The history of hormone replacement therapy HRT started in the s, with very high popularity in the s. The negative results of the study received wide publicity, creating panic among some users and new guidance for doctors on prescribing HRT. The clear message from the media was that HRT had more risks than benefits for all women. In the following years, a reanalysis of the WHI trial was performed, and new studies showed that the use of HRT in younger women or in early postmenopausal women had a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality.
Hormone replacement therapy HRT was presented as a therapy that could allow women to free themselves from the malediction of estrogen loss and conserve their femininity. Ziel et al. Nevertheless, in the following years, researchers discovered that reducing the dosage of estrogen and combining it with progesterone could reduce the risk of endometrial cancer [ 6 ].
Such combined therapy was recommended for women with an intact uterus, raising renewed enthusiasm for HRT treatment. The FDA initially approved HRT only for the treatment of hot flashes and not for the prevention of chronic conditions, but in the prevention of osteoporosis was included among the FDA-approved indications [ 7 , 8 ]. Furthermore, in the same years, numerous observational studies [ 9 , 10 , 11 , 12 ] suggested that HRT had various benefits, not only with regard to the treatment of menopausal symptoms, but also in the prevention of chronic diseases.
The use of HRT increased further, and the American College of Physicians developed the first guidelines for using HRT as a preventative therapy for the chronic diseases of postmenopausal women [ 13 , 14 ], even if experts raised some concern about the impact that progestin may have on estrogen benefits, particularly in the cardiovascular system [ 15 ]. On the basis of the claimed positive effect of HRT on cardiovascular health, the FDA required that this supposed HRT-induced cardiovascular benefit be confirmed by randomized clinical trials.
This study enrolled postmenopausal women with established coronary heart disease. Enrolled women were randomized to receive HRT 0. No difference was found between the two groups after four years of follow-up, but in the HRT group, an increase of coronary events nonfatal myocardial infarction or coronary heart disease CHD death was found after one year. This induced increase declined in the subsequent years [ 16 ].
Women with uteri 16, participants were randomized and received a combination of 0. The first results of the WHI were published in after a mean follow-up period of 5. In the group with intact uteri, an increased incidence of coronary heart disease and breast cancer was observed in concomitance with a reduction of osteoporotic fractures and colorectal cancer [ 17 ].
Given these results, it seemed that the risks outweighed the benefits, and the trial was prematurely discontinued. The data were largely disseminated to the media, creating panic among HRT users and forcing new guidance for doctors on prescribing HRT. The message was that HRT, with no specification of type and route of administration, was associated with more risks than benefits.
However, no distinction was made between users and their age. The trial with only estrogen performed in hysterectomized women continued, and the preliminary data were published in [ 18 ]. In addition, this trial was stopped prematurely after 6.
In spite of the benefits such as a reduction of osteoporotic fracture and colon cancer and of the not-increased risk of breast cancer or cardiovascular disease, the overall message on HRT remained negative. After these announcements, the UK regulatory authorities issued an urgent safety restriction about HRT, recommending that doctors should prescribe the lowest effective dose for symptom relief, should use it only as a second-line treatment for the prevention of osteoporosis, and should not use it in asymptomatic postmenopausal women.
Since that time, there have been ongoing discussions and controversies about the WHI design and conclusions, and many of its results have been extensively debated. It emerged that one important limitation of the WHI was that most of the participants were more than a decade past their final menstrual period, raising the question of whether the results of the trial could be applied to younger women.
Furthermore, the WHI tested only CEE either alone or in combination with a single progestin, medroxyprogesterone acetate. As a result, the WHI findings did not answer doubts about the safety and effectiveness of other HRT formulations, regimens, and delivery methods. It has been suggested that the conflicting findings between the WHI and previous observational studies were the consequence of the different ages of the enrolled women.
Some observational studies had included symptomatic women who had started HRT near the onset of menopause, while women enrolled in the WHI trial were asymptomatic, older average age The follow-up of the WHI continued for 13 years, and some results, including an age stratification of the cardiovascular outcomes, were published in the following years [ 20 , 21 , 22 , 23 ].
