gestational stress produces opposite effects. Stress. 2007 Aug;10(3):251-60
3. Nathorst-Boos J, von Schoultz B, Carlstrom K. Elective ovarian removal and estrogen replacement therapy – effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol. 1993 Dec;14(4):283-93
4. Best NR, Rees MP, Barlow DH, Cowen PJ. Effect of estradiol implant on noradrenergic function and mood in menopausal subjects. Psychoneuroendocrinology. 1992;17(1):87-93
5. Montgomery JC, Appleby L, Brincat M, Versi E, Tapp A, Fenwick PB, Studd JW. Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet. 1987 Feb 7;1(8528):297-9

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Anxiety: the improvement with progesterone treatment alone (5 references)

1. Wieland S, Lan NC, Mirasedeghi S, Gee KW. Anxiolytic activity of the progesterone metabolite 5 alpha-pregnan-3 alpha-o1-20-one. Brain Res. 1991 Nov 29;565(2):263-8
2. Picazo O, Fernandez-Guasti A. Anti-anxiety effects of progesterone and some of its reduced metabolites: an evaluation using the burying behavior test. Brain Res. 1995 May 22;680(1-2):135-41.
3. Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol. 1995 Mar;7(3):171-7
4. Baker ER, Best RG, Manfredi RL, Demers LM, Wolf GC. Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome. J Assist Reprod Genet. 1995 Mar;12(3):205-9
5. Bitran D, Purdy RH, Kellogg CK. Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav. 1993 Jun;45(2):423-8

Anxiety: the improvement with estrogen and progestogen treatments (1 reference)

1. Collins A, Hanson U, Eneroth P, Hagenfeldt K, Lundberg U, Frankenhaeuser M. Psychophysiological stress responses in postmenopausal women before and after hormonal replacement therapy. Hum Neurobiol. 1982;1(2):153-9

Memory loss, cognitive impairment: the association with lower estrogen levels (7 references)

1. Gholizadeh S, Sadatmahalleh SJ, Ziaei S. The association between estradiol levels and cognitive function in postmenopausal women. Int J Reprod Biomed (Yazd). 2018 Jul;16(7):455-458.
2. Hu J, Chu K, Song Y, Chatooah ND, Ying Q, Ma L, Zhou J, Qu F, Zhou J. Higher level of circulating estradiol is associated with lower frequency of cognitive impairment in Southeast China. Gynecol Endocrinol. 2017 Nov;33(11):840-844.
3. Antov MI, Stockhorst U. Women with high estradiol status are protected against declarative memory impairment by pre-learning stress. Neurobiol Learn Mem. 2018 Nov;155:403-411.
4. Hampson E, Morley EE. Estradiol concentrations and working memory performance in women of reproductive age. 2013 Dec;38(12):2897-904.
5. Bittner DM, Bittner V, Riepe MW. Verbal episodic memory and endogenous estradiol: an association in patients with mild cognitive impairment and Alzheimer’s disease. Curr Gerontol Geriatr Res. 2011;2011:673012.

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Memory and attention loss: the association with lower estrogen and progesterone levels (1 reference)

1. Solís-Ortiz S, Corsi-Cabrera M. Sustained attention is favored by progesterone during early luteal phase and visuo-spatial memory by estrogens during ovulatory phase in young

Memory loss, cognitive impairment: the improvement with estrogen treatment alone (3 references)

1. Herrera AY, Hodis HN, Mack WJ, Mather M. Estradiol therapy after menopause mitigates effects of stress on cortisol and working memory. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4457-4466.
2. Imtiaz B, Tolppanen AM, Solomon A, Soininen H, Kivipelto M. Estradiol and cognition in the cardiovascular risk factors, aging and dementia (caide) cohort study. J Alzheimers Dis. 2017;56(2):453-458.
3. Dumas J, Hancur-Bucci C, Naylor M, Sites C, Newhouse P. Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Horm Behav. 2008 Jan;53(1):159-69

Memory loss, cognitive impairment: the improvement with progestogen treatment (1 reference)

1. Sofuoglu M, Mouratidis M, Mooney M. Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. 2011 Jan;36(1):123-32.

Memory loss, cognitive impairment: the improvement with estrogen and progestogen treatments (6 references)

1. Stephens C, Bristow V, Pachana NA. HRT and everyday memory at menopause: a comparison of two samples of mid-aged women. Women Health. 2006;43(1):37-57
2. Linzmayer L, Semlitsch HV, Saletu B, Bock G, Saletu-Zyhlarz G, Zoghlami A, Gruber D, Metka M, Huber J, Oettel M, Graser T, Grunberger J. Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen-progestin regimen versus estrogen alone on performance, mood and personality of menopausal syndrome patients. Arzneimittelforschung. 2001;51(3):238-45
3. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13(4):345-57
4. Smith YR, Giordani B, Lajiness-O’Neill R, Zubieta JK. Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women. Fertil Steril. 2001 Dec;76(6):1101-7
5. Stein DG. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci. 2001 Jul;24(7):386-91

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Alzheimer’s disease: the association with low estradiol levels (1 reference)

1. Bittner DM, Bittner V, Riepe MW. Verbal episodic memory and endogenous estradiol: an association in patients with mild cognitive impairment and Alzheimer’s disease. Curr Gerontol Geriatr Res. 2011;2011:673012.

