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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynaecology, North Middlesex Hospital and Royal Free and University College Medical School, Royal Free Campus, London, United Kingdom; Ella Gordon Unit, St. Mary’s Hospital, Portsmouth, United Kingdom; and Solvay Healthcare Ltd, Southampton, United Kingdom.
Address reprint requests to: Jose J. Nieto, MRCOG, Department of Obstetrics and Gynecology, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London, NW3 2QG, United Kingdom
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Abstract |
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Methods: The lipid effects of transdermal estradiol (E2) (80 µg/day continuously) and oral dydrogesterone (10 mg from days 15–28 of each cycle) were assessed in a multicenter, prospective, open, baseline-controlled study. Subjects were 42 healthy, postmenopausal women who had not had hysterectomies. Fasting blood samples were taken at baseline, day 14 of cycle 3 (estrogen alone), and day 25 of cycle 6 (estrogen and progestogen). The main outcome measures were changes from baseline in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides after six cycles.
Results: Thirty-six subjects completed six cycles and in the 28 with complete data, HDL cholesterol increased by 10.6% from 65.25 to 72.2 mg/dL (95% confidence interval [CI] 2.32, 11.58, P = .005) and LDL cholesterol fell by 5.1% from 130.9 to 124.3 mg/dL (95% CI 13.9, 1.16, P = .07). There was a nonsignificant decrease in LDL cholesterol from 130.9 at baseline to 124.3 mg/dL at 6 months and in triglycerides from 110.6 to 107.1 mg/dL.
Conclusion: Sequential treatment with transdermal E2 and oral dydrogesterone increased HDL cholesterol, without the accompanying increase in triglycerides that occurs with oral estrogen replacement therapy.
Postmenopausal hormone replacement therapy (HRT) reduces mortality from cardiovascular disease by 25–50%,1–3 a reduction believed to result in part from changes in lipid profiles. The precise effects of HRT depend on the type and route of estrogen and progestogen. An ideal regimen would increase high-density lipoprotein (HDL) cholesterol while reducing low-density lipoprotein (LDL) cholesterol and triglycerides.4
Estradiol (E2), the characteristic estrogen of reproductive life, and the most physiologic form of replacement therapy when administered orally unopposed by progestogen, increases synthesis of HDL cholesterol and decreases LDL cholesterol.4 Triglycerides also can be increased by E2.4 Transdermal estrogens bypass the portal circulation initially, inducing less alteration of hepatic metabolism.5 Compared with oral E2, the increase in HDL might be negligible with transdermal therapy and is probably dependent on dose and type of patch used.6 A recent review concluded that transdermal monotherapy neither increased nor decreased HDL.6 Transdermal estrogens were reported to decrease triglycerides by 5–20%.4,6
It is believed that oral progestogens, given to women with intact uteri to prevent endometrial hyperplasia, oppose the favorable estrogen-induced changes in lipid and lipoprotein metabolism,4 an effect dependent on dose and type of progestogen. C19 progestogens related to testosterone, such as oral norethisterone, cause a decrease in HDL with transdermal E2; however, triglycerides also are decreased.7 C21 progestogens related to progesterone also are used in transdermal HRT regimens. When transdermal E2 is given with the C21 progestogen medroxyprogesterone, HDL and triglycerides fall, although less markedly than with norethisterone.8,9
Dydrogesterone, a C21 progestogen related closely to progesterone, has been used to oppose oral HRT for many years. Dydrogesterone, unlike medroxyprogesterone, has been shown not to reverse the favorable lipid and lipoprotein changes induced by oral estrogens.10–13 Its effect with transdermal matrix patches has not been studied. The purpose of the present study was to assess the effect of dydrogesterone on lipid and lipoprotein metabolism when used to oppose a sequential matrix patch (Fematrix; Solvay Healthcare Ltd., Southampton, UK). We measured lipids and lipoproteins at baseline and in the estrogen and estrogendydrogesterone phases of treatment.
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Materials and Methods |
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This was an open, baseline-controlled study, with measurements at baseline and 3 and 6 months after starting six consecutive 28-day cycles of transdermal patches (80 µg/day) and oral dydrogesterone 10 mg from days 15–28. Written informed consent was given by all women before entry. Our study was conducted in accordance with the guidelines of Good Clinical Practice in the European Community, which incorporates the principles of the Declaration of Helsinki, and was approved by the ethics committees at each center.
