Hormone Choices

When we talk about hormone replacement therapy (HRT), it can encompass several hormones. The most studied hormone for HRT is estrogen; therapy with just this hormone is often referred to as ERT.  However, for most women a progesterone compound, whether "natural" or synthetic, is often included to eliminate the uterine cancer risk that is associated with using estrogen alone.  For years these were the only two hormones considered in HRT.

Recently there has been attention drawn to testosterone and some of its precursors (DHEA).  It seems that some women may benefit from small doses of these hormones.

Once you decide to use hormones, the next step is to choose which form to use -- pills, patches, or creams. Should the hormones be "natural"?  And exactly what makes a hormone natural?

 

Natural Hormones
Estrogen
Phytoestrogen
Progesterone
Testosterone and DHEA
SERMS (designer estrogens)
Pills, Patches or Creams

 

Natural Hormones
 

"Natural" is the buzzword in marketing today.  Consumers generally need to be highly suspect of the use of the word natural.   Medical consumers particularly need to look for clear definitions in relation to the use of the word natural in regard to health claims.

Although the word natural usually implies something positive, this is not always the case. One meaning of natural defines the source of the product as being found in nature.  Using this definition, cigarettes are natural  because tobacco is a plant.  Therefore, the word natural doesn’t always connote safety, and  medical consumers should be aware of the variety of meanings that the word can have when applied to medicine and treatment.

In the case of hormone replacement therapy (HRT), most of the hormones are derived from natural sources--animals and plants.  The plant source, usually yams or soy, provides sterols that are converted in the laboratory to usable hormones, which are biologically identical to the body’s hormones. This means that they have the exact chemical structure as the hormones that your body has produced for your entire life.  The animal source is usually the urine of pregnant mares; half of the hormones from this source are not biologically identical to the body's hormones.

Many feel that the best hormones for HRT are those that are biologically identical. Therefore, when considering natural hormones, remember that the chemical structure not the source will provide the most natural hormone to your body. It is also important to remember that just because a hormone is natural does not mean that it is completely without side effects.

It is well known that one of the risks of breast cancer is the combination of an early puberty and  a late menopause because this situation increases your lifetime exposure to your own natural estrogen.

Estrogen

Types of Estrogen:

Human Estrogen

There are three estrogens produced by the body.  Estradiol is the primary hormone produced before menopause; estrone is the primary hormone produced after menopause, and estriol (the primary hormone during pregnancy) is converted from estradiol and estrone.

Conjugated Equine Estrogens

Premarin, whose generic name is conjugated estrogen, is the most prescribed estrogen primarily because it has been the most studied.  Because it originates from horse urine, the manufacturer claims on every bottle: "obtained exclusively from natural sources".

Although Premarin contains estrone, almost half of the estrogen is in the form of equine (horse) estrogen, which is not found in the human body.  Premarin seems to produce higher estrogen levels and has more of an effect on the liver than the non-equine estrogens.  For this reason, for long-term therapy there is more interest in prescribing the 0.3 mg (green tablet) as the standard  dose instead of the 0.625 mg (maroon tablet).

Some primary care providers feel that the equine estrogens in Premarin may be responsible for the breast tenderness and other side effects some women experience.  Others attribute these effects to Premarin’s higher estrogenic blood levels.

A recently published study suggested that one of the minor ingredients in Premarin may be capable of inducing DNA damage in hormone sensitive cells.

Premarin has been combined with medroxyprogesterone in two products Prempro and Premphase.

Laboratory Estrogen Synthesized From Plant Sources

Estradiol and Estrone are two estrogens produced from substances found in plants.  They are chemically identical to those produced by the body and have been shown to have all the benefits of estrogen mentioned previously.

Estradiol is also called 17beta-estradiol or E2 and is considered the most potent of the estrogens.  Some evidence indicates that it may be more effective than other estrogens on the cardiovascular system, although the degree of benefit of estrogens for this purpose is a subject of debate.

Estradiol is found in Estrace tablets and cream. It is also the active ingredient in all of the commercial transdermal patches--Alora, Climara, CombiPatch, Estraderm, Fempatch, and Vivelle. The new combo products FemHRT and Ortho-Prefest also contain estradiol as their estrogen. The compounded product Bi-Est contains 20% estradiol and Tri-Est contains 10% estradiol.

Estrone or E1 is the primary estrogen in estropipate (Ogen, Ortho-Est).  It is also found in the estrogens Menest and Estratab, although both of these have between 6-15 % equine estrogens.  Cenestin is a mixture of both estrone and estradiol, although it too has a small amount of equine estrogens. The compounded product Tri-Est contains 10% estrone. 

Estriol or E3 is the weakest estrogen. There are several provocative studies that suggest women with higher natural levels of estriol have a lower incidence of breast cancer.  It is thought that estriol may act as an antiestrogen in the breast tissue. However, much more research is needed in this area before any conclusions can be made.

