Abstract
Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel’s recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12–14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3–5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.
Introduction
The steroid hormone progesterone plays a key role in female reproductionCitation1. For therapeutic reasons, micronized progesterone (MP) can be used for endometrial protection when estrogens are applied in menopausal women with an intact uterusCitation2. However, there is considerable debate about whether and at which dosage MP provides effective endometrial protection if applied orally, vaginally, or transdermallyCitation3. To discuss various topics on MP, an international expert meeting of gynecological endocrinologists from the German-speaking countries Austria, Germany and Switzerland was held in April 2015 aiming to provide scientifically proven statements on MP treatment in peri- and postmenopausal women, based on a systematic literature search and discussion of the results. Endometrial protection by MP will be the first topic of the planned series.
Material and methods
A systematic literature search was performed using databases (Medline (Pubmed), Biosis (Medpilot) and Cochrane (Cochrane Library)), clinical trial registers (www.clinicaltrialsregister.eu, www.clinicaltrial.gov, http://apps.who.int/trialsearch/), and the experts’ own literature collection). Searches were performed using a combination of keywords and Mesh-terms and text words related to “(post-/peri)menopause” or “hormone/estrogen replacement therapy”, “progesterone”, “endometrial cancer/neoplasm/hyperplasia” or “endometrial biopsy” or “endometrial proliferation/atrophy”. Estrogen dosages were classified as high-dose, standard-dose, low-dose and ultra-low-dose by the expert group according to the definition of the International Menopause SocietyCitation4. No time restriction was applied. The selection process involved a pre-selection via title and/or abstracts by two independent reviewers (A.L., B.H.) based on the PICO criteria (). Discrepancies between the reviewers were discussed and resolved by consensus. Included abstracts were ordered as full articles. The selection process for full articles was performed accordingly. Meta-analyses and systematic reviews were searched for secondary literature. The final eligibility assessment and evaluation of the studies’ quality were performed by the expert group (P.S., J.N., L.W.)
Table 1. Literature search strategy (PICO criteria); status March 2015.
Results
Of 1028 hits, 40 studies were selected for the systematic review and expert panel’s discussionCitation5–45.
Oral application of MP
The effect of oral MP on the endometrium has been assessed by transvaginal ultrasound (TVUS)Citation5,Citation6,Citation10,Citation16,Citation21, endometrial biopsyCitation10–26 and endometrial cancer incidenceCitation7–9 ().
Table 2. Overview of trials investigating menopausal hormone therapy (MHT) containing oral micronized progestin (MP).
Endometrial thickness
Endometrial thickness measured by TVUS was assessed in postmenopausal women in one 3-year, placebo-controlled, randomized, controlled trial (RCT) (n = 167)Citation21 and two 1-year RCTs (n = 100) with head-to-head comparisonsCitation5,Citation6. Participants received continuous, transdermal estradiol (E2) (25Citation21–50Citation5,Citation6 μg/day) which was sequentially combined with either different oral progestogens (medroxyprogesterone acetate (MPA), nomegestrol acetate (NOMAC), dydrogesterone (DYD), MP)Citation6, MP applied orally or vaginally at different dosages (100 or 200 mg/day)Citation5 or oral MP 100 mg/day for 2 weeks every 6 months (extended cycle)Citation21. In those studies with head-to-head comparisons, there were no significant group differences for endometrial thickness at baseline and after 12 cyclesCitation5,Citation6. When comparing the baseline endometrial thickness with that at study closure, there was either no change (extended cycle regimen at oral MP 100 mg/dayCitation21, sequential regimen at vaginal MP 200 mg/dayCitation5), or a significant increaseCitation5,Citation6. Another two small, non-controlled studies using either oral MP 200–300 mg/day for 10 days per monthCitation16 or 100 mg/day for 23 days per monthCitation10 reported no changeCitation10 or an endometrial thickness of less than 2 mm after 1 yearCitation16.
The method of endometrial thickness assessment was described by two authors onlyCitation5,Citation6 using the maximal thickness of the endometrium in the longitudinal plane of the uterus.
