Hormone replacement therapy: What is available now, and what is on the horizon

Issue: BCMJ, vol. 43 , No. 9 , November 2001 , Pages 521-526 Clinical Articles

Postmenopausal women wishing to use hormone replacement therapy currently have a wide variety of options from which to choose. Women who have had a hysterectomy can use estrogen-only therapy; women retaining a uterus must use cyclical or continuous progestin, in addition to estrogen, in order to minimize the risk of developing endometrial hyperplasia and carcinoma. Since many women experience unwanted effects from the use of hormone replacement therapy, especially uterine bleeding, the pharmaceutical industry is energetically searching for more acceptable forms of treatment. The ideal HRT would reduce the postmenopausal risk of osteoporosis, cardiovascular disease, breast cancer, and urogenital atrophy, while enhancing cognitive function and general well-being—without side-effects such as uterine bleeding. Such an ideal may be attainable.

Postmenopausal women wishing to use HRT have a wide variety of options, though many experience unwanted side effects. More products—with fewer side effects—are on their way.


The term hormone replacement therapy is generally accepted to mean treatment of postmenopausal women with a combination of estrogen and progestin. The fact that it is referred to as hormone replacement therapy implies that such treatment should be with hormones that are identical to those that were secreted by the ovaries before menopause. It is not known, however, whether this is necessarily so—or even if it may be preferable to use other treatment.

Similarly, much is made of whether a compound is natural or synthetic. There is much confusion over what “natural” hormone replacement therapy (HRT) actually means: some interpret it as meaning a chemical structure identical to human estrogen or progesterone, while others interpret it as meaning derived from a plant or animal source. Again, it is not known if there is any practical advantage or disadvantage to the use of natural HRT, regardless of what this is taken to mean.

The largest prospective, randomized, placebo-controlled study of HRT, current or past, is the Women’s Health Initiative. One segment of this study is comparing the effects of HRT (using an estrogen from equine source and a synthetic progestin) with placebo on postmenopausal health, and initial results are expected to appear in 2007. Until then, prescribers and their patients must rely on the results of observational studies, and theoretical projections of outcomes, in order to make decisions about HRT. Even subsequently, this study will have provided information about only one potential estrogen-progestin combination, and only one route of administration. There is reason to believe that different combinations and routes of administration may themselves affect morbidity differently.[1]

What are the options?


Estrogens may be administered orally, transdermally, vaginally, or by injection (see Table 1). Only oral conjugated estrogens are a Pharmacare benefit in British Columbia.

Making a choice of estrogen preparation for HRT will be a product of a number of biases. Among these will be the prescriber’s clinical experience with the effects of different products; the patient’s perceptions of risks and benefits of different products, often garnered from the experience of acquaintances; increasingly, the Internet; whether a compound has a natural or synthetic source; and cost. The same biases will apply to the choice of progestin to be used in women who have not had a hysterectomy.

There have been no direct comparisons of the effect of different preparations on morbidity and mortality, so there is no definitive basis for choosing one preparation over another. There are, however, comparative studies of preparations on markers for morbidity and mortality, and, to the extent that these are reliable predictors, the information derived from these studies enables clinicians to make an educated guess about the optimal treatment for an individual.


Progestins for HRT may be administered orally or transdermally (from an estrogen-progestin combination patch). Vaginal progesterone suppositories may be compounded and dispensed by pharmacists on prescription, but with uncertain absorption and endometrial effects. Progesterone cream for transdermal administration is available from different sources without prescription, but it appears to have no endometrial effect.[2] Please see Table 2 and Table 3.

Methods of use

Postmenopausal women who have had a hysterectomy have no known physiological consequences from the loss of cyclical progesterone production. Hence, these women can use estrogen alone for HRT. Postmenopausal women who retain a uterus require protection against the possible development of endometrial hyperplasia resulting from unopposed estrogen activity, so their HRT must include use of a progestin.

