[Canada]
Extract from an informative file on PROGESTINS AND PROGESTERONE at http://www.pangea.ca/~afi/volxino1/progesterone.html

The great attraction of Pro-Gest® cream (aside from the fact that a prescription is not required) is its putative ability  to reverse osteoporosis. Dr. Lee, who is now retired but who continues to follow a number of patients, has claimed that the use of Pro-Gest® cream was instrumental in increasing bone density (by an average of 8%) of 63  elderly female patients who used the cream over a period of three years. The patients with the lowest bone density  prior to treatment experienced the greatest gains.

     There is certainly some basis for this claim. Isolated studies since the 1970s have suggested a bone effect. In 1990, Dr. Prior showed, in a one-year study of 66 healthy, exercising women with good dietary calcium, that  normal progesterone levels (meaning normal ovulation each month) were necessary or bone would be lost. A  more recent study examined a group of physically fit younger women who had abnormal menstrual cycles. After administration of cyclic Provera (10mg a day for 10 days each month) it was found that bone mass had increased. If progestins can build bone, why not natural progesterone? In fact, I have been told of a few holistic doctors (such as Christiane Northrup, MD, gynecologist -- and popular speaker about women's health -- from Yarmouth  ME) who encourage their patients to use Pro-Gest® Cream to protect against osteoporosis.

     However, the excitement about 63 elderly women who gained bone as a result of using Pro-Gest® cream gets in the way of some other details regarding this project. In addition to using the cream, Dr. Lee told his patients to avoid soft drinks and eat red meat no more than three times a week (thus reducing phosphorus intake). They were  told to limit the use of alcohol and not to smoke. They also took daily supplements: 350-400 IU of vitamin D, 2000 mg of vitamin C, 25 mg. of betacarotene, 800-1000mg of calcium (in diet or supplement form). They were  instructed to exercise for at least 20 minutes a day, or 30 minutes three times a week. Then they were given  conjugated equine estrogens (Premarin® ), either .3mg or .625mg for three weeks of each month.

     In Dr. Lee's original report (Osteoporosis reversal: The role of progesterone, International Clinical Nutrition  Review, 1990; 10(3): 384-391), we are led to believe that all the women were on estrogen. In a subsequent letter  published in the British medical journal, Lancet (336:Nov. 24, 1990), Dr. Lee qualifies this and states that "some  patients, those with hot flushes or vaginal dryness, were also supplemented with low-dose Premarin. The bone benefits found were unaffected by supplemental estrogen." A subsequent article (Is natural progesterone the missing link in osteoporosis prevention and treatment?) Medical Hypotheses 1991;35:316-318) makes no mention  of the estrogen supplementation, and a printed addendum to his original 1990 article, dated May 16, 1991, says  that, "Well over one-third of the progesterone-treated patients in the study group received no supplemental estrogens." Dr. Lee continues, " ... it was obvious that the bone-building benefits of the progesterone therapy were  independent of the presence or absence of supplemental estrogen."

     Unfortunately this is not obvious at all. These women were instructed to take every possible step to reduce bone loss. We know that estrogen plus calcium plus exercise can, and often does, result in increased bone. Because  there are so many confounding variables, it cannot be concluded that the gains in bone resulted solely, or even  partially, from the use of Pro-Gest®Cream. Dr. Lee argues that it would be unethical to withhold from his patients any and all means to rebuild bone, and that it is therefore impossible to do such a study with a control group. But his report is just not good science.

     This is not to say that Pro-Gest® cream is a waste of money. It is to say that the data are not in yet.

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The effectiveness of progesterone creams is still largely untested. One small study conducted by Dr. John Lee, who strongly advocates the use of "natural"  progesterone, suggested that it might increase bone density.24 However, this  study had many flaws and really doesn't prove anything at all. For example,  while the participants took a very small dose of progesterone, they also made numerous positive lifestyle changes that may have been more important than the progesterone cream itself. 