Endometrial histology
Endometrial biopsies were performed in 17 studiesCitation10–26 of which eight were RCTsCitation12,Citation13,Citation15,Citation17,Citation18,Citation21,Citation22,Citation24 including two placebo-controlled RCTsCitation15,Citation21. Endometrial biopsy procedure was described by all but six authorsCitation12,Citation13,Citation16,Citation20,Citation21,Citation25. The majority either used a pipelle de CornierCitation14,Citation15,Citation18,Citation22,Citation24,Citation26 or Novak’s curetteCitation14,Citation15,Citation18,Citation22,Citation26. Others used a needle aspiration (pistolet method)Citation23, vabra suction curettageCitation10,Citation11,Citation15,Citation19 or performed a conventional dilatation and curettageCitation17,Citation19. A hysteroscopy was only performed in one study if no tissue was obtainedCitation20. The sample size ranged from 17Citation16 to 596Citation15 women being postmenopausal in all but one studyCitation16. Treatment duration ranged from 4 monthsCitation12,Citation24 to 5 yearsCitation20. Conjugated equine estrogens (CEE) were the most common estrogen component of menopausal hormone therapy (MHT) while others used 17β-estradiol. Estrogen dosage was either high-doseCitation14,Citation17,Citation19, standard-doseCitation10–16,Citation18,Citation20,Citation22–26, low-doseCitation25 or ultra-low-doseCitation21. Estrogens were applied either orally or transdermally. MP was examined either at different dosages ranging from 50 mg/dayCitation12, 100 mg/dayCitation10–12,Citation14,Citation19,Citation21,Citation24–26, 200 mg/dayCitation9,Citation13,Citation15–20,Citation22,Citation23, 300 mg/dayCitation14,Citation16,Citation17,Citation19,Citation24 to 400 mg/dayCitation24 or compared to other progestins (intrauterine levonorgestrel (LNG)Citation23, oral chlormadinone acetate (CMA)Citation18,Citation22, oral MPACitation15,Citation16). The regimen of combined MHT differed, ranging from continuously combined MHT (28 days per cycle/whole month), intermittently combined MHT (25 days per cycle followed by a 5-day hormone break) to sequentially combined MHT (continuous estrogen therapy combined with a progestogen for 10–14 days per cycle/month). Endometrial biopsies were taken at the end of all trials and also at baseline in all but four studiesCitation14,Citation19–21. Evaluation of tissue biopsies differed tremendously. Histomorphology was the most common method used to differentiate between proliferative, secretory and atrophic endometriumCitation10–14,Citation16–20,Citation22–26, and, if applicable, normal, hyperplastic and cancerous endometriumCitation10,Citation11,Citation15,Citation19–21,Citation24. Treatment success may be defined as yielding an atrophic, inactive or secretory endometrium whereas treatment failure corresponds to a proliferative endometrium response or hyperplasiaCitation22. In addition, some investigators assessed histomorphometryCitation17, mitotic countCitation14,Citation26, mitotic indexCitation20, DNA synthesisCitation26, proliferation index (MIB)Citation24, or used transmission electron microscopy and biochemistry markersCitation19.
