Progestogens in hormonal replacement therapy: new molecules, risks, and benefits.

While the benefits of progestogen use in hormone replacement therapy (HRT) are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. Several risks are attributed to progestogens as a class-effect; however, the progestogens used in HRT have varying pharmacological properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones (Nestorone, nomegestrol acetate, trimegestone), do not bind to the androgen receptor and, hence, do not exert androgenic side effects. Newly synthesized molecules such as drospirenone or dienogest have no androgenic effect but do have a partial antiandrogenic effect. Drospirenone derives from spironolactone and binds to the mineralocorticoid receptor. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on the lipid profile as well as the vasomotion. On the other hand, other progestogens devoid of androgenic properties do not exert these deleterious effects. The epidemiological data do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease, HRT may not protect against further heart attacks when the progestogen selected possesses androgenic properties. The data related to the progestogen effect on breast tissue has been interpreted differently from country to country. However, it has been admitted that, according to the type of progestogen used and the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any significant difference between the estrogens given alone or combined with progestogens in HRT. Complying with the classic contraindications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.     

Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. The different types of HRT offer to many extent comparable efficacies on symptoms control; however, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. This paper reviews the role of the non-oral route of administration of sex steroids in the clinical management of postmenopausal women. Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens. In addition, recent indications suggest potential advantages for blood pressure control with non-oral estrogens. To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Recent evidence indeed shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins. In conclusion, while all types of hormone replacement therapies are safe and effective and confer significant benefits in the long-term when initiated in young postmenopausal women, in specific clinical settings the choice of the transdermal route of administration of estrogens and the use of natural progesterone might offer significant benefits and added safety.     

Androgenic progestins amplify the breast cancer risk associated with hormone replacement therapy by boosting IGF-I activity.

Recent epidemiology indicates that unopposed oral estrogen replacement therapy has a surprisingly small impact on breast cancer risk--little if any in overweight women--whereas combined regimens featuring synthetic progestins are attended by a much larger increase in this risk. These findings may reflect the fact that oral estrogen acts on the liver to down-regulate systemic IGF-I activity, whereas concurrent administration of androgens--including the androgenic progestins often used in replacement therapy--abrogates this effect. Increased systemic IGF-I activity has been linked to increased breast cancer risk, and may be largely responsible for the greater incidence of breast cancer in overweight postmenopausal women--who thus should have the most to gain from suppression of IGF-I activity by oral estrogen. Down-regulation of IGF-I may likewise account for the marked reduction in colon cancer risk associated with current estrogen replacement therapy. Fortunately, natural progesterone--now available in micronized oral preparations--does not oppose the hepatic effects of oral estrogen, and moreover may be preferable to androgenic progestins with respect to vascular function. Oral replacement therapy featuring micronized progesterone, if administered throughout postmenopausal life, can be expected to have a highly positive impact on vascular health, bone density, and risks for Alzheimer's disease and colon cancer--benefits which, in most women, may vastly outweigh the associated increase in risk for breast and endometrial cancers.     

New progestagens for contraceptive use

The progestins have different pharmacologic properties depending upon the parent molecule, usually testosterone or progesterone (P), from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. In hormonal contraceptives, progestins represent the major agent designed for suppressing ovulation and are used in combination with estrogen (E) usually ethinyl-estradiol (EE). The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone receptor (PR) agonists have been synthesized as well, although the latter are still in a very early stage of development. Several new progestins, have been synthesized in the last two decades. These include dienogest (DNG), drospirenone (DRSP), Nestorone (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG). These new progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone P. DRSP differs from the classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. TMG and NES are the most potent progestins synthesized to date, followed by two of the older progestins, keto-desogestrel (keto-DSG) and levonorgestrel (LNG). The new molecules TMG, DRSP and DNG also have antiandrogenic activity. Striking differences exist regarding the side effects among the progestins and the combination with EE leads to other reactions related to the E itself and whether the associated progestin counterbalances, more or less, the estrogenic action. The 19-norprogesterone molecules and the new molecules DRSP and DNG are not androgenic and, therefore, have no negative effect on the lipid profile. Given their pharmacological properties, it is likely that the new progestins may have neutral effects on metabolic or vascular risks. However, this hypothesis must be confirmed in large clinical trials.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

