Female Hormone Replacement Therapy in Postmenopausal Women : Where are we today?

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1 UPDATE ARTICLE Female Hormone Replacement Therapy in Postmenopausal Women : Where are we today? AK Datta*, A Sundarka*, MK Sundarka**, P Shankar** Abstract Our knowledge of beneficial role of female sex hormone in postmenopausal women is expanding rapidly. Apart from the relief of menopausal symptoms, oestrogens have proved to be effective in prevention of cardiovascular disease and osteoporotic fractures the two leading causes of death in geriatric age. There is growing evidence that these hormones improve cognitive functions and thus, may arrest Alzheimers dementia. While oestrogen replacement therapy in elderly women is gaining momentum, the risk of breast and endometrial carcinoma, albeit small, exists. Venous thrombo-embolism is another concern. Judicious use of the hormones by appropriate route along with regular monitoring and screening programme, however, minimises the risk. Advent of other related compounds like tibolone and new generation selective oestrogen receptor modulators (SERMs) have made the choice wider, particularly in those who are not suitable candidates for oestrogen therapy. We are perhaps approaching towards the hormone replacement therapy for all following menopause, in one form or the other. Keywords HRT, Oestrogen. Progestin, Menopause, Hormone replacement. Introduction Once introduced to combat postmenopausal symptoms in oestrogen deprived women, Hormone Replacement Therapy (HRT) has now gained wider spectrum of utility, its use is no longer limited to the gynaecologists practice (Box 1). Being attracted by the multifaceted activities of female sex hormones, physicians, cardiologists, orthopaedicians, or even psychiatrists now consider HRT for their postmenopausal patients. This is of particular importance in today s world where the population of elderly women is expanding with the upwardly mobile life expectancy. Like any other drugs however, female hormones are not without risk in humans, hence risk-benefit assessment is an essential pre-requisite to prescribing these agents specifically to the elderly women. This article mainly focuses on nongynaecological conditions where HRT can be of value. * Department of Obstetrics and Gynaecology, ** Department of Medicine, Manipal College of Medical Sciences and Manipal Teaching Hospital, Pokhara, Nepal. Box 1 : HRT Indications after menopause Postmenopausal symptoms Prevention and treatment of osteoporosis Prevention of cardiovascular disease Abnormal lipid profile Urinary incontinence The hormones for replacement Natural oestrogens, by virtue of their less affinity for the receptors than that of synthetic derivatives, maintain a low oestrogenic level ( pmol/ L) which is sufficient enough to overcome menopausal problems. Thus, conjugated equine oestrone (Premarin) at a dose of mg/day, micronised oestradiol 1 mg/day, or 17-beta oestradiol 50 microgm dermal patches or gel offer a better safety profile compared to synthetic oestrogens, e.g., ethinylestradiol used in oral contraceptive pills. 1% oestriol cream for local application is well absorbed from the vaginal mucosa but is rapidly eliminated due to its weaker binding with plasma proteins. Among the progestins, C-21 derivatives like medroxyprogesterone acetate (MPA) 2.5 mg, 5 mg, or 10 mg/day, dydrogesterone 10 mg/day

2 and C-19 nortestosterone derivatives like norethindrone acetate 1 mg/day are commonly used. While cyclical progestins are likely to cause cyclical bleeding, continuous combined preparations (daily oestrogen + progestin) are suitable for those menopausal ladies who do not accept bleeding. Although, breakthrough spotting sometimes occurs at the initiation of therapy, ultimately a non-bleeding state is achieved in most of the cases. Levo-norgestrel containing intrauterine device, which releases 20 microgram of the active drug daily, could be a viable alternative to oral progestins. Role of HRT in non-gynaecological problems (a) HRT and heart One of the greatest advantages of hormone replacement in elderly women is its ability to resist cardiovascular disease (CVD). Contrary to popular belief, a recent report suggests that mortality from CVD does not rise abruptly following menopause, rather its risk increases with age, just as that of men, irrespective of the oestrogen level 1. Nevertheless, various epidemiological studies consistently showed that HRT reduces the risk of ischaemic heart disease (IHD) by around 50% among the current users and up to 35% after prolonged use 2. This results in