Hormone replacement therapy

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Following the menopause the reduction in regular cycles of oestrogen release can cause troublesome symptoms for some women. As older women are at increased risk of complications such as coronary events and osteoporosis than their younger counterparts, HRT has been proposed to treat a number of "illnesses" of older women. However it is important to realise that age is a significant risk factor for other complications such as VTE and indeed use of HRT reduced markedly when results of studies in the more elderly were published.

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  1. That women with a uterus given exogenous oestrogen will always need a progestagen to prevent endometrial hyperplasia.
  2. Within 2 years of the menopause there is a still a risk of fertility and HRT is not effective as contraception in this circumstance.
  3. Mortality in long term use is in equipoise[1].
  4. Morbidity in long term[2] and late primary and secondary prevention in osteoporosis appear to outweigh benefits.

Contents

Use

  • Menopausal women whose lives are inconvenienced by vasomotor instability or vaginal atrophy
  • Reducing risk of osteoporosis. Especially in those with early natural or surgical menopause (<45) who are at the greatest risk and those with multiple risk factors.
  • Had been considered as reducing risk of ischaemic heart disease but actually unlikely to be benefical [3][4].

Proposed benefits

  • Amelioration / reversal of menopausal effect is beneficial
  • Reduced osteoporosis. While is beneficial for the indication alone, the net effect is unlikely to be benefical
  • Reduction in myocardial infarction but in fact unlikely to be benefical [3]
  • Reduced risk of Alzheimer's Disease but in fact unlikely to be benefical[5]

Risk Benefit Analysis

This is complex, being a function of individual age, risk of various diseases and product used. In the decade up to 59 years of age there is a net mortality benefit of about 1 in 5000 per year (just statistically significant) but by the 70 to 79 age group oestogen therapy alone could be killing up to 13 in 5000 per year (HR=1.21 (95% CI 0.95-1.56). Problematically this ends up with no net benefit [6] and much of the quoted literature on such trends has data which does not reach even the 95%CI which is less appropriate perhaps than 99%CI given the multiple comparisons[7]. However some data from the big trials is consistent with outcomes from other datasets, sometimes on the same patients[8], so does probably have real meaning. Some associations such as with cognitive deterioration in those prediposed to diabetes mellitus on oestrogens only became apparent on secondary analysis[9]. The issues have been recently reviewed in a wider context including oral contraceptive data[10]. Some risks/benefits are almost immediately manifest, others can persist for a while and then you have catch up, and others such as fracture risk reduction seem to persist for over 10 years.

Difference in event rate/1000 women over 5 years between placebo and either conjugated equine oestogen alone and medroprogesterone acetate combined with conjugated equine oestogen for women(95% statistically significant results in bold ![6])
Event Conjugated equine oestogen Medroprogesterone acetate combined with conjugated equine oestogen
Nonfatal myocardial infarction or coronary death -2.0 1.5
Any stroke 2.5 2.5
Pulmonary embolism 1.0 2.0
Invasive breast cancer -3.5 4.5
Colorectal cancer -1.5 1
All cancer -4 2.5
Hip fracture -1.0 -2.5
Diabetes mellitus -5.0 1.5
Death from any cause -0.5 -0.5

Options

  • Unopposed oestrogens - after hysterectomy
  • Cyclic progestagens - bleeding every 1, 3 or 6 months
  • Continuous progestagens - but not within one year of menopause, 10% get continuous spotting

Administration

  • Oral - but large 1st pass effect on liver
  • Transdermal patch
  • Transdermal gel
  • Implants
  • Topical / Vaginal

Alternatives

  • Raloxifene
    • Selective oestrogen receptor modifier, no effect on endometrium, prevents osteoporosis

Contra-indications

Cautions

Side-effects

  • Increased risk of:
    • Breast cancer - is likely to be ineffective or harmful - there has been a worldwide fall in age specific breast cancer incidence in those over 50 years after this risk was recognised in 2001[11]
    • Endometrial cancer
    • Venous thromboembolism / Pulmonary Embolism is likely to be ineffective or harmful[4]
    • Stroke is likely to be ineffective or harmful[4]
  • Nausea and vomiting
  • Abdominal cramps and bloating
  • Weight changes
  • Breast enlargement and tenderness
  • Premenstrual-like syndrome
  • Sodium and fluid retention
  • Changes in liver function
  • Changes in libido
  • Depression
  • Headache, migraine and dizziness.

References

  1. Wise J. No overall increase in all cause mortality with HRT, study finds. BMJ : British Medical Journal. 2017 Sep; 358:j4230.(Electronic) (Link to article – subscription may be required.)
  2. <Farquhar CM, Marjoribanks J, Lethaby A, Lamberts Q, Suckling JA. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane database of systematic reviews (Online). 2005; (3):CD004143.(Epub) (Link to article – subscription may be required.)
  3. a b Gabriel SR, Carmona L, Roque M, Sánchez GL, Bonfill X. Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women. Cochrane database of systematic reviews (Online). 2005; (2):CD002229.(Epub) (Link to article – subscription may be required.)
  4. a b c Sare GM, Gray LJ, Bath PM. Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. European heart journal. 2008 Aug; 29(16):2031-41.(Link to article – subscription may be required.)
  5. Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane database of systematic reviews (Online). 2008; (1):CD003122.(Epub) (Link to article – subscription may be required.)
  6. a b Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2; 310(13):1353-68.(Link to article – subscription may be required.)
  7. Prentice RL, Manson JE, Anderson GL, Lacroix AZ, Shumaker SA, Chlebowski RT, Howard BV, Stefanick ML, Jackson RD, Wactawski-Wende J, Rossouw JE. Women's health initiative view of estrogen avoidance and all-cause mortality. American journal of public health. 2013 Dec; 103(12):e2.(Link to article – subscription may be required.)
  8. Hlatky MA, Ray RM, Burwen DR, Margolis KL, Johnson KC, Kucharska-Newton A, Manson JE, Robinson JG, Safford MM, Allison M, Assimes TL, Bavry AA, Berger J, Cooper-DeHoff RM, Heckbert SR, Li W, Liu S, Martin LW, Perez MV, Tindle HA, Winkelmayer WC, Stefanick ML. Use of Medicare data to identify coronary heart disease outcomes in the Women's Health Initiative. Circulation. Cardiovascular quality and outcomes. 2014 Jan; 7(1):157-62.(Link to article – subscription may be required.)
  9. Espeland MA, Brinton RD, Hugenschmidt C, Manson JE, Craft S, Yaffe K, Weitlauf J, Vaughan L, Johnson KC, Padula CB, Jackson RD, Resnick SM. Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women. Diabetes care. 2015 Dec; 38(12):2316-24.(Link to article – subscription may be required.)
  10. Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Annals of epidemiology. 2015 Mar; 25(3):193-200.(Link to article – subscription may be required.)
  11. Canfell K, Banks E, Moa AM, Beral V. Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia. The Medical journal of Australia. 2008 Jun 2; 188(11):641-4.