Choice of progestogen for endometrial protection in combination with transdermal estradiol in menopausal women

Alfred O Mueck, Thomas Römer, Alfred O Mueck, Thomas Römer

Abstract

Transdermal estradiol (TE) application (using gels, patches or a novel spray) is now a preferred route of hormone therapy (HT) in menopausal women, because various risks such as venous thromboembolism, stroke and unwanted hepatic effects can be reduced compared with oral HT. However, in the presence of an intact uterus, concurrent administration of progestogen is needed for endometrial protection. Due to the variety of progestogens available and differences in their clinical effects, the selection of the most appropriate substance and dosing for individual combination therapy can be difficult. This is especially true for TE gels and the novel spray because no fixed combination products are commercially available, meaning all progestogens must be added separately, and even for patches only two transdermal synthetic progestogens are available. The aim of this review was to summarize data on the endometrial effects of the different progestogens and to provide practical recommendations for the choice of progestogen (type and dosing), with a focus on endometrial protection when using TE, especially when using the novel estradiol (E2) spray.

Keywords: endometrial efficacy; endometrial histology; hormone therapy; progestogens; transdermal estradiol spray.

References

    1. NICE Guidelines. Menopause: diagnosis and management (12 Nov 2015). .
    1. Baber RJ, Panay N, Fenton A, IMS Writing Group. 2016 Recommendations on women’s health and menopause therapy. Climacteric. 2016;19:109–50.
    1. Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95:s1–s66.
    1. North American Menopause Society. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728–53.
    1. Mueck AO. Guidelines for hormone replacement therapy during peri- and postmenopause. Gynäkologische Endokrinologie. 2015;13:270–3.
    1. Utian WH, Woods NF. Impact of hormone therapy on quality of life after menopause. Menopause. 2013;20:1098–105.
    1. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005;8:3–63.
    1. Furness S, Roberts H, Marjoribanks J, Lethaby A. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev. 2012;CD000402.
    1. Sjogren LL, Morch LS, Lokkegaard E. Hormone replacement therapy and the risk of endometrial cancer: a systematic review. Maturitas. 2016;91:25–35.
    1. Beral V, Bull D, Reeves G, Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–5.
    1. Kuhl H. Pharmacology of progestogens. J Reproduktionsmed Endokrinol. 2011;8:157–77.
    1. Committee for Medicinal Products for Human Use (2006). Clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. CPMP/EWP/021/97 Rev. 1. London: European Medicines Agency, 2006.
    1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J Am Med Assoc. 2002;288:321–33.
    1. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. J Am Med Assoc. 2007;297:1465–77.
    1. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. J Am Med Assoc. 2004;291:1701–12.
    1. LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. J Am Med Assoc. 2011;305:1305–14.
    1. Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. J Am Med Assoc. 2017;318:927–38.
    1. Manson JE, Kaunitz AM. Menopause management – getting clinical care back on track. N Engl J Med. 2016;374:803–6.
    1. The North American Menopause Society 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 Hormone Therapy Position Statement of The North American Menopause Society. Menopause. 2017;24:728–53.
    1. L’Hermite M. Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal. Climacteric. 2017;20:331–8.
    1. Pickar JH, Archer DF, Kagan R, Pinkerton JV, Taylor HS. Safety and benefit considerations for menopausal hormone therapy. Expert Opin Drug Saf. 2017;16:941–54.
    1. Ortmann O, Lattrich C. The treatment of climacteric symptoms. Dtsch Arztebl Int. 2012;109:316–23.
    1. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, et al. Classification and pharmacology of progestins. Maturitas. 2003;46:S7–S16.
    1. Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34:171–208.
    1. Simon JA, Robinson DE, Andrews MC, Hildebrand JR 3rd, Rocci ML Jr, Blake RE, et al. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril. 1993;60:26–33.
    1. Levine H, Watson N. Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women. Fertil Steril. 2000;73:516–21.
    1. Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric. 2016;19:316–28.
    1. Di Carlo C, Sammartino A, Di Spiezio Sardo A, Tommaselli GA, Guida M, Mandato VD, et al. Bleeding patterns during continuous estradiol with different sequential progestogens therapy. Menopause. 2005;12:520–5.
    1. Di Carlo C, Tommaselli GA, Gargano V, Savoia F, Bifulco G, Nappi C. Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns. Climacteric. 2010;13:442–6.
