Introduction

Menopause is defined as the final menstrual period in a woman’s reproductive life and reflects the loss of ovarian follicular function, and thus when the ovaries cease to produce estrogen and progesterone in the monthly rhythmical cycle. It is this monthly cycling of estrogen and progesterone which elicit a menstrual period in women of reproductive age. Menopause, perimenopause and postmenopause all refer to the time in a woman’s life when the ovaries have completely ceased to produce estrogen and progesterone to elicit a normal cyclical menstrual period. Post-menopause refers to the time period when a woman has not had a menstrual period of greater than 12 months. Perimenopause refers to the time period where a woman’s ovaries are beginning to wax and wane resulting in erratic estrogen and progesterone production. For most women as we age, estrogen levels begin to fluctuate then decline, progesterone levels generally decline and androgens decline. Thyroid disease may become evident at the time of menopause. The average age of menopause is 52 years, but the age of natural menopause varies widely from 40 to 58 years.

Many women as they pass through menopause, will experience significant changes in their overall health and quality of life. As women enter their postmenopausal years the risk of cardiac disease, bone loss, and unfavorable metabolic alterations occur. Mood issues, such as depression and anxiety may occur or be exacerbated. Temperature instability, commonly referred to as hotflashes, and sleep disturbances can also be present for many women. More recently, estrogen’s impact on cognitive function is being recognized, and some women may have cognitive decline at menopause.

As life expectancy is increasing, more and more women will experience longer years and a greater proportion of their life in a low estrogen state. Thus, the overall impact of menopause and the resulting lower estrogen, progesterone and androgen levels require a renewed and modernized attention in women’s health. By 2030, the world population of menopausal and postmenopausal women is projected to increase to 1.2 billion, with 47 million new entrants each year. In order to improve quality of life and treat menopausal symptoms, many women have been considered candidates for estrogen supplementation, so called “hormone replacement therapy” or HRT. Hormone therapy is a combination of medications which contain female hormones, either estrogen alone or estrogen and progestin together, to replace the hormones the body is no longer making at the levels of the reproductive years.. HRT may also include androgen supplementation, such as DHEA and testosterone. Premarin, a combination of equine estrogens ad used for women, was first form of HRT introduced in 1941, progestins were introduced in the 1950’s.

Widespread Premarin usage was employed in women’s health in the 1950s until 2002, when the Women’s Health Initiative Study findings were published. Initially, it was thought that the protective effects of estrogen against cardiac disease outweigh the risks of HRT, as cardiac disease was and remains the leading cause of death in women. In 2002 the results of this large randomized trial investigating the risks and benefits of HRT for menopausal women, abruptly altered recommendations and prescribing practices for HRT The findings overwhelmed the medical community, establishing that HRT in fact did NOT decrease a woman’s chance of getting heart disease, but rather definitively increased her risk of blood clotting, stroke and breast cancer. Controversy continues as to whether the early findings were conclusive and applicable to more modern hormone replacement regimens and practices.

The Women’s Health Initiative (WHI) Study randomized over 16,000 menopausal women, regardless of her time since her last menstrual period, to either Prempro (a combination of Premarin and Provera) or placebo, if she had her uterus in place. Women who were post hysterectomy were randomized to Premarin alone or placebo. Thus some women were very close in years to their last menstrual period and some were many years from their last menstrual period, when randomized and treated. The practice altering important findings of this study included: the combination of Prempro significantly increased the risk of breast cancer , heart attack, and stroke; there was a 25 percent increase in the risk of invasive breast cancer in Prempro users; and Prempro as well as Premarin was noted the reduce the risk of: hip fracture and colorectal cancer. The notion of using HRT for protection from diseases of aging fell into disfavor when this large multicenter trial demonstrated equivocal effects or even increased risks of adverse health outcomes with HRT. Because of these study results, physicians quickly and abruptly abandoned female hormone replacement therapy. Women were called and letters were sent, asking those who were already using HRT to stop. Prescriptions for new patients were halted. Many women were left with few alternatives for treatment of symptomatic menopause. More recently however, the application of the WHI's findings to all HRT regimens and women’s health, have been called into question.

Currently controversy exists concerning the wide scale application of the results of the WHI study to all menopausal women and is based on the following two important factors: timing of initiation of HRT and the type of HRT employed. Current data indicates that that there are differences between the effects of estrogens and progestins for a 50-year-old woman placed on HRT, when compared to a woman who initiates therapies ten or more years after menopause. Researchers have been reexamining the data from the WHI study to see if there is a subset of women who might benefit from replacement hormones, as well as identifying subsets who should avoid it. In addition to the timing of initiation of HRT, the type of HRT is also important. The WHI study evaluated the effects of Premarin and Provera or Premarin alone. Premarin, which is a mixture of conjugated estrogens derived from pregnant equine urine (also referred to as CEE, or conjugated equine estrogen) and Provera (a synthetic progestin) have been historically employed in HRT regimens since the 1950s. More modern regimens employ hormones which are structurally identical to human estradiol and progesterone. These regimens employ estradiol instead of Premarin and progesterone instead of the synthetic Provera. More recent studies have begun to re‐evaluate the possible benefits of HRT including stress reduction, enhancement of cardiovascular and bone health, improvement in cognitive performance, and a delay in the onset of dementia

Persistent negative attitudes towards hormone replacement therapy (HRT) following publication of the Women’s Health Initiative (WHI) studies in the early 2000s led to a virtual abandonment of HRT use for women and of medical education about menopause and HRT. Currently, HRT risks and benefits may be poorly taught in some medical education programs. Many women who may benefit from HRT, suffer significant menopausal symptoms and health issues due to the knowledge gap between the perceptions of risks and the reality of risks and from a lack of knowledge of benefits of hormone replacement therapies. The use of more modern HRT regimens should be critically examined and reviewed with perimenopausal and menopausal women, so that they can be proactive in the aging process and achieve best their best health possible. The risks of hormone therapy differ based on route of administration, dose, duration of use, timing of initiation, and whether a natural progesterone is used.

We will begin to explore in a comprehensive fashion, the published data concerning the risks, benefits and alternatives of hormone replacement therapy.