Steroidal hormones and proliferation, differentiation and apoptosis in breast cells

The impact of estrogens (E) and progestins (P) on the breast is crucial. Recent epidemiological studies raised a great concern concerning breast cancer risk and hormone replacement therapy (HRT). However, the effects of HRT in breast tissue remain unclear. Biological data predominantly show that P are antiproliferative and proapoptotic at least for normal breast cells. These antiproliferative effects of P are well described at the cellular level. Whereas E2 increases the level of the various cyclins involved in the cell cycle progression and decreases the cyclin kinase inhibitors, p21 and p27, progestins act in an opposite manner. In addition, they both modulate the phosphorylated rate of Rb involved into the S phase progression. Various proteins of the apoptotic cascade are also targets for E2 and P. We showed that bcl-2, p53 and caspase 3 are oppositely modulated by E2 and P in normal and breast cancer cell cultures. It is very possible that in vivo the balance between E2/P, the type of P, specific phenotypes could explain increasing risk during HRT, which appears to be mainly a promoter effect on preexisting transformed cells.     

Antiestrogen action of progesterone in the breast

This review analyzes recent data from international literature concerning the antiestrogen action of progesterone, progestins and the antiprogesterone RU 486 at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone, progestins and even RU 486 have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.     

Comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate

Objectives

In combined hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads to enhanced proliferation of mammary epithelial cells. In a quantitative mouse model, we assessed the balance between uterine and undesired mammary gland effects for two progestins that are widely used in HRT, progesterone and medroxyprogesterone acetate.

Study design

Mice were ovariectomized and after 14 days they were treated subcutaneously with either vehicle, estradiol (100 ng) or estradiol plus increasing doses of progesterone or medroxyprogesterone acetate for three weeks.

Main outcome measures

Measures for progestogenic mammary gland activity were stimulation of side-branching and stimulation of epithelial cell proliferation. Progestogenic activity in the uterus was assessed by measuring inhibition of estradiol-activated uterine epithelial cell proliferation. ED₅₀ and ID₅₀ values for the distinct readouts were obtained and dissociation factors for uterine versus mammary gland activity were calculated.

Results

MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, progesterone showed uterine activity at doses lower than those leading to significant stimulation of epithelial cell proliferation in the mammary gland.

Conclusions

Progestins do not behave the same. Use of the natural hormone progesterone, but not MPA, in combined hormone therapy might offer a safety window between uterine effects and undesired proliferative activity in the mammary gland.     

Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone^® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.     

Curcumin inhibits MPA-induced secretion of VEGF from T47-D human breast cancer cells

OBJECTIVE: Recent clinical trials show that women who receive combined estrogen and progestin hormone therapy (HT) have a higher risk of breast cancer than women who receive estrogen alone or placebo. We have shown that progestins stimulate expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human breast cancer cells that express the progesterone receptors and mutant p53 protein. Because increased levels of VEGF promote tumor progression, compounds that prevent progestin-induced expression of VEGF could be clinically useful. The objective of this study was to examine whether the polyphenol compound curcumin has the capacity to block progestin-induced secretion of VEGF from T47-D human breast cancer cells. DESIGN: The estrogen and progesterone receptor containing T47-D human breast cancer cells was exposed to 10 nM progesterone or synthetic progestins and varying concentrations of curcumin to determine whether curcumin blocks progestin-dependent production of VEGF from tumor cells. RESULTS: Curcumin (0.001-10 microM for 18 h) reduced medroxyprogesterone acetate (MPA)-induced secretion of VEGF from T47-D cells in a dose-dependent manner. Secretion of VEGF from cells treated with progesterone or progestins other than MPA was unaffected by curcumin. CONCLUSIONS: MPA is the most widely used progestin in HT. Curcumin may therefore provide a clinically useful tool for the suppression of MPA-induced elaboration of VEGF by tumor cells. We propose therefore that clinical trials to assess the beneficial effects of curcumin in postmenopausal women are warranted.     