    1. Pélissier C, Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Jondet M. Chlormadinone acetate versus micronized progesterone in the sequential combined hormone replacement therapy of the menopause. Maturitas. 2001;40:85–94.
    1. Jondet M, Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Pélissier C. Comparative endometrial histology in postmenopausal women with sequential hormone replacement therapy of estradiol and, either chlormadinone acetate or micronized progesterone. Maturitas. 2002;41:115–21.
    1. Moyer DL, de Lignieres B, Driguez P, Pez JP. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993;59:992–7.
    1. Suvanto-Luukkonen E, Sundström H, Penttinen J, Kauppila A, Rutanen EM. Insulin-like growth factor-binding protein-1: a biochemical marker of endometrial response to progestin during hormone replacement therapy. Maturitas. 1995;22:255–62.
    1. Suvanto-Luukkonen E, Malinen H, Sundström H, Penttinen J, Kauppila A. Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone. Acta Obstet Gynecol Scand. 1998;77:758–63.
    1. Cicinelli E, de Ziegler D, Galantino P, Pinto V, Barba B, Morgese S, et al. Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Am J Obstet Gynecol. 2002;187:556–60.
    1. Cicinelli E, de Ziegler D, Alfonso R, Nicoletti R, Bellavia M, Colafiglio G. Endometrial effects, bleeding control, and compliance with a new postmenopausal hormone therapy regimen based on transdermal estradiol gel and every-other-day vaginal progesterone in capsules: a 3-year pilot study. Fertil Steril. 2005;83:1859–63.
    1. Fernández-Murga L, Hermenegildo C, Tarín JJ, García-Pérez MÁ, Cano A. Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol. Climacteric. 2012;15:455–9.
    1. Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P. Vaginal micronized progesterone in continuous hormone replacement therapy. A prospective randomized study. Minerva Ginecol. 2002;54:519–30.
    1. Clisham PR, Cedars MI, Greendale G, Fu YS, Gambone J, Judd HL. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol. 1992;79:196–201.
    1. Cano A, Tarín JJ, Dueñas JL. Two-year prospective, randomized trial comparing an innovative twice-a-week progestin regimen with a continuous combined regimen as postmenopausal hormone therapy. Fertil Steril. 1999;71:129–36.
    1. Judd HL, Mebane-Sims I, Legault C; The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Am Med Assoc. 1996;75:370–5.
    1. AinMelk Y. Comparison of two continuous combined estrogen progestogen regimens in postmenopausal women: a randomized trial. Fertil Steril. 1996;66:962–8.
    1. Hsu SC, Long CY, Yang CH, Wu CH, Chen CH, Liu FI. Cyclooxygenase-2 expression in the endometrium at the end of 2 years’ continuous combined hormone replacement therapy. Maturitas. 2003;46:295–9.
    1. Yildirim G, Tugrul S, Uslu H, Pekin O, Eren S. Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding. Arch Gynecol Obstet. 2006;273:268–73.
    1. Chang TC, Chen M, Lien YR, Chen RJ, Chow SN. Comparison of the difference in histopathology and cell cycle kinetics among the postmenopausal endometrium treated with different progestins in sequential-combined hormone replacement therapy. Menopause. 2003;10:172–8.
    1. Dahmoun M, Odmark IS, Risberg B, Karlsson MG, Pavlenko T, Bäckström T. Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT. Maturitas. 2004;49:114–23.
    1. Heikkinen JE, Vaheri RT, Ahomäki SM, Kainulainen PM, Viitanen AT, Timonen UM. Optimizing continuous-combined hormone replacement therapy for postmenopausal women: a comparison of six different treatment regimens. Am J Obstet Gynecol. 2000;182:560–7.
    1. Nand SL, Webster MA, Baber R, O’Connor V. Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy. The Ogen/Provera Study Group. Obstet Gynecol. 1998;91:678–84.
    1. Exacoustòs C, Lello S, Caporale E, Minghetti MC, Angelozzi D, Arduini D, et al. Monitoring of hormone replacement therapy in postmenopausal women by transvaginal sonography and color flow doppler: study in different phases of sequential therapy. Fertil Steril. 1999;71:536–43.
    1. Gräser T, Koytchev R, Müller A, Oettel M. Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women. Climacteric. 2000;3:109–18.
