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The importance of the progestogenic component of hormone replacement therapy in women with a uterus
Dr John C Stevenson, Consultant Physician and Endocrinologist, Royal Brompton Hospital; Reader in Metabolic Medicine, Imperial College London
Dr Sophia Tsiligiannis, Specialty Trainee in Obstetrics and Gynaecology, Chelsea and Westminster Hospital; Clinical Research Fellow, Imperial College London
The menopause transition is a critical stage in women’s health. The oestrogen deficiency that accompanies the menopause is associated with irregular periods, eventual amenorrhoea, and multiple other symptoms—the most common being hot flushes and night sweats, vaginal dryness, mood changes, sexual dysfunction (including loss of libido), memory and concentration changes, headaches, and joint and muscle complaints. Around 80% of women will experience vasomotor symptoms,1 with most rating these as moderate to severe.2 An American observational study indicated that the median vasomotor symptom duration is 7.4 years.3 Furthermore, vasomotor symptoms are independently associated with multiple indicators of elevated cardiovascular risk,4 and reduction in bone mineral density (BMD).5
NICE guidance advises offering hormone replacement therapy (HRT) for vasomotor symptoms after discussing with women the short‑term (up to 5 years) and longer-term benefits and risks.6 However, the management of menopausal symptoms often presents a clinical challenge to prescribers. Concerns about breast cancer risk have contributed to reduced prescribing of HRT in the UK. Initial data from the 2002 Women’s Health Initiative (WHI) trial showed an increased risk of breast cancer, albeit not statistically significant, and possible early harm from coronary heart disease (CHD) in women receiving combined oestrogen and progesterone.7 Subsequently, follow-up data from the same study published in 2013 showed no detrimental effect on CHD.8 With careful consideration of the risks and benefits, around 1 million women in the UK currently use HRT to manage their symptoms.6
Rationale behind progestogen prescribing
Oestrogen alone can be offered to women without a uterus, whereas the addition of a progestogen is required for women with a uterus.6 A regimen containing bazedoxifene (BZA; a selective oestrogen receptor modulator) combined with conjugated equine oestrogens (CEE) is available as a progestogen-free alternative for use in women with a uterus.9 Tibolone is a synthetic compound with weak oestrogenic, progestogenic, and androgenic activity, and is also licensed for HRT use in the UK.10 It may be given to women with low libido, but adverse metabolic effects limit its use.
The association between unopposed oestrogen therapy and endometrial hyperplasia/neoplasia is established.11 A 20% incidence of endometrial hyperplasia was shown with 1 year of unopposed oestrogen use.12 Cyclical progestogen given in combination with low‑dose oestrogen for 10 days monthly reduced endometrial hyperplasia to placebo rate,13 and the WHI trial, which used continuous combined HRT, demonstrated a 19% reduction (non‑significant) in endometrial hyperplasia compared with placebo.14
In some cases, progestogens (in a combined HRT regimen) are prescribed to women without a uterus but with a history of severe endometriosis to prevent symptom reactivation (e.g. pelvic pain), recurrence, and malignant transformation of endometriotic foci.15 Despite a lack of high‑quality studies, case reports consistently show a predominance of oestrogen‑only HRT in women with recurrence of endometriosis and malignancy.15 As a result, combined preparations are often favoured.15
Progestogens currently available for prescription
Broadly speaking, progestogens have one effect in common: the induction of a characteristic effect on the oestrogen-primed endometrium.16 There are, however, large variations in the myriad other biological effects elicited by different progestogens.16 The progestogenic activity of any substance also depends on its timing and route of administration. A list of progestogens currently licenced for use in the UK as part of combined HRT and their receptor activities is provided in Table 1.
Progestogens also exhibit antigonadotropic effects, which inhibit ovulation when prescribed for contraceptive use.16
Table 1: Progestogens currently licenced for use in the UK as part of combined HRT
Contraindications and side-effects
Specific side-effects depend on the type of receptor activity exhibited by each progestogen, as demonstrated in Table 1. Common side‑effects for most progestogens include headache, menstrual cycle irregularities, breast pain, skin reactions, and gastrointestinal discomfort.17 General contraindications include breast, ovarian, or uterine cancer, a history of blood clots, and liver disease,17 with specific contraindications for each preparation.