A reanalysis of the WHI trial with new studies and a metanalysis showed that the use of HRT in younger women 50—59 years or in early postmenopausal women within 10 years of menopausal onset had a beneficial effect on the cardiovascular system, reducing coronary diseases and all-cause mortality [ 22 , 24 , 25 , 26 , 27 ]. Furthermore, a large controlled trial from Denmark reported in demonstrated that healthy women taking combined HRT for 10 years immediately after menopause had a reduced risk of heart disease and death from heart disease [ 28 ].
Unfortunately, these data did not receive appropriate coverage by the media, and the fear regarding HRT has persisted. Thus, the story of HRT over the years has shown a trend with two peaks of utilization: a first rise in the s and a second, higher increase in the years —, before the publication of the WHI data. After these years, there was a precipitous decline in HRT use in many countries [ 29 ].
Observational studies have tried to show trends of hormone-related cancers and chronic conditions following the WHI publications. Cancer and chronic conditions are multifactorial, and modification of a single factor, such as HRT use, may not result in a clear epidemiological change.
Over the years, data regarding the impact of HRT on breast safety and breast cancer mortality have been controversial. Most of the meta-analyses and observational studies performed in the s reported no increase in the risk of breast cancer with estrogen use [ 35 ]. However, some increased risks related to dose and duration of use were found with the administration of combined estrogen—progesterone therapies [ 36 ].
The WHI reported an increased risk of breast cancer in the women treated with a combination of conjugated estrogen and medroxyprogesterone acetate [ 17 ], a risk that was significantly higher than in placebo users after 5. Vice versa, the risk of breast cancer was significantly lower than in placebo users for those women treated with only conjugated estrogen [ 37 , 39 ]. However, this study did not distinguish between de novo tumor development and the growth of an occult tumor present before the beginning of therapy.
After analyses of the biology of occult tumors, current opinion about breast safety with HRT has changed. The modern thinking is that estrogen could have a promotional and noncarcinogenic effect on occult tumor cells and that this effect is probably greater with an estrogen—progesterone therapy [ 40 ].
Following the publication of the WHI results and the associated drop of HRT use, some envisioned a concomitant decline of breast cancer incidence. However, the impact of HRT cessation showed an important variability between nations. Clarke and colleagues were the first to publish data about the incidence of breast cancer between and [ 41 ]. A study performed in California between and [ 42 ] similarly hypothesized that a decline in breast cancer incidence was linked to reduced HRT use.
Other western countries documented a reduction in breast cancer incidence after the reduced use of HRT [ 43 ]. In Germany, breast cancer incidence declined by 8. In France, the breast cancer rate decreased by In Australia, a 6. In Italy, the Netherlands, and Spain, the absolute decline of therapy after did not translate into a decline in breast cancer rates [ 43 ].
In spite of that, breast cancer incidence declined 0. Interestingly, the incidence of estrogen receptor-positive breast cancer in the USA increased to a maximum in , with a downward trend starting in , at least two years prior to the WHI publications [ 43 , 49 ]. Moreover, after some years, there was a new rise in breast cancer incidence for both lobular and ductal breast cancer , such that by , the rates were like those of This could mean that other factors besides HRT can explain the trend in breast cancer.
Likely, some of these data can be explained by changes in the national screening programs for breast cancer. High rates of mammography, which has been extended to younger women, may have resulted in a greater incidence of breast cancer in the years following screening implementation, followed by a decline of breast cancer incidence as a consequence of the early diagnoses of the previous years [ 50 , 51 ].
The use of unopposed estrogen has been associated with an increased risk of endometrial cancer [ 4 ]. Consequently, guidelines have indicated that in women with uteri, estrogen therapy should be prescribed together with a progestin molecule [ 8 ].
Evidence of reduced endometrial cancer risk with combined HRT was well represented in the HERS trial, which showed seven fewer endometrial cancer cases per 10, in women using HRT than in placebo users [ 52 ]. Continuous combined therapy has better endometrial safety than sequential therapy does [ 54 , 55 ].