Treatment success by oral MP was reported by 11 studiesCitation10–14,Citation16,Citation18,Citation19,Citation22,Citation24,Citation25. Seven studies used a continuousCitation11,Citation12,Citation16 or intermittentCitation10,Citation14,Citation24,Citation25, and four studies a sequentialCitation13,Citation18,Citation19,Citation22 MHT regimen. Treatment success was achieved by MP 100–400 mg/day if an intermittent MHT regimen was appliedCitation10,Citation12,Citation14,Citation16,Citation24,Citation25. However, absolute numbers ranged between 3.8% (MP 100 mg/day)Citation14 and 100% (MP 200 mg/day)Citation12 for atrophic, and between 0% (MP 200 mg/day)Citation12 and 64% (MP 400 mg/day)Citation24 for secretory endometrium, while a proliferative or mildly active endometrium was found in 0% (MP 100–200 mg/day)Citation12 to 23.1% (MP 100 mg/day)Citation14. Accordingly, treatment success was achieved with a sequential MHT regimen if MP 200–300 mg/day was appliedCitation13,Citation18,Citation19,Citation22. In detail, the endometrium was found to be atrophic in 20.8%Citation22 to 56% (MP 200 mg/day)Citation13, secretory in 62.5% (MP 200 mg/day)Citation18,Citation22 to 83% (MP 300 mg/day)Citation19 and proliferative in 8.3%Citation22 to 31%Citation13 (MP 200 mg/day). In contrast, other studies found an insufficient endometrial transformation if oral MP was applied intermittently or continuously at 100–200 mg/dayCitation23,Citation26 or sequentially at 100–300 mg/dayCitation17,Citation19,Citation20. The heterogeneity of results and their interpretation by the authors may be attributed to the differences between cohorts, study designs, endometrium evaluation techniques, thresholds for treatment success, and also to the lack of sufficient correlation between histomorphology and endometrial safety. For example, the lack of complete glandular and stromal progestational changes has not been found to be associated with any detectable impairment in antiproliferative effects. Thus, the inhibition of endometrial proliferation may be dissociated from secretory maturational changesCitation20 and therefore a complete secretory maturation may not be required for the prevention of hyperplasiaCitation14. Jondet and colleagues even stated that the histological classification using proliferative and secretory items does not represent the physiological aspects seen in normal cycles but rather indicates whether the pathologist is able to detect any progestogenic actionCitation18.
That said, it might be more revealing to assess the prevalence of endometrial hyperplasia in endometrium biopsies. Two small (n = 40–50)Citation10,Citation11,Citation19, one short (4 months)Citation24 and one study using an extended cycle regimen (MP every 6 months)Citation21 reported one case with (simple) hyperplasia eachCitation21,Citation24, or an 1% increase of the prevalence of simple hyperplasiaCitation10,Citation11, respectively, using a sequentiallyCitation19 or quasi continuously combined MHTCitation7,Citation8 with MP 100 mg/day. In contrast, the study with the longest intervention (5 years) did not find any case of endometrial hyperplasia or carcinoma in women having applied an 17β-estradiol (E2) patch sequentially combined with MP 200 mg/dayCitation20. However, there were only 53 endometrial biopsies with adequate tissue in 153 women completing the study. Thus, the largest study to date (n = 596) is the placebo-controlled RCT Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) with a 3-year intervention phase using a sequentially combined MHT with MP 200 mg/day among othersCitation15. In this study, all combined MHT regimens were effective in preventing hyperplasia comparable to placebo.
Endometrial cancer incidence
Endometrial cancer incidence in respect to MHT containing oral MP was assessed by two prospective cohort studies, the European Prospective Investigation into Cancer and Nutrition study (EPIC)Citation7 and the E3NCitation8, with E3N being the French cohort of EPIC. The sample size ranged from 65 630Citation8 to 115 474Citation7 postmenopausal women; the mean follow-up was 9.0Citation7 and 10.8Citation8 years, respectively. A self-administered questionnaire containing information on MHT use was sent to participants once at baselineCitation7 or every 2–3 yearsCitation8. Within the E3N cohort, a woman who successively took different types of MHT simultaneously contributed to each category. The study designs did not include gynecological examinations. Information on the type of estrogen–progestogen therapy (EPT) regimen (sequential or continuous) was available for 61% of EPT users in EPICCitation7 and missing in E3NCitation8. Data on adherence to medication, prescription and diagnostic bias were not assessed. While E3N only included EPT users with oral MP, EPIC did not differentiate between oral, vaginal and transdermal MP application. MP dosage was not reported in both, EPIC and E3N. Mean duration of EPT use was 2.5 years in EPIC (irrespective of progestogen constituent)Citation7, and 4.2 years in users of MP-containing EPT in E3NCitation8. During follow-up, 601Citation7 and 301Citation8 incident endometrial cancers were reported (e.g. self-report, population cancer registries, health insurance records). Tumor histology was reported in EPICCitation7 (not in E3N) and tumor stage in E3NCitation8 (not in EPIC). In current users of MP-containing EPT, there were 26 endometrial cancer cases in EPIC (2231 non-cases) and 54 cases in E3N (number of non-cases not given). Current use of MP-containing EPT was associated with a significantly increased risk of endometrial cancer in both, EPIC (hazard ratio (HR) 2.42; 95% confidence interval (CI) 1.53–3.83)Citation7 and E3N (HR 1.96; 95% CI 1.41–2.73)Citation8. The impact of treatment duration was only analyzed in E3N, showing an increased risk after more than 5 years of use but not belowCitation8. Endometrial cancer risk was not assessed in respect to tumor histology, specifically to hormone dependency or independency of the tumor. There is only one 4-year RCT, the Kronos Early Estrogen Prevention Study (KEEPS), comparing oral sequential MHT containing MP (200 mg/day) to placeboCitation9. The incidence of endometrial cancer was assessed as an adverse event. There was no significant difference in endometrial cancer cases between MHT users (n = 3) and placebo (n = 0).