a 37% decrease in mortality due to IHD 3. The benefit however, reduces considerably following 3-5 years of cessation of therapy. The role of HRT in primary prevention of CVD is well established, but it is still controversial in secondary prevention. Recently the Heart and Oestrogen/Progestin Replacement Study (HERS) failed to find any protective effect of oestrogen in those who had already experienced angina or myocardial infarction 4. Recently it has been seen in one study that HRT lowers the risk of peripheral arterial disease by 52% 5. i) How oestrogen replacement helps? At least 25% of cardio-protective property of oestrogen is attributed to its favourable influence over lipid and lipoprotein metabolism. Oestrogens, particularly given by oral route, lower total and LDL cholesterol and increase HDL 2 cholesterol. Other possible mechanisms include: a direct anti-atherogenic effect on arterial wall, augmentation of vasodilators like nitric oxide and prostacycline, reduction of the level of renin and angiotensin converting enzyme (ACE), an increase in fibrinolytic activity, decreased insulin resistance, and inhibition of LDL oxidation. The overall impact is comparable to what we gain after abandoning smoking or satisfactory control of hypertension 6. ii) What is the impact of adding progestin? While addition of progestin is mandatory in women with intact uterus (to counter endometrial stimulation), this hormone appears to blunt few benefits of oestrogen (due to its androgenic properties) 7. iii) What route? Although oral oestrogens offer the unique advantage of significant rise in HDL 2 level, they undergo first-pass hepatic metabolism and result in release of renin-substrate (thereby aggravation of hypertension), a fall in antithrombin III level (therefore induction of venous thrombo-embolism in susceptible women), and a small increase in triglyceride level. In contrast, non-oral routes like dermal patches, gel, or implants are devoid of such effect on liver and thus, would be the preferred route in clinical settings like hypertension, family history of venous thrombo-embolism, or hypertriglyceridaemia. It can be inferred that oestrogen patch could, to a great extent, cut down the necessity for nitroglycerine patch. (b) Lipid and HRT Abnormal lipid profile, per se, is an indication for HRT. Apart from hypertriglyceridaemia with oral oestrogen, all other parameters tend to Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December

3 normalise following oestrogen replacement. (c) Impact of HRT on functional disorders of brain Oestrogen supplementation alleviates most of the menopause-related psychological symptoms like depressed mood, anxiety, irritability, and insomnia. There is also improvement in cognitive functions. Preliminary findings indicate that it may delay, or arrest the disease progression in dementia of Alzheimer s type 8. Hopefully, if this comes out to be true in future, HRT will be of great value in improving the quality of life in potential elderly women. (d) Skin and HRT Oestrogen prevents collagen loss from the dermis, so possesses the ability of checking menopause-associated skin changes. This may be of interest to the cosmetologists and dermatologists as the means of offering the older women a younger look. (e) Role in prevention of osteoporosis Most of the fractures occurring in postmenopausal women result from the bone loss, particularly from the trabecular bones due to oestrogen deficiency. Oestrogen supplement may arrest bone resorption and increase the bone mineral density (BMD) in dosedependent and duration-dependent manner and consequently reduce the risk of fractures by 50% 9. Addition of calcium (at least 500 mg/ d) promotes this oestrogenic action on bone. When combined with 19- nortestosterone group of progestin (not C 21 derivative) bone resorption seems even lesser 10. Contrary to the earlier concept, efficacy of HRT in preventing osteoporosis or fracture is in no extent less if the therapy is started long after menopause 11. However, bone mineral density rapidly declines after cessation of HRT, such that the risk of fracture equals that of non-users in next 10 years time 12. (f) HRT and cancer Although concerns about the proven or unproven relationship between HRT and several cancers continue, the HRT appears to lessen the risk of colo-rectal cancer by as much as 35% 13. It is most pronounced for distal colon and in current hormone user 14. Role of HRT in gynaecological problems Most of the postmenopausal symptoms including hot flushes and psychological disorders are effectively cured by oestrogen replacement. Local application