POSTMENOPOSAL HORMONE TREATMENT AFTER WHI RESEARCH
Prof. Dr. Fatih DURMUŞOĞLU

Pre and Current Menopause Management;;

vasomotor symptoms;

These complaints, which are seen in 70% of menopausal women, may be severe enough to impair their quality of life. Since the primary aim of the WHI studies was not to treat such complaints, the results of a small group in the study group were reported as secondary output. In current menopausal management, vasomotor complaints in the early perimenopausal and postmenopausal periods are considered the most important indication for starting hormone therapy(5)(6)(7).

Estrogen dosing;

Reduction in the risk of venous thromboembolism is achieved by choosing the lowest possible dose of Estrogen. Hot flashes are successfully treated even by reducing the doses used in the WHI study by ½ and ¼. Management of symptomatic vasomotor complaints with the lowest possible doses also reduces thromboembolic events that are dependent on estrogen doses(6)(7)(8).

Progestin use;

The use of Estrogen alone in women who have not undergone hysterectomy increases the risk of endometrial hyperplasia and cancer. The old and current approach remains the same here, and Estrogen continues to be necessary in women with a uterus in combination with Progesterone (E+P), not alone. In the WHI results, the risk of invasive breast cancer was higher in the group receiving E+P than in the group receiving only E. Medroxyprogesterone acetate in the WHI study was claimed to have a proliferative effect on the breast, and it was suggested that the preference should be made by Micronized progesterones. In addition to the positive effects of micronized progesterones on adequate endometrial protection, less vaginal bleeding and lipid profile, it is an important reason for preference that they are safer in breast tissue(9)(10)(11).

Hormone replacement (HRT) form;

It has been preferred over cyclic HRT application due to amenorrhea that occurs in continuous use. Features: Consecutive HRT reduces adherence to treatment in women over 50 years of age who are disturbed and worried about vaginal bleeding. Protocol searches and applications, such as giving as little progesterone as possible after WHI, appear as a current approach (12)(13).

The mode of administration of hormone replacement;

It is thought that pro-thrombotic factors lead to thrombotic events as a result of changes in hepatic transmission after oral estrogen use(14). Studies have been presented that estrogen has better effects on lipid profile, C-reactive protein, blood pressure and will be less risky in terms of stroke and cardiovascular disease. Systemic and vaginal estrogen therapy has been recommended for symptoms related to vulvar and vaginal atrophy. It has been suggested that oral estrogen doses are not always beneficial in terms of vaginal symptoms of the vulva due to keeping the doses as low as possible, instead the use of vaginal estrogen would be more appropriate (16).

Ospemifene has recently been approved in the United States as an oral selective estrogen uptake inhibitor for complaints related to local vaginal atrophy. There are not enough studies yet on how much risk it carries in terms of thromboembolism (17).

Progesterone-containing uterine devices provide local endometrial protection, giving the chance to administer oral or transdermal estrogen alone. Although there are sufficient data in terms of endometrial protection, the questions about the breast and systemic effects of Levonorgestrel, which is mixed into the serum in a small amount, are not fully answered (18)(19).

Within the framework of new developments, Tissue Selective Estrogen Complex (TSEC) creates selective properties in tissues with the combination of SERM and estrogen (20). These substances, which are free of unwanted proliferative properties on the breast and endometrium, but have positive effects on bone, especially vasomotor symptoms, seem to guide the treatment of menopause in the near future (21).

Conclusion and Current Status;

• Hormone replacement therapy is the most effective treatment for menopausal vasomotor symptoms before the age of 60 and in the first 10 years after menopause.
• Hormone replacement therapy is the most effective method of protection for menopausal-related osteoporotic fractures before the age of 60 and in the first 10 years following menopause.
• Randomized clinical studies, observational studies, and meta-analyses suggest that low-dose estrogen alone will result in a reduction in coronary heart disease and all-cause mortality rates. While there was a decrease in all-cause mortality in the groups given E+P, no statistically significant decrease or increase was detected in coronary heart diseases. The positive effects observed in these two groups are valid when the rule is applied before the age of 60 and within the first 10 years following menopause.
• The most effective approach in vulvar and vaginal symptoms is local estrogen administration regardless of age.
• The risk of venous thromboembolism and ischemic attacks may increase with oral hormone therapy. However, the absolute risk is rare under the age of 60. Observational studies suggest that this risk will be reduced with transdermal treatment.
• It is understood that the increase in breast cancer increases over time with the addition of progesterone to estrogen therapy. The increased risk due to hormone therapy appears to decrease with discontinuation of therapy.
• Hormone therapy should be administered within a targeted and acceptable timeframe. The safety rules regarding treatment should be applied on a case-by-case basis.
• In cases with early menopause, hormone therapy should be applied until the peer age group enters menopause.
• The use of bio-similar substances and herbal medicines is not recommended.
• Hormone therapy is not recommended in patients who have had breast cancer.
• Factors such as quality of life, personal risk factors, age, time from onset of menopause, venous thromboembolism, stroke, ischemic heart disease should be planned with a case-specific approach.
• Global Consensus Statement on Menopausal Hormone Therapy; CLIMACTERIC 2013;16:203–204