Vaginal application of MP
The effect of vaginal MP on the endometrium has been assessed by TVUSCitation5,Citation27–36, endometrial biopsyCitation23,Citation27–39 and endometrial cancer incidenceCitation40 ().
Table 3. Overview of trials investigating menopausal hormone therapy (MHT) containing vaginal micronized progestin (MP).
Endometrial thickness
Endometrial thickness measured by TVUS was assessed in 11 studiesCitation5,Citation27–36 of which four were RCTsCitation5,Citation27,Citation28,Citation34. In RCTs, vaginal MP was either compared at different dosagesCitation5,Citation28,Citation34 or to intrauterine LNGCitation27. The sample size ranged from 20Citation32,Citation36 to 136Citation29 postmenopausal women, and treatment duration from 21 daysCitation32 to 3 yearsCitation33. Estrogens were either applied as a vaginal ringCitation27,Citation28, orally in standard doseCitation29, or transdermally in standard doseCitation5,Citation27,Citation29,Citation31,Citation33–36 and low-doseCitation30. Vaginal MP was applied as either a capsule or gel at different dosages ranging from 45 mg/dayCitation29,Citation31, 100 mg/dayCitation5,Citation27,Citation30,Citation33,Citation35,Citation36 to 200 mg/dayCitation5,Citation32,Citation35 or as a vaginal ringCitation28,Citation34. Application regimens were either sequential (7–12 days/month)Citation5,Citation27,Citation29, intermittentCitation29–31,Citation33,Citation35,Citation36 or continuousCitation28,Citation32,Citation34. The method of endometrial thickness assessment was described by six authors onlyCitation5,Citation27,Citation30,Citation32,Citation33,Citation35. Endometrial thickness was measured at the maximal thickness of the endometrium in the longitudinal plane of the uterus, specified as double layer in some studiesCitation27,Citation30,Citation35. In most studies, endometrial thickness remained unchanged with a sequential (45 mg/dayCitation29, 100 mg/dayCitation27, 200 mg/dayCitation5) or intermittent (100 mg/dayCitation30,Citation33,Citation36,Citation35, 200 mg/dayCitation35) regimen. In contrast, three studies reported a significant increase of endometrial thickness with a sequential (100 mg/day5), intermittent (45 mg/dayCitation31) or continuous (vaginal MP ringCitation34).