of oestrogen dramatically improves urogenital symptoms like dysuria, urinary incontinence, atrophic vaginitis, or dyspareunia. Although progestins are also capable of relieving menopause-related vasomotor symptoms, it necessitates much higher dosage (medroxy progesterone acetate 20 mg/day) which blunts some of the beneficial effects of oestrogen (as discussed above). Progestins are also ineffective in controlling psychological or urogenital problems. Return of libido is also achieved by testosterone but its other obvious unwanted sideeffects render the drug inappropriate for this purpose. Risk benefit study Compared to the overwhelming benefits gained by HRT, serious complications are few. Minor side effects are usually well tolerated by the patients but a thorough counselling is required before hand (Box 2). Box 2 : Minor complications of HRT Oestrogen Oestrogen + Progestin Progestin Leg cramps Heavy cyclical bleeding Bloating Breast tenderness Break-through spotting Breast heaviness Fluid retention Greasy skin Nausea Depression Vaginal discharge Irritability Oestrogen therapy without progestin support carries 2 to 10-fold increased risk of developing endometrial hyperplasia or even carcinoma, depending on the dose and duration of use. 300 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December 2001

4 Addition of progestin (medroxy-progesterone acetate 5 mg or equivalent) for at least 12 days each cycle confers almost complete protection against endometrial stimulation. An association between breast cancer and oestrogen replacement has been implicated in different studies. Recent re-analysis of 51 epidemiological studies concluded that use of postmenopausal HRT is associated with about 2.3% increase in breast cancer risk per year 15. A relative risk of 1.35 is reached after 5 years of use and it continues to rise with time 15. The risk disappears 5 years after cessation of therapy. In terms of absolute risk however, the impact is not so high. Two extra case per 1000 are attributed to HRT after 5 years of use; further rises to 6 extra cases at the end of 10 years, and 12 cases after 15 years of HRT. The study also supported the view that breast tumour in HRT users tends to be more localised and less aggressive. This feature, along with intense surveillance, in fact reduces the case fatality or mortality from breast carcinoma. Whether family history of breast cancer increases the risk further is a matter of controversy. Addition of progestins in HRT regimes appears to have no influence over the risk of breast cancer 16. The exact relationship between HRT and cancer of ovary as well as cutaneous malignant melanoma is inconclusive as yet; the risk of the latter appears statistically insignificant 17. Oral oestrogen replacement stimulates cholesterol secretion into bile, which predisposes women to cholelithiasis. A 2-3-fold risk of venous thrombo-embolism among the recent starters of HRT is a matter of concern 18. Although, only one in 3000 HRT users may develop venous thrombosis, it necessitates congenital thrombophilia screening in those having a family history of embolic disease before prescribing oestrogen replacement. Obesity potentiates the risk of venous thrombo-embolism, but the risk can be overshadowed by the benefits obtained from arterial diseases. Likewise, presence of severe degree of varicose veins is a relative contra-indication to oestrogen, which should be avoided unless clearly indicated. Migraine or seizure disorders may be precipitated by oestrogen replacement. Hence, close observation is required in those for whom hormone therapy is contemplated (Box 3). Box 3 : Contraindications to HRT Absolute : Bleeding PV of unknown cause Active liver disease Endometrial carcinoma except adequately treated early disease Congenital thrombophilia Breast carcinoma Relative : Severe degree of varicose veins Migraine/Seizure disorder Acute intermittent porphyria Otosclerosis Family history of breast/endometrial carcinoma Symptomatic fibroid/endometriosis Past history of breast cancer As in the case of obesity, HRT is not a contraindication for a smoker, diabetic, or hypertensive patient; instead, they are the suitable candidates who need cardio-protection. It can be inferred that proper selection of the candidate is of paramount importance before initiation of hormone replacement therapy (Box 4). Fortunately, we have now several other options available for those who are misfit for oestrogen replacement. When to start and how long The protective effect of HRT on CVD and bones decreases consistently after discontinuation and as mentioned earlier, it tends to disappear in next few years. Current consensus about the optimum duration of HRT is 5-10 years. Thus, the benefits are enjoyed over a considerable length of time Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December