A large Finnish case—control study [ 56 ] showed that sequential therapy induced an elevated risk of endometrial cancer when used for longer than 10 years.
However, the roles of different types of progestagen remain to be assessed. In two observational studies, the most commonly used progestin molecules, norethisterone acetate and medroxyprogesterone acetate, did not differ in their protection from endometrial cancer [ 53 , 56 ].
However, for treatments longer than five years in the E3N cohort study [ 58 ], combined therapy with oral micronized progesterone or dydrogesterone was associated with an increased risk of endometrial cancer [ 59 ]. After the WHI publication and the drop in HRT prescription, endometrial carcinoma rates increased between and [ 60 ].
Similarly, in England, Martin and colleagues observed a change in endometrial cancer mortality after , with nine additional endometrial cancer deaths per year [ 51 ]. The incidence of cardiovascular events increases in postmenopausal women, particularly in those experiencing severe vasomotor symptoms. The clinical efficacy could be related to early treatment, but also could be related to the administration of HRT to those with a higher cardiovascular risk due to their symptoms.
Thus, it is not surprising that the results of the WHI trial did not confirm a protective effect of HRT against coronary heart disease, stroke, and venous thromboembolism [ 17 ]. However, a reanalysis of the data using age stratification reported that in women within 10 years of the onset of menopause, the administration of HRT decreased the rate of coronary artery disease and all-cause mortality [ 22 ].
Two subsequent meta-analyses, which used cumulated data from 23 and 30 randomized clinical trials, respectively, reported a decrease in CVD and all-cause mortality in HRT users younger than 60 years of age or in those who began menopause less than 10 years prior [ 24 , 25 ]. From the above data, it could be expected that a lack of treatment of symptomatic postmenopausal women may have translated into an increase in cardiovascular events after A Finnish study reported increased deaths from myocardial infarctions and strokes in women discontinuing HRT, especially in those younger than 60 years of age [ 72 ].
In the USA, a report comparing male and female mortality between two periods, the mids and between and [ 73 ], reported a reduction in male mortality but an increase in female mortality in the same timeframe. An English ecological study reported unfavorable changes in myocardial infarctions and strokes subsequent to the HRT fall following the WHI publication [ 51 ].
In contrast, one ecological study performed in the USA after reported a correlation between the fall in HRT use and a reduced incidence of acute myocardial infarction [ 74 ]. Postmenopausal osteoporosis is a consequence of estrogen withdrawal in which inflammation plays a multifactorial role [ 75 , 76 ]. Clinical studies have unanimously shown that any kind of HRT is capable of reducing bone turnover, reducing bone reabsorption, and increasing bone mineral density.
Both high bone turnover and low bone mineral density are risk factors for bone fractures. The supposed preventive effect of HRT on bone fractures has been reported by many observational studies [ 77 , 78 ]. The same data were obtained in the DOPS study [ 79 ]. The effect was demonstrated in a population of normal women that was not specifically suffering from osteoporosis, i.
In another observational study after 15 years of follow-up , conserved beneficial effects on bone were reported in women who used HRT for more than five years [ 81 ]. However, in a large study, Islam and colleagues found that the risk of fractures in postmenopausal women increased in the three years following the publication of the WHI [ 82 ]. The controversial history of HRT is about the history of a powerful pathogenetic therapy for all postmenopausal disturbances.
Its effects on symptoms are and were immediately visible, at first prompting rapidly growing estrogen use. A lack of knowledge about its side effects and complications, particularly in the endometrium, prompted consequences that limited HRT use.
Unfortunately, the surge in HRT use and its consolidation was abruptly stopped by the publication of the WHI trial, which was inadequately designed, evaluated, and reported. These new findings also show the additional benefits of HRT use for those initiating HRT in the age group, or for those less than 10 years past the menopause — trends to a lower risk from heart disease; a lower risk of death from any cause; no clear increased risk from stroke.
