Introduction to Menopause and Hormone Replacement Therapy
Menopause is the permanent cessation of menses following the loss of ovarian follicular activity. The median age at the onset of menopause in the United States is 51 years, while the average life expectancy for women is 79.7 years. Thus, American women can expect to be postmenopausal for more than one-third of their lives. Menopause is important because the decline of sex steroids in approximately two-thirds of women results in symptoms that adversely affect quality of life and increase the risk for osteoporosis and possibly coronary heart disease. Menopausal symptoms may include hot flashes, night sweats, vaginal dryness, mood swings, depression, insomnia, myalgia, and urinary frequency.
Morbidity and mortality attributed to sex-steroid deficiency may be modified by the use of hormone replacement therapy (HRT). HRT is associated with increased life expectancy in post-menopausal women. HRT involves replacing the low levels of estrogen and progesterone to relieve the symptoms of peri- and post-menopausal women. The proposed benefits of estrogen replacement therapy include prevention and treatment of bone loss, protection against urogenital atrophy, preservation of cognitive function, and possibly prevention of cardiovascular disease and dementia.
HRT traditionally has been a “one-size-fits-all” type of therapy in which synthetic hormones have been a woman’s only option for this treatment, with many unaware of natural alternatives such as bio-identical hormones. Now however, the use of bio-identical hormones may help meet a woman’s individual needs.
What is the difference between synthetic and bio-identical hormones?
Provera®, Premarin®, Prempro®, and Estrace® are examples of synthetic hormones. These are molecular cousins of the natural agents: estrogen, progesterone, and testosterone. However, they are not identical in structure nor activity to the natural hormones that they emulate.
Bio-identical hormones are a natural alternative to synthetic hormones. They are derived from a natural source, soybean or yam. Bio-identical hormones are molecularly identical to the ovarian steroid hormones that your own body creates: progesterone, estradiol, and testosterone.
Since bio-identical hormones are derived from plants and are identical to human hormones, they are as effective and better tolerated than conventional HRT. Based on your prescriber’s recommendation, our compounding pharmacy can customize plant-derived bio-identical hormones to address your unique needs. This may include customization in dosage or dosage form, including transdermal systems, suppositories (vaginal or rectal), gels, creams, lozenges or capsules.
There are 3 main estrogens produced by the human body. These 3 estrogens are generally 60-80% estriol, 10-20% estradiol, and 10-20% estrone. In menopause, this balance shifts to where estrone accumulates more than both estriol and estradiol than in the younger stages of a woman’s life. By using bio-identical hormone replacement, this naturally occurring balance may be restored.
Estradiol, produced from testosterone, is the most active form of endogenous estrogens and the one produced most predominantly by a woman’s ovaries before menopause. Estradiol levels fall after menopause and after hysterectomy when the ovaries are removed.
Estradiol has many functions and may protect against osteoporosis, Alzheimer’s disease, colon cancer, elevated cholesterol levels, urinary incontinence, and tooth loss or decay. It may also enhance your sleep, mood, memory, digestion, and sex drive.
Estriol is known as the “weak” estrogen. It is only produced in significant amounts during pregnancy as it is secreted in large amounts by the placenta. Levels of estriol do not change significantly in non-pregnant women compared to after menopause.
Estriol was until very recently considered the “forgotten” estrogen because of its weakness in comparison to estradiol and estrone. Now, there are many health advocates that will report estriol as a "safer" form of estrogen for use in HRT because of its possible anti-carcinogenic effects on breast and endometrial tissues. However, estriol alone does not provide the cardiovascular benefits of estradiol, and very large doses are required to achieve increases in bone density.
Estriol is not commercially available in the U.S., although it is available through compounding.
Estrone is the predominant estrogen in a woman’s body after menopause. When the functions of the ovaries declines, the fat cells in a woman’s body take over the role of synthesizing estrone.
Estrone has been thought to be more carcinogenic than estradiol, and yet the commonly prescribed synthetic HRT’s contain the highest percentage of estrone in its formulation.
Bio-identical estrogens can contain a combination that more closely mimics what our body naturally produces, including a smaller percentage of estrone, the most carcinogenic estrogen, and a higher percentage of estriol, which has anti-carcinogenic effects and is only available through compounding pharmacies.
