Combined continuous hormone replacement therapy: A critical review

doi:10.1016/0029-7844(95)00115-8

Obstetrics & Gynecology

Volume 86, Issue 2, August 1995, Pages 306-316

https://doi.org/10.1016/0029-7844(95)00115-8 Get rights and content

Objective: To evaluate the putative benefits of combined continuous hormone replacement therapy for postmenopausal women.

Data Sources: A Medline search was performed for relevant English-language studies published during 1981–1995.

Method of Study Selection: Forty-two studies were identified, all using a continuous daily regimen of an estrogen and a progestin given to postmenopausal women with intact uteri.

Data Extraction and Synthesis: Each study was reviewed for the design, number of subjects enrolled, duration of protocol, and type and dosage of medications used. Data were extracted from texts, tables, figures, or personal communications regarding the effects of treatment on patient compliance (ie, drop-out rates), the occurrence of vasomotor symptoms, uterine bleeding patterns, endometrial histology, and lipid and bone density measurements. These data were then arranged in tabular form for the purpose of comparing and identifying trends. The lipid data from six randomized, double-blind studies that compared sequential and combined continuous regimens of conjugated equine estrogen and medroxyprogesterone acetate were further analyzed by meta-analysis. Findings revealed compliance rates of approximately 80% (range 35–100). Vasomotor symptoms improved almost universally. Irregular uterine bleeding was noted to be a common problem in the first 6 months of treatment; thereafter, most studies reported rates of amenorrhea of 75% or greater. In patients undergoing endometrial biopsy, rates of atrophic endometrium were noted to be 90–100%, and rates of endometrial hyperplasia were less than 1%. Adenocarcinoma of the endometrium was documented in two patients with a history of atypical endometrial hyperplasia and bleeding after established amenorrhea. The effects of treatment on lipid levels varied from study to study, but a meta-analysis revealed the combined continuous and sequential regimens to produce a treatmentassociated decline in total and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol. Studies examining bone density documented either no change or an increase with treatment.

Conclusion: Combined continuous hormone replacement is well accepted by patients in clinical trials, effective in relieving vasomotor symptoms, and produces amenorrhea (though often after an initial period of irregular bleeding), an atrophic endometrium, and favorable changes in circulating lipids as well as maintaining bone density. Data on the impact of this regimen on long-term patient compliance, cardiovascular disease risk, and urogenital atrophy are lacking.

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Cited by (118)

