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Use of Pro-Gest cream in postmenopausal women
CORRESPONDENCE
Use of Pro-Gest cream in postmenopausal women Sir—Transitions For Health, the maker of Pro-Gest, has no authority over physicians who prescribe Pro-Gest, natural progesterone cream, for the benefit of their patients. For over 20 years it has been our mission to provide quality products that improve the health and lives of women. The Pro-Gest formula is under strict controls, at 465 mg per ounce or 1·5% US Pharmacopeia grade progesterone by weight. A Cooper and colleagues (April 25, p 1255)1 states that the product tested measured 200 mg of progesterone, which is certainly in error. The laboratory that did this test was contracted to clarify the method and verify their results. We have had no response from them. Since the measurement of progesterone in Pro-Gest cream was inaccurate and unsupported by regular laboratory testing in the UK as well as the USA, the results of all the tests reported by Cooper and co-workers are questionable. We do not believe there is adequate scientific evidence to support any claims or assertions with respect to osteoporosis or to conclude that Pro-Gest does not protect the endometrium from stimulation by oestrogen. Sharon A MacFarland Transitions for Health Inc, 621 SW Alder, Portland, OR 97205, USA 1
Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJR, Collins WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998; 351: 1255–56.
Sir—A Cooper and colleagues1 conclude that topical progesterone (Pro-Gest cream) is not well absorbed and, therefore, “will not protect the endometrium from stimulation by oestrogen and will not conserve bone”. This conclusion was based not on actual clinical studies, but, rather, on their finding that daily “teaspoon” doses of a transdermal cream in postmenopausal women result in only a slight rise in plasma progesterone (median 2·9 vs 0·8 nmol/L for placebo), which is less than the typical plasma concentration in ovulating women during the luteal phase. These workers err in their assumption that plasma (or serum) progesterone accurately reflects the true bioavailable concentrations of progesterone circulating in blood. Plasma values indicate mainly proteinbound progesterone, of which only 2–5% is available to target tissue and
THE LANCET • Vol 352 • September 12, 1998
saliva. Since almost all endogenous progesterone is protein-bound and therefore water soluble, plasma values of endogenous progesterone are at least ten times greater than those in saliva. However, progesterone entry through the skin is quite different. Progesterone, per se, is very lipophilic (hydrophobic) and is non-polar. As a result, it is well absorbed through the skin2 and enters the blood stream by seeking out a similar, or non-polar, environment, such as the fatty membrane of red blood cells, and not by absorption into plasma. Since red blood cells are the major cellular components of blood, it is reasonable that progesterone is transported in the blood in this way. When progesterone is added directly to whole blood, about 80% of it is taken up by red blood cells.3 Furthermore, progesterone (and other steroids) bound to red blood cells can dissociate within milliseconds, allowing rapid transport of progesterone into target tissues.4 The importance of red blood cells for steroid transport is underestimated.4 Since progesterone bound to red blood cells more readily delivers progesterone into target tissues and into saliva, its transdermal absorption is more accurately measured by saliva assay than by plasma or serum tests. For example, in a comparison of saliva and serum concentrations when different doses of progesterone are applied topically to menopausal women, the results clearly show the difference in these two testing techniques.5 Progesterone cream (daily dose)
Serum (ng/mL)
Saliva (ng/mL)
0 mg 0·34 mg 30 mg
3·36 (0·06) 0·50 (0·09) 1·8 (0·3)
0·03 (0·006) 0·152 (0·025) 8·7 (3·5)
Since the transport of bioavailable progesterone from blood through the saliva glands is passive (simple filtration), saliva values are far more accurate than plasma or serum concentrations for measurement of the true bioavailable fraction of progesterone when it is delivered transdermally. Because there is far more bioavailable progesterone with transdermal application than indicated by serum or plasma tests, it would behove Cooper and colleagues to repeat the study and measure salivary progesterone concentrations. John R Lee 9620 Bodega Hwy, Sebastopol, CA 95472, USA 1
Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJR, Collins WP.