HRT and breast cancer risk: a clue for interpreting the available data

Epidemiological and biological data on HRT and breast cancer risk are reviewed. Some aspects deserve consideration. (1) The majority of epidemiological data have been gathered from populations where high estrogen doses (≥1.25 mg daily of conjugated estrogens) were used as first line therapy. (2) HRT does not increase the risk in overweight women, even in the series in which a risk increase (in longterm users) is found. This could be as a result of the fact that oral estrogens, through their metabolic and hepatocellular effects, reverse some biological features of obesity (e.g. increased insulin-like growth factor I activity and decreased sex hormone binding globulin level) which potentially increase breast cancer risk, so balancing the estrogen stimulation. (3) The progestin addition seems to increase the risk when the 19 nor-testosterone derivatives are used. These androgenic compounds contrast the metabolic and hepatocellular effects of oral estrogens. To sum up, the possibility does exist that even the longterm use of oral estrogens at the right (‘low’) dose, with the addition of a non-androgenic progestin, will be shown to be associated with a very limited breast cancer risk increase.     

Differential effects of progestins on hemostasis

Recently large, prospective, randomized studies on hormone replacement therapy (HRT) have indicated that the progestin use might interfere with hemostasis and thus increase venous thrombotic events. Therefore, available publications were evaluated to determine whether progestins interfere with hemostasis, either when given alone via oral or parenteral routes or in combination with ethinylestradiol as synthetic estrogen or natural estrogens. There are indications that such interference is dependent upon the type and dose of the progestin, the route of application, the length of treatment and the type and dose of the estrogen with which it is combined. For natural progesterone, no negative effects on the hemostatic system were seen with either oral or parenteral application, in cyclic or continuous regimens, for the doses investigated. Similarly, no unwanted effects were seen with progestin only pills (POP), independent of the type and dose of progestin, or parenteral progestins. With the high-dose progestins used in gynaecological oncology, the increased activation of the hemostatic system resulting from the disease itself has to be taken into account when looking at any increased incidence of thromboembolic events in these patients. For estrogen/progestin combinations, the risk of venous thromboembolism is attributed to the estrogen used. Recent studies showed an increased rate of thromboembolic events in association with desogestrel-and gestodene-containing oral contraceptives, compared with those containing levonorgestrel. With HRT, a decrease in antithrombin factors could explain the increased rate of venous thrombotic events. In conclusion, progestins seems to have different effects on the hemostatic system due to their different pattern of biological activities. This was also shown in the arterial vascular system, where some progestins may reduce the endothelium-dependent vasodilating action of estrogens and stimulate intima proliferation and upregulate thrombin receptor expression while other progestins did not.     

Antiproliferative and apoptotic effect of epigallocatechin-3-gallate on Ishikawa cells is accompanied by sex steroid receptor downregulation

Endometrial cancer is a significant malignancy in developed countries. Unopposed estrogen stimulation is considered as an important risk factor for endometrial cancer. Epigallocathechin-3-gallate (EGCG), biological active component of green tea, inhibits cancer cell proliferation. However, it is unknown whether EGCG has anticancer effects on endometrial cancer and what the molecular mechanism(s) are. We investigated the anticancer effects of EGCG on a human endometrial adenocarcinoma cell line (Ishikawa cells) with or without 17β-estradiol (E2) treatment. Cell proliferation assay was performed using 3-(4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide (MTT). The cell cycle was determined by flow cytometry and real-time analysis of cyclin and cdk genes. The apoptosis was measured by Annexin V-PI staining and real-time analysis of bcl-2, Bax and caspase genes. The MAPK signal, Akt and caspase-3 were determined by immunoblotting. Decreased estrogen and progesterone receptor expression was observed in EGCG-treated Ishikawa cells, and decreased MAPK signals and phospho-Akt were observed as well. EGCG caused the arrest of cells in the G0/G1 phase of the cell cycle. This compound interfered with Akt activation and MAPK signals, and increased apoptosis signals leading to a controlled caspases, Bcl-2, Bax genes and protein expression. Taken together, EGCG inhibits cell proliferation and induces apoptosis through Akt and MAPK signals. These findings suggest that EGCG may exert growth-inhibitory and apoptosis-inducing effects on endometrial cancer cells, accompanied by decreased estrogen and progesterone receptor. EGCG may have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in endometrial cancer.     