Alzheimer’s disease: the improvement with estradiol treatment (8 references)

1. Wharton W, Baker LD, Gleason CE, Dowling M, Barnet JH, Johnson S, Carlsson C, Craft S, Asthana S. Short-term hormone therapy with transdermal estradiol improves cognition for postmenopausal women with Alzheimer’s disease: results of a randomized controlled trial. J Alzheimers Dis. 2011;26(3):495-505.
2. Valen-Sendstad A, Engedal K, Stray-Pedersen B; ADACT Study Group, Strobel C, Barnett L, Meyer N, Nurminemi M. Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Am J Geriatr Psychiatry. 2010 Jan;18(1):11-20.
3. Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 2001 Aug 28;57(4):605-12
4. Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet. 1996 Aug 17;348(9025):429-32
5. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996 Oct 28;156(19):2213-7

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Sleep disorder: the association with lower estrogen levels (2 references)

1. Merklinger-Gruchala A, Ellison PT, Lipson SF, Thune I, Jasienska G. Low estradiol levels in women of reproductive age having low sleep variation. Eur J Cancer Prev. 2008 Oct;17(5):467-72
2. Hollander LE, Freeman EW, Sammel MD, Berlin JA, Grisso JA, Battistini M. Sleep quality, estradiol levels, and behavioral factors in late reproductive age women. Obstet Gynecol. 2001 Sep;98(3):391-7

Sleep disorders, insomnia: no association with estradiol levels (1 reference)

1. Drozdowicz-Jastrzębska E, Skalski M, Gdańska P, Mach A, Januszko P, Nowak RJ, Węgrzyn P, Wielgoś M, Radziwoń-Zaleska M. Insomnia, postpartum depression and estradiol in women after delivery. Metab Brain Dis. 2017 Dec;32(6):1913-1918.

Sleep disorder: the improvement with estrogen treatment (2 references)

1. Antonijevic IA, Stalla GK, Steiger A. Modulation of the sleep electroencephalogram by estrogen replacement in postmenopausal women. Am J Obstet Gynecol. 2000 Feb;182(2):277-82.
2. Schiff I, Regestein Q, Tulchinsky D, Ryan KJ. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA. 1979 Nov 30;242(22):2405-4

Sleep disorder: the improvement with progesterone treatment (3 references)

1. Caufriez A, Leproult R, L’Hermite-Balériaux M, Kerkhofs M, Copinschi G. Progesterone prevents sleep disturbances and modulates GH, TSH, and melatonin secretion in postmenopausal women. J Clin Endocrinol Metab. 2011 Apr;96(4):E614-23.
2. Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause. 2001 Jan-Feb;8(1):10-6
3. Schüssler P, Kluge M, Yassouridis A, Dresler M, Held K, Zihl J, Steiger A. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. 2008 Sep;33(8):1124-31

Sleep disorder: the improvement with estrogen and progesterone treatments (6 references)

1. Kagan R, Constantine G, Kaunitz AM, Bernick B, Mirkin S. Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women. Menopause. 2018 Dec 21. Menopause. 2018 Dec 21.
2. Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Dowling NM, Dunn M, Gleason CE, Hodis HN, Isaac B, Magnani M, Manson JE, Miller VM, Taylor HS, Wharton W, Wolff E, Zepeda V, Harman SM. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos early estrogen prevention study. Menopause. 2017 Mar;24(3):238-246.
3. Hachul H, Bittencourt LR, Andersen ML, Haidar MA, Baracat EC, Tufik S. Effects of hormone therapy with estrogen and/or progesterone on sleep pattern in postmenopausal women. Int J Gynaecol Obstet. 2008 Dec;103(3):207-12
4. Soares CN, Arsenio H, Joffe H, Bankier B, Cassano P, Petrillo LF, Cohen LS. Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life. 2006 Sep-Oct;13(5):780-6
5. Keefe DL, Watson R, Naftolin F. Hormone replacement therapy may alleviate sleep apnea in menopausal women: a pilot study. Menopause. 1999 Fall;6(3):196-200.

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Sleep apnea: the association with low estradiol levels (1 reference)

1. Galvan T, Camuso J, Sullivan K, Kim S, White D, Redline S, Joffe H. Association of estradiol with sleep apnea in depressed perimenopausal and postmenopausal women: a preliminary study. 2017 Jan;24(1):112-117.