Progesterone and Osteoporosis

Lee conducted a study that shows a positive effect of progesterone on bone. This one study has been published in several different publications, and all of these multiple publications lack details about how the study was done (Lee 1990a, Lee 1990b, Lee 1991). This study is not really an experimental trial but is an unselected case series of 100 postmenopausal patients, ages 38-83. It appears that Lee simply tracked his own patients over time. There is no control group and no apparent entry criteria, beyond being postmenopausal. There is not even evidence presented that the women enrolled actually suffered from osteoporosis, beyond the very general statement that "the majority had already experienced height loss, some as much as five inches" (Lee 1990b). 

Abstract: Increasing numbers of midlife women with concerns about the potential long-term sequelae of hormone replacement therapy are looking to over-the-counter progesterone creams for a "natural" solution. Claims made by the manufacturers of these "natural" compounds range from "...7-8% bone mass density increase in the first year [of use]," to "...relief of the symptoms of PMS and menopause, as well as osteoporosis." In an attempt to separate fact from fiction, Menopause Management asked practitioners with expertise in this area for their take on what we know -- and what we don't know -- about these products, some of which are likely being used by your patients, with or without your knowledge. 

Relevant extracts: (Be sure to read the whole article before using any over the counter "natural hormone" product.)

Dr. Kronenberg:  The concern is that many of the creams are being marketed on the basis of wild yam extract content, when they also contain micronized progesterone, which is what is responsible for the progestogenic actions the cream might have. Many women buy the creams thinking that because wild yam extract is "natural," it must be "better" than pharmaceutical products. They don't realize that many of the creams contain micronized progesterone (which is natural progesterone, derived from plant precursors). Other creams contain no progesterone (only wild yam extract), so they likely have no progestogenic action. Still others contain other herbal extracts, such as black cohosh root, which may themselves have some activity. 

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Dr. Kronenberg: People think that, because these creams are marketed as progesterones, they can use them for that purpose, unaware that they haven't been adequately tested for these purposes. Problems may arise when they use the cream without consulting their clinician, thinking it's accomplishing something that it's not. So it's important to get across that there is no evidence that these creams can prevent endometrial hyperplasia. I would add that some of the clinicians whose patients use the creams do say that there is no evidence to date that the progestogenic effect is sufficient to be using them in place of oral progesterone to oppose estrogen and prevent hyperplasia. 

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Dr. Kronenberg: Some of these manufacturers are taking advantage of the mood of the public; the desire to do something healthy, and the belief that "natural" is better and that herbs in general must be safe because they're natural. What the public doesn't adequately appreciate is that these products have physiologic effects, and that some may be beneficial while others may be contraindicated for some people. Manufacturers aren't providing the proper information, and some are trying to sell a product that may or may not have any effect, at least not the effect it's being touted to have. I don't know of research on thyroid function, and while some studies related to bone are intriguing, the data are not all in yet. 

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Dr. Liu: I don't think that progesterone creams themselves are harmful in the amounts that are absorbed. Of course, their effectiveness for a particular indication is unknown, and therein lies the judgment call. There are really two issues here. If a woman uses a cream to treat hot flashes, and it doesn't work, the only "harm" is in the failure to relieve her symptoms. The potential for real harm exists when these creams are used in place of a progestin that's required to treat a medical condition. Using the creams, for example, instead of the progestin prescribed for use with estrogen for a woman with a uterus would place her at risk because there's no evidence that these products can reverse endometrial hyperplasia. Of course, the potential for harm would be very real if these creams were used to treat osteoporosis 

This is one of our most frequently asked questions and it is much more complicated than it seems. To answer it, we'll have to discuss several issues.
 

First, I think it is important to establish that it is not natural to have progesterone postmenopausally. <major snip>

Second, is the nature of natural progesterone creams. <major snip of possible problems>

Third, the scientific evidence for any of the uses of progesterone cream is anything but solid. It is summarized below: [with footnoted references, Tishy]

Does it prevent breast cancer? <snip>
Does it prevent hot flashes? <snip>
Does it build bone? <snip>

In December 1997, the Therapeutic Goods Administration prohibited progesterone creams from general sale, making them available on prescription only.

Effectiveness of natural progesterone

                 Natural progesterone has been recommended for treating everything from menopausal symptoms, migraine, loss of libido and depression to water retention and fibrocystic breasts. One of the main supporters of natural progesterone and its benefits is Dr John R. Lee who is based in California. His books on the subject include Natural Progesterone: The Multiple Roles of a Remarkable Hormone and What your Doctor May Not Tell you about Menopause. In Australia, Dr Lee's writings on natural progesterone have gained great popularity. Consequently, many local distributors of natural progesterone quote his research findings and recommendations.