References;

1- Altman MA. Hormone replacement and quality of life:2 experts comment on the latest WHI findings. OBGMAN AG EMENT • May 2 0 0 3
2- Writing Group for the Women's Health Initiative Investigators. Risks and ben-efits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA2002;288:321–33.
3- Anderson GL, Limacher M, Assaf AR, et al., Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal womenwith hysterectomy: the Women's Health Initiative randomized controlled trial.JAMA 2004;291:1701–12.
4- Keating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. Use of hormone replacement therapy by postmenopausal women in the United States. AnnIntern Med 1999;130:545–53.
5- Daly EA, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ 1993;307:836–40.
6- Barnabei VM, Cochrane BB, Aragaki AK, et al., for the Women's Health Initiative Investigators. Menopausal symptoms and treatment-related effectsof estrogen and progestin in the Women's Health Initiative. Obstet Gynecol2005;105:1063–73
7- Maclennan A, Broadbent J, Lester S, Moore V. Oral estrogen and com-bined oestrogen/progestogen therapy versus placebo for hot flushes. CochraneDatabase Sys Rev 2004;4:CD002978.
8- Majmudar SR, Almasi EA, Stafford RS. Promotion and prescribing of hor-mone therapy after report of harm by the Women's Health Initiative. JAMA2004;292:1983.
9- Goletiani NV, Keith DR, Gorsky SJ. Progesterone: review of safety for clinical studies. Exp Clin Psychopharmacol 2007;15(October (5)):427–44.
10- Gompel A. Micronized progesterone and its impact on the endometrium andbreast vs. progestogens. Climacteric 2012;15(Suppl. 1):18–25.
11- Gadducci A, Biglia N, Cosio S, Sismondi P, Genazzani AR. Progestogencomponent in combined hormone replacement therapy in postmenopausalwomen and breast cancer risk: a debated clinical issue. Gynecol Endocrinol2009;25(December (12)):807–15 [Review].
12- North American Menopause Society. The 2012 hormone therapy posi-tion statement of The North American Menopause Society. Menopause2012;19(3):257–71.
13- Stuenkel CA, Gass MLS, Manson JE, et al. A decade after the women's health initiative – the experts do agree. Menopause 2012;19(8):1–2.
14- L'hermite M. HRT optimization, using transdermal estradiol plus micronizedprogesterone, a safer HRT. Climacteric 2013;16(Suppl. 1):44–53.
15- Laliberte F, Dea K, Dub MS, Kahler KH, Rolli M, Lefebvre P. Does the route ofadministration for estrogen hormone therapy impact the risk of venous throm-boembolism? Estradiol transdermal system versus oral estrogen-only hormonetherapy. Menopause 2011;17:1052–9.
16- The North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position state-ment of The North American Menopause Society. Menopause 2007;14:357–69.
17- Elkinson S, Yang LP. Ospemifene: first global approval. Drugs 2013;73(6):605–12.
18- Gemzell-Danielsson K, Inki P, Heikinheimo O. Recent developments in the clini-cal use of the levonorgestrel-releasing intrauterine system. Acta Obstet GynecolScandinavica 2011;90:1177–88.
19- Lundström E, Söderqvist G, Svane G, et al. Digitized assessment of mam-mographic breast density in patients who received low-dose intrauterinelevonorgestrel in continuous combination with oral estradiol valerate: a pilotstudy. Fertil Sterile 2006;85(4):989–95.
20- Kagan R. The tissue selective estrogen complex: a novel approach to the treat-ment of menopausal symptoms. J Womens Health 2012;21:975–81.
21- Pinkerton JV, Komm BS, Mirkin S. Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model. Climacteric 2013June