At first visits, subjects had general examinations including blood pressure (BP), height, and weight. Endometrial biopsies (Pipelle biopsy; Prodimed, Neuillyen-Thelle, France), cervical cytology, and mammography were done. Blood samples were collected for FSH level, biochemistry, thyroid function, full blood count, and lipid profile. Women with triglyceride values greater than 4 mmol/L or total cholesterol greater than 8 mmol/L after 12 hours fasting were excluded. Numbers of hot flushes and degree of vaginal bleeding while on study were recorded by subjects on diary cards daily. Associated menopausal symptoms were recorded at baseline and each visit. Diary cards did not include assessments of dietary, exercise, or smoking patterns because subjects were not advised to alter those during the study.
Each woman was reviewed on day 14 of cycle 3 (estrogen-only phase), day 1 of cycle 5, and day 25 of cycle 6 (estrogen-progestin phase). At each of those visits, BP and adverse events or changes in concomitant medications were recorded, and subjects were asked to complete an integrated symptom evaluation and quality-of-life scale. Diary cards were reviewed and compliance was checked by counting patches applied and tablets taken since previous visits. Repeat endometrial biopsies were done at the cycle 5 visit.
Blood for lipid profiles after overnight fasting was collected at screening, during the second week of estrogen treatment in cycle 3, and during the second week of dydrogesterone addition in cycle 6. Whole blood was dispatched in ethylenediaminetetra-acetic acid tubes to one central laboratory (Wynn Institute, London, UK) and analyzed within 48 hours. Concentrations of plasma lipoprotein cholesterol and triglycerides were measured by enzymatic procedures. High-density lipoprotein cholesterol concentration was measured after sequential precipitation with heparin and manganese ions14 and dextran sulphate,15 respectively. Very-low-density lipoproteins were isolated by preparative ultracentrifugation. Low-density lipoprotein cholesterol concentrations were calculated as differences between plasma total cholesterol concentrations and those of very-low-density lipoproteins and HDLs. Apoproteins were measured by immunoturbidimetry16 using the Cobas biocentrifugal analyzer (Roche Products Ltd., Welwyn Garden City, Hestfordshire, UK).
Center-to-center variation was assessed, using analysis of variance to compare mean change in HDL cholesterol values from baseline to month 6 in the five centers. Changes in lipid concentrations from baseline to 6 months were assessed using paired t tests. The Wilcoxon signed-rank test was used to assess changes in the integrated symptom and quality-of-life scores. MacNemar test was used to assess significance of changes in endometrial histology.
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Results |
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The mean (range) age of the population was 51.1 (41–60) years. Mean body weight did not change significantly from 66.9 kg at baseline, to 67.4 kg at 6 months. Mean BP was unchanged, 123.2/78.9 mmHg at baseline and 122.4/75.8 mmHg at 6 months. Of 36 subjects who completed six treatment cycles, eight were excluded from analysis, one for not providing a baseline sample, four for providing nonfasting samples, and three for providing samples at the wrong points in the cycle.
Results for the cohort of 28 subjects who could be evaluated are shown in Table 1
. There were few statistically significant changes at estrogen-only visits at cycle 3; however, during the combined phase at cycle 6, HDL increased significantly by 10% (P = .005) compared with baseline. There were no significant differences between centers in mean change in HDL. There was a nonsignificant fall in LDL at 6 months, and triglycerides were unchanged.
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Analysis of the integrated symptom and quality-of-life questionnaire showed a significant reduction in vasomotor symptoms from 2.16 at baseline to 0.61 at 6 months (median reduction 1.60, 95% confidence interval [CI] of the difference 1.20, 1.90) and sexual symptoms from 1.39 to 0.59, respectively (median reduction 0.83, 95% CI of the difference 0.33, 1.17).
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Discussion |
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In a study10 with sequential oral estrogen and dydrogesterone, when the estrogen-only phase was compared with the combined phase under controlled conditions, the estrogen rise in HDL appeared to be enhanced by addition of dydrogesterone. Several other studies with oral estrogen confirmed the rise in HDL during the combined dydrogesterone phase.11,12 Therefore, unlike other progestogens, dydrogesterone does not seem to blunt the effect of estrogens on HDL when given orally or transdermally.