Progestins and their effects on the breast

Nowadays, when the available scientific data on the in vivo effects of progestins on mammary gland tissue remain controversial, it is of utmost importance to establish adequate criteria to evaluate their actions. One of the reasons for this situation is that a variety of progestins have been studied using a number of different study designs. In addition, data relating to the effects of progestins on breast tissue have been interpreted differently from country to country. Recent data indicate that some progestins clearly oppose the favourable effects of estrogens on a number of important metabolic processes, e.g. influencing insulin-like-growth-factor (IGF)-1 serum levels. IGF-1 is a mitogenic and antiapoptotic peptide involved in growth regulation of breast epithelial cells. Circulating IGF-1 exerts endocrine action, it regulates growth hormone secretion by a negative feedback mechanism. In the past few years, both laboratory investigations and epidemiologic studies provided strong evidence that the IGF-1/growth hormone axis is involved in human cancer risk [Maturitas 29 (1998) 61; Horm. Res. 51 (1999) 34; Eur. J. Cancer 36 (2000) 1224; Maturitas 41 (2002) 299] Some progestins also have effects on the enzymes in breast tissue that are responsible for the local synthesis of estradiol. Thus, whilst progestins without androgenic action have been found to markedly inhibit these enzymes, an equivalent degree of inhibition is not achieved with testosterone-derivatives. Therefore, special attention should be paid to the various partial actions of the different progestins and their effects on breast tissue. Furthermore, factors such as the duration of breast tissue exposure to progestin activity, the influence of different regimens on protective apoptotic mechanisms in the breasts, as well as dose levels and the degree of mammary gland tissue differentiation throughout treatment, should also be considered.     

Progesterone receptor isoform functions in normal breast development and breast cancer

Progesterone acting through two isoforms of the progesterone receptor (PR), PRA and PRB, regulates proliferation and differentiation in the normal mammary gland in mouse, rat, and human. Progesterone and PR have also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is recent advances in understanding the role of the PR isoform-specific functions in the normal breast and in breast cancer. Also discussed is information obtained from rodent studies and their relevance to our understanding of the role of progestins in breast cancer etiology.     

Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop.

The role of progestins in the pathogenesis of breast cancer in women remains controversial. To advance this discussion, we report the demonstration and localization of progestin-induced biosynthesis of growth hormone (GH) in canine mammary gland tissue. Nontumorous mammary tissues and tumors, both benign and malignant, were obtained from private household dogs. Immunoreactive GH was localized in mammary epithelial cells and correlated with the presence of GH mRNA. Local synthesis of GH was also proven immunoelectron microscopically by demonstrating GH-containing secretory granules. Cellular GH production in nontumorous tissues was more extensive during the progesterone-dominated luteal phase of the ovarian cycle or during exposure to synthetic progestins than during anestrus. GH was also associated with areas of hyperplastic mammary epithelium, which may indicate that locally produced GH enhances proliferation, acting in an autocrine and/or paracrine manner. In 41 of 44 tumors, GH was present. Of 3 GH-negative tumor samples, 2 were from progestin-depleted, castrated bitches. In nonmalignant mammary tissues, GH production is stimulated by progesterone and synthetic progestins interacting with progesterone receptors. In some progesterone-receptor-negative malignant tumors, GH expression was found, indicating loss of this control. Progestin-induced GH probably participates in the cyclic development of the mammary gland but may promote mammary tumorigenesis by stimulating proliferation of susceptible, and sometimes transformed, mammary epithelial cells.     