Sexual dysfunction (loss of sexual drive, sensitivity and orgasm): the association with lower estrogen levels (2 references)

1. Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata AR. Role of oestrogen in male sexual behavior: insights from the natural model of aromatase deficiency. Clin Endocrinol (Oxf) 1999 Oct;51(4):517-24
2. Cutler WB, Garcia CR, McCoy N. Perimenopausal sexuality. Arch Sex Behav 1987;16(3):225-34

Sexual dysfunction: the association with lower estradiol levels (review study) (1 reference)

1. Simon JA. Identifying and treating sexual dysfunction in postmenopausal women: the role of estrogen. J Womens Health (Larchmt). 2011 Oct;20(10):1453-65. (Estrogen deficiency also can affect other aspects of sexual function

Sexual dysfunction: the improvement with estradiol treatment alone (3 references)

1. Zilio Rech CM, Clapauch R, Bouskela E. Sexual function under adequate estrogen therapy in women after oophorectomy versus natural menopause. J Womens Health (Larchmt). 2019 Jan 25.
2. Taylor HS, Tal A, Pal L, Li F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Du W, Hodis HN, Lobo RA, Manson JE, Merriam GR, Miller VM, Naftolin F, Neal-Perry G, Santoro NF, Harman SM. Effects of oral vs transdermal estrogen therapy on sexual function in early postmenopause: ancillary study of the kronos early estrogen prevention study (keeps). JAMA Intern Med. 2017 Oct 1;177(10):1471-1479.
3. Gardella B, Iacobone AD, Porru D, Musacchi V, Dominoni M, Tinelli C, Spinillo A, Nappi RE. Effect of local estrogen therapy (LET) on urinary and sexual symptoms in premenopausal women with interstitial cystitis/bladder pain syndrome (IC/BPS). Gynecol Endocrinol. 2015 Oct;31(10):828-32.  

Sexual dysfunction: the improvement with estradiol treatment alone (review study) (1 reference)

1. Simon JA. Identifying and treating sexual dysfunction in postmenopausal women: the role of estrogen. J Womens Health (Larchmt). 2011 Oct;20(10):1453-65.

Sexual dysfunction: the improvement with estradiol and progestogen treatments (1 reference)

1. Matuszkiewicz-Rowinska J, Skorzewska K, Radowicki S, Sokalski A, Przedlacki J, Niemczyk S, Wlodarczyk D, Puka J, Switalski M. The benefits of hormone replacement therapy in pre-menopausal women with oestrogen deficiency on haemodialysis. Nephrol Dial Transplant 1999 May;14(5):1238-43

Sexual dysfunction: the improvement with estradiol and androgen treatments (3 references)

1. Chaikittisilpa S, Soimongkol K, Jaisamrarn U. Efficacy of oral estrogen plus testosterone gel to improve sexual function in postmenopausal women. Climacteric. 2019 Oct;22(5):460-465.
2. Sherwin BB. Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning. Fertil Steril. 2002 Apr;77 Suppl 4:S49-54
3. Castelo-Branco C, Vicente JJ, Figueras F, Sanjuan A, Martinez de Osaba MJ, Casals E, Pons F, Balasch J, Vanrell JA. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas. 2000 Feb 15;34(2):161-8

Hypercholesterolemia: the association with lower estrogen levels (2 references)

1. Reddy Kilim S, Chandala SR. A comparative study of lipid profile and oestradiol in pre- and post-menopausal women. J Clin Diagn Res. 2013 Aug;7(8):1596-8.
2. Lamon-Fava S, Barnett JB, Woods MN, McCormack C, McNamara JR, Schaefer EJ, Longcope C, Rosner B, Gorbach SL. Differences in serum sex hormone and plasma lipid levels in caucasian and african-american premenopausal women J Clin Endocrinol Metab. 2005 Aug;90(8):4516-20

LDL cholesterol: the inverse association with serum estradiol levels (1 reference)

1. Ali ZA, Al-Zaidi MS. The association between body mass index, lipid profile and serum estradiol levels in a sample of Iraqi diabetic premenopausal women. Oman Med J. 2011 Jul;26(4):263-6.