Heart: It is uncertain whether estriol by itself will provide cardiovascular protection. Although it appears to have an effect on blood vessels, it does not seem to have a beneficial effect on cholesterol levels.

Bone: There are contradictory reports about the effects of estriol on osteoporosis prevention. Early studies indicated that high levels (8-12 mg/day) were necessary to exhibit bone density benefits. Several recent studies have shown beneficial effects (comparable to Premarin 0.625 mg) on doses as low as 2 mg /day.

Uterus: It had been thought (and often reported in many books on natural hormones) that oral estriol did not require the addition of a progesterone compound to prevent uterine cancer.  This may be true for short-term treatment (6-12 months). However, a recent study has shown that oral estriol  taken alone for a 5-year period caused a threefold increase in uterine cancer--which would indicate a need for the addition of progesterone.

Hot Flashes: Estriol has been shown to be effective in treating menopausal symptoms. Although oral doses of 2 mg/day have been shown to be effective in the improvement of symptoms such as hot flashes and insomnia, some women may require doses as high as 8 mg/day. At this higher dosage, nausea may be a limiting factor.

Urinary/Vaginal: Estriol, in the form of a vaginal cream or suppository has clearly been shown to be effective in the treatment of postmenopausal vaginal dryness, chronic vaginitis, and recurrent urinary tract infections.

Availability: Estriol is not commercially available in the U.S. at this time. Compounding pharmacies are able to formulate it in a variety of forms.  Estriol is often added to the other human estrogens in an 80% concentration in either a Bi-Est or Tri-Est formulation. These products try to mimic the ratio of hormones that are naturally found in the body and try to take advantage of the relative safety of estriol along with a low dose of the potent estrogens.  Bi-Est and Tri-Est are not commercially available, and there are no studies regarding their effectiveness.  It is generally thought that the 2.5 mg dose is equivalent to 0.625 mg conjugated estrogens.

Bi-Est contains:  80% estriol, 20% estradiol. 

Tri-Est contains:  80% estriol, 10% estradiol, and 10% estrone.

Phytoestrogens
 

Phyto is the Greek word for plant. Phytoestrogens are plants that bind with estrogen receptors in the body to produce an estrogen-like effect.

Put simply: Many body tissues are composed of cells that have estrogen receptors. These receptors act like tiny locks, and  estrogen acts like a key to open them. Because phytoestrogens have molecules similar to estrogen, they also can act like a key.

Phytoestrogens compete at the receptor site with other estrogens--whether your own or those taken as a part of HRT.  They may have the ability to enhance estrogen's beneficial effect and/or block estrogen's negative effects. 

Many plants have phytoestrogenic activity, but the strongest still only have 2% of the potency of estradiol.  For this reason, only the most potent phytoestrogens are listed below:

Isoflavones: soy protein, soy isoflavone supplements, and red clover supplements (Promensil).

Lignans: found in flaxseed and whole grains.

Herbal supplements: such as black cohosh (Remifemin).

Isoflavones

There is much interest about the role of the isoflavones in soy protein for the treatment of the menopausal symptoms of hot flashes, vaginal dryness, cardiovascular disease, bone metabolism, and cancer prevention. The sale of isoflavone supplements is increasing, and even the large pharmaceutical companies are introducing their own products.

A  growing amount of evidence shows that isoflavones have a physiologic effect, but it is uncertain whether the effect can be attributed to the isoflavones alone or to the isoflavones combination with some other substance in the whole food.  Studies seem to be indicating that the best source of isoflavones may be in whole food, particularly soy.  Although there seems to be no problem with soy, many researchers are concerned about the use of high-dose isoflavone supplements because no one knows what the long-term side effects may be.

The amount of isoflavones in different soy products varies depending on the type and degree of processing: The least processed soy products have the most isoflavones.  Green soy beans (often sold in stores as edamame) have the highest content of isoflavones.  While moderately processed products like tofu and tempeh are good sources, heavily processed products like tofu dogs and tofu breakfast sausage are not.  Soy protein found in powdered supplements may have high or low isoflavone contents depending on how they are manufactured.  Look for those that are labeled soy protein isolate for the most isoflavones.  IP Supro is the brand most often used in clinical studies.  (See the Resources page for an excellent book about adding soy to your diet).

A look at the evidence for the various benefits of soy:

Menopausal Symptoms: Although isoflavones are generally thought to be effective, there has been conflicting evidence on their ability to reduce the severity of hot flashes and vaginal dryness.  If you are concerned about HRT side effects, consider adding isoflavones to your diet first. There is little harm in trying them, and you will know if it works for you.