Bi-Est, as its name suggests, contains 2 types of estrogen, commonly as 20% estradiol and 80% estriol. Ratios can be modified to address individual patient response. Bi-Est provides the anti-carcinogenic effects of estriol while also providing the cardiovascular benefit, prevention of bone loss, and menopausal symptom relief of estradiol.
Tri-Est is a combination of 3 types of estrogen: 10% estradiol, 10% estrone, and 80% estriol. Ratios can be modified to address individual patient response.
Both formulations contain a high percentage of estriol, the weakest, yet safest form of estrogen that has been shown to blunt the negative effects of the stronger estrogens. By adding estradiol, the most active estrogen, it enhances its effects. Some health professionals, however, may advocate the use of Bi-Est versus Tri-Est because they prefer not to add estrone since it is already quite plentiful in most post-menopausal women.
Progesterone is a sex steroid that is produced by the ovaries and adrenal glands in women and plays an important role in pregnancy, preparing the uterus' lining for implantation of a fertile egg and then helping to maintain it during pregnancy. It also signals the uterus to shed its lining if pregnancy doesn't occur, prompting monthly menstruation in pre-menopausal women. Progesterone is not produced by the body after menopause.
Because of the increased risk of endometrial hyperplasia and endometrial cancer with estrogen monotherapy, women who have not undergone hysterectomy should be concurrently treated with a progestin, which counteracts the action of estrogen in the uterine lining. Some alternative health practitioners now promote progesterone as a necessary component of HRT for all women, claiming that it prevents osteoarthritis, breast cancer, reduces peri-menopausal symptoms, decreases cholesterol levels, improves mood, increases libido, and much more.
Natural vs. Synthetic Progesterone
“Progestin” or “progestogen” refers to the wide range of synthetic, non-bio-identical progesterone products that are currently on the market. These synthetic progesterones are what have been tested in the majority of clinical trials on progesterone use in women, especially in relation to endometrial and breast cancer.
"Progesterone" refers to the naturally occurring hormone that your body produces, it is bio-identical. The only major study performed to date using natural progesterone is the PEPI trial, which compared estrogen, estrogen/synthetic progesterone, and estrogen/natural progesterone in their effects on heart disease (cholesterol levels), and in which the use of natural progesterone showed significant benefits versus the synthetic progesterone on cholesterol levels. These results were not anticipated because it was assumed that the close chemical composition of synthetic progesterone and natural progesterone would produce similar results, which they did not.
There are a couple of current theories about progesterone and breast cancer. One is that intermittent doses (cycling) may stimulate growth, while another suggests constant dosing may prevent tissue growth by triggering apoptosis (programmed cell death). In any case, most studies suggest that there is a strong correlation between breast cancer and synthetic progesterone use, and very little data is available regarding the use of natural progesterone and incidence of breast cancer. Given the surprising results of the PEPI trial in regard to the dissimilar effects of natural vs. synthetic progesterone on cholesterol levels, the question needs to be asked whether natural progesterone has the same adverse effects on breast tissue as synthetic progesterone. There are no definitive answers.
The therapeutic use of testosterone in women, although controversial, is becoming more widespread. Nonetheless, data to support this practice are limited, as only a few randomized trials have been conducted. There is a cluster of symptoms that appear to characterize androgen deficiency in women: loss of sexual desire; diminished well-being; loss of energy; and, over time, decreased bone mass and reduced muscle strength. There is substantial evidence that androgen replacement, usually in the form of testosterone, is effective in alleviating these physical and psychological symptoms of androgen insufficiency. Testosterone replacement therapy is accepted for women who have undergone surgical menopause, but should also be considered for naturally menopausal women and those who have experienced premature ovarian failure.
In women, androgens may act directly via the androgen receptor or indirectly after conversion to estrogen. Androgens are the precursor hormones for estrogen production in the ovaries, as well as in extragonadal sites, including bone, adipose tissue, and the brain.
Although estrogen replacement improves vaginal dryness, vasomotor symptoms, and general well being, it has minimal effect on libido. Estrogen combined with androgen significantly improves sexual activity, satisfaction, and pleasure more than that reported with estrogen monotherapy.