They also show a general increased risk for those starting HRT after the age of 60, which is later than normal UK clinical practice. It reported that women using estrogen only HRT had a reduced risk of breast cancer incidence and mortality but those on combined HRT had a slight increased risk of breast cancer incidence. Importantly, this did not translate into an increased risk of mortality.
They also reported on an increased risk of invasive breast cancer and breast cancer mortality in obese women. Regarding cardiovascular disease, they reported that women commencing HRT within 10 years on the onset of menopause or under 60 years old having a lower risk of cardiovascular disease, cardiovascular related death and all cause mortality.
An increase in body fat, especially around the abdomen, can occur during menopause because of hormonal changes, although exactly why this happens is not clear. Normal age-related decrease in muscle tissue, and a decrease in exercise levels, can also contribute to weight gain.
Most studies do not show a link between weight gain and HRT use. If a woman is prone to weight gain during her middle years, she will put on weight whether or not she uses HRT. Some women may experience symptoms at the start of treatment, including bloating, fluid retention and breast fullness, which may be misinterpreted as weight gain.
These symptoms usually disappear once the therapy doses are changed to suit the individual. HRT is not a form of contraception. The treatment does not contain high enough levels of hormones to suppress ovulation, so pregnancy is still possible in women in the perimenopause the time of hormonal instability leading up to menopause. Periods can be erratic in perimenopause, and egg production will be less frequent, but can still occur until menopause.
For women younger than 50, contraception is recommended for at least two years after the final period. For women aged 50 and above, contraception is recommended for at least one year after their final period. It is currently believed that, overall, the risks of long-term more than five years use of HRT outweigh the benefits. HRT should not be recommended for disease prevention, except for women under 60 years of age with substantially increased risk of bone fractures, or in the setting of premature menopause.
Women with liver disease, migraine headaches, epilepsy, diabetes, gall bladder disease, fibroids, endometriosis or hypertension high blood pressure need special consideration before being prescribed HRT. In these situations HRT is often given through the skin transdermally.
Despite the risks of long-term use, in women with severe and persistent menopausal symptoms, HRT may be the only effective therapy. Women with premature or early menopause are prescribed HRT long-term because of their increased risks of earlier onset of heart disease, osteoporosis, and some neurological conditions compared to women undergoing menopause around the age of 50 years.
Seek specialist advice from a menopause clinic or menopause specialist. Regular check-ups are recommended. It is advisable for women with a history of breast cancer to avoid HRT unless other treatments are ineffective, and their quality of life is made intolerable by menopausal symptoms.
Evidence has not conclusively shown that HRT will increase the risk of breast cancer recurring in a woman with a history of the disease. However, oestrogen and progestogens forms of progesterone may stimulate some types of cells in the breast and some types of HRT use have been associated with an increase in the risk of breast cancer in women without a history of breast cancer.
It is not recommended that women at high risk of breast cancer , or breast cancer survivors, take highly processed soy supplements which are high in phytoestrogens , but eating moderate amounts of whole soy foods appears to be healthy.
Studies have shown that some prescription medications can reduce hot flushes and sweats. These treatments may be an option if HRT cannot be used for health or other reasons, and should be discussed with a doctor. The herbal medicine , black cohosh, may take the edge off hot flushes and sweats, but there is no data to support long-term use.
There is also a rare liver condition that may be associated with the use of black cohosh. Commercially available vaginal moisturisers such as Replens may reduce vaginal dryness if used regularly. Consult your doctor about what will work best for you. This page has been produced in consultation with and approved by:. Content on this website is provided for information purposes only. Information about a therapy, service, product or treatment does not in any way endorse or support such therapy, service, product or treatment and is not intended to replace advice from your doctor or other registered health professional.
The information and materials contained on this website are not intended to constitute a comprehensive guide concerning all aspects of the therapy, product or treatment described on the website. All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions and to ascertain whether the particular therapy, service, product or treatment described on the website is suitable in their circumstances.
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