Progesterone Cream for Osteoporosis
Part I of a Series on "Natural" Hormones
April 1999; Volume 1: 33-36
By Adriane Fugh-Berman, MD
For years, a topical form of natural progesterone has been touted as a treatment for osteoporosis, hot flashes, and PMS, and as a prophylactic against breast cancer. Natural progesterone is derived from diosgenin in either soybeans or an inedible Mexican wild yam (Diascorea villosa) that is unrelated to sweet potatoes and edible yams. Oral wild yam preparations have been used in herbal medicine, primarily to treat gastrointestinal cramping. Topical wild yam creams are available; it is unclear whether any active components of wild yam can be absorbed through the skin. Diosgenin is a chemical precursor to progesterone, but a lengthy laboratory process is involved in the conversion. In any case, eating or applying wild yam extract or diosgenin will not result in increased progesterone levels because humans cannot convert diosgenin into progesterone.
Natural progesterone creams are available over the counter. Almost all claims about natural progesterone cream can be traced to John M. Lee, MD. Lee published a popular booklet, Natural Progesterone: The Multiple Roles of a Remarkable Hormone, in which he claims that fibroids, breast cancer, fibrocystic breasts, PMS, and osteoporosis are all linked to "estrogen dominance secondary to a relative insufficiency of progesterone."1
Lee conducted a single study that shows a positive effect of natural progesterone cream on bone. This one study has appeared in several different publications.2,3,4 Each version lacks crucial details. It is unfortunate that the Lancet published such an incomplete report2 even as a letter. The study appears to be an unselected case series of 100 postmenopausal patients, ages 38-83 (apparently, Lee simply tracked his own patients over time). It’s not clear how many women were diagnosed with osteoporosis. Generalities characterize these reports, one of which states that "the majority had already experienced height loss, some as much as five inches."3 Another states that "The majority had already noted height loss, a cardinal sign of osteoporosis, and many had experienced one or more fractures."
Lumbar bone mineral density measurements (by dual photon absorptiometry) were done on 63 of the 100 patients and Lee claims that over three years, average bone density increased 15.4%, with those with the lowest bone densities experiencing the most benefit. Although there is a table indicating averages of lumbar bone density at baseline and after three years, no report indicates how many patients were in each group. Also, none of the reports gives a breakdown of patients by age, menopausal status, diagnosis of osteoporosis, risk factors, or prior fracture history. Needless to say, no statistical analysis is presented.
Besides treatment with progesterone cream, an unspecified number of women in this case series were also taking estrogen. Although it is stated that bone benefits "were unaffected by supplemental estrogen,"2 that statement is impossible to evaluate because there is no information presented on how many patients were taking estrogen, and the group taking estrogen is not analyzed separately. One 74-year-old patient in the case series developed endometrial cancer during the study.
Another factor that confounds this study is that women were advised to stop smoking; to exercise for 30 minutes three times weekly; and to take a supplement regimen including calcium, vitamin D, beta carotene, and vitamin C. It is not stated what the compliance was for these instructions, but smoking contributes to osteoporosis and estrogen, exercise, calcium, and vitamin D all help to prevent bone loss, so all of these factors are potential confounders.
Appropriate, objective endpoints are lacking. Lee writes, "The addition of progesterone to the conventional treatment program in postmenopausal women was found to be consistently beneficial. By the third month the patients generally experienced a sense of well-being.... During the three-year follow-up observation, patient height was stabilized, aches and pains diminished, mobility and energy levels rose, normal libido returned, and no side effects emerged."3 Most of these results are subjective, placebo-responsive, and unconnected to osteoporosis. Height loss does indicate vertebral osteoporosis, but "height stabilization" is not a reasonable osteoporosis endpoint because loss of height does not occur at a predictable, linear rate.
Lee states that "the occurrence of osteoporotic fractures dropped to zero." Three fractures occurred; one knee fracture occurred in an 80-year-old in a car accident, another subject in her 70s fell while hiking, and the third fell down a flight of stairs. Lee states in one report that "Three traumatic fractures did occur and, in each case, these healed normally with the treating orthopedist commenting on the good quality of their bones."
Progesterone and Bone
It is clear there are progesterone receptors on bone, and that in vitro, progesterone stimulates osteoblasts,5,6 but in humans, studies are not so clear. It is unclear whether progestogens increase bone or decrease it, and results may be specific to the progestogen. One study of 66 premenopausal women found that short luteal phases correlated with decreases in spinal bone density;7 women with the shortest luteal phases lost 2-4% of bone a year. Another study of amenorrheic athletes found that those given 10 mg of medroxyprogesterone acetate (Provera®) for 10 days a month had significant increases in trabecular bone.8
Lactation reduces bone density temporarily, and progestin-only contraception such as Depo-Provera® (depot medroxyprogesterone acetate or DMPA) seems to reduce postpartum bone loss.9 Long-term users of DMPA (which usually produces amenorrhea) show decreases in spinal bone.10 After discontinuing DMPA, spinal bone density increases almost to pretreatment levels.11
There is some evidence to suggest that estrogen and progesterone may have synergistic effects on bone, and that progestin alone may have a mild bone preserving effect in patients treated with GnRH agonists.5,12 It is also possible that some benefits attributed to progestins are actually due to estrogenic effects. Norethindrone appears to have estrogen-like qualities in animal models;13 a very small percentage (2.3%) of orally administered progestin is converted into ethinyl estradiol.5 More work needs to be done in this area.