2
3
4
5
Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998; 351: 1255–56. Johnson ME, et al. Permeation of steroids through human skin. J Pharmaceutical Sci 1995; 84: 1144–46. Devenuto F, et al. Human erythrocyte membrane: uptake of progesterone and chemical alterations. Biochim Biophys Acta 1969; 193: 36–47. Koefoed P, Brahm J. The permeability of the human red cell membrane to steroid sex hormones. Biochim Biophys Acta 1994; 1195: 55–62. Dollbaum CM, Duwe GF. Absorption of progesterone after topical applications: serum and saliva levels. Presented at the 7th Annual Meeting of the American Menopause Society, 1997.
Sir—A Cooper and colleagues1 report a careful and well designed study to examine whether a transdermal progesterone gel is absorbed adequately. They state that this product is used for the prevention of osteoporosis1 and their results thus question whether the absorption is sufficient for biological activity, as well as showing that the sample jar of gel used was low in progesterone content. However, we seriously question whether this product should be used at all by qualified clinicians, irrespective of its apparent inadequate dosage and unsubstantiated absorption characteristics. There is no evidence for any effect of progesterone alone, as opposed to progestagens, on the human skeleton. The report cited as supporting a beneficial effect of transdermally administrated progesterone on the skeleton2 is a collection of unsupported anecdotes rather than a scientific study. The many criticisms that could be made about this publication include the facts that selection of patients was arbitrary, there was no randomisation or contemporary control, there was no evidence of quality control of the methods used (which was in any case inadequately described), and there was no appropriate statistical presentation of the data. We also have major concerns that an unproven treatment was being offered to these patients without any published evidence of either ethics review board permission or patients’ informed consent. Evidence that progesterone has a beneficial effect on the human skeleton is absent, as is evidence for endogenous progesterone having such an effect.3 Osteoporosis is a major public-health problem, and treatments such as hormone replacement therapy (HRT), bisphosphonates, and calcitonin have been shown to be effective in the conservation of bone density and prevention of osteoporotic fractures.4,5 We know of no convincing evidence
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Use of Pro-Gest cream in postmenopausal women Sir—Transitions For Health, the maker of Pro-Gest, has no authority over physicians who prescribe Pro-Gest, natural progesterone cream, for the benefit of their patients. For over 20 years it has been our mission to provide quality products that improve the health and lives of women. The Pro-Gest formula is under strict controls, at 465 mg per ounce or 1·5% US Pharmacopeia grade progesterone by weight. A Cooper and colleagues (April 25, p 1255)1 states that the product tested measured 200 mg of progesterone, which is certainly in error. The laboratory that did this test was contracted to clarify the method and verify their results. We have had no response from them. Since the measurement of progesterone in Pro-Gest cream was inaccurate and unsupported by regular laboratory testing in the UK as well as the USA, the results of all the tests reported by Cooper and co-workers are questionable. We do not believe there is adequate scientific evidence to support any claims or assertions with respect to osteoporosis or to conclude that Pro-Gest does not protect the endometrium from stimulation by oestrogen. Sharon A MacFarland Transitions for Health Inc, 621 SW Alder, Portland, OR 97205, USA 1
Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJR, Collins WP. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998; 351: 1255–56.