Hypercholesterolemia: the improvement with estrogen treatment (14 references)

1. Ruszala A, Wojcik M, Zygmunt-Gorska A, Janus D, Wojtys J, Starzyk JB. Prepubertal ultra-low-dose estrogen therapy is associated with healthier lipid profile than conventional estrogen replacement for pubertal induction in adolescent girls with Turner syndrome: preliminary results. J Endocrinol Invest. 2017 Aug;40(8):875-879.
2. Nanda S, Gupta N, Mehta HC, Sangwan K. Effect of oestrogen replacement therapy on serum lipid profile. Aust N Z J Obstet Gynaecol. 2003 Jun;43(3):213-6
3. Dansuk R, Unal O, Karageyim Y, Esim E, Turan C. Evaluation of the effect of tibolone and transdermal estradiol on triglyceride level in hypertriglyceridemic and normotriglyceridemic postmenopausal women. Gynecol Endocrinol. 2004 May;18(5):233-9
4. Balci H, Altunyurt S, Acar B, Fadiloglu M, Kirkali G, Onvural B. Effects of transdermal estrogen replacement therapy on plasma levels of nitric oxide and plasma lipids in postmenopausal women. Maturitas. 2005 Apr 11;50(4):289-93
5. Sanada M, Tsuda M, Kodama I, Sakashita T, Nakagawa H, Ohama K. Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause. 2004 May-Jun;11(3):331-6

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Hypercholesterolemia: the improvement with progesterone treatment (1 reference)

43. Houser SL, Aretz HT, Quist WC, Chang Y, Schreiber AD. Serum lipids and arterial plaque load are altered independently with high-dose progesterone in hypercholesterolemic male rabbits. Cardiovasc Pathol. 2000 Nov-Dec;9(6):317-22

Hypercholesterolemia: the improvement with estrogen and progestogen treatments (8 references)

1. Casanova G, Spritzer PM. Effects of micronized progesterone added to non-oral estradiol on lipids and cardiovascular risk factors in early postmenopause: a clinical trial. Lipids Health Dis. 2012 Oct 9;11:133.
2. Terauchi M, Honjo H, Mizunuma H, Aso T. Effects of oral estradiol and levonorgestrel on cardiovascular risk markers in postmenopausal women. Arch Gynecol Obstet. 2012 Jun;285(6):1647-56.
3. Darko DA, Dornhorst A, Kennedy G, Mandeno RC, Seed M. Glycaemic control and plasma lipoproteins in menopausal women with Type 2 diabetes treated with oral and transdermal combined hormone replacement therapy. Diabetes Res Clin Pract 2001 Dec;54(3):157-64
4. Sanada M, Tsuda M, Kodama I, Sakashita T, Nakagawa H, Ohama K. Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause. 2004 May-Jun;11(3):331-6
5. Vigna GB, Donega P, Zanca R, Barban A, Passaro A, Pansini F, Bonaccorsi G, Mollica G, Fellin R. Simvastatin, transdermal patch, and oral estrogen-progestogen preparation in early-postmenopausal hypercholesterolemic women: a randomized, placebo-controlled clinical trial. Metabolism. 2002 Nov;51(11):1463-70

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Hypercholesterolemia: the improvement with estrogen and testosterone treatments (1 reference)

1. Britto R, Araújo L, Barbosa I, Silva L. Improvement of the lipid profile in postmenopausal women who use estradiol and testosterone implants. Gynecol Endocrinol. 2012 Oct;28(10):767-9.

Atherosclerosis: the association with lower estrogen levels (4 references)

1. El Khoudary SR, Santoro N, Chen HY, Tepper PG, Brooks MM, Thurston RC, Janssen I, Harlow SD, Barinas-Mitchell E, Selzer F, Derby CA, Jackson EA, McConnell D, Matthews KA. Trajectories of estradiol and follicle-stimulating hormone over the menopause transition and early markers of atherosclerosis after menopause. Eur J Prev Cardiol. 2016 May;23(7):694-703.
2. Sriprasert I, Hodis HN, Karim R, Stanczyk FZ, Shoupe D, Henderson VW, Mack WJ. Differential effect of plasma estradiol on subclinical atherosclerosis progression in early vs late postmenopause. J Clin Endocrinol Metab. 2019 Feb 1;104(2):293-300.
3. Bernini GP, Moretti A, Sgro M, Argenio GF, Barlascini CO, Cristofani R, Salvetti A. Influence of endogenous androgens on carotid wall in postmenopausal women. Menopause. 2001 Jan-Feb;8(1):43-50
4. Smith JC, Bennett S, Evans LM, Kynaston HG, Parmar M, Mason MD, Cockcroft JR, Scanlon MF, Davies JS. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab. 2001 Sep;86(9):4261-7

Atherosclerosis: the improvement with estrogen treatment (10 references)

1. Coksuer H, Koplay M, Oghan F, Coksuer C, Keskin N, Ozveren O. Effects of estradiol-drospirenone hormone treatment on carotid artery intima-media thickness and vertigo/dizziness in postmenopausal women. Arch Gynecol Obstet. 2011 May;283(5):1045-51.
2. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31.
3. Mullick AE, Walsh BA, Reiser KM, Rutledge JC. Chronic estradiol treatment attenuates stiffening, glycoxidation, and permeability in rat carotid arteries. Am J Physiol Heart Circ Physiol. 2001 Nov;281(5):H2204-10
4. Walsh BA, Mullick AE, Banka CE, Rutledge JC. 17beta-estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation. J Lipid Res. 2000 Jan;41(1):134-41
5. Cagnacci A, Arangino S, Angiolucci M, Melis GB, Tarquini R, Renzi A, Volpe A. Different circulatory response to melatonin in postmenopausal women without and with hormone replacement therapy. J Pineal Res. 2000 Oct;29(3):152-8