Effect on Endometrium
Some menopausal patients believe that natural progesterone cream can be substituted for the progestin component of hormone replacement therapy (HRT).14 Since the entire purpose of the progestational component of HRT is to decrease the risk of estrogen-induced endometrial cancer, the issue of whether natural progesterone cream provides adequate progestational effect on the uterus is of much concern to clinicians. A recent study of absorption of a popular natural progesterone cream calls into question whether enough progesterone is absorbed transdermally to have any systemic effect.
A crossover study of 20 surgically menopausal women (not receiving HRT) compared plasma progesterone and 17-hydroxyprogesterone (17-OHP) and pregnanediol-3alpha-glucoronide (P3G) after topical application of Pro-Gest® cream, topical application of placebo, and oral natural progesterone (Uterogestan). In this 10-day study, women were randomly assigned to apply one teaspoon of Pro-Gest cream or an emollient cream placebo bid (this is 2-4 times the recommended daily dose); there was a four-day washout period prior to switching creams. Each subject then took oral natural progesterone (100 mg qam and 200 mg qpm) for five days. Blood was drawn 4-6 hours after treatment; urinary P3G was from first morning urine. Compared to placebo, Pro-Gest significantly increased urinary P3G and plasma progesterone levels, but median plasma levels after 10 days of treatment were only 2.9 nmol/L, compared to 9.5 nmol/L with oral progesterone. 17-OHP values were similar (1.1 with Pro-Gest, 1.2 with Uterogestan); P3G levels in urine were 4.2 µmol with Pro-Gest and 291 µmol with Uterogestan. The authors note that plasma levels were insufficient to protect the endometrium from estrogen stimulation. This study also found that each two-ounce jar contained 200 mg progesterone (as opposed to the 930 mg claimed by the manufacturers).
Both John Lee and Transitions for Health, the manufacturers of Progest, wrote letters to the Lancet. The manufacturer stated that the product contains 465 mg/oz, not 200 mg/2 oz, and calls the other results into question.15 John Lee’s letter stated that plasma progesterone does not accurately reflect bioavailable levels, because progesterone preferentially enters red blood cell membranes; Lee suggests that saliva levels are more predictive of bioavailable progesterone.16 Cooper and Whitehead, authors of the study, respond that "we find it difficult to envisage how progesterone could bind to red blood cells, but not to serum albumin, corticosteroid binding globulin, and alpha-1 glycoprotein, and yet be readily released into salivawe remain very concerned about the clinical use of Pro-Gest because of the absence of scientifically valid studies on endometrial protection and bone conservation. Prescription should follow scientific evaluation not the reverse."
No argument here. Certainly, natural progesterone may have different effects than synthetic progestin. In the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial, oral micronized progesterone reduced estrogen’s beneficial effect on lipids to a lesser degree than synthetic progestins.17 More research is needed to delineate the differences between natural progesterone and synthetic progestins. But there is scant basis for claims that progesterone cream is an effective treatment or prophylactic for osteoporosis (or any other condition).
References
1. Lee JR. Natural progesterone: The multiple roles of a remarkable hormone. Sebastopol, CA: BLL Publishing; 1993.
2. Lee JR. Osteoporosis reversal with transdermal progesterone. Lancet 1990;336:1327.
3. Lee JR. Osteoporosis reversal: The role of progesterone. Int Clin Nut Rev 1990;10:384.
4. Lee JR. Is natural progesterone the missing link in osteoporosis prevention and treatment? Med Hypotheses 1991;35:316-318.
5. Panay N, Studd J. Do progestogens and progesterone reduce bone loss? Menopause 996;3:13-19.
6. Verhaar HJ, et al. A comparison of the action of progestins and estrogen on the growth and differentiation of normal adult human osteoblast-like cells in vitro. Bone 1994;15:307-311.
7. Prior JC, et al. Spinal bone loss and ovulatory disturbances. N Engl J Med 1990;323:1221-1227.
8. Prior JC, et al. Cyclic medroxyprogesterone treatment increases bone density: A controlled trial in active women with menstrual cycle disturbances. Am J Med 1994;96:521-530.
9. Caird LE, et al. Oral progestogen-only contraception may protect against loss of bone mass in breast-feeding women. Clin Endocrinol 1994;41:739-745.
10. Cundy T, et al. Bone density in women receiving DMPA for contraception. BMJ 1991;303:13-16.
11. Cundy T, et al. Recovery of bone density in women who stopped using medroxyprogesterone acetate. BMJ 1994;308:247-248.
12. Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990a;11:386-398.
13. DeCherney A. Bone-sparing properties of oral contraceptives. Am J Obstet Gynecol 1996;174:15-20.
14. Cooper A, et al. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998;351:1255-1256.
15. MacFarland SA. Use of Pro-Gest cream in postmenopausal women. Lancet 1998;352:905.
16. Lee JR. Use of Pro-Gest cream in postmenopausal women. Lancet 1998;352:905.
17. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. The Writing Group for the PEPI trial. JAMA 1995;273:199-208.
April 1999; Volume 1: 33-36You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content