Estrogen

The three main estrogens produced by the human body are estrone (E1), estradiol (E2), and estriol (E3).

Estrone accounts for 10% of the circulating estrogen in a reproductive female. Estradiol and estrone can be converted to one another in the body by enzymes. In addition to being produced by the ovary, estrone is also formed from androstenedione in fatty tissue. Androstenedione is in the androgen family of hormones like testosterone. After menopause, when the ovary stops producing estrogen, a woman's only source of endogenous estrogen comes from the peripheral conversion of androstenedione to estrone; hence estrone accounts for the majority of estrogen in a menopausal woman. Estradiol accounts for another 10% of the circulating estrogen in pre-menopausal women. Most traditional prescriptions of estrogen have either estrone or estradiol. Premarin has estrone, as well as thirty other equine estrogens. Estrace and estrogen patches consist of estradiol.

Estriol accounts for the remaining 80% of circulating estrogen. It is the weakest and most benign of the estrogen family. It is also the predominant estrogen in pregnancy. It is felt to be protective by counterbalancing the aggressive effects of estrone and estradiol. Some studies show it has a protective effect against breast cancer. Vegetarians and Asian women have higher levels of estriol and lower levels of breast cancer. Women with breast cancer were found to have lower levels of estriol relative to estrone and estradiol. Sisters and daughters of women with breast cancer were found to have lower than normal levels of estriol. One of the reasons why an early pregnancy is protective against breast cancer is possibly because of high estriol levels. Estriol is extremely effective in preserving the lower genital tract. As a vaginal cream it is very effective at alleviating vaginal atrophy, preventing urinary and vaginal infections, and preventing urinary incontinence. Estriol has not been shown to be protective to the heart or bones. Vitamin E can increase estriol levels. Estriol is often referred to as the forgotten estrogen because it is rarely prescribed. Although research on estriol is limited, all evidence points to its protective nature, so I believe it is a mistake not to prescribe it with the other estrogens.

Women who take supplemental estrogen should take either Biest or Triest. Triest is an exact ratio of the hormones described above. It consists of 10% estrone, 10% estradiol, and 80% estriol. Biest is 20% estradiol and 80% estriol. The theory behind using Biest instead of Triest is that estrone is the most aggressive of the estrogens and menopausal women already have enough estrone in their bodies. In reality, estrone and estradiol are readily converted to one another so whether you take one or the other, both estrone and estradiol are going to be in the body.

There are several ways to take estrogens; the most common way is oral administration. Swallowing a pill is very easy and oral administration improves the cholesterol profile more than other routes of administration. Oral estrogen reduces insulin-like growth factor-I (IGF-I) and increases growth hormone. The downside of oral estrogens is the “first pass liver effect”. Anything we ingest immediately goes to the liver. When the liver processes the hormones, it makes steroid hormone binding globulin (SHBG). SHBG binds hormones, making them unable to perform their functions. The liver also is responsible for making clotting enzymes, and oral estrogen leads to a greater production of these enzymes. Oral estrogens increase the risk for gallbladder disease and raise triglyceride levels. Oral estrogen showed a reduction in lean body mass and an increase in fat mass, when compared with transdermal estrogen. I prefer transdermal, via creams or gels, or sublingual (under the tongue) administration of estrogen. This causes the estrogen to go right into the bloodstream without the “first pass liver effect”. When the ovary produces estrogen, it immediately gets into the blood stream via the ovarian vessels. The transdermal and sublingual routes closely resembles this physiologic process. Transdermal application of estrogen does not increase the risk of gallbladder disease or raise triglyceride levels like oral administration does. Transdermal estrogen also is less of a risk factor for blood clotting because the estrogen does not initially go through the liver.

Despite what recent studies have led many physicians and women to believe, estrogen is protective to the heart. The American College of Obstetrics and Gynecology (ACOG) now recommends that women no longer take HRT for cardiovascular protection. This is based on the findings from the Women's Health Initiative (WHI) study, but only the effects of synthetic hormones on older women were studied. See the chapter on research on HRT. More than 40 observational studies have shown that menopausal women receiving estrogen have less heart disease than menopausal women not on estrogen. We cannot just ignore the other studies. Heart disease is the leading cause of death in women and they usually do not develop heart disease until after menopause, when estrogen is deficient. In multiple studies, estrogen also has been shown to prevent artherosclerosis. It does this by lowering total cholesterol, lowering low density lipoprotein (LDL) cholesterol, raising high density lipoprotein (HDL) cholesterol, and lowering lipoprotein (a), homocysteine, and C-reactive protein (CRP). Estrogen also has direct vascular effects. It increases vascular dilatation by relaxing the smooth muscle cells within the vessel wall. Estrogen increases endothelial cell growth, increases insulin sensitivity, and decreases coagulation factors. It also decreases uptake of LDL cholesterol in the coronary arteries and inhibits the oxidation of LDL. This results in a decrease in artherosclerosis and an overall protection to the coronary arteries.

Nothing is better than estrogen at preventing osteoporosis. The majority of bone loss occurs in the first five years of menopause without estrogen supplementation. Without estrogen women lose approximately 3-5% of their bone mass per year for the first five years, and then approximately 1% per year thereafter. Not only does estrogen prevent osteoporosis by reducing bone resorption, studies have shown that it helps to rebuild bone mass as well. Estrogen has also been shown to reduce the chance of a fracture in weaker bones. Menopausal women have a 15% chance of developing a hip or wrist fracture, and a 20% chance of developing a vertebral fracture. When long-term estrogen replacement is complemented with adequate calcium intake, hip and wrist fractures are reduced by 55% and vertebral fractures are reduced by 80%. Hip fractures are so serious that approximately 20% of women hospitalized because of a hip fracture die within a year.