Testosterone is certainly not strictly a male hormone. While men produce significantly more testosterone than women, women naturally produce testosterone and their bodies use it in a number of ways. Testosterone is an anabolic hormone, which means that it also works to build strong muscles, bones, and ligaments and counters the tearing-down process that your body naturally experiences when it undergoes stress or exercise. By the time you hit natural menopause, your testosterone level has dropped about 50% from what it was when you were a teenager. This can cause some of the symptoms of androgen deficiency as discussed above.
Libido enhancement isn't the only function of testosterone. There is a great deal of data to suggest that testosterone plays a key role in preventing osteoporosis, both by protecting against bone loss and by stimulating bone formation, as well as increasing muscle mass and tone, which is important in maintaining bone strength. Additionally, studies have shown that a combination of estrogen and androgen replacement produces a significant increase in spinal bone mineral density vs. estrogen replacement only, and recent studies have suggested that testosterone replacement may actually help prevent heart attack, stroke, and help counteract breast tenderness related to estrogen use (when used in healthy levels -- high levels of any hormone, including testosterone, have been directly linked to increased risk of breast cancer). Further benefits of testosterone replacement include reducing hot flashes (some women who don't get relief on estrogen alone do get relief with estrogen/testosterone replacement).
Testosterone isn't the only androgen at work in the healthy pre-menopausal female body. DHEA is a precursor to testosterone that is produced by the adrenal glands, skin, and brain, and which can cascade into both testosterone and estrogen. DHEA has also been getting a lot of attention in alternative medicine circles as the “hormone of youth”, able to not only restore sexual drive, but also to restore a youthful appearance, energy, memory, and reduce cholesterol levels. However, very limited research has been done on the long-term effects of DHEA supplementation.
Progesterone: Nature=s Anti-Estrogen
Progesterone controls and balances the effects of estrogen in the body. It is produced during the last half of the menstrual cycle, after ovulations, and is essential for a pregnancy to occur and be carried to term. Progesterone can be deficient during several stages of a woman=s life, including during PMS, peri-menopause and beyond menopause. We are noticing that progesterone production tends to decline long before periods actually stop, during the peri-menopausal years, as the ovary ages. It is this drop in progesterone that often causes the first menopausal symptoms, even while still menstruating. This lack of progesterone to balance estrogen in the body is known as Aestrogen dominance.@ Estrogen dominance can be defined as having normal or high levels of estrogen in the absence of sufficient progesterone to balance estrogen effects. Progesterone - estrogen balance is essential in eliminating menopausal symptoms, and in preventing breast cancer.
Much confusion exists between the hormones progesterone and the synthetic progestins. Unfortunately, the two terms have often been mistakenly used interchangeably, even in the scientific literature. There are vast difference between these hormones, as noted in the comparison chart on the next page. The recent Women=s Health Initiative study with Prempro7 that was halted in July 2002, as well as previous studies reported on in the Journal of the American Medical Association and the Lancet, have reported an increased risk of breast cancer when estrogen is combined with a synthetic progestin. Bio-identical progesterone is completely different, and plays many important roles in breast cancer prevention. Progestins tend to cause many of the same menopausal symptoms women seek to relieve; progesterone is well-tolerated and can often be used alone to control menopausal symptoms. Side effects can occur with excessive doses, but are usually not problematic with normal physiologic doses.
Do you need progesterone if you have had a hysterectomy? Yes. Progesterone would not be necessary if the intent of using it was merely to slough off endometrial tissue. However, a May 2000 study by Mayo Clinic researchers determined that there were impressive improvements in quality of life issues such as hot flashes, menstrual problems, sexual functioning, anxiety and depression with bio-identical progesterone. A recent study by Leonetti and Anasti noted an 83% improvement in hot flashes in postmenopausal women as compared to placebo. These are important issues for women with and without a uterus.
Progesterone is not as well-absorbed orally as topically. More than 90% of an oral dose can be lost to metabolism, depending on the type of oral dosage form. Topical dosing via cream or gels provides more efficient absorption, and lower doses can be used because of bypassing liver and intestinal metabolism of the hormone.