Progesterone

Q:I am 48. My doctor has prescribed natural rub-on progesterone for me to help me through the menopause. As I'm a singer, it's also important for me to look young. What are the known dangers? I've heard that because it's natural, there aren't any. A

A:Lately, everyone is jumping on the "natural" progesterone supplement bandwagon, prescribing it for everything from PMS and recurrent miscarriage to breast pain, menopausal symptoms, vague hormonal imbalances and even, in your case, for just being female and over 40.

Progesterone is the female sex hormone secreted by the corpus luteum during the second half of the menstrual cycle, the adrenal cortex or the placenta during pregnancy. Its function is to prepare the uterus for pregnancy and then to maintain the pregnancy once it has occurred. Recently, several in medicine, particularly Dr John Lee of California, have put forward the theory that many women these days are suffering from "estrogen dominance" and that this accounts for breast cancer, recurrent miscarriage and other complaints. Hence, why women who are low in progesterone or menopausal should be given supplements of natural progesterone.

For anyone who hasn't heard of it, progesterone is mainly administered as a rub-on cream, in a micronized form given orally dissolved in oil, as vaginal pessaries or as a shot. The reason it's given every way but orally is that when taken by mouth, the liver quickly breaks it down, rendering it mostly ineffective. Rubbing on or injecting progesterone enables it to bypass the liver and supposedly reach the bloodstream directly.

Many people are seduced by the fact that this progesterone is "natural", derived from soybeans or wild yam, and therefore presumed to be safe. This is a critical point because so-called synthetic progestogens (also known as progestins) have been examined in many studies and found to have many side effects, including the possible ability to cause cancer.

In fact, no supplemental progesterone or any other hormone is "natural" in the sense of being identical to what women produce in their own bodies. These new forms of progesterone are made from wild yam or soybeans, which contain substances which are converted into progesterone only after undergoing a series of synthetic chemical steps.

With the wild yam, progesterone is made from a substance called diosgenine.In an information sheet, one manufacturer says that it derives from a sterol compound called stigmasterol, extracted from soybean oil. "The sigmasterol is then synthesized to progesterone," says a company handout.

As Dr Alan Gaby points out in the Townsend Letter for Doctors (August/September 1995), another "natural" hormone is derived from horse estrogen, which "differs substantially from the hormones secreted by the human ovary".

Many forms of progesterone released on the market in the UK and the US have not been evaluated for their safety and effectiveness.

Ordinarily, when a drug company wants to market a new drug, it must register a new drug application with the FDA and undergo or provide evidence of both animal and human studies to demonstrate safety and effectiveness before the drug gains FDA approval. However, if you don't intend to promote or distribute a product on the open market, there is nothing to prevent a drug company from producing a drug or substance, such as powdered progesterone, and selling it to licensed chemists, so long as the drug company adheres to the US Pharmacopoeia standards of purity. It is also perfectly legal for licensed pharmacists to "compound" this product say, mix it up in a gel or as suppositories if a doctor requests it or writes a prescription for it. As one FDA spokeperson put it, "Extemporaneous compounding by licensed pharmacists is normally done when certain medical needs of individual patients cannot be met by the use of approved commercial drug products." So long as the use is, in the FDA's words, "medically acceptable" which can tend to be a moveable feast any doctor can prescribe to a patient any drug he feels like, even those that haven't been tested for FDA-approved safety and effectiveness.

The only progesterone product listed in the Physician's Desk Reference or the official FDA drug handbook is Progestasert, an intrauterine device containing slow-release progesterone. At the moment, doctors around the country have progesterone made up as a compound for specific patients. The point is, since nobody has applied for FDA approval, there is very little in the way of published studies about the safety or effectiveness of progesterone, and little knowledge about who shouldn't take it and why. Klim McPherson, leading epidemiologist on pill risks and professor of public health epidemiology at the London School of Hygiene and Tropical Medicine, said progesterone is "hopelessly, poorly understood."

The rub-on progesterone cream hasn't undergone review by the Food and Drug Administration because numerous companies sell the product as a cosmetic. It is possible to get the rub-on cream in the States by mail

order, but only by prescription in the UK.

Recently when we rang one manufacturer as ordinary customers and asked if their cream was good for menopausal symptoms, a woman called Alisha told me that her company couldn't make any claims for their cream, or discuss the amount of progesterone in it, since "our deal with the FDA is that it's a cosmetic." She told me that they were selling the cream "as a moisturizer for dry skin", but if I wanted to know what else it was good for, I should get hold of Dr John Lee's book, and she helpfully supplied me with the publisher and address. Dr Lee's book, Natural Progesterone: The Multiple Roles of a Remarkable Hormone, claims that supplemental progesterone will help to alleviate many female problems, from infertility and PMS, fibroids, endometriosis, pelvic cysts to osteoporosis. She also said she could send me directions for usage, and indicated that they varied depending upon whether you were "menopausing" or not. Her company recommends using it daily for three weeks and then refraining for a week.

We then moved onto the FDA. According to Alan Halper, compliance officer in the Office of Cosmetics and Colors, cosmetic products are not specifically required to register with the FDA. "If you wanted to come out with a cosmetic tomorrow, you could formulate, label and sell it without telling the FDA," he said. The industry is largely self-policing; they rely on a product causing gross injury to generate complaints.

