The Effect of 17β-Estradiol Plus Norethisterone Acetate on Estradiol, Testosterone, IGF-1 and SHBG in Postmenopausal Women: A Meta-Analysis of Randomized Controlled Trials

Abstract

We conducted this meta-analysis of randomized controlled trials (RCTs) with the aim of assessing the effect of 17β-estradiol plus norethisterone acetate on estradiol, testosterone, IGF-1, and SHBG in postmenopausal women. To our knowledge, this is the first meta-analysis of RCTs to assess these effects. Databases including the Web of Science, PubMed/Medline, Scopus, and EMBASE were searched to identify publications up to July 2024. The results were reported as weighted mean difference (WMD) and 95% confidence intervals (CI) generated by using a random-effects model according to the Der-Simonian–Laird model. Fifteen publications were included in current meta-analysis. Overall results from the random-effects model manifested a significant increase in estradiol (WMD: 55.30 pg/ml, 95% CI: 39.32, 7128, p<0.001) and SHBG (WMD: 18.48 nmol/l, 95% CI: 3.64, 33.33, p=0.015) levels, a significant decrease in FSH (WMD: –41.55 IU/l, 95% CI: –53.17, –29.92, p<0.001) and testosterone (WMD: –4.29 ng/dl, 95% CI: –5.38, –3.21, p=0.000) levels, and a non-significant decrease in IGF-1 levels (WMD: –9.70 μg/l, 95% CI: –34.21, 14.80, p=0.438) after treatment with 17β-estradiol plus norethisterone acetate on postmenopausal women. In conclusion, 17β-estradiol plus norethisterone acetate in postmenopausal women increases estradiol and SHBG concentrations and decreases FSH and testosterone concentrations, with no statistically significant effect on IGF-1.

Keywords

estradiol - pituitary - FSH - testosterone - cancer - IGF-1 - 17β-estradiol plus norethisterone acetate - SHBG