Bone Health: This is another area of conflicting studies.  Animal and some human studies indicate a potential benefit to the spine but not to the hip.  If you are at high risk for osteoporosis, there is not enough evidence to recommend soy or isoflavones alone as preventative treatment.  If you want to" hedge your bets", add some soy to your diet.

Cancer Prevention: There is a great interest in the benefit of soy protein in reducing cancer risk. Many studies have shown that groups of people with high soy intake had lower cancer rates, but few studies have been able to isolate the soy as the only factor.  Soy protein in addition to isoflavones contains other phytochemicals that offer cancer protection,  so it is probably more effective than isoflavone supplements. Some nutritionists feel that isoflavones supplements are absorbed better when taken with soy foods.

The major debate is about soy and breast cancer.  When it comes to prevention, it seems that the greatest benefit comes from a high soy protein diet before puberty. Pre-menopausal women will get some benefit, but postmenopausal women seem  to receive no protection.

For those women with estrogen dependent breast cancer, most experts feel that they should avoid phtyoestrogen supplements.  These experts differ on the issue of the risk of soy protein in whole foods--some say because there is no conclusive evidence showing any harm, soy foods are ok;  others believe that phytoestrogens from any source pose a risk.

Cardiovascular Risk: This is the area with the greatest evidence of the benefits of isoflavones.  It appears that the soy protein from whole foods has a greater effect than those found in supplements.

Soy has a positive effect on blood cholesterol--raising HDL ("good" cholesterol), lowering LDL ("bad" cholesterol), and lowering triglycerides. Soy reduces the formation of plaque in the arteries.

Soy improves the elasticity of the arteries.  Many researchers feel that, like

estrogen, its ability to improve the flexibility of the arteries has a more profound effect on the reduction of coronary artery disease than on its ability to lower cholesterol.

In conclusion, it appears that most women (and men also) will benefit from adding soy to their diet.  Although there hasn't been an exact amount of soy recommended, the FDA has allowed the claim that "25 grams/day of soy protein as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease".  This 25 grams would have approximately 50 mg of isoflavones, which is also the amount usually recommended to help bone health and to reduce menopausal symptoms.

A short list of food items that can be used to provide the 25 grams:

Frozen shelled soybeans (Japanese edamame) ½ cup = 10 grams

Soy protein powder (quantities vary--make sure the main ingredient is soy  protein isolate).  Use it in shakes: 2 scoops = 20 – 25 grams.

Soy nuts (choose the dry-roasted ) ½ cup = 30 grams

Tofu 3 oz = 6 grams

Soy milk 8 oz = 5 grams

(See the Resources section for an excellent cookbook)

Lignans or Flaxseed

Flaxseed is not as widely studied as soy, but flaxseed contains lignans, which are another form of phytoestrogen.  Although other grain and vegetables sources contain lignans, flaxseed contains up to 600 times that of any other source.

Flaxseed has other components that help to prevent disease and is a good source of soluble fiber that has been shown to reduce cholesterol.  It also contains alpha-linoleic acid, a substance similar to the omega-3 fatty acids found in fish oil that helps the cardiovascular system.

Flaxseed may likely have many of the same benefits as soy protein.  Although flaxseed oil probably protects the heart, some of the lignans and all of the fiber is removed in processing. Therefore, the best source of flaxseed may be the seed itself.  It can be ground very easily in a coffee grinder and sprinkled on food.  Two tablespoonfuls a day should provide adequate lignans and fiber. (See the Resources section for an excellent cookbook).

Herbal supplements

A walk down the women’s health aisle in any store will surely convince you that there are a wide variety of herbal products claiming to help menopausal symptoms--evening primrose oil, black cohosh root extract, dong quai, and chaste tree berry to name a few. Only recently has scientific research demonstrated the active ingredients, mechanism of action, and effectiveness of these plant products.

In the treatment of menopausal symptoms, only one herb has clearly been shown to be effective--black cohosh root extract.  The majority of the studies have been done on a commercial product called Remifemin.  It has been proven effective in relieving hot flashes and reducing some of the mental symptoms such as mood swings and anxiety.

Black cohosh root extract attaches to estrogen receptors, so there has been some concern as to whether it is safe to use in women with breast cancer.  Preliminary studies show that it does not stimulate breast cells.  Some experts feel that if no other therapy works for a breast cancer patient and a choice comes down to either prescription estrogen or black cohosh, it may be safer to try the black cohosh first.

Despite wide spread belief of its effectiveness, the Chinese herb dong quai itself has not been shown to help with menopausal symptoms.  In fairness, it must be said that Chinese herbs are not meant to be purchased off the shelf as single ingredients.  Yet,  when combined with other herbs in traditional formulas, dong quai does seem to help with PMS and menstrual irregularities. Chinese herbs are best taken under the supervision of an experienced herbalist.