Risks associated with progestogen prescribing
NICE guidance advises explaining to women around the natural age of menopause that the baseline risk of breast cancer varies according to the presence of underlying risk factors.6 HRT with oestrogen alone is associated with little or no change in the risk of breast cancer relative to baseline risk, whereas HRT with oestrogen and progestogen can be associated with a slightly increased risk of breast cancer.6
NICE guidance reports a baseline population risk of breast cancer of 22.48 per 1000 women over 7.5 years.6 Follow-up data from the WHI trial demonstrated that, for current HRT users, there were four fewer cases of breast cancer per 1000 women among women using oestrogen alone relative to baseline, although this was not statistically significant.8 There were five additional cases of breast cancer per 1000 women among women using oestrogen and progestogen relative to baseline.8 In simple terms, use of combined HRT is associated with approximately one extra case of breast cancer for every 1000 users per year compared with use of oestrogen alone.8
In the WHI trial, combined HRT consisted of CEE with medroxyprogesterone acetate (MPA),7,8 and the same risk may not apply to different types of progestogen. Two cohort studies showed that oestrogen combined with either progesterone or dydrogesterone is not associated with a statistically significantly increased risk of breast cancer.18,19 This may be because some progestogens reduce proliferation; however, their effects on breast tissue are complex and poorly understood.18 A case‑control analysis by the UK-based General Practice Research Database also demonstrated that use of oestrogen with dydrogesterone is not associated with an increased risk of breast cancer.20
The risk of venous thromboembolism (VTE) is increased by oral HRT relative to baseline population risk.8 Conversely, epidemiological studies have not identified a risk of VTE above baseline population risk with the use of transdermal HRT.21–23 This is likely because transdermal delivery avoids first‑pass liver metabolism of oestrone (the main metabolite of oral oestradiol) in the liver, which increases thrombin generation.24
When defining VTE risk, observational studies have also outlined the importance of the type of progestogen associated with oestradiol.21 The addition of MPA to oral oestrogen may be associated with an increased risk of VTE, and continuous combined regimes may present a greater risk of VTE than sequential regimes.25
The ESTHER study, however, demonstrated no significant association between VTE and micronized progesterone.21 In addition, a recent case-control study confirmed that transdermal HRT preparations were not associated with VTE risk; conversely, oral HRT increased the risk of VTE, and the highest risk of VTE was evident with CEE combined with MPA.26 Oral oestradiol used in combination with dydrogesterone was not associated with a significantly increased risk of VTE (Figure 1).26
Figure 1: Adjusted odds ratios for VTE risk with different types of HRT and different doses of oestrogen26
Odds ratios are adjusted for current use of conjugated equine oestrogen cream, estradiol pessaries, oral progestogen, progesterone cream or vaginal preparations, past use of HRT, smoking status, alcohol consumption, Townsend deprivation fifth (QResearch only), body mass index, comorbidities, recent events, current and past use of antidepressants, antipsychotics, aspirin, oral contraceptives, tamoxifen, and years of data. Cases are matched to controls by age, general practice, and index date. *p<0.01
Adapted from Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019; 364: k4810. Reproduced under the terms of the CC BY 4.0 license (creativecommons.org/licenses/by/4.0/)
HRT has the potential to improve cardiovascular risk because of beneficial effects on lipids, vascular function, and glucose metabolism.27 An updated analysis of the WHI trial showed that initiating oestrogen alone closer to the onset of menopause was associated with lower CHD risk and a reduction in total mortality.8,28 Randomised controlled trials, observational studies, and metaanalyses consistently support primary prevention of CHD and reduction in overall mortality in women initiating HRT nearer to the onset of menopause. The data suggest that the ‘window of opportunity’ for reducing CHD and overall mortality is initiation of HRT prior to 60 years of age and/or within 10 years of the menopause.29
All CEE and CEE/MPA regimens have favourable effects on lipid profiles, including reductions in low‑density lipoprotein cholesterol (LDL) and increases in high-density lipoprotein cholesterol (HDL), although triglyceride increases have also been observed with oral therapy.30 Similarly, an analysis of 248 studies showed that all oestrogen-only regimes raised HDL and lowered LDL.31 Oral oestrogens raised triglycerides, but transdermal 17β-oestradiol lowered triglyceride levels.31 This study also showed that progestogens had little effect on oestrogen‑induced reductions in total and LDL cholesterol.31 These positive effects were opposed least by dydrogesterone.31
In the SMART trials (a series of phase-3 trials), CEE 0.45 mg/BZA 20 mg and CEE 0.625 mg/BZA 20 mg were shown to have generally positive effects on most lipid parameters for up to 2 years of treatment,32 although there was some blunting of the oestrogen-induced rise in HDL.