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Arterial hypertension: the association with lower estrogen levels (7 references)

1. Brun S, Cleemann L, Holm K, Salskov G, Erlandsen M, Berglund A, Andersen NH, Gravholt CH. Five-year randomized study demonstrates blood pressure increases in young women with turner syndrome regardless of estradiol dose. Hypertension. 2019 Jan;73(1):242-248.
2. Yeasmin N, Akhter QS, Mahmuda S, Banu N, Yeasmin S, Akhter S, Nahar S. Association of hypertension with serum estrogen level in postmenopausal women. Mymensingh Med J. 2017 Jul;26(3):635-641.
3. Tomczy R, Paluch K, Gałuszka-Bednarczyk A, Milewicz T, Janeczko J, Klocek M. Changes in blood pressure and heart rate by an increase in serum estradiol in women undergoing controlled ovarian hyperstimulation. Przegl Lek. 2015;72(4):174-7.
4. Masi CM, Hawkley LC, Xu X, Veenstra TD, Cacioppo JT. Serum estrogen metabolites and systolic blood pressure among middle-aged and older women and men. Am J Hypertens. 2009 Nov;22(11):1148-53.
5. Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension. 2003 Dec;42(6):1157-63

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Hypertension: association with lower progesterone levels (1 reference)

1. Zhang Q, Huang Y, Zhang K, Yan Y, Wu J, Wang F, Zhao Y, Xu H, Jiang W, Yu D, Chen Y, Ye D. Progesterone attenuates hypertension and autoantibody levels to the angiotensin II type 1 receptor in response to elevated cadmium during pregnancy. Placenta. 2018 Feb;62:16-24.

Hypertension: the improvement with treatment in rats (1 reference)

1. Amaral LM, Kiprono L, Cornelius DC, Shoemaker C, Wallace K, Moseley J, Wallukat G, Martin JN Jr, Dechend R, LaMarca B. Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy. Am J Obstet Gynecol. 2014 Aug;211(2):158.e1-6.

Thrombosis: the improvement with transdermal estradiol and progestogen treatments (1 reference)

1. Perera M, Sattar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2001 Mar;86(3):1140-3.

Thrombosis, hypercoagulation: the adverse effects of oral estradiol treatment, but no effects of transdermal estradiol and progestogen treatments (2 references)

1. Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, Virkamäki A, Hovatta O, Hamsten A, Taskinen MR, Yki-Järvinen H. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001 Apr;85(4):619-25.
2. Chu MC, Cushman M, Solomon R, Lobo RA. Metabolic syndrome in postmenopausal women: the influence of oral or transdermal estradiol on inflammation and coagulation markers. Am J Obstet Gynecol. 2008 Nov;199(5):526.e1-7.

Arterial hypertension: the improvement with estrogen treatment (9 references)

1. Babic GM, Markovic SD, Varjacic M, Djordjevic NZ, Nikolic T, Stojic I, Jakovljevic V. Estradiol decreases blood pressure in association with redox regulation in preeclampsia. Clin Exp Hypertens. 2018;40(3):281-286.
2. Campos C, Sartorio CL, Casali KR, Fernandes RO, Llesuy S, da Rosa Araujo AS, Belló-Klein A, Rigatto KV. Low-dose estrogen is as effective as high-dose treatment in rats with postmenopausal hypertension. J Cardiovasc Pharmacol. 2014 Feb;63(2):144-51
3. Fung MM, Poddar S, Bettencourt R, Jassal SK, Barrett-Connor E. A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria: the Rancho Bernardo Study. Menopause. 2011 Jun;18(6):629-37.
4. Mercuro G, Zoncu S, Piano D, Pilia I, Lao A, Melis GB, Cherchi A. Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension. Am J Hypertens. 1998 Aug;11(8 Pt 1):909-13
5. Del Rio G, Velardo A, Zizzo G, Avogaro A, Cipolli C, Della Casa L, Marrama P, MacDonald IA. Effect of estradiol on the sympathoadrenal response to mental stress in normal men. J Clin Endocrinol Metab. 1994 Sep;79(3):836-40

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Arterial hypertension: the improvement with estrogen and progestogen treatments (6 references)