Endometrial histology
Endometrial histology was assessed by biopsy in 14 studiesCitation23,Citation27–39 of which five were RCTsCitation27,Citation28,Citation34,Citation38,Citation39. In RCTs, vaginal MP was either compared at different dosagesCitation28,Citation34,Citation39 to oral MPA or transdermal norethisterone sacetate (NETA)Citation38 or to intrauterine LNGCitation27. Baseline biopsies were performed in all but four studiesCitation32,Citation33,Citation36,Citation37. In few studies, endometrial biopsies were only performed if indicated (e.g. suspect TVUS, uterine bleeding)Citation28–30. Endometrial biopsy procedure was described by all authors. The majority either used a pipelle de CornierCitation28,Citation30,Citation32,Citation34 or performed a hysteroscopy-guided targeted biopsyCitation29,Citation33,Citation36,Citation38. Others used a Novak’s curetteCitation31,Citation37, needle aspiration (pistolet method)Citation23,Citation35, Gynoscan methodCitation27 or vabra endometrial biopsyCitation39. The sample size ranged from 9Citation37 to 136Citation29 postmenopausal women, and treatment duration from 21 daysCitation32 to 3 yearsCitation33. Systemic estrogens at highCitation37, standardCitation23,Citation27,Citation29,Citation31,Citation33–36,Citation38,Citation39 or lowCitation30 dose were applied either orallyCitation29,Citation39, transdermallyCitation23,Citation27,Citation29–31,Citation33–38 or vaginallyCitation27,Citation28. Vaginal MP was applied as a capsule or as gel at different dosages ranging from 45 mg/dayCitation29,Citation31,Citation39, 90 mg/dayCitation39, 100 mg/dayCitation23,Citation27,Citation30,Citation33,Citation35–38 to 200 mg/dayCitation23,Citation32,Citation35, as intramuscular injectionCitation32 or a vaginal ringCitation28,Citation34. Application regimens were either sequential (7–12 days/month)Citation27,Citation29,Citation37,Citation38, intermittentCitation23,Citation29–31,Citation33,Citation35,Citation36,Citation39 or continuousCitation28,Citation34. Treatment successCitation22 was reported by the majority of studies, yielding a predominantly atrophic (intermittent MP 45 mg/dayCitation31, sequential or intermittent MP 100 mg/dayCitation30,Citation33,Citation36,Citation27,Citation38, MP vaginal ringCitation28,Citation34) or secretory (intermittent MP 45–90 mg/dayCitation39, sequentialCitation37,Citation38 or intermittent MP 100–200 mg/dayCitation23,Citation36 endometrial response. Treatment failureCitation22 was reported by three studies showing some proliferative endometrial responses (MP vaginal ringCitation34, sequential or intermittent MP 100–200 mg/dayCitation35,Citation38). Only one study reported a hyperplastic endometrium in 10% of women after 1 year without remarkable difference between groups (sequential vaginal MP cream 100 mg/day, oral MPA 10 mg/day, or transdermal NETA 0.25 mg/day)Citation38.
Endometrial cancer incidence
There was only one 5-year RCT, Early versus Late Intervention Trial with Estradiol (ELITE), comparing sequential MHT containing vaginal MP (45 mg/day) to placeboCitation40. The incidence of endometrial cancer was assessed as an adverse event. There was no significant difference in endometrial cancer cases between MHT users and placebo (preliminary data presented at World Congress of International Menopause Society, Cancun, 2014).
Transdermal application of MP
Five studies have been identified investigating the impact of transdermal MP on the endometriumCitation41–45 (). All but one studyCitation43 were RCTs, some of which had placeboCitation41 or a progestinCitation42 as comparator. Sample size ranged from 27Citation44,Citation45 to 54Citation43 postmenopausal women, and study duration from 4Citation41 to 48Citation43 weeks. Estrogens were applied either orallyCitation41,Citation42 or transdermallyCitation43–45 with the dosage falling either within the high-doseCitation44,Citation45 or moderate-doseCitation41–43 categoryCitation46. Transdermal MP cream was applied either sequentiallyCitation41,Citation44,Citation45 or continuouslyCitation42,Citation43, and the dosage ranged from 16 mg/day to 64 mg/dayCitation44,Citation45. Transvaginal ultrasound for endometrial thickness assessment was only performed in one studyCitation43 showing a significant increase when combining estrogens with transdermal MP cream. Endometrial biopsy was performed by all studies comparing pre- and post-treatment histology. While two studies indicated an adequate progesterone opposing effectCitation41,Citation42, the remainder did notCitation43–45. There were two cases of complex hyperplasiaCitation43 but no endometrial cancer was found.
Table 4. Overview of trials investigating menopausal hormone therapy (MHT) containing transdermal micronized progestin (MP).
