Estrogen through the ages

There are many ways to take estrogens and many philosophies of management. The views expressed on this page represent the opinion of the author and may or may not conform to the current "standard of care" prevalent in the United States today. These opinions are not meant to constitute medical advice-- merely one person's philosophy. The ultimate decision and responsibility for medical management is between you and your health care practitioner.

Each woman is unique and each woman has different needs at different times in her lifetime. There has been a prevalent philosophy in the US for many years that "one dose (of Premarin) fits all". I disagree with this and I hope this page will offer some justification for my philosophy.

Lets start with some basic biology. Throughout the body, there are cells which respond to stimulation by estrogen. These cells are found in the brain, breast, skin, liver, uterus, vagina, and bladder as well as other site. On the surface of these cells are small areas called receptors. A receptor is like a keyhole. It something touches it which fits, than the cell responds in a certain way (like growth of the lining of the uterus). Conversely, the absence of stimulation of a receptor site can cause the cell to act in a different way (such as triggering hot flashes). Interestingly enough, when there is a lot of a substance around for a long period of time, more receptor sites become established. Likewise, if there is an absence of a substance for a long period of time, the receptor sites become fewer. From a practical perspective, this means:

• that an individual (a young woman) who had a lot of receptor sites because their body is accustomed to the presence of a lot of estrogen will need more estrogen to achieve the same effect than the individual who has fewer receptors
• that the individual (an elderly woman) who has few receptor sites will need less hormone
• As estrogen receptors are induced by hormone administration or production, or depleted by lowering levels of estrogen, an individual may need more or less estrogen over time to achieve the same biological effect.

The reverse is also true. The individual with few receptor sites will bind less estrogen so there is more available in the circulation of the blood for each site. This can result in overstimulation and symptoms of hormone excess with relatively low dosages in estrogen depleted individuals.

Finally, a cell does not have a brain and it cannot distinguish between estrogen and estrogen-receptor stimulating compounds. Whatever fits the keyhole will work. It does not matter to the receptor site if the substance is natural, synthetic, derived from a plant, or is a toxic chemical (for example, did you know that DDT binds to estrogen receptors?)

Let us look at the use of estrogen:

Clinical Example #1

A 16 year old girl has never had a period and had no breast development. She is tall for her age. She does not have functioning ovaries and needs to be taken through puberty artificially and than maintained as a woman for the duration of her adult life.

Obviously this girl has very low levels of estrogen receptors and the natural evolution of puberty needs to be simulated. She would be started on low dosages of estrogen alone which would be increased every few months (receptor induction) over the course of 1-3 years until she feminizes. Measurements of serum estrogen and FSH levels would be done to ensure adult female hormone levels. Than progesterone, the hormone of the second half of the menstrual cycle would be added for 10-14 days each month. She might also need low dosages of testosterone since the ovary is a complex organ which produces many substances. Once full development and feminization is completed, birth control pills could be substituted because the packaging is convenient. Contraception obviously is not needed.

A comment on taking testosterone is appropriate here for this and the next several discussions. Testosterone for women is discussed on another page. One way of doing this is to create a daily "foundation" of estrogen by continuous use of estrogen patches and/or pills and than allowing the woman to "play with" her testosterone dose by taking Estratest HS or Estratest (see below) anywhere from 2-7 times a week. If she takes too much, she will develop acne, increased facial and abdominal hair growth or even slight loss of hair on the sides of her forehead. So she can adjust the dose until she feels well and still has no side effects realizing that her estrogen dosage is being held relatively constant. Testosterone supplementation is not necessary for users of oral contraceptives since the progestin found in oral contraceptives have mild male directed tissue effects.

Clinical example #2

A 29 year old woman has had a pelvic infection resulting in the removal of both ovaries (surgical castration). She has been placed on the "standard menopause" dose of Premarin (0.625mg) and she is miserable. She has hot flashes, irritability, trouble sleeping, loss of energy, vaginal dryness, and loss of sex drive. She is told that her problems are "psychological" because she will not be able to have children.

Obviously, this young woman is loaded with estrogen receptors since she was acutely castrated in the prime of her reproductive life and she needs replacement with high dosages of estrogen as well as small amounts of testosterone to feel well and function well. There is good data suggesting that "standard menopause" doses of estrogen will not give her adequate long term protection from osteoporosis and heart disease. Birth control pills provide higher than physiological levels of estrogen and contain progesterone-like compounds with mild male directed activities and could be very appropriate for her until age 50 (assuming she does not smoke).

Clinical example #3

A 29 year old woman has had endometriosis resulting in the removal of both ovaries (surgical castration). She has been told she cannot take estrogen since this will stimulate the return of endometriosis and she is miserable. She has hot flashes, irritability, trouble sleeping, loss of energy, vaginal dryness, and loss of sex drive. She has been told that if she waits a few years, the symptoms of menopause will subside (receptor depletion) and she will feel better. She has tried all sorts of naturopathic remedies with mixed results. Her marriage is about to end.

