Postmenopausal hormonal therapy: Current status.

Many trials of the pros and cons of postmenopausal hormone replacement therapy have been done and this treatment has evolved over time. Here, we present a review and current status of this therapy.

INTRODUCTION

The first clinical usage of hormone replacement therapy (HRT) in the setting of menopause began in the 1950s, with the administered estrogen purified from the urine of pregnant mares. From that time until 1975, estrogen was administered without supplemental progesterone or progestin. A study demonstrated that in the absence of progesterone, patients were at increased risk of endometrial cancer with unopposed estrogen therapy. After this, progestin was supplemented in women who had not received surgical hysterectomy, to reduce the incidence of endometrial hyperplasia and cancer. This was followed by the Women's Health Initiative (WHI) in 2002.

WOMENS HEALTH INITIATIVE

In 2002, the WHI[1] was published looking at the effects of hormonal replacement therapy in postmenopausal women. There was a slight higher incidence of breast cancer; heart attack and stroke were increased in older patients, although not in younger participants.

Progesterone is the major anabolic hormone for breast tissue, and accordingly breast cancer was not increased in patients who were on estrogen therapy alone after hysterectomy.[2]

Sole therapy with estrogen is contraindicated if the uterus is still present due its proliferative effect on the endometrium.

The WHI also found a reduced incidence of bone fracture, colorectal cancer when estrogen and progesterone were used together. Ultimately, the study found disparate results for all-cause mortality with hormone replacement, finding it to be lower when HRT was begun during the 5th decade of life, but higher when begun after age 60 years.[3]

Coverage of the WHI findings led to a reduction in the number of postmenopausal women on HRT.[3] WHI recommended that women with nonsurgical menopause take the lowest feasible dose of HRT, and for the shortest possible time, to minimize risk.[4]

PREMATURE STOPPAGE OF WOMEN'S HEALTH INITIATIVE

Clinical medical practice changed with WHI studies of postmenopausal HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. The WHI studies were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women.

The WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined conjugated equine estrogen (CEE) and progestin exceeded their benefits. The estrogen-alone trial, performed on women who had hysterectomy, due to the proliferative effect of the hormone on endometrial tissue, did not show such problems and was continued. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in estrogen only arm, risks of stroke and pulmonary embolism were increased, predominantly in patients who began HRT over the age of 60 years.

The first report on the halted WHI estrogen-plus-progestin study came out in July 2002. It followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of medroxyprogesterone acetate (MPA) and estrogen.

The study reported statistically significant increases in rates of breast cancer, coronary heart disease (CHD), strokes, and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia. The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits.

A sharp drop in breast cancer rates was observed following decrease in hormone replacement in subsequent years.

WOMEN'S HEALTH INITIATIVE LIMITATIONS AND CRITICISMS

The WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens. The double blinding limited validity of study results due to its effects on patient exclusion criteria. Patients who were experiencing symptoms of menopause were excluded from the study. As a result, while the average age of menopause is at age 51 years, study participants were on average 62 years of age. Demographically, the vast majority was Caucasian, and tended to be slightly overweight and former smokers.[5]

Some findings of the WHI were reconfirmed in a larger national study done in the UK, known as The Million Women Study.[6]

The Million Women Study is a study of women's health analyzing data from more than 1 million women aged 50 years and over. It is a collaborative project between Cancer Research UK and the National Health Service (NHS), with additional funding from the Medical Research Council (UK).

The study has abundantly fulfilled its aims of illuminating the answers to crucial questions about factors affecting the health of women in this age group, as its collaborators continue their frequent contribution to prestigious medical journals of what has become an impressive series of landmark medical papers.[678]

One key focus of the study relates to the effects of HRT use on women's health. The study has confirmed the findings in the WHI that women currently using HRT are more likely to develop breast cancer than those who are not using HRT.

