- Email: [email protected]
Progestins
MATURITAS JOURNAL OF THE CLIMACTERIC & POSTMENOPAUSE
ELSEVIER
Maturitas 23 Suppl. (1996) S13-S18
Progestins Erkki Hirvonen Departments of Obstetrics and Gynecology, Helsinki University Central Hospital Haartamanin-Kartin 2, 00290 HelsinkL Finland
Abstract The history of progesterone and hormone replacement therapy goes back to 1934 when Butenandt obtained crystalline progesterone and Kaufmann started to treat ovariectomized women with both estrogens and progesterone (Table 1). Today synthetic perorally active 19-nortestosterone and 17-a-hydroxyprogesterone derivatives are used in addition to contraception and hormone replacement therapy in a variety of gynecological disorders. In hormone replacement therapy progestin is added only to prevent development of hyperplasia of the endometrium and its consequences. However, because progestins may cause both subjective and metabolic adverse effects minimum effective antiproliferative doses are recommended. The duration of the progestin phase cannot be shortened to less than 10 days whereas the frequency of administration apparently can be reduced without increased risk of hyperplasia. Development of new modes of administration may further help in reduction of the doses. Keywords: Progestin; Estrogen; Hormone replacement therapy; Endometrium; Progestogenic side-effects; Cardiovas-
cular risk
1. Types of progestins There are three different types of progestins: 17alpha-hydroxy progestins, retrosteroids and 19nor-progestins (Table 2). Today natural progesterone is only one of the progestins. Perorally Table 1 Development of indications for progestins 1934 Substitution of ovariectomizedwomen (Kaufmann) 1937 Treatment of oligo- and hypomenorrhea(von Kehrer) 1938 Treatment of anovulation (Glauberg) 1953 Treatment of menorrhagia (Kaufmann) 1956 Contraception with norethynodrel (Pincus) 1960 Endometriosis (Kistner) 1970s Postmenopausal hormone replacement
administered effective transformation doses presented in Table 2 should better be called antiproliferative doses, ones that are shown to prevent development of hyperplasia. The other properties of progestins, such as androgenic and antiandrogenic activities, are mainly due to unspecific binding to steroid hormone receptors other than those of progesterone. Thus, progestins have different hormonal activities; most 19nortestosterone derivatives have some androgenic activity whereas cyproterone acetate is strongly antiandrogenic.
2. Antiproliferative effect The antiproliferative effect is important both in
0378-5122/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PII S0378-5122(96)01005-5
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18
St4
Table 5 Determinants of progestogenic side-effects
Table 2 Different types and properties of progestins Progestin
17-a-OH-progestins Medroxyprogesterone acetate Megestrole acetate Cyproterone acetate
Anti- AntiAndro- Transforestro- andro- genie mation genie genic dose (rag/day)
+
-
-
5-10
+ +
+++
-
5 !
Retrosteroids Dydrogesterone
-
-
-
10-20
Progesterone (micronized)
-
-
-
300
19-Norprogestins Norethisterone Norethisterone acetate Levonorgestrel Desogestrel Gestodene Norgestimate
+ + ++ + ++ +
-
++ ++ ++ + + -
0.3-1 0.7 0.150 O. 150 0.075 0.250
• • • • •
Type and properties of progestin Unspecific binding to other hormone receptors Dose Non-receptor mediated effects Genetic factors
potent mitogens in endometrial cancer cells. Specific binding proteins modulate the biological action of IGFs. IGFBP-1 inhibits the receptor binding and mitogenic effects of IGFs in the endometrium. Stimulation of IGFBP-I mRNA by progesterone is important from the viewpoint of hormone replacement therapy. Recently, Rutanen et al. showed suppressed IGFBP-I expression in endometrial carcinoma cells [11 which may be a trigger of uncontrolled cell proliferation. The common factor among women with highest risk of endometrial carcinoma (obesity, hypertension, PCO) is insulin resistance. 3. Adverse effects
contraception and in hormone replacement therapy. It is composed of several different mechanisms, as presented in Table 3. The insulin-like growth factors (IGF) are mediators of steroid hormone actions in the endometrium. IGF-I and IGF-II are Table 3 Antiproliferative effect of progestins in the endometriurn • • • • •
Decrease of DNA synthesis Decrease of mitotic activity Down-regulation of estrogen receptors Activation of 17-#-hydroxysteroid-dehydrogenase Stimulation of IGEBP-1 gene expression
Table 4 Adverse effects of progestins Subjective side-effects
Metabolic side-effects
Headache Nervousness Depression Anxiety
Increase of LDL Decrease of HDL Hyperinsulinemia Deterioration of glucose tolerance
Subjective and metabolic side-effects (Table 4) are either receptor mediated or non-receptor mediated responses of progestins. Several factors determine the appearance of adverse effects (Table 5). Most women tolerate all progestins but for some 20% of women it is difficult to find any. 4. Effect of progestins on Hpoproteins