Sir—A Cooper and colleagues1 conclude that topical progesterone (Pro-Gest cream) is not well absorbed and, therefore, “will not protect the endometrium from stimulation by oestrogen and will not conserve bone”. This conclusion was based not on actual clinical studies, but, rather, on their finding that daily “teaspoon” doses of a transdermal cream in postmenopausal women result in only a slight rise in plasma progesterone (median 2·9 vs 0·8 nmol/L for placebo), which is less than the typical plasma concentration in ovulating women during the luteal phase. These workers err in their assumption that plasma (or serum) progesterone accurately reflects the true bioavailable concentrations of progesterone circulating in blood. Plasma values indicate mainly proteinbound progesterone, of which only 2–5% is available to target tissue and
THE LANCET • Vol 352 • September 12, 1998
saliva. Since almost all endogenous progesterone is protein-bound and therefore water soluble, plasma values of endogenous progesterone are at least ten times greater than those in saliva. However, progesterone entry through the skin is quite different. Progesterone, per se, is very lipophilic (hydrophobic) and is non-polar. As a result, it is well absorbed through the skin2 and enters the blood stream by seeking out a similar, or non-polar, environment, such as the fatty membrane of red blood cells, and not by absorption into plasma. Since red blood cells are the major cellular components of blood, it is reasonable that progesterone is transported in the blood in this way. When progesterone is added directly to whole blood, about 80% of it is taken up by red blood cells.3 Furthermore, progesterone (and other steroids) bound to red blood cells can dissociate within milliseconds, allowing rapid transport of progesterone into target tissues.4 The importance of red blood cells for steroid transport is underestimated.4 Since progesterone bound to red blood cells more readily delivers progesterone into target tissues and into saliva, its transdermal absorption is more accurately measured by saliva assay than by plasma or serum tests. For example, in a comparison of saliva and serum concentrations when different doses of progesterone are applied topically to menopausal women, the results clearly show the difference in these two testing techniques.5 Progesterone cream (daily dose)
Serum (ng/mL)
Saliva (ng/mL)
0 mg 0·34 mg 30 mg
3·36 (0·06) 0·50 (0·09) 1·8 (0·3)
0·03 (0·006) 0·152 (0·025) 8·7 (3·5)
Since the transport of bioavailable progesterone from blood through the saliva glands is passive (simple filtration), saliva values are far more accurate than plasma or serum concentrations for measurement of the true bioavailable fraction of progesterone when it is delivered transdermally. Because there is far more bioavailable progesterone with transdermal application than indicated by serum or plasma tests, it would behove Cooper and colleagues to repeat the study and measure salivary progesterone concentrations. John R Lee 9620 Bodega Hwy, Sebastopol, CA 95472, USA 1
Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJR, Collins WP.
2
3
4
5
Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet 1998; 351: 1255–56. Johnson ME, et al. Permeation of steroids through human skin. J Pharmaceutical Sci 1995; 84: 1144–46. Devenuto F, et al. Human erythrocyte membrane: uptake of progesterone and chemical alterations. Biochim Biophys Acta 1969; 193: 36–47. Koefoed P, Brahm J. The permeability of the human red cell membrane to steroid sex hormones. Biochim Biophys Acta 1994; 1195: 55–62. Dollbaum CM, Duwe GF. Absorption of progesterone after topical applications: serum and saliva levels. Presented at the 7th Annual Meeting of the American Menopause Society, 1997.
Sir—A Cooper and colleagues1 report a careful and well designed study to examine whether a transdermal progesterone gel is absorbed adequately. They state that this product is used for the prevention of osteoporosis1 and their results thus question whether the absorption is sufficient for biological activity, as well as showing that the sample jar of gel used was low in progesterone content. However, we seriously question whether this product should be used at all by qualified clinicians, irrespective of its apparent inadequate dosage and unsubstantiated absorption characteristics. There is no evidence for any effect of progesterone alone, as opposed to progestagens, on the human skeleton. The report cited as supporting a beneficial effect of transdermally administrated progesterone on the skeleton2 is a collection of unsupported anecdotes rather than a scientific study. The many criticisms that could be made about this publication include the facts that selection of patients was arbitrary, there was no randomisation or contemporary control, there was no evidence of quality control of the methods used (which was in any case inadequately described), and there was no appropriate statistical presentation of the data. We also have major concerns that an unproven treatment was being offered to these patients without any published evidence of either ethics review board permission or patients’ informed consent. Evidence that progesterone has a beneficial effect on the human skeleton is absent, as is evidence for endogenous progesterone having such an effect.3 Osteoporosis is a major public-health problem, and treatments such as hormone replacement therapy (HRT), bisphosphonates, and calcitonin have been shown to be effective in the conservation of bone density and prevention of osteoporotic fractures.4,5 We know of no convincing evidence
905