Dr. Ron’s Research Review – May 13, 2020

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This week’s research review focuses on bleeding during HRT.

There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today. (Dören, 2000)

Adjusting the Regimen

Abnormal bleeding with progesterone/progestogen only, combined sequential, or combined continuous regimens may be corrected by changing the progestogen, adjusting the progestogen or estrogen/progestogen doses, or even switching the initial regimen to other formulation. (de Medeiros et al., 2013)

Estriol and Estradiol

Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. (Dören, 2000)
An older review found that single daily treatment with intravaginal estriol in the recommended doses in postmenopausal women is safe and without an increased risk of endometrial proliferation or hyperplasia. (Vooijs and Geurts, 1995) (Coelingh Bennink, 2004)

Minimum Dose of Progestogen

Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia. (Furness et al., 2012)
A review identified the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo.
Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events).

Minimize Risk

To minimize the risk of endometrial neoplastic proliferation the following is recommended: (1) to give a weak estrogen, like estriol, thus avoiding proliferation of the endometrium; (2) to give estrogens cyclically giving the endometrium a chance to regress during the pause of medication, and (3) to add progestogenic compounds to change the proliferative state into a secretory state. So far secretory states of the endometrium have not been suspected of being pre-cancerous; (4) to give the patient a regular check-up with a curettage if an irregular bleeding occurs. (Myhre, 1977)

Transvaginal Sonography

Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. (Dören, 2000)

 

Dr. Ron

 


Articles

 

Are all estrogens the same
            (Coelingh Bennink, 2004)  Download
This paper focuses on the question whether different estrogens (E) have different qualitative pharmacodynamic effects when used by women for contraception, Hormone Replacement Therapy (HRT) or prevention of osteoporosis. In this context estrogens have been defined as the estrogen agonists estradiol (E2), estrone (E1), estriol (E3), conjugated equine estrogens (CEE), diethylstilbestrol (DES) and ethinylestradiol (EE). Selective Estrogen Receptor Modulator's (SERM's) have been excluded from this analysis primarily because of lack of comparative (clinical) data with estrogen agonists. A major problem when addressing the issue of comparability of estrogen agonists is the lack of data from head-to-head estrogen-only comparative studies. Comparative studies have been performed almost exclusively with estrogen agonists combined with a series of different progestogens (P), that have been added to protect the uterus from endometrial hyperplasia. Since progestogens are known to exhibit different intrinsic pharmacodynamic properties and interactions with estrogens, it is impossible to judge which role the estrogen plays when qualitative differences between different combined E/P preparations are observed. In summary, no convincing evidence has been found that the estrogens mentioned differ qualitatively. Obviously quantitative differences are present due to differences in e.g. receptor affinity, metabolism (half life) and route of administration (transdermal/vaginal). Since DES has been discarded for human use due to teratogenicity, EE used in all combined E/P oral contraceptives is the most potent estrogen agonist available at present. In HRT, E2 and CEE are equally effective for the treatment of hot flushes and urogenital atrophy and superior to any other treatment option. For long term treatment to prevent osteoporosis and even for short term HRT, estrogen agonists are heavily debated recently because of a small increased risk of breast cancer, that has been known for a long time already. Well informed and individualised choice of treatment seems the appropriate solution.

Abnormal bleeding during menopause hormone therapy: insights for clinical management.
            (de Medeiros et al., 2013)  Download
OBJECTIVE:  Our objective was to review the involved mechanisms and propose actions for controlling/treating abnormal uterine bleeding during climacteric hormone therapy. METHODS:  A systemic search of the databases SciELO, MEDLINE, and Pubmed was performed for identifying relevant publications on normal endometrial bleeding, abnormal uterine bleeding, and hormone therapy bleeding. RESULTS:  Before starting hormone therapy, it is essential to exclude any abnormal organic condition, identify women at higher risk for bleeding, and adapt the regimen to suit eachwoman's characteristics. Abnormal bleeding with progesterone/progestogen only, combined sequential, or combined continuous regimens may be corrected by changing the progestogen, adjusting the progestogen or estrogen/progestogen doses, or even switching the initial regimen to other formulation. CONCLUSION:  To diminish the occurrence of abnormal bleeding during hormone therapy (HT), it is important to tailor the regimen to the needs of individual women and identify those with higher risk of bleeding. The use of new agents as adjuvant therapies for decreasing abnormal bleeding in women on HT awaits future studies.