    1. Gräser T, Römer T, Wiedey KD, Janaud A. Climodien (estradiol valerate 2 mg plus dienogest 2 mg) is safe and effective in the treatment of postmenopausal complaints. Climacteric. 2001;4:332–42.
    1. Polatti F, Capuzzo E, Viazzo F, Colleoni R, Abbiati I, Nappi RE. Long-term sequential treatment with combined estradiol valerate and cyproterone acetate in early postmenopause. Acta Obstet Gynecol Scand. 1999;78:49–53.
    1. Mueck AO, Sitruk-Ware R. Nomegestrol acetate, a novel progestogen for oral contraception. Steroids. 2011;76:531–9.
    1. Foidart JM, Béliard A, Hedon B, Ochsenbein E, Bernard AM, Bergeron C, et al. Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium. Br J Obstet Gynaecol. 1997;104:305–10.
    1. Ruan X, Seeger H, Mueck AO. The pharmacology of nomegestrol acetate. Maturitas. 2012;71:345–53.
    1. Seeger H, Mueck AO. Effects of dydrogesterone on the vascular system. Gynecol Endocrinol. 2007;23:2–8.
    1. van der Mooren MJ, Hanselaar AG, Borm GF, Rolland R. Changes in the withdrawal bleeding pattern and endometrial histology during 17 beta-estradiol-dydrogesterone therapy in postmenopausal women: a 2 year prospective study. Maturitas. 1994;20:175–80.
    1. Ferenczy A, Gelfand MM. Endometrial histology and bleeding patterns in post-menopausal women taking sequential, combined estradiol and dydrogesterone. Maturitas. 1997;26:219–26.
    1. Ferenczy A, Gelfand MM, van de Weijer PH, Rioux JE. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 beta-estradiol combined with sequential 5–20 mg dydrogesterone. Climacteric. 2002;5:26–35.
    1. van de Weijer PH, Scholten PC, van der Mooren MJ, Barentsen R, Kenemans P. Bleeding patterns and endometrial histology during administration of low-dose estradiol sequentially combined with dydrogesterone. Climacteric. 1999;2:101–9.
    1. Bergeron C, Fox H. Low incidence of endometrial hyperplasia with acceptable bleeding patterns in women taking sequential hormone replacement therapy with dydrogesterone. Gynecol Endocrinol. 2000;14:275–81.
    1. Bergeron C, Ferenczy A. Endometrial safety of continuous combined hormone replacement therapy with 17beta-oestradiol (1 or 2 mg) and dydrogesterone. Maturitas. 2001;37:191–9.
    1. Bergeron C, Nogales FF, Rechberger T, Tatarchjuk T, Zipfel L. Ultra low dose continuous combined hormone replacement therapy with 0.5 mg 17beta-oestradiol and 2.5 mg dydrogesterone: protection of the endometrium and amenorrhoea rate. Maturitas. 2010;66:201–5.
    1. Mueck AO, Seeger H, Bühling KJ. Use of dydrogesterone in hormone replacement therapy. Maturitas. 2009;655:S51–60.
    1. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol. 1999;94:498–503.
    1. Johannisson E, Holinka CF, Arrenbrecht S. Transdermal sequential and continuous hormone replacement regimens with estradiol and norethisterone acetate in postmenopausal women: effects on the endometrium. Int J Fertil Womens Med. 1997;42:388–98.
    1. Samsioe G, Boschitsch E, Concin H, De Geyter C, Ehrenborg A, Heikkinen J, et al. Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study. Climacteric. 2006;9:368–79.
    1. Warming L, Ravn P, Christiansen C. Levonorgestrel and 17beta-estradiol given transdermally for the prevention of postmenopausal osteoporosis. Maturitas. 2005;50:78–85.
    1. Shulman LP, Yankov V, Uhl K. Safety and efficacy of a continuous once-a-week 17beta-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials. Menopause. 2002;9:195–207.
    1. Sturdee DW, van de Weijer P, von Holst T. Endometrial safety of a transdermal sequential estradiol-levonorgestrel combination. Climacteric. 2002;5:170–7.
    1. Archer DF, Thorneycroft IH, Foegh M, Hanes V, Glant MD, Bitterman P, et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause. 2005;12:716–27.
    1. Obel EB, Munk-Jensen N, Svenstrup B, Bennett P, Micic S, Henrik-Nielsen R, et al. A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Maturitas. 1993;16:13–21.