1. Junge W, El-Samalouti V, Gerlinger C, Schaefers M. Effects of menopausal hormone therapy on hemostatic parameters, blood pressure, and body weight: open-label comparison of randomized treatment with estradiol plus drospirenone versus estradiol plus norethisterone acetate. Eur J Obstet Gynecol Reprod Biol. 2009 Dec;147(2):195-200
2. Ichikawa A, Sumino H, Ogawa T, Ichikawa S, Nitta K. Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma bradykinin levels and blood pressure in normotensive postmenopausal women. Geriatr Gerontol Int. 2008 Dec;8(4):259-64
3. Kaya C, Cengiz SD, Cengiz B, Akgun G. Long-term effects of low-dose 17beta-estradiol plus dydrogesterone on 24-h ambulatory blood pressure in healthy postmenopausal women: a 1-year, randomized, prospective study. Gynecol Endocrinol. 2007 Oct;23 Suppl 1:62-7
4. Preston RA, Norris PM, Alonso AB, Ni P, Hanes V, Karara AH. Randomized, placebo-controlled trial of the effects of drospirenone-estradiol on blood pressure and potassium balance in hypertensive postmenopausal women receiving hydrochlorothiazide. 2007 May-Jun;14(3 Pt 1):408-14
5. Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation. 1998 Sep 22;98(12):1158-63

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Coronary heart disease the association with lower estrogen levels (4 references)

1. Liu X, Guo C, Ma X, Tian R, Zhang Y, Yin H. Relationship between serum estrogen levels and blood stasis syndrome in postmenopausal women with coronary heart disease. Pak J Med Sci. 2015 Jan-Feb;31(1):25-30.
2. Guo C, Zhang S, Zhang J, Liu H, Li P, Liu H, Wang Y. Correlation between the severity of coronary artery lesions and levels of estrogen, hs-CRP and MMP-9. Exp Ther Med. 2014 May;7(5):1177-1180.
3. Jeon GH, Kim SH, Yun SC, Chae HD, Kim CH, Kang BM. Association between serum estradiol level and coronary artery calcification in postmenopausal women. Menopause. 2010 Sep-Oct;17(5):902-7.
4. Hanke H, Hanke S, Ickrath O, Lange K, Bruck B, Muck AO, Seeger H, Zwirner M, Voisard R, Haasis R, Hombach V. Estradiol concentrations in premenopausal women with coronary heart disease. Coron Artery Dis. 1997 Aug-Sep;8(8-9):511-5

Coronary heart disease: the improvement with estrogen treatment (10 references)

1. Sun LM, Liang JA, Chang SN, Sung FC, Muo CH, Kao CH. Estrogen decrease coronary artery disease risk in patients with cervical cancer after treatment. Gynecol Oncol. 2012 Oct;127(1):186-90.
2. Puntawangkoon C, Morgan TM, Herrington DM, Hamilton CA, Hundley WG. Submaximal exercise coronary artery flow increases in postmenopausal women without coronary artery disease after estrogen and atorvastatin. 2010 Jan-Feb;17(1):114-20.
3. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000 Dec;36(7):2154-9
4. Hulley S, Grady D, 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. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13
5. Roque M, Heras M, Roig E, Masotti M, Rigol M, Betriu A, Balasch J, Sanz G. Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol. 1998 Jan;31(1):139-43

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Coronary heart: the improvement with progesterone treatment (animal studies) (3 references)

1. Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, Illingworth DR, Juan C, Nordt FJ. Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol. 2004 May;24(5):955-61.
2. Minshall RD, Pavcnik D, Browne DL, Hermsmeyer K. Nongenomic vasodilator action of progesterone on primate coronary arteries. J Appl Physiol (1985). 2002 Feb;92(2):701-8.
3. Molinari C, Battaglia A, Grossini E, Mary DA, Stoker JB, Surico N, Vacca G. The effect of progesterone on coronary blood flow in anaesthesized pigs. Exp Physiol. 2001 Jan;86(1):101-8.

Coronary heart disease: the improvement with estrogen and progestogen treatments (1 reference)

1. Collins P, Flather M, Lees B, Mister R, Proudler AJ, Stevenson JC; WHISP (Women’s Hormone Intervention Secondary Prevention Study) Pilot Study Investigators. Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study. Eur Heart J. 2006 Sep;27(17):2046-53

Heart failure: the improvement with estrogen treatment (1 reference)

1. Reis SE, Holubkov R, Young JB, White BG, Cohn JN, Feldman AM. Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies. J Am Coll Cardiol. 2000 Aug;36(2):529-33

Cardiovascular disease: the improvement with estrogen treatment (2 references)

1. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000 Dec 19;133(12):933-41
2. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991 Sep 12;325(11):756-62

Cardiovascular disease: the improvement with estrogen and progestogen treatments (4 references)

1. Cagnacci A, Arangino S, Angiolucci M, Melis GB, Tarquini R, Renzi A, Volpe A. Different circulatory response to melatonin in postmenopausal women without and with hormone replacement therapy. J Pineal Res. 2000 Oct;29(3):152-8
2. Chen FP, Lee N, Wang CH, Cherng WJ, Soong YK. Effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women. Fertil Steril. 1998 Feb;69(2):267-73
3. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996 Aug 15;335(7):453-61
4. Paganini Hill A. The Leisure World Cohort Study. In The Treatment of the postmenopausal women- Lobo RA, Ed Paven Press – NY, 1994; p. 401: table 1

Obesity: the association with lower estrogen levels (5 references)

1. Biundo B, Gogola M. Estradiol: the emerging evidence for a protective role against insulin resistance and obesity. Int J Pharm Compd. 2015 Jul-Aug;19(4):289-93.
2. Cheng KH, Huang SP, Huang CN, Lee YC, Chu CS, Chang CF, Lai WT, Liu CC. The impact of estradiol and 1,25(OH)2D3 on metabolic syndrome in middle-aged Taiwanese males. PLoS One. 2013;8(3):e60295.
3. Rehman R, Hussain Z, Faraz N. Effect of estradiol levels on pregnancy outcome in obese women. J Ayub Med Coll Abbottabad. 2012 Jul-Dec;24(3-4):3-5.
4. Tchernof A, Poehlman ET, Despres JP. Body fat distribution, the menopause transition, and hormone replacement therapy. Diabetes Metab. 2000 Feb;26(1):12-20
5. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003 Jun;88(6):2404-11

Obesity: the association with lower progesterone levels (2 references)

1. Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab. 2007 Jul;92(7):2468-73
2. Westhoff C, Gentile G, Lee J, Zacur H, Helbig D. Predictors of ovarian steroid secretion in reproductive-age women. Am J Epidemiol. 1996 Aug 15;144(4):381-8.  

Obesity: the improvement with estrogen treatment (7 references)

1. Finan B, Yang B, Ottaway N, Stemmer K, Müller TD, Yi CX, Habegger K, Schriever SC, García-Cáceres C, Kabra DG, Hembree J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, de Angelis MH, Tiano JP, Mauvais-Jarvis F, Perez-Tilve D, Pfluger P, Zhang L, Gelfanov V, DiMarchi RD, Tschöp MH. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med. 2012 Dec;18(12):1847-56.
2. Korljan B, Bagatin J, Kokić S, Berović Matulić N, Barsić Ostojić S, Deković A. The impact of hormone replacement therapy on metabolic syndrome components in perimenopausal women. Med Hypotheses. 2010 Jan;74(1):162-3.
3. Odabasi AR, Yuksel H, Karul A, Kozaci D, Sezer SD, Onur E. Effects of standard and low dose 17beta-estradiol plus norethisterone acetate on body composition and leptin in postmenopausal women at risk of body mass index and waist girth related cardiovascular and metabolic disease. Saudi Med J. 2007 Jun;28(6):855-61
4. Sorensen MB, Rosenfalck AM, Hojgaard L, Ottesen B. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Obes Res. 2001 Oct;9(10):622-6
5. Tofovic SP, Dubey RK, Jackson EK. 2-Hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats. J Pharmacol Exp Ther. 2001 Dec;299(3):973-7

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Type 1 diabetes: the association with low estradiol levels in women with short-term diabetes (≤ 9 years) unsuppressed (by birth-control pill) ovarian function (1 reference)

1. Hassan LS, Monson RS, Danielson KK. Oestradiol levels may differ between premenopausal women, ages 18-50, with type 1 diabetes and matched controls. Diabetes Metab Res Rev. 2017 Feb;33(2)

Type 1 diabetes: the association with high estradiol levels in women with long-term diabetes (> 9 years) unsuppressed (by birth-control pill) ovarian function (1 reference)

1. Hassan LS, Monson RS, Danielson KK. Oestradiol levels may differ between premenopausal women, ages 18-50, with type 1 diabetes and matched controls. Diabetes Metab Res Rev. 2017 Feb;33(2

Type 2 diabetes: the association with lower estrogen levels (2 references)

1. Tong PC, Ho CS, Yeung VT, Ng MC, So WY, Ozaki R, Ko GT, Ma RC, Poon E, Chan NN, Lam CW, Chan JC. Association of testosterone, insulin-like growth factor-I, and C-reactive protein with metabolic syndrome in Chinese middle-aged men with a family history of type 2 diabetes. J Clin Endocrinol Metab. 2005 Dec;90(12):6418-23
2. Gorodeski GI. Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women. Exp Gerontol. 1994 May-Aug;29(3-4):357-75

Tpe 2 diabetes, insulin resistance: the improvement with estrogen treatment (6 references)