The dose of estrogen or progestin appropriate for an individual will be a product of effectiveness and tolerability. In other words, treatment with higher doses will generally increase beneficial effects on menopausal symptoms and morbidity, but will also increase the likelihood of troublesome side effects. For maintenance of bone density postmenopausally, the minimally effective daily doses of estrogens appear to be 0.625 mg of conjugated equine estrogens (CEE) or estropipate, 0.5 mg of micronized estradiol, or 50 mg of transdermal estradiol.[3] Lower doses of estrogen combined with high doses of calcium, however, may also maintain bone density.[4]

There is a dose-response relationship between the daily dose of estrogen used in HRT and the risk of endometrial hyperplasia. Therefore, in general, higher doses of estrogen in women with a uterus (above 0.625 mg of CEE or the equivalent) require higher doses of progestin (10 mg of medroxyprogesterone acetate or the equivalent).[5]

Cyclical use of estrogen and progestin

Initial administration methods for HRT copied the cyclical method of combined oral contraceptives, with a part of each month being a pill-free rest period. The fact that there was no physiological basis for this form of administration, combined with the recurrence of symptoms in many women during the few days off medication, led to the current trend of administering estrogen continuously throughout each month.

Progestin, however, may be administered cyclically or continuously. In cyclical use, progestin is administered in addition to estrogen for a fixed number of days per month. There is evidence that administration of progestin for at least 12 days per month is required to minimize the risk of endometrial hyperplasia.[6]

A number of alternative strategies for progestin administration have been proposed on the basis of short-term evidence of safety. Among these strategies are:

• Cyclophasic administration of HRT, in which continuous oral administration of estrogen is combined with administration of progestin in phased cycles of 3-days-on therapy and 3-days-off therapy.[7]

• Twice-weekly administration of medroxyprogesterone acetate on the days on which a transdermal estradiol patch is changed.[8] The long-term safety and acceptability of these modes of administration are unknown.

Continuous-combined administration of estrogen and progestin

Continuous administration of progestin was proposed as a means of avoiding the withdrawal bleeding that follows cyclical use of progestin. There have been few large-scale prospective studies to confirm the safety and efficacy of this approach, and the wide range of possible combinations and doses complicates our ability to predict acceptability in individual patients. Most experience in North America has been with the combination of conjugated estrogens (most commonly 0.625 mg daily) and medroxyprogesterone acetate (most commonly 2.5 mg daily). This combination is marketed in the United States as the single tablet combination Prempo and in Canada as the two-tablet combination PremPlus. Two new preparations, FemHRT (oral) and Estalis (transdermal) have been released recently in Canada. In Europe, the most popular single-tablet combination is a preparation called Kliogest or Kliofem. This contains 2 mg of 17ß-estradiol and 1 mg of norethindrone acetate in each daily dose.

Clinical studies of this form of HRT are generally short term. In reports to date, lipid changes with treatment are generally similar to the effects of cyclical HRT,[9] but a randomized study (HERS[10]) has indicated that in women with established coronary artery disease, continuous-combined therapy may not provide protection against myocardial infarction. On the other hand, continuous-combined therapy may offer better protection against osteoporosis than cyclical HRT.[11] The acceptability of continuous-combined HRT is limited by unpredictable bleeding in the first few months of treatment, but the majority of women are amenorrheic after 6 months of treatment.[12]

Counseling patients about continuous-combined HRT

In providing continuous-combined HRT to postmenopausal women, it is prudent to counsel such women that the known risks and benefits of cyclical HRT apply, with the following additional comments:[13]

• Unexpected vaginal bleeding may occur for up to the first 6 months of therapy. If bleeding continues beyond this time, it is appropriate to rule out pathological causes (usually by endometrial sampling) and to consider switching to a form of HRT providing predictable withdrawal bleeding.

• Vaginal bleeding that occurs after amenorrhea has been established with continuous-combined HRT should be vigorously investigated to rule out endometrial pathology. The overall risk of endometrial hyperplasia and cancer is very small.

• The available evidence indicates that in women without evidence of CHD, the use of continuous-combined HRT provides similar cardioprotection to that provided by cyclical HRT, and that continuous-combined therapy may be the preferred method for prevention and treatment of osteoporosis.

• Women with established coronary heart disease should not begin using continuous-combined CEE and medroxyprogesterone acetate for the purpose of secondary prevention of CHD events.