A further study indicated that sequential combinations of either 1 mg or 2 mg 17β-oestradiol with dydrogesterone are associated with long-term favourable changes in serum lipid profile, and there is no evidence that dydrogesterone compromises these 17β-oestradiol-induced improvements.33
Overall, HRT in the form of CEE, oral esterified oestrogens, or transdermal oestrogen—alone or in combination with progestogens—reduces insulin resistance.34 Although the androgenic progestogen MPA has shown adverse effects on glucose and insulin metabolism,35 dydrogesterone does not appear to oppose the potentially beneficial effects of oestradiol on insulin.36
Choosing the most appropriate progestogen for patients
There is no official UK guidance on choice of progestogen when prescribing combined HRT. The effects of different progestogens on lipids, cardiovascular disease, VTE, glucose metabolism, and risk of breast cancer should therefore be considered by clinicians. Patient preference, side-effect profile, and clinical requirements (e.g. if patient has bothersome bleeding) should also factor in the decision‑making process.
Progestogens can be used in continuous or sequential combined HRT regimens. Sequential regimens are most commonly used for women who are perimenopausal or still menstruating.
‘Bio-identical’ natural progesterone is synthesised from yams, but it is only licensed for HRT use as an oral micronized progesterone capsule. Cohort studies have shown it may not be associated with increased risk of breast cancer, and it is often favoured for this reason.18,19
Use of a combination patch or combined oral therapy may be convenient, but it is also limited to the available doses, which may not effectively treat symptoms in individual women. Therefore, separate transdermal oestradiol (patch or gel), in combination with progesterone/an alternative progestogen, may offer greater flexibility to individualise treatment.
The HRT-related risk of serious VTE events increases with age, and is positively associated with obesity and thrombophilia.25 NICE guidance advises considering transdermal HRT for menopausal women who are at increased risk of VTE, including those with a body mass index over 30 kg/m2.6 A suitable choice may therefore be the use of transdermal oestradiol in combination with micronized progesterone in women at increased risk of VTE. Progestogen-delivering intrauterine devices are often used if contraception is required in conjunction with HRT. This is often the case in perimenopausal women or women with premature ovarian insufficiency, where a spontaneous pregnancy rate of 5% is assumed.
Use of CEE/BZA may be considered in women with progestogen intolerance.
Switching patients to a more suitable progestogen
If transferring from sequential combined HRT, start the new treatment the day after finishing the oestrogen plus progestogen phase. If transferring from continuous combined HRT, start the new treatment at any time.
HRT is used to alleviate menopausal symptoms and maintain BMD,6 and may reduce cardiovascular risk, particularly if started early postmenopause.28 Oestrogen with the addition of a progestogen is required for women with a uterus.6 Although the inclusion of progestogens in HRT regimens is associated with approximately one extra case of breast cancer per 1000 women per year for current HRT users,8 micronized progesterone or dydrogesterone may be associated with a lower risk.18,19 The type of progestogen is also important when considering VTE risk, with micronized progesterone and dydrogesterone appearing to demonstrate the lowest risk.21 CEE and CEE/MPA regimens have favourable effects on lipids,30,31 but progestogens have little effect on oestrogen-induced reductions in total and LDL cholesterol.31 Dydrogesterone does not appear to oppose the potentially beneficial effects of oestradiol on insulin.36 There is no current guidance on choice of progestogen for use in HRT in the UK; therefore, individual risk factors, patient preference, and the clinical scenario should to be taken into consideration.
Conflicts of interest
Dr John Stevenson has received grants/research support from Abbott, Mylan, and Pfizer, consulting fees from Abbott and Pfizer, and speaker’s honoraria from Abbott, Bayer, Gedeon Richter, Menarini, Mylan, and Pfizer.
Dr Sophia Tsiligiannis has received funding for events from Novo Nordisk.
- Gold E, Colvin A, Avis N et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women’s health across the nation. Am J Public Health 2006; 96 (7): 1226–1235.
- Freeman E, Sammel M, Sanders R. Risk of long-term hot flashes after natural menopause. Menopause 2014; 21 (9): 924–932.
- Avis N, Crawford S, Greendale G et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175 (4): 531–539.
- Thurston R, Sutton-Tyrrell K, Everson-Rose S et al. Hot flashes and carotid intima media thickness among midlife women. Menopause 2011; 18 (4): 352–358.
- Crandall C, Tseng C-H, Crawford S et al. Association of menopausal vasomotor symptoms with increased bone turnover during the menopausal transition. J Bone Miner Res 2011; 26 (4): 840–849.