Evening primose oil and chaste tree berry may be effective in treating PMS and other menstrual irregularities. Most controlled studies have shown no benefit of these herbs for menopausal symptoms.

Progesterone

 

Progesterone is a female sex hormone whose primary use in postmenopausal women is to prevent the endometrial lining of the uterus from building up. If this lining gets too thick, it results in heavy or irregular bleeding and may become pre-cancerous.  Like estrogen, progesterone levels are greatly reduced in menopause.

When hormone replacement therapy (HRT) first began in the 1960’s, the only hormone used was estrogen. At that time, it was hailed as a miracle drug.  It took almost a decade before it become evident that estrogen therapy alone greatly increased the rate of endometrial cancer.  A progesterone was added to the estrogen for two weeks each month because of its natural effect on the uterine wall to prevent this endometrial problem. 

Progestins

Unfortunately in the early years of HRT, there was no oral way of delivering progesterone--the same hormone the body produced.  Progesterone is poorly absorbed in the stomach and undergoes almost immediate inactivation in the liver.  For this reason, a synthetic progesterone called medroxyprogesterone (Provera,Cycrin) was used to oppose estrogen’s stimulatory effect on the uterus.

Medroxyprogesterone is referred to as a progestin, a substance that has some of the same effects as the body’s own progesterone but other effects as well.  For over 20 years, it was and still is the most widely prescribed progestin.  It is one of the active ingredients in the best selling Prempro and Premphase.

Several new progestins have been recently introduced.  Norethindrone is a potent progestin that has more androgenic (male hormone) effects and  is more likely to produce side effects of acne, greasy hair, and greasy skin.  However, it does have the benefit of lowering trigliycerides.  It is found in FemHRT and CombiPatch.  Norgestimate, found in OrthoPrefest, is a newer progestin.

There are quite a few ways a progestin is used in HRT. Two main ways are:

Cyclical therapy is the term used when estrogen is taken either daily or 25 days a month. A high dose of progestin is added for 12-15 days a month. As the progestin is stopped, your period begins. Premphase and Ortho-Prefest use this regimen. In order to reduce the monthly periods, some use progestin only every 3 months. A recent study has shown that this regimen may offer slightly less protection from endometrial cancer than the monthly therapy.

Continuous therapy  is the term used when estrogen and a low dose of progestin are taken every day. This regimen causes significantly less bleeding and seems to offer the same protection. For the first 6 months there may be irregular bleeding or spotting, but the majority of women experience a complete cessation of bleeding after 6-8 months. Prempro, FemHRT, and CombiPatch use this regimen.

It does not appear that a progestin by itself has any significant therapeutic benefit.  It is only added to HRT to prevent uterine cancer.  Unfortunately, progestins like medroxyprogesterone (Provera) are responsible for many of the PMS-like side effects that cause women to discontinue HRT--depression, irritability, bloating, fluid retention, cramping, breast tenderness, and headaches.

Progestins can also affect the liver with mixed results. They have a positive effect of lowering triglycerides but have a negative effect in lowering HDL ("good" cholesterol). They also block estrogen’s beneficial effect on blood vessels. Weight gain, acne, and negative effects on libido have also been a problem.

A major study (July 2002) revealed that the addition of a progestin (in this case medroxprogesterone) to estrogen increased the rate of breast cancer by 24% compared to estrogen alone.

"Natural Progesterone"

History

Because of all of the problems associated with progestins, researchers were determined to find a way to use oral progesterone, the same hormone the body produces naturally.  The first attempt was to micronize the progesterone, which involved the manufacturing of the progesterone in way that broke it up into superfine particles.  Medical literature refers to this type of progesterone as micronized progesterone, which is often called natural progesterone.

This micronization was an improvement and allowed the product to be absorbed, but there was still the problem of the liver immediately inactivating the progesterone. In the mid 1980’s, researchers in France discovered that by mixing the progesterone in long-chain fatty acids (in this case peanut oil) they could bypass the liver’s effect.  Since then, micronized progesterone in oil oral capsules has become the" gold standard " in progesterone therapy.

Books began to refer to micronized progesterone as "natural" progesterone because the starting block for making this was either soy or mexican yam.  Many authors gave the mistaken impression that natural progesterone was simply ground up yams and that you could get progesterone by using products that contained mexican yams.  However, the body has no enzyme that can break down yams into progesterone, so this process must be done in the laboratory.  Because micronized progesterone is chemically identical to the hormone produced by the body, it can be considered natural.

Because natural progesterone was not commercially available,  most compounding pharmacies began formulating micronized progesterone powder capsules. A select few pharmacies compounded micronized progesterone in oil capsules, considered the "gold standard" of therapy.