The Million Women Study is a multicenter, population-based prospective cohort study of women aged 50 years and over invited to routine breast cancer screening in the UK. Between 1996 and 2001, women were invited to join the Million Women Study when they received their invitation to attend breast screening at one of the 66 participating NHS Breast Screening Centers in the UK. At these centers, women received a study questionnaire with their invitation, which they were asked to complete and return at the time of screening. Around 70% of those attending the program returned questionnaires and agreed to take part in the study, over one in four women in the UK in the target age group.

Follow-up of over 1 million women in the Million Women Study confirmed findings from other recent studies that women currently using HRT are more likely to develop breast cancer than those who are not using HRT.[6] Past users are not at increased risk. The study was able to show that this effect is substantially greater for combined (estrogen-progestogen) HRT than for estrogen-only HRT; and that the effects were similar for all specific types and doses of estrogen and progestogen, for oral, transdermal, and implanted HRT, and for continuous and sequential patterns of use. Current users of estrogen-progestogen HRT were at two-fold increased risk of developing breast cancer, and current users of estrogen-only HRT at 1.3-fold risk. Use of HRT by women aged 50–64 years in the UK in the decade from 1993 to 2003 resulted in an estimated 20,000 extra breast cancers.

HRT AND ENDOMETRIAL CANCER

It is well known that postmenopausal women who have not had a hysterectomy are at increased risk of cancer of the endometrium if they take estrogen-only HRT. Follow-up of over 700,000 women in the Million Women Study confirmed this and showed that the risk of endometrial cancer is also increased in women who take tibolone; but is not altered, or may even be reduced, in women taking combined estrogen-progestogen HRT.[7]

HRT AND OVARIAN CANCER

Results of the study show a small increase in risk of ovarian cancer in women taking HRT.[8] Such an increased risk had been suspected from some previous studies, and has now been confirmed with the larger numbers available in this study. The findings come from analyses on 948,576 postmenopausal women in the study, followed-up for about 5 years. Women currently taking HRT were at higher risk of developing and of dying from ovarian cancer than women not using HRT. Past users were not at increased risk. The risk in current users was increased about 1.2 fold; for every 1,000 women using HRT, 2.6 developed ovarian cancer over 5 years, compared with 2.2 in those not taking HRT. The risk was the same for estrogen-only, combined estrogen-progestogen and other types of HRT (including tibolone) and did not vary by specific type of estrogen or progestogen, or between oral and transdermal (patch) administration.

These results are equivalent to one extra case of ovarian cancer for every 2,500 women taking HRT, and one extra death from ovarian cancer per 3,300 women taking HRT, over 5 years. According to the findings, in women aged 50–69 years, about 19 of these cancers (breast, endometrium, and ovary) will develop over 5 years in every 1,000 women not taking HRT. In women taking HRT, the estimate is for the number of cancers to be increased to about 31. The overall increased risk is higher in women using combined estrogen-progestogen HRT than in women using estrogen-only HRT because most of the overall increase is due to an increase in breast cancer, and users of combined HRT have a higher risk of breast cancer than users of estrogen-only HRT.

PUBLIC HEALTH IMPLICATIONS: IMPACT OF THE MILLION WOMEN STUDY

Results from the Million Women Study, together with those from other studies such as the WHI trial from the USA, have influenced national policy, including recommendations on the prescribing and use of HRT from the Royal College of Obstetricians and Gynecologists and from the Commission on Human Medicines.

Public awareness of the study and its findings has led to significant behavioral changes, predominately resulting in the swift decline of HRT prescriptions throughout Europe and the US from 2003. In contrast to the increase in HRT prescriptions between 1991 and 1996, which remained stable through to 2001, sales of HRT fell by 50% between 2002 and 2005 following the publication of the Million Women Study and the WHI study.