- NICE. Menopause: diagnosis and management. NICE Guideline 23. NICE, 2015. Available at: www.nice.org.uk/ng23
- Rossouw J, Anderson G, Prentice R et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288 (3): 321–333.
- Manson J, Chlebowski R, Stefanick M et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310 (13): 1353–1368.
- British National Formulary. Conjugated oestrogens with bazedoxifene acetate. bnf.nice.org.uk/drug/conjugated-oestrogens-with-bazedoxifene-acetate.html (accessed 17 July 2019).
- Manassiev N, Godsland I, Proudler A et al. Effects of tibolone or continuous combined oestradiol/norethisterone acetate on glucose and insulin metabolism. Clin Endocr (Oxf) 2013; 76 (2): 297–302.
- Woodruff J, Pickar J. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994; 170 (5 Pt 1): 1213–1223.
- Judd H, Mebane-Sims I, Legault C. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996; 275 (5): 370–375.
- Lethaby A, Suckling J, Barlow D et al. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004; (3): CD000402.
- Anderson G, Judd H, Kaunitz A et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA 2003; 290 (13): 1739–1748.
- Gemmell L, Webster K, Kirtley S et al. The management of menopause in women with a history of endometriosis: a systematic review. Hum Reprod Update 2017; 23 (4): 481–500.
- Schindler A, Campagnoli C, Druckmann R et al. Classification and pharmacology of progestins. Maturitas 2003; 46 (Suppl 1): S7–S16.
- NHS. Hormone replacement therapy (HRT). www.nhs.uk/conditions/hormone-replacement-therapy-hrt/ (accessed 17 July 2019).
- Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008; 107 (1): 103–111.
- Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol–progestogen therapy. Obstet Gynecol 2009; 113 (1): 65–73.
- Schneider C, Jick S, Meier C. Risk of gynecological cancers in users of estradiol/dydrogesterone or other HRT preparations. Climacteric 2009; 12 (6): 514–524.
- Canonico M, Oger E, Plu-Bureau G et al. Hormone therapy and venous thromboembolism among postmenopausal women. Circulation 2007; 115 (7): 840–845.
- Renoux C, Dell’Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010; 8 (5): 979–986.
- Canonico M, Fournier A, Carcaillon L et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism. Arterioscler Thromb Vasc Biol 2010; 30 (2): 340–345.
- Mueck A. Postmenopausal hormone replacement therapy and cardiovascular disease: the value of transdermal estradiol and micronized progesterone. Climacteric 2012; 15 (Suppl 1): 11–17.
- Baber R, Panay N, Fenton A; IMS Writing Group. 2016 IMS recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016; 19 (2): 109–150.
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019; 364: k4810.
- Lobo R, Davis S, De Villiers T et al. Prevention of diseases after menopause. Climacteric 2014; 17 (5): 540–556.
- Rossouw J, Prentice R, Manson J et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297 (13): 1465–1477.
- Hodis H, Collins P, Mack W, Schierbeck L. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric 2012; 15 (3): 217–228.
- Lobo R, Bush T, Carr B et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001; 76 (1): 13–24.
- Godsland I. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001; 75 (5): 898–915.
- Stevenson J, Chines A, Pan K et al. A pooled analysis of the effects of conjugated estrogens/bazedoxifene on lipid parameters in postmenopausal women from the selective estrogens, menopause, and response to therapy (SMART) trials. J Clin Endocrinol Metab 2015; 100 (6): 2329–2338.
- Stevenson J, Rioux J, Komer L et al. 1 and 2 mg 17betaestradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women. Climacteric 2005; 8 (4): 352–359.
- Salpeter S, Walsh J, Ormiston T et al. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006; 8 (5): 538–554.
- Lindheim S, Presser S, Ditkoff E et al. A possible bimodal effect of estrogen on insulin sensitivity in postmenopausal women and the attenuating effect of added progestin. Fertil Steril 1993; 60 (4): 664–667.
- Crook D, Godsland I, Hull J, Stevenson J. Hormone replacement therapy with dydrogesterone and 17 beta-oestradiol: effects on serum lipoproteins and glucose tolerance during 24 month follow up. Br J Obstet Gynaecol 1997; 104 (3): 298–304.
Guidelines approached Mylan for an educational grant to support the production of a supplement. The grant included honoraria for the authors. Mylan has had no influence over the selection of the authors or the content of the supplement and has reviewed it for technical accuracy and to ensure compliance with regulations.
The views and opinions of the authors are not necessarily those of Mylan, or of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.
Date of preparation: July 2019