1. Mattsson LA, Hahn L, Marin P, Lapidus L, Holm G, Bengtsson BA, Bjorntorp P. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997 Feb;82(2):638-43
2. Rossi R, Origliani G, Modena MG. Transdermal 17-beta-estradiol and risk of developing type 2 diabetes in a population of healthy, nonobese postmenopausal women. Diabetes Care. 2004 Mar;27(3):645-9
3. Cagnacci A, Tuveri F, Cirillo R, Setteneri AM, Melis GB, Volpe A. The effect of transdermal 17-beta-estradiol on glucose metabolism of postmenopausal women is evident during the oral but not the intravenous glucose administration. Maturitas 1997 Dec 15;28(2):163-7
4. O’Sullivan AJ, Ho KK. A comparison of the effects of oral and transdermal estrogen replacement on insulin sensitivity in postmenopausal women. J Clin Endocrinol Metab 1995 Jun;80(6):1783-8
5. Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, Melis GB. Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992 Jun;74(6):1396-400

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Type 2 diabetes: the improvement with estrogen and progestogen treatments (8 references)

1. Kernohan AF, Sattar N, Hilditch T, Cleland SJ, Small M, Lumsden MA, Connell JM, Petrie JR. Effects of low-dose continuous combined hormone replacement therapy on glucose homeostasis and markers of cardiovascular risk in women with type 2 diabetes. Clin Endocrinol (Oxf). 2007 Jan;66(1):27-34.
2. Sztejnsznajd C, Silva ME, Nussbacher A, Gebara OE, D’Amico EA, Rocha DM, da Rocha TR, Santos RF, Wajngarten M, Fukui RT, Correia MR, Wajchenberg BL, Ursich MJ. Estrogen treatment improves arterial distensibility, fibrinolysis, and metabolic profile in postmenopausal women with type 2 diabetes mellitus.
3. McKenzie J, Jaap AJ, Gallacher S, Kelly A, Crawford L, Greer IA, Rumley A, Petrie JR, Lowe GD, Paterson K, Sattar N. Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk? Clin Endocrinol (Oxf). 2003 Dec;59(6):682-9.
4. Raudaskoski T, Tomas C, Laatikainen T. Insulin sensitivity during postmenopausal hormone replacement with transdermal estradiol and intrauterine levonorgestrel. Acta Obstet Gynecol Scand 1999 Jul;78(6):540-5
5. Cucinelli F, Paparella P, Soranna L, Barini A, Cinque B, Mancuso S, Lanzone A. Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion. Eur J Endocrinol 1999 Mar;140(3):215-23

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Osteoporosis, low bone density: the association with lower estrogen levels (11 references)

1. van Geel TA, Geusens PP, Winkens B, Sels JP, Dinant GJ. Measures of bioavailable serum testosterone and Huitrón-Bravo G, Denova-Gutiérrez E, Talavera JO, Moran-Villota C, Tamayo J, Omaña-Covarrubias A, Salmerón J. Levels of serum estradiol and lifestyle factors related with bone mineral density in premenopausal Mexican women: a cross-sectional analysis. BMC Musculoskelet Disord. 2016 Oct 19;17(1):437.
2. Shea KL, Gavin KM, Melanson EL, Gibbons E, Stavros A, Wolfe P, Kittelson JM, Vondracek SF, Schwartz RS, Wierman ME, Kohrt WM. Body composition and bone mineral density after ovarian hormone suppression with or without estradiol treatment. Menopause. 2015 Oct;22(10):1045-52.
3. Sheikholeslami H, Sotodeh M, Javadi A, Nasirian N, Kazemifar AM, Abbasi M. Relationship between bone mineral density and maturity index in cervical smears, serum estradiol levels and body mass index. Glob J Health Sci. 2013 Sep 29;5(6):209-13.
4. Corina M, Vulpoi C, Brănişteanu D. Relationship between bone mineral density, weight, and estrogen levels in pre and postmenopausal women. Rev Med Chir Soc Med Nat Iasi. 2012 Oct-Dec;116(4):946-50.
5. estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study. Eur J Endocrinol. 2009 Apr;160(4):681-7

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Osteoporosis, low bone density: no association with estrogen levels (1 reference)

1. Yoldemir T, Erenus M, Durmusoglu F. The impact of serum FSH and estradiol on postmenopausal osteoporosis related to time since menopause. Gynecol Endocrinol. 2012 Nov;28(11):884-8.

Osteoporosis: the association with lower estrogens and androgen levels (4 references)

1. Deutsch S, Benjamin F, Seltzer V, Tafreshi M, Kocheril G, Frank A. The correlation of serum estrogens and androgens with bone density in the late postmenopause. Int J Gynaecol Obstet. 1987 Jun;25(3):217-22
2. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res. 2000 Aug;15(8):1526-36
3. Lau EM, Suriwongpaisal P, Lee JK, Das De S, Festin MR, Saw SM, Khir A, Torralba T, Sham A, Sambrook P. Risk factors for hip fracture in Asian men and women: the Asian osteoporosis study. J Bone Miner Res. 2001 Mar;16(3):572-80
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