Several books have been written extolling the benefits of "natural"  progesterone.  It is now accepted that natural progesterone is probably better than a synthetic progestin.  But  these books have exaggerated the extent of natural progesterone's  benefits--going as far as to say that progesterone, and not estrogen, provided all of the therapeutic benefits of HRT.  This conclusion does not agree with the multitude of studies that have been published.

Nevertheless, these books started the dialogue about natural progesterone and created enough interest that women began to ask their primary care providers about it.  Few studies had been done on natural progesterone, so many providers were reluctant to prescribe it--until a major study, the PEPI trials,  was published in 1995.  This study  demonstrated that, unlike progestins, micronized progesterone in oil did not block any of estrogen’s beneficial effect on cholesterol.

The PEPI study created enough interest so that a pharmaceutical company decided to market a natural progesterone, Prometrium.  Although more expensive than some compounding pharmacies’ products, Prometrium allowed women nationwide to get a chance to use a hormone that had lower side effects than the existing progestins.

Products

Oral micronized progesterone in oil (Prometrium(using peanut oil) or compounded product(using sesame il)): These capsules should be considered the" gold standard" of therapy. This formulation produces over 3 times the blood levels of progesterone powder and 2 times that of micronized progesterone powder. The compounded product is often less expensive than Prometrium, especially when combined in the same capsule with an estrogen.

Oral micronized progesterone powder (compounded): These capsules are not absorbed as well as the oil capsules and should only be considered for those women who cannot tolerate the peanut oil in the above capsules.

Transdermal creams and gels: These are applied to the skin and come in two versions.

Over-the-counter: Despite all of the claims regarding mexican yam content, these products are only as effective as the amount of micronized progesterone that is added to them.  Their actual potency varies considerably with the strongest containing 600 mg/oz (2%). The absorption is also influenced by the type of cream utilized as a vehicle.

Prescription: These products come in a much higher concentration, typically 6-10%. They are often compounded in a special trans-organo gel that has lipids and lecithin added to increase absorption. They are also considerably less expensive because they are so concentrated. A 1 ounce of jar of  prescription Progesterone 10% transdermal gel typically costs around $28. It has more progesterone than a 5 ounce  jar of the strongest over-the-counter product.

Progesterone suppositories (compounded) and vaginal creams (Crinone): These products are used primarily for the treatment of infertility when high vaginal doses are required.

Benefits

Entire books have been written about the benefits of natural progesterone; some of these benefits are usually not well documented from a scientific viewpoint. The writers claim that the lack of evidence of effectiveness is due to the fact that most studies are funded by drug companies who have a product to sell.  Now, with the availability of Prometrium, we should see more studies on its benefits.

Documented benefits of "natural" progesterone:

Uterine cancer protection in HRT: When used with estrogen therapy, it has been shown that oral micronized progesterone in oil whether 100 mg daily or 200 mg cyclically does not cause endometrial hyperplasia (thickening of the uterine lining to a precancerous condition).  There are no studies confirming that topically applied progesterone cream will be strong enough to offset the negative effects of estrogen on the uterus; although in Europe, high strength prescription creams are used for this purpose.  Most experts feel that the over-the-counter creams are not strong enough to provide uterine cancer protection.

Treatment of hot flashes: Evidence supports the use of progesterone for the treatment of hot flashes.  Even the low doses available in the non-prescription creams have proven useful.  Although it is not as effective as estrogen, doses of 35-50 mg have helped relieve symptoms. Oral low-dose capsules (50 mg) also have been used for this purpose.

Bone health: Despite widespread claims that the use of progesterone cream will help bone density, there is little evidence to support it.  Some writers even go as far as to say that progesterone is more effective than estrogen for this use--a claim that goes against the volume of information known about estrogen.  There is, however, some intriguing evidence that oral progesterone may help with bone growth.  Some animal studies have shown that progesterone added to estrogen increases bone strength and density. There is an ongoing study to examine what effects micronized progesterone 300 mg /day will have on bone health.

Taking the conflicting information into consideration,  it would not be appropriate to use natural progesterone as the primary treatment for a patient with low bone density or for a patient at high risk of osteoporosis.  It may prove to be a helpful addition to estrogen for this purpose.
 

Testosterone and DHEA

 

Women naturally produce small amounts of the male hormone testosterone.  The ovaries produce most of the testosterone, and the adrenal glands and fat tissue also produce a small amount.  If the ovaries are removed surgically, there will be a major drop in testosterone levels. Menopause also causes testosterone levels to decrease.

The majority of testosterone is bound by a plasma protein, SHBG (serum hormone-binding globulin), and only the small amount that is " free" is active in the body. SHBG also binds estrogen but has much more of an affinity for testosterone.  Paradoxically, the estrogen that women use in HRT for positive benefits has the effect of increasing SHBG, resulting in even lower testosterone levels.