Guideline No. 422a: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition, and Lifestyle
2021, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
Breakthrough bleeding is the most common adverse event with MHT and is often cited as the reason for discontinuation within the first 3 to 12 months.68–70 Patients should be informed that it is normal to see breakthrough bleeding up to 6 months after starting continuous MHT, with most women having amenorrhea by 12 months (<10% of women report ongoing breakthrough bleeding).31,70 Heavy vaginal bleeding or continued breakthrough bleeding beyond 6 months should be investigated.
Provide strategies for improving the care of perimenopausal and postmenopausal women based on the most recent published evidence.
Perimenopausal and postmenopausal women.
Target population will benefit from the most recent published scientific evidence provided via the information from their health care provider. No harms or costs are involved with this information since women will have the opportunity to choose among the different therapeutic options for the management of the symptoms and morbidities associated with menopause, including the option to choose no treatment.
Databases consulted were PubMed, MEDLINE, and the Cochrane Library for the years 2002–2020, and MeSH search terms were specific for each topic developed through the 7 chapters.
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).
physicians, including gynaecologists, obstetricians, family physicians, internists, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; pharmacists; medical trainees, including medical students, residents, fellows; and other providers of health care for the target population.
- 1
  The vast majority of women in mid-life experience menopausal symptoms, the hallmark being vasomotor symptoms. A significant portion of these women have severe symptoms that greatly affect their quality of life (high).
- 2
  For the management of vasomotor symptoms, menopausal hormone therapy is the most effective option and can be safely initiated in women without contraindications who are younger than 60 years of age or less than 10 years post-menopause (high).
- 3
  Options for menopausal hormone therapy for vasomotor symptoms in women with a uterus include estrogen-progestogen therapy, a tissue-selective estrogen complex, or tibolone. Estrogen alone can be used in women who have had a hysterectomy (high).
- 4
  The safety and efficacy of compounded bioidentical hormone therapy have not been assessed with the same rigour as those of menopausal hormone therapy products approved by Health Canada (moderate).
- 5
  Non-hormonal prescription therapies, including certain antidepressant agents, gabapentinoids, clonidine, and oxybutynin, may offer some relief from hot flashes but have their own adverse effects (moderate).
- 6
  There is emerging evidence that cognitive behavioural therapy may have positive effects on vasomotor symptoms (high).
- 7
  There is insufficient evidence to support the effectiveness of any one natural health product for the management of moderate to severe hot flashes (low).
- 8
  A healthy diet during menopause can reduce the risk of future chronic conditions, aid in weight management, and improve energy levels (high).
- 1
  Health care providers should offer menopausal hormone therapy as the most effective option for managing vasomotor symptoms (strong, high).
- 2
  Menopausal hormone therapy can be safely initiated in women without contraindications who are younger than 60 years of age or less than 10 years post-menopause (strong, high).
- 3
  Menopausal hormone therapy should be individualized after careful consideration of symptoms, medical conditions, health risks, family history, treatment goals, patient preferences, and timing of last menstrual period (strong, high).
- 4
  Duration of menopausal hormone therapy should be individualized to the patient, based on ongoing symptoms, benefits, and personal risks. Periodic re-evaluation of menopausal hormone therapy is recommended (strong, high).
- 5
  Women who have experienced loss of ovarian function or with decreased ovarian function before the age of 45 years should consider replacement hormone therapy until the average age of menopause (strong, high).
- 6
  Estrogen-progestogen regimens can be continuous (i.e., estrogen-progestogen taken every day) or follow a cyclic regimen, with estrogen taken every day and progestogen taken for 12–14 days every month. In women with hysterectomy, estrogen alone can be taken every day (strong, high).
- 7
  Options for perimenopausal women include progestogen alone, low-dose combined hormonal contraceptives, menopausal hormone therapy, or estrogen in combination with a levonorgestrel-releasing intrauterine system. (strong, moderate)
- 8
  Non-hormonal prescription therapies can be considered when hormone therapy is contraindicated or not desired (strong, moderate).
- 9
  For cultural traditional therapies, women should be offered the opportunity to work with a cultural leader; health care providers can discuss this option in partnership with women, in order to ensure cultural humility and cultural safety (strong, moderate).
Directive clinique n<sup>o</sup> 422a : Ménopause : symptômes vasomoteurs, agents thérapeutiques d'ordonnance, médecines douces et complémentaires, nutrition et mode de vie
2021, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
La métrorragie constitue l'effet indésirable le plus fréquent du THM et est souvent mentionnée comme la raison de l'arrêt du traitement dans les 3 à 12 premiers mois68–70. Les patientes doivent savoir que la métrorragie est normale jusqu’à 6 mois après l'instauration d'un THM continu, la plupart des femmes ayant une aménorrhée à 12 mois ou avant (< 10 % des femmes déclarent une métrorragie persistante)31,70. Les saignements vaginaux abondants ou une métrorragie persistante au-delà de 6 mois doivent faire l'objet d'une évaluation.
Proposer des stratégies pour améliorer les soins aux femmes ménopausées ou en périménopause d'après les plus récentes données probantes publiées.
Femmes ménopausées ou en périménopause.
La population cible bénéficiera des plus récentes données scientifiques publiées que leur communiqueront les fournisseurs de soins de santé. Aucun coût ni préjudice ne sont associés à cette information, car les femmes seront libres de choisir parmi les différentes options thérapeutiques offertes pour la prise en charge des symptômes et morbidités associés à la ménopause, y compris l'abstention thérapeutique.
Les auteurs ont interrogé les bases de données PubMed, Medline et Cochrane Library pour extraire des articles publiés entre 2002 et 2020 en utilisant des termes MeSH spécifiques à chacun des sujets abordés dans les 7 chapitres.
Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique d’évaluation, de développement et d’évaluation (GRADE). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles).
médecins, y compris gynécologues, obstétriciens, médecins de famille, internistes, urgentologues; infirmières, y compris infirmières autorisées et infirmières praticiennes; pharmaciens; stagiaires, y compris étudiants en médecine, résidents, moniteurs cliniques; et autres fournisseurs de soins auprès de la population cible.
- 1
  La vaste majorité des femmes autour de la cinquantaine éprouvent des symptômes ménopausiques, les plus typiques étant les symptômes vasomoteurs. Une proportion importante de ces femmes éprouvent des symptômes sévères qui nuisent considérablement à leur qualité de vie (élevée).