Discussion
Current international guidelines on MHT recommend to combine a progestogen when using estrogen therapy in peri- and postmenopausal women with an intact uterus for endometrial protectionCitation2,Citation47–49. Progestogen addition should be continuous or sequential for at least 12 days per month, as recently again pointed out by the US Endocrine Society. However, long-term endometrial safety of sequential progestogen addition may be reduced since the combination of estrogens with MP (or dydrogesterone) is associated with an increased risk of endometrial cancer if used for more than 5 yearsCitation48. Yet, compliance, dosage and route of application of MP were not exactly known. Internationally, systemic MP is available at different dosages and routes of application. Also, indication and approval by regulatory authorities may differ from country to country. In Europe, systemic MP is available as a capsule (100 mg, 200 mg) for vaginal or oral application or as vaginal gel (8% corresponding to 90 mg).
During the last years, the debate about (compounded) bioidentical hormones has increased tremendouslyCitation50–52. Therefore, the aim of this international expert group was to provide recommendations on the use of estrogens combined with MP in postmenopausal women in respect to endometrial safety.
The European Medicines Agency (EMA) recommends endometrial biopsies at baseline and study closure as the gold-standard method for evaluation for endometrial hyperplasia during MHTCitation53. Per definition, a biopsy is evaluable if there is 'endometrial tissue sufficient for diagnosis'. Endometrial biopsies should be classified into the general classes of atrophic, proliferative, secretory, hyperplasia without atypia, hyperplasia with atypia, cancer and others. Biopsies with insufficient tissue for diagnosis may be categorized as 'atrophic endometrium' if the sonographic endometrial thickness is <5 mm. For a new MHT, combination studies of at least 12 months' duration are required. The upper limit of the 95% confidence interval of the incidence of hyperplasia or carcinoma should not exceed 2% after 1 year, requiring a sample size of 300 patients.
For oral MP, there are only three RCTs following EMA’s guidelineCitation15,Citation18,Citation22 All studies used sequential (12–14 days/month) MP at 200 mg/day for either 1.5Citation18,Citation22 or 3Citation15 years. When comparing sequential CMA (10 mg/day) to sequential MP (200 mg/day), CMA provided a more complete progestogenic transformationCitation18,Citation22. However, according to the PEPI trial, sequential MP (200 mg/day) provided adequate endometrial protection for up to 3 years, comparable to sequential or continuous MPACitation15. When further taking into account the results from KEEPS (sequential MP at 200 mg/day for 4 years)Citation9 and E3NCitation8, the panel concluded that in postmenopausal women combining estrogens with sequential (12–14 days/month) oral MP at 200 mg/day (EMA approval) for up to 5 years provides sufficient endometrial protection. If oral MP is to be applied continuously, the initial dosage should also be 200 mg/day. This dose may be lowered off-label to 100 mg/day if an (ultra-) low-dose estrogen therapy has been chosen and amenorrhea persists.
For vaginal MP, no study completely followed EMA’s guideline and gained approval as an adjunct to menopausal estrogen therapy. However, six studies investigated vaginal MP for at least 1 year and performed endometrial biopsies at baseline and at study closureCitation23,Citation27,Citation31,Citation35,Citation36,Citation38. Vaginal MP (45–200 mg/day) was applied either sequentially (7–12 days/month)Citation27,Citation38 or intermittently (25 days/month)Citation23,Citation35,Citation36. The majority of investigators concluded that sequential vaginal MP (100–200 mg/day) was insufficient to produce an adequate endometrial responseCitation23,Citation35,Citation36,Citation38. When taking into account long-term studies (3–5 years)Citation33,Citation40, the use of sequential or intermittent vaginal MP does not seem to increase the risk of endometrial hyperplasia or cancer. However, due to the heterogeneity of studies and lack of sufficient data, the panel concluded that in postmenopausal women combining estrogens with sequential (4% corresponding to 45 mg/day on 10 days per month) or intermittent (100 mg every other day) vaginal MP for up to 3–5 years may be safe (off-label use). However, 4% MP vaginal gel is not available on the European market. Finally, the use of transdermal MP for endometrial protection cannot be recommended in postmenopausal women using estrogen therapy.