Effects of Testosterone

Low levels of testosterone in women have been associated with sexual dysfunction, fatigue, loss of pubic hair, and decreased bone and muscle mass.  High levels of testosterone have been associated with "male" side effects such as acne, hair growth, and voice changes.  High doses will also have a negative effect on HDL ("good" cholesterol).  For this reason, it is very important that only small doses of this hormone be used in women.  The term often referred to is "physiologic doses"--just the amount to replace what your body naturally produced.

Bone Health: Testosterone may also have a positive effect on bone health, although there is much more research needed.  There have been a few studies demonstrating that estrogen and testosterone taken together have more of a positive effect on bone density than estrogen taken alone.

Libido: The use of testosterone to improve libido is the current hot topic on the afternoon talk-shows.  The loss of sexual desire in women can be due to a variety of factors.  Therefore, it would seem that testosterone therapy would be most appropriate for women who have an actual deficiency of the hormone.  It is doubtful that testosterone therapy would be useful when the loss of libido is caused by certain medications.  The antidepressants Prozac, Paxil, and Zoloft often cause a loss of libido due to their effect on serotonin, not on testosterone.

Treatment:  Women seem to have a variable response to testosterone therapy, possibly due to genetic differences in the amount of receptor sites and due to age-related diminished receptor sites.  Also, there appears to be a lag time of as long as several weeks before benefits occur.

Testosterone therapy does not seem to follow a normal dose response curve, where increasing the dose increases the benefits.  Research has shown that increasing testosterone to above normal levels does not give a resulting increase in libido but will actually increase side effects.  High doses of testosterone will unnecessarily increase existing estrogen levels in those women taking hormone replacement therapy (HRT) because the body converts testosterone to estradiol.  Therefore, some primary care providers feel that women on testosterone therapy can use lower doses of estrogen.

At the moment, there are not a lot of studies regarding testosterone therapy for women. Some primary care providers will take a blood sample and test for "free" testosterone; others feel that blood testing may not be necessary and may give a small dose while monitoring the results over a few months.  It must be noted that many endocrine specialists do not feel that the "do-it-yourself salivary tests ", despite their popularity, are as accurate as blood tests.

Types of Therapy

Oral

Testosterone is often referred to as "natural "testosterone.  It is manufactured in the laboratory from soybeans; however, the ability of the final compound to be biologically identical to what the body naturally produces is the best description of natural.  In this sense, testosterone can be considered natural. 

The drawback of natural testosterone is that it is poorly absorbed in the stomach and rapidly inactivated by the liver.  Its oral uses are limited. Testosterone can be compounded in a lozenge, which allows for absorption and bypasses the liver effect. 

Methyltestosterone is the most widely used oral testosterone. It is a synthetic form of testosterone that was developed to circumvent the absorption problems of testosterone. However, unlike testosterone, it is not converted in the body to estradiol and may prove useful for women who want to limit their exposure to estrogen.

Methyltestosterone is combined with estrogen in the commercial products Estratest (2.5 mg) and Estratest Half Strength (1.25 mg).  Some researchers have suggested that the doses in even the half-strength product may be too high for many women, producing acne and hair growth.  The suggested doses are in the range of 0.25 mg – 0.75 mg, which are available as capsules a compounding pharmacy.

Topical

 At present, compounding pharmacies are the only source of topical testosterone formulations for women.   In Europe, studies are being done on a low dose testosterone transdermal patch, which is not available in the U.S. yet.  The commercial transdermal patches for men are too strong for female use.

Vaginal

Testosterone vaginal ointment has been used for years to treat a certain type of vaginal atrophy called lichens sclerosus.  However for this use, testosterone is only used daily until tissue health is restored; then it is only used once or twice a week. The long term  daily genital use of testosterone has been associated with unwanted side effects such as clitoral enlargement.  The most prescribed strength is Testosterone Ointment 2%.

Transdermal

The transdermal creams and gels are the most utilized formulations in testosterone therapy.  Special gels have been developed because the mineral oil and petrolatum in ointments tend to reduce the absorption of testosterone on intact skin.  One of the most popular gels is called organogel (or PLO gel), which is a water-based product mixed with special skin penetrating lipids.

Although the transdermal formulations can be applied anywhere, many primary care providers feel that they work best in an area where the skin is thin and there are less fat cells. For this reason, it is usually prescribed for application to the inside of the forearm or upper arm (at bedtime).  The organogel is not as easy to apply as some of the less effective creams, so doses of  ¼ teaspoonful or less should be used.  Larger amounts may leave a sticky residue.

Transdermal testosterone will bypass the liver effect and produce satisfactory blood levels.  It seems strange to some that as little as 1/8 teaspoonful of testosterone gel will work, but in an effective base (like organogel) this hormone is very well absorbed through the skin.   Many of you will remember the Brylcreem ad of the 1960’s--"a little dab will do you".  Keep this in mind with transdermal testosterone.  You should not exceed the dose prescribed by your primary care provider.  It is important that the doses be kept low to eliminate side effects.

Transdermal testosterone is compounded in a wide variety of strengths (0.25 % - 2.5 %). There are no major studies to indicate exactly what blood level postmenopausal women should have and what the daily dose should be.  Many primary care providers have found that a dose in the range of 2.5 mg – 5.0 mg has proved satisfactory for many women with testosterone deficiency.

DHEA

Fortunately we have acronyms in medicine. Can you imagine having to continually refer to "dehydroepiandrosterone" instead of DHEA?  In the past few years, an abundance of medical claims have been made about this substance--often referred to as a prohormone because it is converted into other hormones (in this case testosterone) in the body.

Benefits: There are few studies on testosterone therapy for women, and there are even fewer on DHEA.  Many of the benefits attributed to DHEA--anti-aging, disease reduction, and weight loss--were done on animals that don’t normally produce DHEA.  It is not known what the effects would be on humans, particularly females.

It appears that DHEA may have some effect on the brain and might possibly be used for depressed postmenopausal women.   However,  large scale studies of DHEA are needed before it becomes widely used for the treatment of depression.

DHEA is converted to testosterone in the body and may have a therapeutic role in raising testosterone levels in women.  Like testosterone, high doses can lead to side effects such as masculinization and the lowering of HDL ("good" cholesterol).  For this reason, primary care providers often use it in doses 25 mg or lower.

Availability: DHEA is available without a prescription as an over-the-counter (OTC) supplement, and many take it without medical supervision.  DHEA will have a significant effect on the levels of other hormones;  it is converted into testosterone and then the testosterone is converted into estrogen.  Guessing how much you need can lead to higher levels of hormones and a greater risk of side effects, so you should consult your primary care provider before you start using DHEA.

Quality control of non-prescription DHEA products can be a problem.  Due to the current unregulated status of supplements, you can't be assured that non-prescription DHEA contains the labeled, or even any, amount of DHEA.  Several studies have shown this to be the case with many other expensive supplements.

Compounded DHEA: Non-prescription tablets usually use relatively inexpensive plain DHEA;  compounding pharmacies formulate micronized (superfine particles) DHEA, often in an oil suspension, to make capsules that are much better absorbed.  Like natural progesterone in oil capsules,  compounded DHEA capsules go directly into the lymph system and bypass much of the liver.

Compounding pharmacies also make a DHEA  transdermal gel in much the same manner as the testosterone gel is formulated.  This gel form bypasses the liver and allows the DHEA to be converted to testosterone and estrogen in peripheral tissues at a much slower rate.  This may prove to be the most appropriate way of administering DHEA.

The DHEA products formulated in a compounding pharmacy are only available on prescription because of their potency.  Doses of these products should probably not exceed 25 mg daily.

SERMS
 

Selective Estrogen Receptor Modulators or SERMs are often referred to as "designer" estrogens.

Estrogen is able to enter the cell through what is termed a receptor site. Each cell is considered to have two receptor sites: an alpha receptor  that allows estrogen into the cell to produce a specific effect, and a beta receptor that acts to keep estrogen out of the cell.  If you think of each receptor site as a lock, then the ideal SERM would only open the alpha "lock " in the brain, bone, and cardiovascular system and produce a positive effect like estrogen.  Conversely, the ideal SERM would only open the beta "lock" in the breast and uterus, therefore providing protection like an antiestrogen.

The ideal SERM would provide all of the benefits and none of the risks of estrogen. Unfortunately, there is no ideal SERM available yet, although there is a great amount of research in this area.

SERMS:

Isoflavones

It may be a surprise to some that the phytoestrogens in soy protein may be considered SERMs. Soy acts like an estrogen and has a positive effect on the brain, bone, hot flashes, and the cardiovascular system.  Soy may also act like an antiestrogen to protect the breast and uterus.  Although not as potent as estrogen, soy protein has many benefits and no risks.

Tamoxifen

The most widely used SERM is tamoxifen, which is used to treat estrogen dependent breast cancer and to prevent breast cancer in those at high risk.  Acting like estrogen, tamoxifen has a negative effect on the uterus (increasing cancer and polyps), a negative effect in producing blood clots, and may have a slightly positive effect on the bone.  Tamoxifen is used mainly for its antiestrogen effect on the breast, but this antiestrogen effect also means that it can cause hot flashes and vaginal atrophy.

Raloxifene

The drug that brought the terms "SERM" and "designer estrogen" into the main stream was raloxifene (Evista).  It was the first SERM developed for postmenopausal women.

Raloxifen acts like an estrogen to produce a positive effect on the bone and a mixed effect on the heart (lowering cholesterol but increasing clots).  It has been approved for the prevention of osteoporosis and has an effect on increasing bone mineral density and in reducing fractures. This effect is approximately half that of conjugated estrogens (Premarin 0.625 mg).  Although it does have a positive effect on the cardiovascular system, it is too soon to conclude that it should be used as a preventive measure. Current studies are underway.

Raloxifen acts like an antiestrogen in that it does not have a negative effect on the breast or the uterus.  Unfortunately because it acts like an antiestrogen, it does not help (and may even cause) hot flashes.  It is also not beneficial for vaginal atrophy.

It is probably too early to consider the SERMS like raloxifen as a replacement for HRT. However they do offer certain women options to conventional HRT. They may prove to be a valuable option for those with breast cancer or at risk for the disease.  SERMS may also be an option for women with osteoporosis risk who do not want to use estrogen and who cannot tolerate medications like Fosamax or Actonel.

Patches, Pills And Creams

History: 

Oral tablets or capsules are the most widely used forms of hormone replacement therapy (HRT). The biggest selling product is Premarin followed by Prempro (a combination of Premarin and medroxyprogesterone).  The first alternative to oral tablets was in the form of a transdermal (through the skin) estrogen patch that was used twice a week; but to prevent uterine cancer many women still had to take an oral progesterone compound along with the patch.  Currently patches are available containing both estrogen and a synthetic progesterone compound referred to as a progestin.  Some of these can be used just once a week.

There was a significant problem with the acceptance of the earlier patches.  Many women developed sensitivity to the adhesive and complained of pink marks that remained on the skin for days after the patch was removed.  Others found that the patches fell off prematurely. Fortunately, many of the newer patches don't have these problems.  Some of the patches are now the size of a quarter, and most use a new "matrix" design that eliminates much of the adhesive sensitivity problem.

Creams and Gels: Compounding pharmacies formulate various hormone creams and gels.  At first, these transdermal formulations were considered as alternatives for women who could not tolerate the adhesive on the patches.  More importantly, they later became useful because the primary care provider could easily alter the amount of the hormone to the patient’s individual needs.  These creams or gels do not seem to be patentable, so it is unlikely that any drug company will go to the expense of conducting studies on their effectiveness.  Also, because of the variable absorption depending on the base of the cream or gel, there is no standardization from pharmacy to pharmacy.

Most primary care providers like to refer to the same pharmacy or to use the same base for transdermal hormones.  Probably the most state-of-the-art base is that of a transorgano gel (also called PLO gel).

This water-based product has lipids added to it to increase skin penetration and to assist in drug delivery.  Studies have shown its effectiveness in the transdermal delivery of a variety of drugs.  This gel does not contain mineral oil that can reduce the absorption of some drugs.

Absorption: 

The use of patches offers a convenience over taking a tablet every day. Creams/gels offer the primary care provider and the patient a way to adjust the dose to the patient’s individual needs. But there is another reason for choosing oral or transdermal therapy--how the drug is utilized by the body.

When a drug is taken orally, if it is absorbed in the digestive system, it then goes to the liver before it goes into the bloodstream.  The liver may act to change the drug into other compounds that may or may not act the same as the original drug. This is known as "first bypass" effect.  Using a transdermal form of hormone circumvents the first bypass effect, and in order to understand whether this circumvention is beneficial, it is necessary to look at the various hormones:

Estrogen

Estrogen goes through significant changes in the "first bypass" effect of the liver. For this reason, transdermal estrogen is better than oral estrogen for women who have:

Liver disease
Gallbladder disease
High blood pressure
History of blood clots
High triglycerides

Transdermal estrogen patches may be a better choice for women who suffer from frequent migraine headaches.  Some headache specialists feel that migraines may be induced by fluctuating hormone levels.  Because the patches deliver estrogen at a constant rate, fluctuating levels are avoided.

Progesterone

Oral micronized progesterone in oil, as the brand Prometrium or a compounded formulation, is the most absorbed type of progesterone. It is the only type of progesterone clinically proven to prevent the endometrial disease that may be caused by estrogen.

Transdermal progesterone may be useful for women to treat hot flashes.  The dose can be easily altered to treat the symptoms.  Due to their higher potency, the prescription strength progesterone gels are probably more effective for this purpose.  They are actually more economical than those purchased over-the-counter.

Testosterone

Testosterone has poor oral absorption.  It can be improved, much like progesterone, by using capsules of micronized testosterone in an oil suspension.  However, even this oral form is not as well absorbed as transdermal forms.  The synthetic methyltestosterone is well absorbed orally.  It would be a good choice for women who do not wish any estrogen effect because, unlike testosterone, it is not converted in the body to estrogen.

Transdermal testosterone is the most widely used form of testosterone.  It is well absorbed through the skin, particularly when a transorgano gel is used as a base.