Unopposed oral estrogens might cause increased triglycerides, depending on type and dose of estrogen, which might not be important, especially in women with normal triglyceride levels, because the estrogen-induced increase in triglycerides is due to increased production of large very-low-density lipoprotein and not small more atherogenic particles.17 Epidemiologic studies, based largely on unopposed estrogen, showed marked reduction in cardiovascular disease,1–3 suggesting that triglyceride increases caused by oral estrogen might not be clinically important in healthy women.
A combination of transdermal E2 and sequential oral dydrogesterone fulfilled desired criteria for an ERT regarding lipids, increasing HDL cholesterol, and avoiding increased triglycerides.4 That regimen might better protect women from cardiovascular disease than conventional forms of estrogen-progestogen replacement therapy.
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Footnotes |
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Financial Disclosure
Financial support for Jose Nieto and for the biochemical analysis was provided by Solvay Healthcare Ltd., Southampton, UK, which markets the preparation studied.
Received February 23, 1999. Received in revised form June 3, 1999. Accepted June 24, 1999.
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References |
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2. Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet 1981;1:858–60.[Medline]
3. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer HE, Hemekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044–9.[Abstract]
4. Crook D, Stevenson YC, Whitehead MI. Estrogen replacement therapy and cardiovascular disease: Effects on plasma lipid risk markers. In: Schwartz DP, ed. Hormonal replacement. Baltimore, Maryland: Williams & Wilkins, 1992:132–70.
5. Judd H. Efficacy of transdermal estradiol. Am J Obstet Gynecol 1987;156:1326–31.[Medline]
6. Crook D, Stevenson SC. Transdermal hormone replacement therapy, serum lipids and lipoprotein. Br J Clin Pract 1996;86(suppl): 17–21.
7. Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: Effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992;166:950–5.[Medline]
8. Adami S, Rossini M, Zainberian N, Bertoldo F, Dorizzi R, Lo Cascio V. Long-term effects of transdermal and oral estrogens on serum lipids in postmenopausal women. Maturitas 1993;17:191–6.[Medline]
9. Mattsson L, Sansioe G, von Shoultz B, Uvebrant M, Wiklund I. Transdermally administered oestradiol combined with oral medroxyprogesterone acetate: The effects of lipoprotein metabolism in postmenopausal women. Br J Obstet Gynaecol 1993;100:450–3.[Medline]
10. Siddle NC, Jesinger DK, Whitehead MI, Turner P, Lewis B, Prescott P. Effect on plasma lipids and lipoproteins of postmenopausal oestrogen therapy with added dydrogesterone. Br J Obstet Gynaecol 1990;97:1093–100.[Medline]
11. Crook D, Godsland IF, Hull S, Stevenson JC. Hormone replacement therapy with dydrogesterone and 17B-oestradiol: Effects on serum lipoproteins and glucose tolerance during 24 month follow up. Br J Obstet Gynaecol 1997;104:298–304.[Medline]
12. Van der Mooren MJ, Dewacker PNM, Thomas CMG, Rolland R. Beneficial effects on serum lipoproteins by 17 beta-oestradioldydrogesterone therapy in postmenopausal women; a prospective study. Eur J Obstet Gynecol Reprod Biol 1992;47:153–60.[Medline]
13. Gelfand MM, Fugere P, Bissonnette F, Wiita B, Yang JM, Lorrain J, et al. Conjugated oestrogens combined with sequential dydrogesterone or medroxyprogesterone acetate in postmenopausal women: Effects on lipoproteins, glucose tolerance, endometrial histology and bleeding. Menopause 1997;4:10–18.
14. Warnick G, Albers J. A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high-density lipoprotein cholesterol. J Lipid Res 1978;19:65–76.[Abstract]
15. Gidez L, Miller G, Burstoin M, Slage S, Elder H. Separation and quantitation of subclasses of human plasma high-density lipoproteins by a simple precipitation procedure. J Lipid Res 1982;23: 1206–23.[Abstract]
16. Mount J, Kearney E, Rosseneu M, Slavin B. Immunoturbidimetric assays for serum apolipoproteins A1 & B using cobas biocentrifugal analyser. J Clin Pathol 1988;41:471–4.
17. Crook D. Postmenopausal hormone replacement therapy, lipoprotein metabolism and coronary heart disease. J Cardiovasc Pharmacol 1996;28(suppl)5:540–5.[Medline]
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