Publication History

Received: 26 October 2024

Accepted after revision: 23 January 2025

Article published online:
06 March 2025

• References

• 1 Hall JE. Endocrinology of the menopause. Endocrinol Metab Clin 2015; 44: 485-496
• 2 Naftolin F, Friedenthal J, Nachtigall R. et al Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment. F1000Research 2019; 8 F1000 Faculty Rev-1576
• 3 Santoro N, Epperson CN, Mathews SB. Menopausal symptoms and their management. Endocrinol Metab Clin 2015; 44: 497-515
• 4 Burger HG, Dudley EC, Cui J. et al. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000; 85: 2832-2838
• 5 Al-Azzawi F, Palacios S. Hormonal changes during menopause. Maturitas 2009; 63: 135-137
• 6 Lee JS, Yaffe K, Lui L-Y. et al. Prospective study of endogenous circulating estradiol and risk of stroke in older women. Archiv Neurol 2010; 67: 195-201
• 7 Karim R, Hodis HN, Stanczyk FZ. et al. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. J Clin Endocrinol Metab 2008; 93: 131-138
• 8 Iorga A, Cunnigham CN, Moazeni S. et al. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Diff 2017; 8: 1-16
• 9 Lee SR, Cho MK, Cho YL. et al. The 2020 menopausal hormone therapy guidelines. J Menop Med 2020; 26: 69-98
• 10 Okada M, Nomura S, Ikoma Y. et al. Effects of postmenopausal hormone replacement therapy on HbA1c levels. Diabetes Care 2003; 26: 1088-1092
• 11 Prelevic G, Kocjan T, Markou A. Hormone replacement therapy in postmenopausal women. Minerva Endocrinol 2005; 30: 27-36
• 12 Gavaler JS. Oral hormone replacement therapy: factors that influence the estradiol concentrations achieved in a multiracial study population. J Clin Pharmacol 2002; 42: 137-144
• 13 Brinton LA, Felix AS. Menopausal hormone therapy and risk of endometrial cancer. J Steroid Biochem Molecul Biol 2014; 142: 83-89
• 14 Goodwin PJ, Dennis M, Pritchard KI. et al. Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes. Breast Cancer Res Treat 2002; 74: 65-76
• 15 Xing C, Zhang J, Zhao H. et al. Effect of sex hormone-binding globulin on polycystic ovary syndrome: mechanisms, manifestations, genetics, and treatment. Int J Women Health 2022; 14: 91-105
• 16 Le TN, Nestler JE, Strauss J. et al. Sex hormone-binding globulin and type 2 diabetes mellitus. Trends Endocrinol Metab 2012; 23: 32-40
• 17 Rocha T, Crespo RP, Yance VVR. et al. Persistent poor metabolic profile in postmenopausal women with ovarian hyperandrogenism after testosterone level normalization. J Endocr Soc 2019; 3: 1087-1096
• 18 Li Y, Chen X, Gong X. et al. The Effect of 17beta-estradiol plus norethisterone acetate on anthropometric indices: a systematic review and meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 2023; 287: 176-185
• 19 Tao W, Cai X, Masri MKL. et al. The effect of transdermal 17β-estradiol combined with norethisterone acetate treatment on the lipid profile in postmenopausal women: a meta-analysis and systematic review of randomized controlled trials. Steroids 2022; 185: 109061
• 20 Tang Z, Gäman M-A, Prabahar K. et al. The effect of 17β-estradiol plus norethisterone acetate treatment on lipoprotein (a), atherogenic and anti-atherogenic apolipoproteins levels in postmenopausal women: a meta-analysis of randomized controlled trials. Exp Gerontol 2022; 172: 112055
• 21 Pöllänen E, Ronkainen PHA, Horttanainen M. et al. Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. Growth Horm IGF Res 2010; 20: 372-379
• 22 Thunell L, Andersson B, Glassell M. et al. The effect of continuous combined HRT on glucose homeostasis and plasma lipids: a placebo-controlled study in postmenopausal women with type 2 diabetes. Maturitas 2006; 53: 430-438
• 23 Moher D, Liberati A, Tetzlaff J. et al. Reprint—preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Phys Ther 2009; 89: 873-880
• 24 Sterne JA, Savovic J, Page MJ. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: 4898
• 25 Higgins J, Green S. Cochrane handbook for systematic reviews of interventions. Hoboken: Wiley. 2011. 5
• 26 Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Method 2005; 5: 13
• 27 Egger M, Smith GD, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634
• 28 Gregersen I, Høibraaten E, Holven KB. et al. Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women. Thromb Res 2019; 184: 1-7
• 29 Pöllänen E, Ronkainen PHA, Horttanainen M. et al. Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. Growth Horm IGF Res 2010; 20: 372-379
• 30 Thunell L, Andersson BJ, Glassell M. et al. The effect of continuous combined HRT on glucose homeostasis and plasma lipids: A placebo-controlled study in postmenopausal women with type 2 diabetes. Maturitas 2006; 53: 430-438
• 31 Arruda CG, Aldrighi JM, Bortolotto LA. et al. Effects of estradiol alone and combined with norethisterone acetate on pulse-wave velocity in hypertensive postmenopausal women. Gynecol Endocrinol 2006; 22: 557-563