Progestins are known to affect lipoprotein and carbohydrate metabolism. When high doses of progestins are given to women in the treatment of endometriosis they not only suppress endogenous estrogen excretion but also have a direct effect on lipoprotein metabolism which is dose dependent [2]. The metabolic effect is also influenced by the properties of a progestin; 1 mg of cyproterone acetate and 0.25 mg of levonorgestrel are equivalent as for ovulation inhibition and the effect on the endometrium. When given together with 50 ttg of ethinylestradiol, cyproterone acetate is unable to oppose the ethinylestradiol-induced increase of HDL-cholesterol level but levonorgestrel reverses
E. Hirvonen/ Maturitas 23 Suppl. (1996) S13-S18
this effect. Comparative studies with different sequential estrogen/progestin treatment regimens have shown smaller differences between different progestins when equivalent doses needed for the transformation of the endometrium are used. Still the HDL-cholesterol decreasing effect is strongest with the use of 75 #g of levonorgestrel daily. In a recently published study, the impact of medroxyprogesterone acetate (MPA) on lipids and carbohydrate metabolism was studied [3]. All five treatment regimens contained 0.625 mg of conjugated estrogens (Premarin). Groups A and B were given continuous combined therapy, group A received 2.5 mg of MPA daily and group B 5 mg. Groups C and D were treated with a sequential treatment regimen and Group E received unopposed Premarin. Thus, Groups A and C received 70 mg of MPA per month sequentially or continuously and B and D received 140 mg of MPA per month, respectively. All doses caused adequate transformation of the endometrium and gave good cycle control. All regimens decreased LDL-cholesterol level. Increase of total HDL-cholesterol level was blunted in all groups receiving MPA compared with the Premarin-only group but the effect on HDL2 cholesterol and the insulin response to glucose challenge was almost similar in all groups, indicating absence of adverse effect of MPA on lipoprotein and carbohydrate metabolism. Such large studies are not available from other progestins but lately Godsland et al. showed that even the modem oral contraceptives (OCs) cause changes in serum lipoproteins, glucose tolerance, insulin and C-peptide which, according to the investigators, correlate positively with the androgenic activity of a progestin [4]. However, the correlation of these findings with cardiovascular morbidity is unclear.
5. Epidemiological studies We studied cardiovascular mortality among Finnish women between 15 and 40 years of age during a 10-year period of low-estrogen oral contraceptive use and showed that there was no increased risk of death from cardiovascular diseases among OC users, except for a tendency to increas-
S15
Table 6 Cardiovascular deaths among women under 40 years of age using low-estrogen oral contraceptives in Finland from 1975 to 1984 [51 OC users Non-users RR P 95% CL value Deaths from pulmonary embolism Women-years Deaths from CHD Women-years Deaths from intracranial hemorrhage (years 1980, 1982, 1984)
4
11
1.2 0.78
0.37-3.68
0.2 0.01
0.05-0.70
1 585 000 5 107 000
2
33
1 585 000 5 107 000 9 73 0.3
0.03
0.18-0.70
ed risk from pulmonary embolism which, however, did not reach statistical significance (RR = 1.2, P = 0.78) [5], but which has been established in several other studies. The relative risk was 0.23 for death from myocardial infarction and 0.3 from intracranial haemorrhage (Table 6). Even though exclusion of women with cardiovascular risk factors and women over 35 who smoked might have greatly influenced these results they also strongly suggest that the doses of progestins used in modem OCs are no longer atherogenic. Similar results have been published by other investigators [6]. Estrogen therapy has been proposed to have
Table 7 Proposed mechanisms of estrogen and progestin action in reducing cardiovascular risk Mechanism
Estrogen
Progestin
LDL cholesterol HDL cholesterol TG Lp(a) Oxidation of LDL Insulin resistance Platel~t aggregation Prostacyclin synthesis EDRF(NO) Arterial blood flow
1 l I 1 ! .~ l ! l I
| .~ 1 l 1 ? ! .-. ? ? ? 1
S16
E. Hirvonen/ Maturitas 23 Suppl. (1996) S13-S18
several cardioprotective mechanisms (Table 7). Some of these have been shown to be attenuated by some progestins. In a cross-sectional study an association of hormone replacement therapy with various cardiovascular risk factors in postmenopausal women was investigated [7]. There was a total of 4145 postmenopausal women assigned to one of four groups; 853 were current unopposed estrogen users, 173 used an estrogen/ progestin combination and 3119 (63%) never used therapy. Current users had higher mean levels of highdensity-lipoprotein cholesterol, its subfraction HDL-2 and apolipoprotein A1 and lower mean levels of low-density-lipoprotein, apolipoprotein B and lipoprotein(a), fibrinogen, fasting glucose and insulin. After making certain assumptions, the authors estimated that the findings, if independent, additive and causal, would translate into a reduction of 42% in the risk of coronary heart disease in estrogen users. Women using estrogen with progestin would have an even better benefit.