5 yet the risk of breast cancer is limited. Box 4 : Evaluation of candidate before and during HRT Ask for past or family history of : Breast, ovary or endometrial carcinoma Deep venous thrombosis Gall-stone Migraine Epilepsy Perform general, systemic, and pelvic examination *Breast examination and mammography *Cervical cytology (pap-smear) Routine tests Blood sugar (FBS, PPBS) Lipid profile Pelvic USG Tests, if indicated Thrombophilia screening Liver function test Bone scan (DEXA) Hormone profile * Include in subsequent screening program also. Obviously, oestrogen replacement should be started immediately after premature menopause (natural or induced) or if there are evidences of menopausal symptoms or osteoporosis. In absence of these factors, the time of initiation of HRT can be modified, so that its long-term benefits are achieved optimally even with a limited period of use. Recent trend in countries with high life expectancy is to start HRT at the age of 60 years and continue up to 70 years of age. A delay in start is no way less effective in protecting heart or bone loss; rather be of help when incidences of cardiovascular morbidity, fracture, and Alzheimer s dementia tend to reach the peak. Hence, beneficial effects can also extend to the seventh decade of life to a considerable extent. Quest for alternatives Two drugs- tibolone, a 19-nortestosterone derivative with oestrogenic, progestogenic, and androgenic activities and raloxifen, a new generation drug of selective oestrogen receptor modulators (SERMS) group have come up as a surrogate for conventional HRT. Both are effective in checking bone loss. Tibolone being as efficient as that of oestrogen in reduction of fracture risks 19. Although relative risk of vertebral fracture is 0.7 with raloxifen, this effect is less marked in nonvertebral fracture 20. Definite role of both the drugs in prevention of CVD is yet to be determined. While the net effect of tibolone on cardiovascular system appears to be marginally favourable (decrease in total triglyceride, cholesterol, and also HDL level) 21, raloxifen causes a significant improvement of lipid profile by reducing LDL cholesterol, lipoprotein, and elevating HDL cholesterol level with no change in triglyceride level 22,23. Another unique advantage of tibolone and raloxifen is their inhibitory effect on endometrium and breast respectively. Unlike its progenitor tamoxifen, raloxifen does not cause endometrial hyperplasia or cancer 22. In addition, it is likely to reduce the risk of breast cancer by 75% overall and up to 90% in oestrogen receptor positive tumour 24. Major drawbacks of raloxifen are its inability to alleviate vasomotor instability, potential to induce venous thrombo-embolism as much as that of oestrogen and occasional leg cramps. Tibolone on the other hand is associated with small incidence of vaginal spotting, oily skin, and hirsutism. As far as bone protection is concerned bisphosphonates like etidronate and alendronate could be an alternative to HRT. Both vertebral and non-vertebral fractures are reduced by 50% 25, though 10% may show no response. Calcitriol (activated Vit D3) and calcitonin are effective but too expensive to be used for a prolonged period. The former may take few years to have full protective effect and carries the risk of hypercalcaemia, whereas calcitonin, being used by subcutaneous and intranasal route may cause systemic immunologic reaction. Combined calcium and vitamin D (800 IU/day) supplementation have shown to be effective only in very old, frail women whose skin is unable to 302 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December 2001

6 produce sufficient vitamin D. High dose oral calcium (1 g/day) alone may check bone loss but its bio-availability remains unpredictable in the absence of oestrogen. Presence of oestrogen related compounds named phyto-oestrogen in legumes such as Soya, Lentils, Chick peas have raised renewed enthusiasm as a simple and safer dietary alternative to pharmacological hormone replacement. Studies on Soya are going on, reports obtained so far suggest some beneficial effects on serum lipid parameter 26 and modest improvement of vasomotor symptom 27. Influences of these compounds on endometrium, breast, or bones are yet to be documented. Conclusion Today we have a wide variety of hormonal or hormone related drugs for a better life of menopausal women. Each has