Estrogen-only therapy

In general, the use of unopposed estrogen for long-term HRT is an option only for women who have undergone hysterectomy. The risk of developing endometrial hyperplasia with administration of estrogen unopposed by progestin is clearly established (the PEPI trial[14] reported atypical endometrial hyperplasia in up to 30% of users of unopposed estrogen). Women retaining a uterus will very occasionally choose to take unopposed estrogen, despite this risk, usually because of intolerable side effects with the use of progestin. Such women should have annual assessments to rule out endometrial hyperplasia, and at present this requires endometrial biopsy.

Progestin-only therapy

Women in whom estrogen is contraindicated can use progestin-only therapy for control of vasomotor symptoms. Controlled studies have shown the superiority of medroxyprogesterone acetate (20 mg daily)[15] or megestrol acetate (40 mg daily)[16] to placebo in relieving flushing episodes.

Most postmenopausal women are hypoestrogenic and will have little or no endometrial proliferation. However, obese women will tend to have increased endogenous levels of estrogens, because of conversion of androgens to estrogen in adipose tissue, and will therefore be less likely than lean women to develop menopausal symptoms. Obese women are at increased risk of developing endometrial cancer, and will benefit from periodic progestin challenges; if bleeding results, the progestin challenges should continue until there is no withdrawal bleeding.[17]

Selective estrogen receptor modulators

Selective estrogen receptor modulators have arisen from the desire to maximize estrogenic effects in the skeleton and cardiovascular systems, where they are generally beneficial, and to minimize estrogen effects in the breast and uterus, where they induce unwanted proliferative effects. The first of these agents to be approved in Canada, raloxifene (Evista), has been approved for the prevention and treatment of osteoporosis in postmenopausal women. Raloxifene has been shown to reduce the risk of invasive breast cancer by 76% during 3 years of treatment in postmenopausal women,[18] and is undergoing a prospective comparison with tamoxifen in primary breast cancer prevention.

Raloxifene is not intended for treatment of symptomatic early postmenopausal women, but instead is intended for treatment of relatively asymptomatic women who are beyond the menopausal transition. Data from long-term use are not available, although the profile of effects suggests that raloxifene may be an appropriate substitute for the use of long-term estrogen-progestin HRT in women with concerns about breast cancer, uterine cancer, or uterine bleeding. A cardioprotective effect with long-term use of raloxifene has not yet been demonstrated, but a prospective trial to assess this (Raloxifene Use for The Heart, or RUTH) is in progress.

New ideas for HRT

There are new pharmacological approaches to optimizing postmenopausal health, either in development or currently in use in other countries. Most are variations of strategies to deliver estrogen-progestin HRT, while some represent new approaches to delivering the benefits of HRT with potential reduction in risks and side effects. The following preparations are some of those recently approved, or awaiting approval, for marketing in Canada.

Single-tablet continuous-combined estrogen-progestin HRT

Activelle (Novo Nordisk)

This preparation, containing 1 mg of 17ß-estradiol and 0.5 mg of norethindrone acetate (NETA), has been available for some years in Europe as Kliovance. A higher dose preparation (Kliogest or Kliofem), containing twice the dose of each component, is widely available in Europe. There are few long-term morbidity studies with this combination, but short-term studies show good tolerability and effects on bone density.[19]

FemHRT (Pfizer)

This preparation, released in Canada in September 2000, combines 1 mg of norethindrone acetate and 5 µg of ethinyl estradiol (EE) in each daily dose. The relatively low dose of EE (relative to oral contraceptive doses) is considered sufficient to maintain beneficial effects in the skeleton, cardiovascular system, and elsewhere while minimizing the potential for endometrial proliferation.[20]

Continuous-combined transdermal estrogen-progestin HRT

Estalis (Novartis)

This combination matrix patch provides transdermal administration of 17ß-estradiol and norethindrone acetate, in patches applied twice-weekly (Estalis). It is now available in Canada.