Hormone therapy in postmenopausal women and risk of endometrial hyperplasia.
            (Furness et al., 2012)  Download
BACKGROUND:  Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well-being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo. OBJECTIVES:  The objective of this review is to assess which hormone therapy regimens provide effective protection against the development of endometrial hyperplasia or carcinoma. SEARCH METHODS:  We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2012), The Cochrane Library (Issue 1, 2012), MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), Current Contents (1993 to May 2008), Biological Abstracts (1969 to 2008), Social Sciences Index (1980 to May 2008), PsycINFO (1972 to January 2012) and CINAHL (1982 to May 2008). Attempts were made to identify trials from citation lists of reviews and studies retrieved, and drug companies were contacted for unpublished data. SELECTION CRITERIA:  Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen-progestogen therapy, sequential estrogen-progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted. DATA COLLECTION AND ANALYSIS:  In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta-analysis for many outcomes. MAIN RESULTS:  Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events). AUTHORS' CONCLUSIONS:  Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia.


 

Endometrial response to different estrogens.
            (Myhre, 1977)  Download
To minimize the risk of endometrial neoplastic proliferation I advise the following: (1) to give a weak estrogen, like estriol, thus avoiding proliferation of the endometrium; (2) to give estrogens cyclically giving the endometrium a chance to regress during the pause of medication, and (3) to add progestogenic compounds to change the proliferative state into a secretory state. So far secretory states of the endometrium have not been suspected of being pre-cancerous; (4) to give the patient a regular check-up with a curettage if an irregular bleeding occurs.

Review of the endometrial safety during intravaginal treatment with estriol.
            (Vooijs and Geurts, 1995)  Download
To gain more insight into whether intravaginal treatment of local urogenital complaints with the mild-acting oestrogen estriol is capable of inducing proliferation of the endometrium, the results of the clinical studies that have been published over the years have been pooled. Of a total of 19 studies that initially had been selected, four were excluded from the analysis because no baseline biopsies were available, two because endometriae had been evaluated using methods other than with histology, and one study because a sustained-release preparation was used. Pooling of 12 studies (214 subjects) revealed a reasonable amount of long-term data on intravaginal estriol treatment with 61 evaluable biopsies after 6 months and 58 after 12 months. In addition, 13 biopsies were available after 2 years. It appeared that intravaginal estriol treatment using the recommended dosages did not result in endometrial proliferation. All 337 post-baseline biopsies that have been reported in the literature were classified as atrophic. It can be concluded that single daily treatment with intravaginal estriol in the recommended doses in postmenopausal women is safe and without an increased risk of endometrial proliferation or hyperplasia. Consequently, there is no need to add sequential progestogens with these preparations and no withdrawal bleedings will be induced.

 


References

Coelingh Bennink, HJ (2004), ‘Are all estrogens the same’, Maturitas, 47 (4), 269-75. PubMed: 15063479
de Medeiros, SF, MM Yamamoto, and JS Barbosa (2013), ‘Abnormal bleeding during menopause hormone therapy: insights for clinical management.’, Clin Med Insights Womens Health, 6 13-24. PubMed: 24665210
Dören, M (2000), ‘Hormonal replacement regimens and bleeding.’, Maturitas, 34 Suppl 1 S17-23. PubMed: 10759060
Furness, S, et al. (2012), ‘Hormone therapy in postmenopausal women and risk of endometrial hyperplasia.’, Cochrane Database Syst Rev, (8), CD000402. PubMed: 22895916
Myhre, E (1977), ‘Endometrial response to different estrogens.’, Front Horm Res, 5 126-44. PubMed: 208879
Vooijs, GP and TB Geurts (1995), ‘Review of the endometrial safety during intravaginal treatment with estriol.’, Eur J Obstet Gynecol Reprod Biol, 62 (1), 101-6. PubMed: 7493689