- 2
  Le traitement hormonal de la ménopause est l'option la plus efficace pour la prise en charge des symptômes vasomoteurs; il peut être instauré en toute sécurité chez les femmes de moins de 60 ans ou ménopausées depuis moins de 10 ans en l'absence de contre-indications (élevée).
- 3
  Les options de traitement hormonal de la ménopause pour la prise en charge des symptômes vasomoteurs chez les femmes ayant un utérus sont l'hormonothérapie combinée (traitement œstroprogestatif), les complexes œstrogéniques à action tissulaire sélective ou la tibolone. L’œstrogène seul peut être utilisé chez les femmes ayant subi une hystérectomie (élevée).
- 4
  L'innocuité et l'efficacité de l'hormonothérapie à base d'hormones bio-identiques n'ont pas été évaluées avec la même rigueur que pour les produits de traitement hormonal de la ménopause approuvés par Santé Canada (moyenne).
- 5
  Les traitements non hormonaux d'ordonnance, tels que certains agents antidépresseurs, les gabapentinoïdes, la clonidine et l'oxybutynine, peuvent offrir un certain soulagement pour les bouffées de chaleur, mais ont leurs propres effets indésirables (moyenne).
- 6
  De nouvelles données probantes suggèrent que la thérapie cognitivo-comportementale peut avoir des effets positifs sur les symptômes vasomoteurs (élevée).
- 7
  Les données probantes sont insuffisantes pour appuyer l'efficacité de tout produit naturel pour la prise en charge des bouffées de chaleur modérées à sévères (faible).
- 8
  L'adoption d'une alimentation saine durant la ménopause peut réduire le risque de problèmes de santé chroniques ultérieurs, favoriser la gestion du poids et augmenter le niveau d’énergie (élevée).
- 1
  Les fournisseurs de soins de santé doivent offrir le traitement hormonal de la ménopause comme étant l'option thérapeutique la plus efficace pour la prise en charge des symptômes vasomoteurs (forte, élevée).
- 2
  Le traitement hormonal de la ménopause peut être instauré en toute sécurité chez les femmes de moins de 60 ans ou ménopausées depuis moins de 10 ans en l'absence de contre-indications (forte, élevée).
- 3
  Le traitement hormonal de la ménopause doit être individualisé après une analyse attentive des symptômes, de l’état de santé, des risques pour la santé, des antécédents familiaux, des objectifs thérapeutiques, des préférences de la patiente et du moment de la dernière menstruation (forte, élevée).
- 4
  La durée du traitement hormonal de la ménopause devrait être adaptée à la patiente, en fonction des symptômes persistants, des bienfaits continus et des risques personnels. Il est recommandé de réévaluer périodiquement le traitement hormonal de la ménopause (forte, élevée).
- 5
  Chez les femmes ayant connu une perte ou une diminution de la fonction ovarienne avant 45 ans, il y a lieu d'envisager une hormonothérapie substitutive jusqu’à l’âge moyen de la ménopause (forte, élevée).
- 6
  Les schémas de l'hormonothérapie combinée (traitement œstroprogestatif) peuvent être continus (traitement œstroprogestatif quotidien) ou cycliques (œstrogénothérapie quotidienne avec prise de progestatifs pendant 12 à 14 jours chaque mois). L’œstrogénothérapie quotidienne est indiquée chez les femmes ayant subi une hystérectomie (forte, élevée).
- 7
  Pour les femmes en périménopause, les options sont l’œstrogénothérapie, la contraception hormonale combinée à faible dose, le traitement hormonal de la ménopause ou l’œstrogénothérapie en combinaison avec un système intra-utérin à libération de lévonorgestrel (forte, moyenne).
- 8
  Il y a lieu d'envisager les traitements non hormonaux d'ordonnance lorsque l'hormonothérapie est contre-indiquée ou n'est pas souhaitée (forte, moyenne).
- 9
  Il convient d'offrir aux femmes qui souhaitent un traitement traditionnel propre à leur culture l'occasion d’être accompagnée par un leader culturel. Les fournisseurs de soins de santé devraient discuter de cette possibilité avec les patientes afin d'assurer l'humilité et la sécurisation culturelles (forte, moyenne).
Chapitre 7: Prise en charge continue des femmes ménopausées et de celles qui présentent des considérations particulières
2019, Journal of Obstetrics and Gynaecology Canada
Chapter 7 Ongoing Management of Menopausal Women and Those With Special Considerations
2014, Journal of Obstetrics and Gynaecology Canada
Comparison of a transdermal continuous combined and an interrupted progestogen HRT
2006, Maturitas
Pilot study to compare the effects of a continuous combined hormone replacement therapy (HRT) regimen with an interrupted progestogen regimen administered transdermally, upon the endometrium of postmenopausal women, the incidence of amenorrhoea and relief of menopausal symptoms.
Fifty-nine postmenopausal women aged 50–63 years were randomised to either (i) continuous combined regimen: combined oestrogen/progestogen skin patches (releasing continuous 50 μg estradiol and 20 μg levonorgestrel/day) or (ii) interrupted regimen: oestrogen-only patches (releasing 80 μg estradiol/day) for 4 days followed by combined oestrogen/progestogen patches (releasing continuous 50 μg estradiol and 20 μg levonorgestrel/day) for 3 days, for 6 months. An endometrial biopsy was performed at end of treatment for histological analysis.
Thirty-three women (56%) completed the study. Significantly higher rates of amenorrhoea were observed with the interrupted than continuous combined regimen (P < 0.0001; 25% versus 7% at 6 months). The interrupted regimen was also associated with fewer days of bleeding overall (total 20 versus 44 days during months 4–6; P = 0.001). Both regimens improved vasomotor symptoms. No endometrial hyperplasia or atypical changes were observed in endometrial biopsies.
Although significantly less bleeding was observed with the interrupted regimen, it did not have a sufficiently high incidence of amenorrhoea to render it clinically useful.
Ovarian aging and bone metabolism in menstruating women aged 35-50 years
2005, Maturitas
The aim of this study was to investigate the relationships between the levels of gonadotrophins, estradiol, inhibin-b and bone mass and turn-over in regularly menstruating women aged 35–50 years.
The study group included 87 healthy volunteers from the community aged 35–50 years. Bone mineral density of lumbar vertebras, wards triangle, throchanter, femur neck, bone resorption and formation markers were studied as well as the serum levels of gonadotrophins, estradiol and inhibin-b on the day 3 of menstrual cycle.
The gonadotrophin levels showed significant positive relation with age, whereas inhibin-b and estradiol levels showed significant negative correlation with age. The gonadotrophins and estradiol levels had no significant association with bone mass and bone formation markers. Increased gonadotrophin (p < 0.001) levels and decreased inhibin-b (p < 0.01) levels independent from age were correlated with increased bone resorption. Gonadotrophins, estradiol, age, inhibin-b, body mass index (BMI) were the confounding factors for bone resorption (p = 0.015, R² = 0.190) and lumbar bone mass (p = 0.041, R² = 0.148). Multivariate analysis showed an independent contribution of inhibin-b and BMI in the prediction of lumbar bone mass.
This findings suggested that estradiol was not the only factor responsible for bone loss and decrease in reproductive function because increased gonadotrophins and decreased inhibin-b levels might trigger some changes in bone metabolism prior to the menopause.