Transdermal estrogen is known to have different effects from oral estrogen on various liver functions, with unique effects on the lipid profile, coagulation factors, and estrogen bioavailability in smokers.[21] There is, therefore, a potential target group of postmenopausal women in whom one route of administration or the other is clearly preferable. Use of combination therapy in transdermal form allows protection from endometrial hyperplasia with satisfactory bleeding patterns for most women.

Other compounds

Livial (Organon)

This compound (tibolone) is a derivative of norethynodrel and has residual estrogenic, progestogenic, and some androgenic activity. As single-agent therapy, it has effectiveness against acute menopausal symptoms,[22] does not induce vaginal bleeding,[23] and has positive effects on bone density.[24] There is growing experience in Europe with this agent, and its potential for use as a single-agent therapy from the time of the menopausal transition gives it appeal for prescribers.

Future options for estrogen and progestin therapy

Sulfamate estrogens (Schering AG)

These compounds have been developed from research seeking a replacement for ethinyl estradiol in oral contraceptives. Described as the oral patch, sulfamate estrogens avoid the “first-pass” effect on liver metabolism by being transported in erythrocyte membranes. This should provide stable end-organ estrogenic effects. Clinical trials in postmenopausal women are being conducted in the United Kingdom.

Crinone (Serono)

This vaginal progesterone gel may be applied every second day to allow stable endometrial progesterone activity with minimal systemic progesterone effect. The cost of this preparation, and possibly its vaginal application, may limit its applicability to the HRT market.

MLS (Berlex)

The levonorgestrel-releasing intrauterine device has been used for contraception (marketed primarily as Mirena) for some years in Europe. It greatly reduces blood loss in menstruating women, and is now developed for use as a local progestin source (the Menopause Levonorgestrel System) for the endometrium in postmenopausal women. The device may therefore be used in combination with oral or transdermal estrogen. Its duration of action is up to 5 years.


The assistance of the pharmacists of Shoppers Drug Mart, Kerrisdale, in providing the drug list costs is appreciated.

Table 1. Commercially available estrogen preparations.


Trade name

Generic name

Doses available

Cost/month (drug only)




conjugated estrogens

0.3 mg
0.625 mg
0.9 mg
1.25 mg




micronized 17ß-estradiol

0.5 mg
1.0 mg
2.0 mg





0.625 mg
1.25 mg
2.5 mg




conjugated equine estrogens

0.3 mg 
0.625 mg 
0.9 mg 
1.25 mg


Transdermal (twice-weekly patch application)




25 µg 
50 µg 
100 µg





25 µg
50 µg





37.5 µg 
50 µg 
75 µg 
100 µg


Transdermal (once-weekly patch application)




50 µg
100 µg


Transdermal (daily gel application)




1.5 mg 
(2.5 G of gel)


Vaginal (cream)



conjugated equine estrogens

0.625 mg/g

$14.86 (43 g)

Vaginal (silastic ring)




2 mg/ring


Table 2. Commercially available progestins.


Trade name

Generic name

Doses available

Cost/month (drug only)



Megestrol acetate

40 mg
160 mg



Medroxyprogesterone acetate

2.5 mg
5 mg
10 mg



Megestrol acetate

40 mg
160 mg




0.35 mg



Norethindrone acetate

5 mg



Micronized progesterone

100 mg



Medroxyprogesterone acetate

2.5 mg
5 mg
10 mg


 Table 3. Commercially available estrogen-progestin combinations.


Trade name

Generic name

Doses available

Cost/month (drug only)



17ß-estradiol and norethindrone acetate

50 µg (estrogen) plus either
140 µg (progestin) or 
250 µg (progestin)




17ß-estradiol and norethindrone acetate

50 µg (estrogen)
250 µg (progestin)

(8 patches)



ethinyl estradiol and norethindrone acetate

5 µg (estrogen) 
1.0 mg (progestin)



conjugated equine estrogens and medroxyprogesterone acetate (separate tablets)

0.625 mg (estrogen) 
2.5 mg (progestin)



1.  Crook D, Cust MP, Gangar KF, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: Effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992;166:950-955. PubMed Abstract


2.  Wren BG, McFarland K, Edwards L. Micronised transdermal progesterone and endometrial response. Lancet 1999; 354:1447-1448. PubMed Citation


3.  Society of Obstetricians and Gynaecologists of Canada. The Canadian Consensus Conference on Menopause and Osteoporosis. J Soc Obstet Gynaecol Can 1998;20:26.