At the moment, any amount of hormone can be put into cosmetics so long as there are no medicinal claims being made for the preparation. However, the FDA would like to see things tightened up. On September 9, 1993, the agency submitted a notice of proposed rule-making which would consider all over-the-counter drugs and cosmetics listing "hormones" in the ingredient statement to be an implied drug claim, and that such labeling would cause the product to come under ordinary drug regulations requiring safety testing. In one of two exceptions, the FDA proposed to limit the use of progesterones in cosmetics products to 5 mg/per ounce of progesterone when used in an amount not exceeding two ounces per month, or 10 mg of progesterone per month.

According to one doctor, the two ounce-per-month supply of rub-on progesterone provides 20 mg of progesterone per day. Although proposed more than two years ago, the final FDA ruling on this issue has not been made, as the regulatory gears grind slowly.

The issue of how much progesterone is contained in the cream is pertinent when you consider the minute doses required by the body to keep things ticking over. During the menstrual cycle of the ordinary woman, progesterone blood levels range from 0.5 to 20 nanograms per ml, according to Harrison's Principles of Internal Medicine. This amount is the equivalent of one part per billion in weight. With the rub-on cream, women could be enhancing the progesterone concentration in the blood by four or five times. To prevent miscarriage when levels needed are higher, women can receive from 25-200 mg per day.

The theory has been that this progesterone would "drip feed" into the system as it would normally. But several studies show that progesterone can tend to accumulate in the skin, causing unknown chemical effects in and under it. In one study of rub-on progesterone applied to breast tissue, both progesterone and estrogen levels increased by four times, and yet any blood levels of progesterone were short-lived (P Mauvis-Jarvis, et al, Percutaneous Absorption of Steroids, Academic Press, 1980). According to this same article, the average amount absorbed is about 10 per cent of the applied dose, so that if you are using 50 mg of progesterone, you'd absorb about 5 mg.

Furthermore, not everyone absorbs progesterone in the same way. In the same book, J De Boever and his colleagues at the University of Ghent in Belgium, conclude: "After topical administration of a single dose of progesterone, there is a wide variation in the results observed in breast tissues".

If this massive increase is happening locally, whether by shot, pessary or cream, we have no idea what on earth it's doing.

Many in medicine attempt to claim that progesterone can protect against such diseases as breast cancer. However, according to Klim McPherson, there is also a good argument for the opposite being true high progesterone levels being a risk factor for breast cancer (BMJ, March 4, 1995). This makes sense because the primary function of progesterone in the breasts is to promote development of breast cells.

Progesterone is listed as a carcinogen in numerous chemical handbooks. In animal studies, progesterone increased the incidence of cancer of the ovary, uterus and breast in mice (IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, December 1979). Several researchers have also hypothesized that breast cancer is caused by increased levels of progesterone (Fertility and Sterility, March 1992).

As for its indications, most studies published demonstrate that progesterone doesn't seem to make much difference alleviating PMS (JAMA, July 5, 1995) or in preventing miscarriage (Hum Repro, March 1992; J Repro Med, March 1992). One study showed that pregnancies may even be viable at very low levels of progesterone and concluded that there was no minimal threshold where anyone could say progesterone was definitely needed (Gyne & Ob Inves, 1992; 34 (3): 133-8). In fact, supplemental progesterone may have deleterious effects. Another set of researchers concluded that the progesterone may not be such a good idea, since it mainly caused "delayed gland maturation", and in those receiving IVF, showed pathological changes in the womb lining (Ann Chir et Gynae, 1994; 208: 33-9), or significantly higher blood estrogen levels (Gyn & Ob Inves, 1992; 34 (4): 206-10).

In the UK, two companies produce progesterone. Hoeschst produce Cyclogest (which are vaginal or rectal pessaries), which is intended to treat PMS and post-natal depression, and Paines & Byrne produce Gestone, which is given by injection, and indicated for the treatment of abnormal uterine bleeding or to prevent miscarriage for women with abnormally low progesterone or undergoing IVF. Both have received UK Committee on Safety of Medicine approval.

Ironically, of Cyclogest, the PMS drug, its manufacturers says that it is "not expected to have adverse effects" during pregnancy that is, cause birth defects although "no evidence is available to this effect." Gestone, the miscarriage drug, on the other hand, says that as it contains "progesterone itself, the same as the naturallys secreted hormone," it is "not associated with masculinization of a female fetus as are synthetic progestins."

On the issue of birth defects and use during pregnancy, the FDA takes a tougher line. "Systemically administered sex steroids, including progestational agents, have been associated with an increased risk of congenital anomalies" it says about Progestasert (Physicians' GenRx, 1993). The reevaluated results of the US Collaborative Perinatal Study of the Drug Epidemiology Unit found that the risk of cardiovascular malformation more than doubled in infants exposed to female sex hormones during the first four months of pregnancy (Teratol, March 1994).

For Gestone, the manufacturer warns that you should stop the drug if you develop loss of vision, bulging of the eyeball, double vision, swelling of the optic disc, vascular lesions in the retina or migraine. Other side effects include changes in the cervix or breast, depression, jaundice, insomnia, nausea, hair loss or growth, darkened skin, weight gain, edema and changes in menstrual flow or cycle.