It remains difficult to interpret these data as there is a broad variety in study designs in terms of dosage per cycle, route of administration, clinical findings, sample size per protocol and even histological readings. Therefore, oral MP at 200 mg daily for at least 12 days per month is the preferred route, dose and duration for postmenopausal women with an intact uterus when using estrogen therapy for up to 5 years due to the currently available data. This conclusion seems to be applicable also for the vaginal treatment route. However, this procedure remains off-label use.
Conclusion
Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on MHT do not specify on progestogen type, dosage, route of application and duration of safe use. Based on a systematic literature review on MP for endometrial protection, an international expert panel’s recommendations on MHT containing MP are as follows: (1) oral MP provides endometrial protection if applied sequentially for 12–14 days/month at 200 mg/day for up to 5 years; (2) vaginal MP may provide endometrial protection if applied sequentially for 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3–5 years (off-label use); (3) transdermal MP does not provide endometrial protection.
Source of funding
This publication was developed by an expert board from Austria, Germany and Switzerland. The board meeting was funded by Dr. Kade/Besins Pharma GmbH without influence on the content.
Acknowledgements
The authors are grateful for the support of Dr. Kade/Besins Pharma GmbH for helping with ordering the identified publications.
Conflict of interest
The authors have been part of an German-speaking expert board funded by Dr. Kade/Besins Pharma GmbH. The authors alone are responsible for the content and writing of the paper.
References
- Csapo AI, Pulkkinen M. Indispensability of the human corpus luteum in the maintenance of early pregnancy. Luteectomy evidence. Obstet Gynecol Surv 1978;33:69–81
- de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316–37
- Ruan X, Mueck AO. Systemic progesterone therapy – oral, vaginal, injections and even transdermal? Maturitas 2014;79:248–55
- Birkhauser MH, Panay N, Archer DF, et al. Updated practical recommendations for hormone replacement therapy in the peri- and postmenopause. Climacteric 2008;11:108–23
- 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
- Di Carlo C, Sammartino A, Di Spiezio Sardo A, et al. Bleeding patterns during continuous estradiol with different sequential progestogens therapy. Menopause 2005;12:520–5
- Allen NE, Tsilidis KK, Key TJ, et al. Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am J Epidemiol 2010;172:1394–403
- Fournier A, Dossus L, Mesrine S, et al. Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992–2008. Am J Epidemiol 2014;180:508–17
- Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249–60
- Bolaji II, Mortimer G, Grimes H, Tallon DF, O'Dwyer E, Fottrell PF. Clinical evaluation of near-continuous oral micronized progesterone therapy in estrogenized postmenopausal women. Gynecol Endocrinol 1996;10:41–7
- Bolaji II, Mortimer G, Grimes H, O'Dwyer EM. Endometrial response in oestrogenised postmenopausal women after treatment with oral progesterone: results of a prospective analysis. J Obstet Gynaecol 1992;12:412–17
- Darj E, Nilsson S, Axelsson O, Hellberg D. Clinical and endometrial effects of oestradiol and progesterone in post-menopausal women. Maturitas 1991;13:109–15
- Dupont A, Dupont P, Cusan L, et al. Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women. Maturitas 1991;13:297–311
- Gillet JY, Andre G, Faguer B, et al. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. A multicenter study. Maturitas 1994;19:103–15
- 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. JAMA 1996;275:370–5
- Hargrove JT, Maxson WS, Wentz AC, Burnett LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol 1989;73:606–12
- Holst J, Cajander S, von Schoultz B. Endometrial response in post-menopausal women during treatment with percutaneous 17 beta-oestradiol opposed by oral progesterone. Maturitas 1986;8:201–7
- Jondet M, Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Pelissier 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
- Lane G, Siddle NC, Ryder TA, Pryse-Davies J, King RJ, Whitehead MI. Dose dependent effects of oral progesterone on the oestrogenised postmenopausal endometrium. Br Med J (Clin Res Ed) 1983;287:1241–5