got its own merits and demerits. As far as versatility is concerned, conventional oestrogen containing HRT is still the best option. We perhaps, seek other alternatives only when oestrogen is contraindicated. Whether HRT is to be offered universally to everybody even without any indication is unanswered. Long-term observational studies only can solve the dispute in the future, till then, consideration for HRT, including the choice of the drug and its route remain individualised. References 1. Tunstal-Pedoe H. Myth and paradox of coronary risk and menopause. Lancet 1998; 351: Grodstein F, Stampfer MJ. The epidemiology of coronary heart disease and oestrogen replacement in post menopausal women. Prog Cardiovasc Dis 1995; 38: Grodstein F, Stampfer MJ, Coldtz GA et al. Post menopausal hormone replacement therapy and mortality. New Engl J Med 1997; 336: Hulley S, Grady D, Bush T et al. For the Heart and Oestrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of Oestrogen plus Progestin. For secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280; News. HRT may protect against peripheral vascular disease. BMJ (SA Ed) 2001; 16 (11): Beard CM, Kottke TE, Annegers JF et al. The Rochester Coronary Heart Disease Project effect: of cigarette smoking, hypertension, diabetes and steroidal oestrogen use on coronary heart disease among years old women, 1960 through Mayo Clinic Proc 1989; 64: Greendale GA, Reboussin BA, Hogan P et al. Symptoms relief and side effects of postmenopausal hormones : result from the postmenopausal oestrogen/progestin intervention (PEPI) trial. Obstet Gynecol 1998; 92: Henderson V W. Oestrogen replacement therapy and Alzheimer s disease In: Whitehead Ml, (Editor): The prescriber s guide to hormone replacement therapy Lancashire: Parthenon, Riggs BL, Metton LJ. Prevention and treatment of osteoporosis. New Eng J Med 1992; 327: Speroff L, Rowan J, Symon J et al. For CHART study group. The comparative effect on bone density, endometrium and lipid of continuous hormone replacement therapy. JAMA 1996; 276: Marx CW, Dailey III GE, Cheney C et al. Do oestrogens improve bone mineral density in osteoporotic women over 65? J Bone Miner Res 1992; 7: Christiansn C, Christiansn MS, Transbol I. Bone mass in postmenopausal women after withdrawal of ostrogen/ gestagen replacement therapy. Lancet 1981; Grodostein F, Martiner E, Platz EA et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann intern Med 1998; 128: Troisi R, Schairer C, Chow WH et al. A prospective study of menopausal hormones and risk of colo-rectal cancer (United states). Cancer Causes Control 1997; 8 (I): Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 1,08,411 women without breast cancer. Lancet 1997; 350: Colditz GA, Hankinson SE, Hunter DJ et al. The use of oestrogen and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332: Holman CDJ, Armstrong BK, Heenan PJ. Cutaneous malignant melanoma in women: exogenous hormones and reproductive factors. Br J Cancer 1984; 50: Daly E, Vessey MP, Hawkins MM et al. Risk of venous thrombo-embolism in users of hormone replacement therapy. Lancet 1996; 348: Lippuner K, Haenggi W, Birkhaeuser MH et al. Prevention of postmenopausal bone loss using tibolone or conventional per oral or trans-dermal hormone Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December

7 replacement therapy with 17-beta estradiol and dydrogesterone. J Bone Miner Res 1997; 12: Ettinger B, Black DM, Mitlak BH et al. The Multiple Out come of Raloxifen (MORE) reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifen. JAMA 1999; 282: Bjarnason NH, Bjarnason K, Haarbo J et al. Tibolone influence on markers of cardio-vascular disease. J Clin Endocrinol Metab 1997; 82: Delmas PD, Bgrnason NH, Mitlak BH et al. Effect of raloxifen on bone mineral density, serum cholesterol concentration and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: Walsh BW, Kuller LH, Wild RA et al. Effect of raloxifen on serum lipid and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: Cummings SR, Eckert S, Krueger KA et al. The effect of raloxifen on risk of breast cancer in postmenopausal women. JAMA 1999; 281: Black DM, Cummings SR, Karpf DB et al. Randomized trial of the effect of alendronate on risk of fracture in women with existing vertebral fracture. Lancet 1994; 348: Anderson JW, Johnstone BM, Cook-newell ME, Metaanalysis of the effects of soyas protein intake on serum lipids. N Engl J Med 1995; 332: Albertazzi P, Pansini F, Bonaccorsi G et al. The effect of soya supplementation on hot flushes. Obstet Gynecol 1998; 91: Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December 2001