• 32 Lazar F, Coata-Paiva L, Pinto-Neto AM. et al. Carotid and uterine vascular resistance in short-term hormone replacement therapy postmenopausal users. Maturitas 2004; 48: 472-478
• 33 Conner P, Christow A, Kersemaekers W. et al. A comparative study of breast cell proliferation during hormone replacement therapy: effects of tibolon and continuous combined estrogen-progestogen treatment. Climacteric 2004; 7: 50-58
• 34 Squadrito F, Altavilla D, Crisafulli A. et al. Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med 2003; 114: 470-476
• 35 McKenzie J, Japp AJ, Gallacher S. et al. 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 2003; 59: 682-689
• 36 Morabito N, Crisafulli A, Vergara C. et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone and Mineral Res 2002; 17: 1904-1912
• 37 Akhan SE, Gürel T, Has R. et al. Effects of long-term oral hormone replacement therapy on plasma nitric oxide and beta-endorphin levels in postmenopausal women. Gynecol Obstet Invest 2002; 54: 196-200
• 38 Sørensen MB, Rosenfalck AM, Højgaard L. et al. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Obes Res 2001; 9: 622-626
• 39 Saitta A, Altavilla D, Cucinotta D. et al. Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma NO concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vasc Biol 2001; 21: 1512-1519
• 40 Darko DA, Dornhost A, Kennedy G. et al. 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; 54: 157-164
• 41 Andersson B, Mattsson LA, Hahn L. et al. 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; 82: 638-643
• 42 Nenseter MS, Volden V, Berg T. et al. Effect of hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidation among postmenopausal hypercholesterolaemic women. Eur J Clin Invest 1996; 26: 1062-1068
• 43 Hashemzadeh M, Haseefa F, Peyton L. et al. The effects of estrogen and hormone replacement therapy on platelet activity: a review. Am J Blood Res 2022; 12: 33
• 44 Blüher M. Importance of estrogen receptors in adipose tissue function. Mol Metab 2013; 2: 130
• 45 Gambacciani M, Ciaponi M, Cappagli B. et al. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 1997; 82: 414-417
• 46 Tiidus PM. Benefits of estrogen replacement for skeletal muscle mass and function in post-menopausal females: evidence from human and animal studies. Eurasian J Med 2011; 43: 109
• 47 Smith GI, Yoshino J, Reeds DN. et al. Testosterone and progesterone, but not estradiol, stimulate muscle protein synthesis in postmenopausal women. J Clin Endocrinol Metab 2014; 99: 256-265
• 48 Taaffe DR, Sipilä S, Cheng S. et al. The effect of hormone replacement therapy and/or exercise on skeletal muscle attenuation in postmenopausal women: a yearlong intervention. Clin Physiol Funct Imaging 2005; 25: 297-304
• 49 Thorneycroft IH, Lindsay R, Pickar JH. Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the womenʼs Health, Osteoporosis, Progestin, Estrogen (HOPE) trial. Am J Obstet Gynecol 2007; 197: 137.e1-7
• 50 Alemany M. The roles of androgens in humans: biology, metabolic regulation and health. Int J Mol Sci 2022; 23: 11952
• 51 Simon JA. Estrogen replacement therapy: effects on the endogenous androgen milieu. Fertil Steril 2002; 77: 77-82
• 52 Lukaszuk K, Liss J, Kunicki M. et al. Estradiol valerate pretreatment in short protocol GnRH-agonist cycles versus combined pretreatment with oral contraceptive pills in long protocol GnRH-agonist cycles: a randomised controlled trial. BioMed Res Int. 2015 2015. 628056
• 53 Kemeter P, Bernaschek G, Altmann G. et al. The effect of 2 mg estradiol-17β plus 1 mg estriol, sequentially combined with 1 mg norethisteroneacetate, on LH, FSH, estradiol-17β, progesterone, testosterone and prolactin after ovarectomy. Arch Gynecol 1984; 234: 219-229
• 54 Odell W, Swerdloff R. Progestogen-induced luteinizing and follicle-stimulating hormone surge in postmenopausal women: a simulated ovulatory peak. Proc Natl Acad Sci U S A 1968; 61: 529-536
• 55 Wildt L, Leyendecker G. Die endokrine Kontrolle des menstruellen Zyklus. Gynäkologe 1981; 14: 64-83
• 56 Zaman A, Rothman MS. Postmenopausal hyperandrogenism: evaluation and treatment strategies. Endocrinol Metab Clin 2021; 50: 97-111
• 57 Ferrando AA, Sheffield-Moore M, Yeckel CW. et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002; 282: E601-E607
• 58 Bleach R, Sherlock M, OʼREilly W. et al. Growth hormone/insulin growth factor axis in sex steroid associated disorders and related cancers. Front Cell Develop Biol 2021; 9: 630503
• 59 Campagnoli C, Clavel-Chapelon F, Kaaks R. et al. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005; 96: 95-108
• 60 Ianza A, Sirico M, Bernocchi O. et al. Role of the IGF-1 axis in overcoming resistance in breast cancer. Front Cell Dev Biol 2021; 9: 641449
• 61 Marsden J. Hormone replacement therapy and female malignancy: what has the million women study added to our knowledge?. J Fam Plan Reprod Health Care 2007; 33: 237