Risks of estrogens and progestogens

The risks and benefits of specific types of postmenopausal estrogens and progestogens are explored: those affecting serum lipids, clotting elements, hepatic proteins synthesis, blood pressure, glucose tolerance, endometrial, breast and cervical cancer. Ethinyl estradiol taken orally is the only estrogen likely to cause gall bladder disease. It also induces liver protein synthesis when taken orally or vaginally. Natural estrogens do not heighten coagulation factors, and may shift towards fibrinolysis. Both ethinyl estradiol and equine estrogens may increase blood pressure, while natural estrogens may decrease it. Similarly natural estrogens induce prostacyclin synthesis, while ethinyl estradiol activates both prostacyclin and thromboxanes. Progestagens, especially so the norprogestins, disturb carbohydrate metabolism and tend to reverse the beneficial effects of estrogens on serum lipids, a 40-70% reduction in risk of mortality from coronary heart disease. A meta- analysis of 23 studies concluded that menopausal estrogens do not increase the risk of breast cancer by a measurable degree, except in high doses and in those predisposed by family history. There is an increased risk of endometrial carcinoma for those taking unopposed estrogens for more than 3-6 years. This can be attenuated by taking combined estrogen-progestins, which will eventually result in absence of bleeding, or a 12-day progestogen course every 4-6 cycles. Oral micronized progesterone decreases blood pressure. The relative androgenic effects of progestins other than the norprogesterone derivatives are less significant. As an alternative to taking a progestogen, a woman could have regular endometrial sampling or abdominal or vaginal sonograms to detect endometrial cancer.     

Why a consensus conference on hormone replacement therapy and the cardiovascular system?

A recent randomized, placebo-control study of a combination of conjugated estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg) known to bring considerable advantages to post-menopausal women, has concluded that the risks associated with its use outweigh the benefits. On the strength of these data the manufacturer began recommending that physicians consider alternatives to their product to treat post-menopausal symptoms. Since women take hormone replacement therapy (HRT) for compelling health reasons, it is important, not only to evaluate the new evidence, but also to translate it into terms which can be understood by women and their physicians. Although the focus of this conference is on the cardiovascular system, in order to place the present controversy in its proper perspective, it is necessary to consider also other adverse effects that frighten women, first and foremost, a possible increased risk of breast cancer. For several years it has been reported that there is an increased risk of invasive breast cancer with increased duration of HRT use, similar to what has been found for oral contraceptives. The situation is however, entirely different when addressing HRT and risk of cardiovascular diseases (CVD). Here, a large body of evidence has, for years, pointed to a protective effect. Therefore, in the case of cardiovascular risk, we must proceed very cautiously and weigh the evidence, before concluding that HRT has indeed a negative effect on cardiovascular diseases. To properly do so, we must evaluate the validity and applicability of the findings presented in the latest study, since evidence indicates that the results of the study may not be applicable to women seeking HRT at the time of menopause. We also need to try and outline an overall “risk-benefit profile” for the use of HRT and we must aim at establishing a true dialogue between all parties concerned. Finally, we must obtain information, or state the lack of it, on possible different effects among the various estrogens, routes of administration and dosages, as well as possible different actions of the various progestins, their dosages and routes of administration.     

Menopause, hormone replacement therapy and cancer

OBJECTIVE: To comparatively review available evidence on hormone replacement therapy (HRT) and cancer. METHODS: Qualitative literature review. RESULTS: Most potential favorable and adverse effects on cancer risk of HRT are restricted to current users. On the basis of observational epidemiological data, the RR of breast cancer is moderately elevated in current and recent HRT users, and increases by about 2.3% per year with longer duration of use, but the effect drops after cessation and largely, if not totally, disappears after about 5 years. Unopposed estrogen use is strongly related to endometrial cancer risk, but cyclic combined oestrogen-progestin treatment appears to largely or totally reduce this side effect, if progestin are used for at least 14 days per cycle. However, combined HRT may be associated with higher risk of breast cancer as compared to unopposed estrogens. HRT has been inversely related to colorectal cancer, although the issue of causal relation remains open to discussion. No consistent association was reported for ovarian, liver, other digestive or lung cancer. CONCLUSIONS: Recommendations for prolonged HRT use must be considered on an individual basis, taking into account the presence of other risk factors mainly for breast cancer, such as family history of breast cancer or a personal history of benign breast disease, as well as individual risk for other chronic diseases.