    1. Raudaskoski TH, Lahti EI, Kauppila AJ, Apaja-Sarkkinen MA, Laatikainen TJ. Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints: clinical and endometrial responses. Am J Obstet Gynecol. 1995;172:114–9.
    1. Wells M, Sturdee DW, Barlow DH, Ulrich LG, O’Brien K, Campbell MJ, et al. Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study. Br Med J. 2002;325:239.
    1. Dören M, Süselbeck B, Schneider HP, Holzgreve W. Uterine perfusion and endometrial thickness in postmenopausal women on long-term continuous combined estrogen and progestogen replacement. Ultrasound Obstet Gynecol. 1997;9:113–9.
    1. Paterson ME, Wade-Evans T, Sturdee DW, Thom MH, Studd JW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. Br Med J. 980;280:822–4.
    1. Ruan X, Seeger H, Mueck AO. The pharmacology of dienogest. Maturitas. 2012;71:337–44.
    1. Raudaskoski T, Tapanainen J, Tomás E, Luotola H, Pekonen F, Ronni-Sivula H, et al. Intrauterine 10 microg and 20 microg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. BJOG. 2002;109:136–44.
    1. Kalogirou D, Antoniou G, Karakitsos P, Kalogirou O, Antoniou D, Giannikos L. A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response. Int J Fertil Menopausal Stud. 1996;41:522–7.
    1. Wildemeersch D. Safety and comfort of long-term continuous combined transdermal estrogen and intrauterine levonorgestrel administration for postmenopausal hormone substitution – a review. Gynecol Endocrinol. 2016;32:598–601.
    1. Varila E, Wahlström T, Rauramo I. A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy. Fertil Steril. 2001;76:969–73.
    1. Suhonen S, Holmström T, Lähteenmäki P. Three-year follow-up of the use of a levonorgestrel-releasing intrauterine system in hormone replacement therapy. Acta Obstet Gynecol Scand. 1997;76:145–50.
    1. Suhonen S, Haukkamaa M, Holmström T, Lähteenmäki P, Rutanen EM. Endometrial response to hormone replacement therapy as assessed by expression of insulin-like growth factor-binding protein-1 in the endometrium. Fertil Steril. 1996;65:776–82.
    1. Paoletti AM, Pilloni M, Orrù M, Floris S, Pistis M, Guerriero S, Ajossa S, Melis GB. Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel. Maturitas. 2002;42:137–47.
    1. Genazzani AR, Schmelter T, Schaefers M, Gerlinger C, Gude K. One-year randomized study of the endometrial safety and bleeding pattern of 0.25 mg drospirenone/0.5 mg 17β-estradiol in postmenopausal women. Climacteric. 2013;16:490–8.
    1. Römer T, Mueck AO. Empfehlungen zur notwendigen Gestagendosis bei Anwendung des transdermalen Estradiol-sprays Lenzetto®. Köln: Gedeon Richter.
    1. Egras AM, Umland EM. The role of transdermal estrogen sprays and estradiol topical emulsion in the management of menopause-associated vasomotor symptoms. Int J Gen Med. 2010;3:147–51.
    1. Taylor MB, Gutierrez MJ. Absorption, bioavailability, and partner transfer of estradiol from a topical emulsion. Pharmacotherapy. 2008;28:712–8.
    1. Buster JE, Koltun WD, Pascual ML, Day WW, Petersen C. Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 208;111:1343–51.
    1. Schumacher RJ, Gattermeir DJ, Peterson CA, Wisdom C, Day WW. The effects of skin-to-skin contact, application site washing, and sunscreen use on the pharmacokinetics of estradiol from a metered-dose transdermal spray. Menopause. 2009;16:177–83.
    1. Morton TL, Gattermeir DJ, Petersen CA, Day WW, Schumacher RJ. Steady-state pharmacokinetics following application of a novel transdermal estradiol spray in healthy postmenopausal women. J Clin Pharmacol. 2009;49:1037–46.
    1. Lenzetto 1.53 mg/spray (transdermal estradiol spray): summary of product characteristics. Budapest: Gedeon Richter, 2016.
    1. Ruan X, Mueck AO. The choice of progestogen for HRT in menopausal women: breast cancer risk is a major issue. Horm Mol Biol Clin Invest. 2018;37. Article ID: 20180019.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться