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.