I get E-Mails from suffering women all over the world who are experiencing this scenario. The management of the patient with endometriosis after surgical castration is complex, difficult, and depends on many factors such as the degree of residual disease. The ultimate management decisions need to be made between the informed woman and her physician. These women are a major risk for heart disease and osteoporosis not to mention the social and emotional consequences of acute defeminization if left without adequate hormone replacement therapy for a number of years. It is true that estrogen alone may stimulate the return of endometriosis. It is important to know that progesterone in whatever form causes endometriosis to shrink and to lose biological activity. Therefore estrogen administered with a fairly potent progesterone can provide adequate estrogen replacement while blocking or slowing the return of endometriosis. Examples could include progestationally dominant birth control pills (which contain higher than physiological estrogen replacement) or administering higher doses of estrogens formulated for menopausal use (which approximate normal estrogen levels in pre-menopausal women) such as Estradiol 2mg or Premarin 1.25-2.5mg along with higher dose progesterone replacement such as norethindrine 5mg (Aygestin) or megestrol (Megace). Again, There is good data suggesting that "standard menopause" doses of estrogen such as (0.625mg of conjugated estrogens (Premarin) or 1mg estradiol (Estrace) will not give her adequate long term protection from osteoporosis and heart disease in young women. Other therapies for endometriosis after removal of ovaries include GnRH agonists {(depo-Lupron) and danacrine (Danazol)} which are no longer appropriate since they are intended to block ovarian functioning, and high dose progestins without estrogen, such as depo-medroxyprogesterone (Depo-Provera) which may alleviate some of the acute symptoms but probably do not provide long term health benefits and may actually be harmful in terms of effects on lipids, depression, and weight gain. In addition, she may need low doses of testosterone to help her with libido and a general sense of energy and well being

Clinical example #4

A 46 year old woman is still menstruating but her cycles are becoming a bit strange with variable and heavier flow and perhaps fewer pre-menstrual symptoms. She is chronically tired and irritable and does not feel right. Her thyroid tests are normal but her FSH and estradiol levels suggest that she in entering menopause. One of the problems of the pre-menopausal period is instability of hormones which create problems with sleeping as well as cycle disturbances. At an extreme, these women can become very depressed and even end up undergoing extensive medical evaluations or even hospitalization for depression, malaise and fatigue, and anxiety. Women in their 40s with strange symptoms related to depression, anxiety, malaise, fatigue, difficulty coping, joint aches should always be assessed for biochemical evidence of early menopause. Problems with hormones should be corrected before more aggressive medical management protocols are undertaken. Often hormonal corrections will help stabilize their condition. This woman is young and still has a lot of hormone receptor activity. If she does not smoke, one appropriate therapy is to return to low dose birth control pills for cycle stabilization and hormone supplementation. The birth control pill is especially nice since the dosing is stable and uniform and may also protect her from a "surprise" late in her reproductive life. Oral contraceptives are contraindicated in women who smoke after age 35 since this is another good reason to quit smoking if she has not done it yet.

Clinical example #5

A 51 year old woman has not had a period for 5 months and she is having 20-30 hot flashes a day. She is embarrassed by this. She is also having problems sleeping and feels bad. Her work performance has deteriorated and she is at risk of losing hew job. This, of course, is the classic menopausal woman. She has been experiencing a gradual decline of estrogen over the previous several years and probably has fewer receptors than the younger woman. The vast majority of these women will respond to classic hormone replacement therapy with a combination of estrogen (conjugated estrogen 0.625mg or Estradiol 1mg) and medroxyprogesterone (Provera). Prempro and Premphase are a convenient packaging which puts it all together. With Premphase, she will probably continue to have a light menstrual period. With Premphase, she might experience irregular menstrual spotting. This is normal.

Clinical example #6

This 61 year old woman never experienced a hot flash and never had menopause symptoms. She has never taken hormones and she was doing fine. Because she had a history of systemic lupus erythematosis and took steroids in the past, her physician suggested she get a bone density study done. This study showed early osteoporosis. She also has a sister with breast cancer.

This woman would be a candidate for one of these newer estrogen-like substances called a SERM. An example is raloxifen (Evista). This medication will help to rebuild her bones along with a high calcium diet, exercise, and medications to stimulate bone growth such as alendronate (Fosamax) or etidronate disodium (Didronil) or salmon calcitonin (Miacalcin). Evista has the advantage of protecting the breast and uterus from cancer, creating a favorable lipid profile for cardiac protection, and rebuilding the bone. It can make hot flashes worse so it is a better agent for a woman who is not acutely menopausal.

Clinical Example #7

This 85 year old woman has never used estrogen. She has just broken her hip and, in addition, is having some mild problems with forgetfulness. An X-Ray show significant osteoporosis. This elderly woman would probably benefit from estrogen particularly since there is some suggestion that estrogen may improve mildly impaired cognitive functioning. Obviously, she had profound depletion of her estrogen receptors and needs to start on the lowest possible dose of estrogen such as conjugated estrogens (0.3mg) or estradiol (0.05mg). Otherwise, she will experience symptoms of estrogen overdose such as breast tenderness, vulvar irritation, or bad dreams. Although recent publications suggest that these low dosages of hormones are adequate for osteoporosis prevention, it might not be inappropriate after 3-6 months to gradually increase the dosing to the standard regimen after induction of receptors has occurred.

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