4.  Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy. Effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997;157:2609-2615. PubMed Abstract


5.  Society of Obstetricians and Gynaecologists of Canada. The Canadian Consensus Conference on Menopause and Osteoporosis. J Soc Obstet Gynaecol Can 1998;20:50.


6.  Whitehead MI, Townsend PT, Pryse-Davies J, et al. Effects of various types and dosages of progestogens on the postmenopausal endometrium. J Reprod Med 1982;27(suppl 8):539-548. PubMed Citation


7.  Casper RF. Estrogen with interrupted progestin HRT: A review of experimental and clinical studies. Maturitas 2000;34: 97-108. PubMed Abstract


8.  Cano A, Tarin JJ, Duenas JL. Two-year prospective, randomized trial comparing an innovative twice-a-week progestin regimen with a continuous combined regimen as postmenopausal hormone therapy. Fertil Steril 1999;71:129-136. PubMed Abstract


9.  The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273:199-208. PubMed Abstract


10. Hulley S, Grady D, Bush T, et al. For the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613. PubMed Abstract


11. The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density: Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;276: 1389-1396. PubMed Abstract


12. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Menopause Study Group. Obstet Gynecol 1994;83:686-692. PubMed Abstract


13. Rowe TC. Continuous-combined hormone replacement therapy. J Soc Obstet Gynaecol Can 1998:11(suppl):10-15.


14. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;275;370-375. PubMed Abstract


15. Schiff I, Tulchinsky D, Cramer D, et al. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA 1980;244:1443-1445. PubMed Abstract


16. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-352. PubMed Abstract Full Text


17. Gambrell RD Jr, Massey FM, Castaneda TA, et al. Use of the progestogen challenge test to reduce the risk of endometrial cancer. Obstet Gynecol 1980;55: 732-738. PubMed Abstract


18. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. JAMA 1999;281:2189-2197. PubMed Abstract


19. Ulrich LG, Barlow DH, Sturdee DW, et al. Quality of life and patient preference for sequential versus continuous combined HRT: The UK Kliofem multicenter study experience. UK Continuous Combined HRT Study Investigators. Int J Gynaecol Obstet 1997;59(suppl 1):S11-S17. PubMed Abstract


20. Product monograph for femHRT, Parke Davis, Division of Warner-Lambert Co., Morris Plains, New Jersey, 1999.


21. Society of Obstetricians and Gynaecologists of Canada. The Canadian Consensus Conference on Menopause and Osteoporosis. J Soc Obstet Gynaecol Can 1998;20:49.


22. Egarter S, Sator M, Berghammer P, et al. Efficacy, tolerability, and rare side effects of tibolone treatment in postmenopausal women. Int J Gynaecol Obstet 1999;64: 281-286. PubMed Abstract


23. Morris EP, Wilson PO, Robinson J, et al. Long term effects of tibolone on the genital tract in postmenopausal women. Br J Obstet Gynaecol 1999;106:954-959. PubMed Abstract


24. Pavlov PW, Ginsburg J, Kicovic PM, et al. Double-blind, placebo-controlled study of the effects of tibolone on bone mineral density in postmenopausal osteoporotic women with and without previous fractures. Gynecol Endocrinol 1999; 13:230-237. PubMed Abstract 


Timothy C. Rowe, MBBS, FRCSC, FRCOG. Hormone replacement therapy: What is available now, and what is on the horizon. BCMJ, Vol. 43, No. 9, November, 2001, Page(s) 521-526 - Clinical Articles.

Above is the information needed to cite this article in your paper or presentation. The International Committee of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

About the ICMJE and citation styles

The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.

An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.

BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:

  • Only the first three authors are listed, followed by "et al."
  • There is no period after the journal name.
  • Page numbers are not abbreviated.

For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org

BCMJ Guidelines for Authors

Leave a Reply