                Although Dr Lee provides concise information on progesterone's function in the body and its role in treating various conditions, he fails to provide any substantial scientific data to validate his findings. Several health practitioners have questioned Dr Lee's research methodology as many of his conclusions involving natural progesterone are based on anecdotal evidence, for example. Of most concern are Dr Lee's claims involving the use of natural progesterone in treating serious age-related diseases such as osteoporosis. It is these, more substantial claims that need to be treated with caution.

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               Despite the scepticism of some in the health field, many women prescribed natural progesterone, for a range of 'symptoms' and disorders, report that they find it to be very effective, finding great relief from premenstrual syndrome, menopausal symptoms, dysfunctional bleeding and endometriosis. It is important, however, that people are not complacent about using natural progesterone, particularly in its cream form. Women should take as much care with administering the correct dosage as they would with any other medicine.

Natural progesterone - help or hype?

   Health care providers and women's health groups report that women are asking about 'natural' progesterone creams and other  preparations for the relief of menopausal symptoms. These products have been promoted in books such as Leslie Kenton's best-selling Passage to Power and there have been reports of sales of such products in New Zealand even though the Ministry of Health says this is not legal.

  Proponents of 'natural' progesterone promise that it is safe, free of the side-effects ¹of hormone replacement therapy and that it is effective at alleviating menstrual disorders and the symptoms of menopause as well as curing a host of other problems. It is said to be a natural antidepressant, to restore libido, prevent blood clots, protect against breast and endometrial cancer, promote bone-building and metabolize fat.

   While there is anecdotal evidence that some women have found relief from hot flushes by using 'natural' progesterone, proof of other claims, such as protecting against osteoporosis, is hard to find. Our request for scientific evidence from a New Zealand importer of progesterone products did not generate a response, and most of  the available material consists of marketing material. A Californian doctor, John Lee, is the most widely quoted source of  information on natural progesterone.

Products containing even the smallest amount of progesterone are deemed to be prescription medicines and consent must be given before they can be marketed. This would involve evaluation for safety, efficacy and quality. So far, no applications have been made for approval for 'natural' progesterone products.

"The King's College Hospital team did a prospective, double-blind, randomised placebo-controlled cross-over study of the cream, using pharmacokinetic data as the endpoint. Postmenopausal women applied one teaspoon of cream (twice the recommended amount) to the arm or thigh, morning and night for 10 days. The average increment in plasma progesterone was 3 nmol/L. "Although this rise was statistically significant, it is difficult to see how such a low blood level could have any biological effect", said Cooper. "We would caution women against using this product until more scientifically rigorous data become available."

This study compares Pro-Gest® with placebo, and later with oral micronised progesterone. The report concludes with: "An increment of plasma progesterone of 3 nmol/L will not protect the endometrium from stimulation by oestrogen and will not conserve bone. Thus, Pro-Gest® should not be substituted for the progestogen in conventional oestrogen/progestogen HRT."

Much later (January 2002) a study (published in Maturitas)  further considered this controversy:
Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women
Conclusion: 

The absorption of progesterone from transdermal creams is low and we caution against the use of saliva measurements to monitor progesterone absorption.  The low systemic absorption of progesterone may not be due to peripheral conversion by 5-reductase(s).  We also conclude that the low level of progesterone associated with red cells suggests they are not important in the delivery of progesterone to target tissues. 

• Natural progesterone creams may be compounded by a compounding pharmacist to contain any percentage of micronized progesterone which the doctor deems desirable.
• Prometrium is the more easily prescribed and obtained formulation as it is a standard off the shelf product. It has the drawback that the soft gelatin capsule contains peanut oil so is contraindicated for women who are allergic to peanuts, but most women find it has fewer unwanted side effects than a "synthetic" progestin. It also has been shown to have less of a negative effect on lipids.
• Crinone is a vaginal gel which is only approved by the FDA for the treatment of infertility, though it is approved in several European countries for use in HRT and is sometimes prescribed "off label" in North America.