The current indications for use of postmenopausal HRT from the US Food and Drug Administration include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or urogenital atrophy and prevention of osteoporosis.[4]

In 2012, the United States Preventive Services Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin are likely to exceed the chronic disease prevention benefits in most women.[3]

A Cochrane database systematic review[9] found that nine trials published since 2002 provided outcome data relevant to USPSTF recommendations for postmenopausal hormone therapy. Trials included the two main WHI trials, two trials consisting of subsamples from the WHI trials (WHI Memory Study (WHIMS) and WHI Study of Cognitive Aging (WHISCA)), Estrogen Memory Study (EMS), Heart and Estrogen/progestin Replacement Study (HERS), Estrogen in the Prevention of Reinfarction Trial (ESPRIT), Ultra-Low-Dose Transdermal Estrogen Assessment (ULTRA) trial, and Women's International Study of Long-Duration Estrogen after Menopause (WISDOM). Only the WHI trials were designed and powered to evaluate the effectiveness of hormone therapy for primary prevention of several conditions that were the focus of this review. The WHI trials met criteria for fair quality, provided most of the estimates of benefits and harms, had 11 years of follow-up, and were most applicable to the target population. Although results of the other trials were consistent with the WHI trials for selected outcomes, they measured few outcomes and were often inadequately powered to detect potentially important differences among groups.

USPSTF update[4] of evidence from trials published since 2002 indicates that both hormone therapy regimens decrease risk for fractures; but increase risk for stroke, thromboembolic events, and gallbladder disease. Estrogen plus progestin also increases risk for breast cancer and probable dementia, whereas estrogen alone decreases risk for breast cancer.

The HERS[[5] was a randomized, double-blind, placebo-controlled trial of daily use of combined CEEs and MPA (progestin) on combined rate of nonfatal myocardial infacrtion (MI) and CHD death among postmenopausal women with coronary disease. They enrolled women with established coronary disease because of their high risk for CHD events and the strong reported association between hormone use and risk of these events.

First, in the population studied in HERS, that is, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of CEEs and MPA did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease.

Second, HERS did not evaluate the cardiovascular effect of treatment with unopposed estrogen, commonly used in women who have had a hysterectomy, or other estrogen plus progestin formulations. They also did not study women without coronary disease.

Third, based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD.

In the HERS trial, with participants having a mean age of 66.7 years, menopausal hormone therapy (MHT) did not reduce in total mortality (risk ratio (RR), 1.08; confidence interval (CI), 0.84–1.38).

The findings in the younger age groups were similar to Nurses’ Health Study findings (RR for mortality, 0.63; CI, 0.56–0.70).[10]

CONTRAINDICATIONS OF POSTMENOPAUSAL HRT

Absolute contraindications

Undiagnosed vaginal bleeding

Severe hepatic disease

Coronary artery disease (CAD)

Venous thrombosis

Endometrial carcinoma

Relative contraindications

Headaches

Personal history of breast cancer

Personal history of ovarian cancer

History of fibroids

Atypical ductal hyperplasia of the breast

Active gallbladder disease (cholangitis, cholecystitis)

ADVERSE EFFECTS

HRT is available in various forms. It generally provides low dosages of one or more estrogens, and often also provides either progesterone. In women who have had a hysterectomy, an estrogen is usually given without any progesterone, a therapy referred to as “unopposed estrogen therapy”. HRT may be delivered to the body via patches, tablets, creams, troches, intrauterine devices (IUDs), vaginal rings, gels, or more rarely by injection. For example, vaginally administered estrogens include those given by intravaginal tablets, creams, and rings; and can have more effect on atrophic vaginitis with fewer systemic effects than estrogens delivered by other means.

Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progesterone or progestins taken for about 2 weeks every month or two; a method called “cyclic HRT” or “sequentially combined HRT” (abbreviated scHRT). An alternate method, a constant dosage with both types of hormones taken daily, is called “continuous combined HRT” or ccHRT, and is a more recent innovation.

CONCLUSIONS AND IMPLICATIONS FOR PRACTICE

HRT is often given as a short-term relief (often 1 or 2 years, usually less than 5) from menopausal symptoms (hot flush, irregular menstruation, fat redistribution, etc.). Younger women with surgical menopause or premature ovarian failure may use HRT for many years, until the age that natural menopause would be expected to occur.