- 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
- Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA 2003;290:1042–8
- Pelissier 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
- Suvanto-Luukkonen E, Sundstrom 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
- Moyer DL, Felix JC, Kurman RJ, Cuffie CA. Micronized progesterone regulation of the endometrial glandular cycling pool. Int J Gynecol Pathol 2001;20:374–9
- Marengo M, Rodriguez Vidal V, Deza EG. Hormonal replacement therapy (HRT). Evaluation of a novel 25 days regimen with percutaneous estradiol (PE2) and micronized oral progesterone (MP). PAMI Institution: Sarmiento 373, Rosario, Argentina, 2000
- Foidart JM, Dombrowicz N, Greimers R, Smet M, de Lignieres B. Endometrial tolerance of long-term combined hormone replacement therapy: analysis of the cell cycle. In von Schoultz B, Christiansen C, eds. Hormone Replacement Therapy: standardized or Individually Adjusted Doses? Lancaster, UK: Parthenon Publishing, 1993:47–58
- Antoniou G, Kalogirou D, Karakitsos P, Antoniou D, Kalogirou O, Giannikos L. Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints versus estradiol-releasing vaginal ring with a vaginal progesterone suppository: clinical and endometrial responses. Maturitas 1997;26:103–11
- Ben-Chetrit A, Hochner-Celnikier D, Lindenberg T, et al. Vaginal ring delivering estradiol and progesterone: a possible alternative to relieve climacteric symptoms. Isr Med Assoc J 2005;7:302–6
- de Ziegler D, Ferriani R, Moraes LA, Bulletti C. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens. Hum Reprod 2000;1(Suppl 1):149–58
- Fernandez-Murga L, Hermenegildo C, Tarin JJ, Garcia-Perez MA, Cano A. Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol. Climacteric 2012;15:455–9
- Cicinelli E, de Ziegler D, Galantino P, 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
- Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril 1994;62:485–90
- 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
- Noe G, Sitruk-Ware R, Zegers-Hochschild F, et al. Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women. Climacteric 2010;13:433–41
- Suvanto-Luukkonen E, Malinen H, Sundstrom 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
- Vilodre LC, Osorio Wender MC, Sisson de Castro JA, et al. Endometrial response to a cyclic regimen of percutaneous 17beta-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension. Gynecol Endocrinol 2003;17:323–8
- Cicinelli E, Borraccino V, Petruzzi D, Mazzotta N, Cerundolo ML, Schonauer LM. Pharmacokinetics and endometrial effects of the vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women. Fertil Steril 1996;65:860–2
- 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
- Ross D, Cooper AJ, Pryse-Davies J, Bergeron C, Collins WP, Whitehead MI. Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am J Obstet Gynecol 1997;177:937–41
- Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause 2015;22:391–401
- Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003;79:221–2
- Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005;11:36–8
- Vashisht A, Wadsworth F, Carey A, Carey B, Studd J. Bleeding profiles and effects on the endometrium for women using a novel combination of transdermal oestradiol and natural progesterone cream as part of a continuous combined hormone replacement regime. BJOG 2005;112:1402–6
- Wren BG, McFarland K, Edwards L. Micronised transdermal progesterone and endometrial response. Lancet 1999;354:1447–8
- Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000;3:155–60
- Jane FM, Davis SR. A practitioner's toolkit for managing the menopause. Climacteric 2014;17:564–79
- Sarri G, Davies M, Lumsden MA, Guideline Development Group. Diagnosis and management of menopause: summary of NICE guidance. BMJ 2015;351:h5746
- Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100:3975–4011
- North American Menopause. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause 2012;19:257–71
- Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause 2015;22:926–36
- Pinkerton JV. Think twice before prescribing custom-compounded bioidentical hormone therapy. J Womens Health (Larchmt) 2014;23:631–3
- Pinkerton JV. What are the concerns about custom-compounded “bioidentical” hormone therapy? Menopause 2014;21:1298–300
- Committee for Medicinal Products for Human Use European Medicines Agency. Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. EMEA/CHMP/021/97 Rev. 1, October 2005