View all citing articles on Scopus

: We thank Trudy L. Bush, PhD, Rogerio A. Lobo, MD, and James H. Pickar, MD, for the use of raw data regarding the impact of combined continuous hormone replacement therapy on circulating lipoprotein levels obtained during their respective clinical trials.

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ReviewCombined continuous hormone replacement therapy: A critical review

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Hormone therapy to prevent disease and prolong life in postmenopausal women

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Prevalence and determinants of estrogen replacement therapy in elderly women

Am J Obstet Gynecol

Compliance difficulties with progestin-supplemented therapy

J Fam Pract

Use of estrogens among middle-aged Massachusetts women

DICP

Compliance with hormonal replacement therapy

Maturitas

Mechanisms of uterine bleeding in postmenopausal patients receiving estrogen alone or with a progestin

Obstet Gyneco1

The role and use of progestogens

Obstet Gynecol

Enhancing patient compliance with hormonal replacement therapy at menopause

Obstet Gynecol

The practicalities of hormone replacement

Baillieres Clin Endocrinol Metab

Menopause medicine: Current treatment options and trends

Compr Ther

Effects of hormonal replacement on lipids and lipoproteins in postmenopausal women

J Clin Endocrinol Metab

Lipid changes after hormone replacement therapy for menopause

J Reprod Med

Evaluation of low-dose estrogen and progestin therapy in postmenopausal women. A double-blind, prospective study of sequential versus continuous therapy

J Reprod Med

Review
Combined continuous hormone replacement therapy: A critical review