Colon cancer is the third leading cause of cancer deaths in women, after lung cancer and breast cancer. The risk for developing colon cancer is reduced by 50% with estrogen use. The longer one uses estrogen, the more protection they receive. This risk reduction is maintained for approximately ten years after discontinuation of estrogen. The WHI did not see as great as a result, but patients were observed for only five years. Between 1960-1990, mortality rates from colon cancer rose in men by 16%, whereas in women they fell by 21%. This time period is when women started using more estrogen replacement, so estrogen could account for these findings.

Studies on estrogen and the risk of Alzheimer's disease have shown mixed results. The Manhattan Cohort Study showed that estrogen reduced the chance of Alzheimer's disease by 60%. It also showed that of those women who get Alzheimer's disease, women on estrogen get it later in life than women not on estrogen. The Leisure World Cohort Study showed that estrogen reduced the risk of Alzheimer's disease by 35%. It also showed that women on larger doses of estrogen and longer duration of use had even more of a reduction in risk. The results of the Women's Health Initiative Memory Study (WHIMS) were published in July 2003. This study evaluated the chance of developing Alzheimer's disease among 4500 women older than 65. Over a five-year period twice as many women on Prempro developed dementia compared with a placebo. Prempro is Premarin and Provera (See the chapter on Reaserch on HRT) and it may be the Provera that was responsible for the increase in adverse outcomes. Provera has been shown to increase the incidence of strokes; thus the memory of the women could have been affected by transient strokes (transient ischemic attacks) within the brain. The WHIMS found no significant increase or decrease in Alzheimer's disease in women taking only Premarin. Additionally, the women studied were much older than the women in previous studies. This might suggest that older women do not get the same protection from hormones as younger women. It is quite possible that estrogen receptors in the brain are down regulated after prolonged absence of estrogen. One of the first things most women notice after estrogen depletion is short-term memory loss and “brain fog”. In many women this is reversed with estrogen supplementation.

The biggest fear of women who use estrogen is breast cancer. Among women surveyed, 40% felt that the leading cause of death in women is breast cancer, where as in reality it is 4%. Whether or not estrogen causes breast cancer is still not known. Prior to the WHI study, there were more than fifty case control and cohort studies with mixed findings; thus the findings have been inconclusive. If there is an increased risk, the risk must be small. (See the chapter on research on hormone replacement therapy.) The largest cohort study looked at 46,355 women who were evaluated for 15 years in the Breast Cancer Demonstration Project. There were 2082 incidents of breast cancer. Women taking estrogen alone had a 1.2 fold increase in breast cancer, whereas women taking estrogen and a progestin had a 1.4 fold increase in breast cancer. Progestins (synthetic progesterone) have recently been shown to be more responsible than estrogen in the rising incidence of breast cancer. These risks are shown to decrease after stopping HRT, and are almost nonexistent five years after stopping.

These studies only looked at unnatural hormones, so the hormones a woman naturally produces have not been properly evaluated. Unnatural estrogens have been shown to increase density and mitotic activity in breast tissue. It is unclear if natural hormones have the same effect. Studies have shown that women who take HRT have a greater chance of surviving breast cancer. The breast cancers in women who use HRT are more likely to be lobular in origin. As a result, there is a 40-60% reduction in mortality when compared with women who developed breast cancer without a history of HRT. Unfortunately studies on bioidentical hormones are limited regarding breast cancer. Estriol has been postulated to be protective but doctors are not using it, so studies will continue to be limited. Every baby a woman has lowers her chance of breast cancer by 7%. It very well could be the high levels of estriol during pregnancy that is responsible for this protection.

Macular degeneration is a major cause of vision loss in the elderly. Because the average age of the population continues to increase, macular degeneration will be more of a concern in the future. Multiple studies have shown that estrogen use decreases the incidence of macular degeneration.

Estrogen has many other benefits. First of all, it is the hormone that makes women feminine. Estrogen is what makes a woman feel like a woman. Estrogen increases libido, preserving sexuality. Estrogen prevents hot flashes and night sweats. Woman lacking estrogen have difficulty sleeping and estrogen restores sleep. It increases stamina, giving a woman more energy. Estrogen keeps the vagina young and healthy by preventing vaginal atrophy. Vaginal atrophy is thinning of the vaginal tissue and shortening and narrowing of the vagina. Vaginal atrophy can result in decreased vaginal secretions and painful intercourse. There are more estrogen receptors in the vagina and urogenital tract than anywhere else in the body. As a result, estrogen protects from bladder and vaginal floor problems such as urinary incontinence and pelvic organ prolapse. Estrogen is also beneficial to the skin. Skin collagen is affected by loss of estrogen. Skin collagen is responsible for keeping the skin youthful by making it more elastic and thicker, which leads to fewer wrinkles. As women age the skin thins and estrogen prevents this thinning. Estrogen also keeps hair and nails youthful. Adequate estrogen levels also can prevent migraine headaches.

I recommend using estrogen daily. The older philosophy is to take estrogen only on days 1-25 of the month. Not only is it less confusing to take it daily, but many women have hot flashes and other side effects from estrogen withdrawl on days 26-31. Some practitioners recommend reproducing the menstrual cycle when replacing estrogen. They tell their patients that if they are not menstruating then they are not putting enough estrogen in their body. Menopausal women do not need to have the estrogen levels of a nineteen year old. The only purpose of having high fluctuating levels of estrogen is for reproduction. Though some menopausal women menstruate with supplemental estrogen, it is not imperative. The only purpose of menstruation is to ready the uterine lining for a pregnancy.