6. Reduction of progestogenic side-effects In reduction of progestogenic side-effects knowledge of the properties of different progestins, use of minimum effective dose, reducing the frequency of administration and the use of new alternatives of administration have to be considered. However, the duration of progestin phase per cycle cannot be shortened. Today it is generally accepted that the length of the progestin phase should be from 10 to 14 days per cycle which usually induces regular withdrawal bleedings and prevents the development of hyperplasia. 6.1. Three-month treatment regimens
In two recent studies the possibility to administer progestin less frequently was investigated [8,9]. Ettinger used 0.625 mg of conjugated estrogens for 91 days and MPA 10 mg per day during the last 14 days. We used 2 mg of E2V for 84 days and 20 mg of MPA during the last 14 days. This was followed by a 7-day drug-free period (Table 8). Continuation rates were high in both studies. Ettinger's patients changed without a washout period to the
Table 8 Three-monthcyclicestrogen/progestintherapy Ettinger et al. [8] Hirvonenet al. [9] Treatment
CE 0.625 rag 91 days + MPA 10 mg/day days 77-91 12 months
Duration of treatment Continuation 199/214 rate (93%) Incidenceof 1.5% hyperplasia
E2V 2 mg 84 days + MPA 20 mg/daydays 70-84 + 7-day drugfree interval 12 months 24 months 227/263 143/146 (86%) (98%) 0.5% --
quarterly regimen. Our patients had a washout period of at least 1 month. After 12 months the percentage of proliferative and secretory changes were almost similar in both studies. Among Ettinger's patients hyperplasia was present in I% of the initial samples and in 1.5% after 12 months. At baseline we had two cases out of 253 women with signs of hyperplasia, one simple and one adenomatous. Adenomatous features were present after 9 months of treatment and the patient was hysterectomized. In the other, hyperplastic changes were still present after 12 months of treatment but disappeared in 4 months after discontinuation of the therapy. These studies suggest that a 3-month treatment regimen is equally effective in prevention of hyperplasia as 1-month treatment regimens but it apparently is not able to reverse a hyperplastic endometrium to normal. It has been suggested that an incidence of 1-2% of hyperplasia has to be accepted. It may reflect the incidence of insulin resistance and an increase of the progestin dose is of no use. The bleeding pattern was acceptable but intermenstrual bleedings were more frequent than during the normal 1-month regimens. Analysis of these bleedings showed that they mainly occurred in women less than 3 years postmenopausal. As expected some of the women had heavier bleedings and in some they were associated with severe pains. In summary, 3-month treatment regimens are suitable for women more than 3 years postmenopausal with normal or scanty bleedings during 1-month treatment regimens.
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18
S17
6.2. Continuous combined treatment
6.3. New alternatives of progestin administration
A continuous combined treatment regimen has been developed for women who do not want to have bleedings at all. This is more common the more years since menopause have passed. Most widely used are a combination of 2 mg of micronized estradiol with 1 mg of norethisterone acetate and 0.625 mg of conjugated estrogens with 2.5-5 mg MPA daily. Estradiol valerate from 1 to 2 mg can be used as well. The first study concerning this kind of treatment is Staland's study with micronized estradiol and norethisterone acetate [10]. Amenorrhea was obtained in 56% in 4 months and in 90% in 12 months. In a large multicenter study with 1724 postmenopausal women treated with two continuous combined regimens (0.625 mg of conjugated estrogens/day combined with either 2.5 mg or 5 mg of MPA/day) amenorrhea was produced in 61.4% and 72.3%, respectively, of all evaluable cycles within 1 year [11]. Continuous combined treatment serves certain advantages such as absence of bleedings, atrophy of the endometrium, good effect in osteoporosis and better compliance among elderly women. It can be used also in hysterectomized women who have had stage I adenocarcinoma of the endometrium, a past history of pelvic endometriosis or endometrioid tumor of the ovary. Progestins decrease high triglyceride levels, particularly together with transdermal estrogen. Most disadvantages of continuous combined treatment are caused by progestin. Appearance of bleedings in a relatively high proportion of patients during the first 6 months decreases compliance and causes discontinuation of treatment. Breakthrough bleedings always require vaginal ultrasound examination or biopsy or both, which makes this kind of treatment more expensive. Androgenic progestins decrease HDL-cholesterol level and may increase the pulsatility index of arterial blood flow. Thus, they should not be prescribed to women with risk factors of coronary heart disease. The effect of continuous combined treatment on the risk of breast cancer is not known.
Progestogenic side-effects can further be diminished by reducing the doses to the minimal effective and by new routes of administration, of which transdermal is already in practice. During the use of Estra-Comb, norethisterone levels correspond to those obtained after 0.75 mg of norethisterone given perorally. Risk of hyperplasia is reported to be 2%. Intrauterine administration of progestin in combination with orally or transdermally administered estrogen has aroused interest because the systemic effects are believed to be minimized. According to Swedish and Finnish studies amenorrhea is achieved in 1 year and the continuation rate is high [12,13]. Development of new levonorgestrel releasing IUDs of smaller size and lower dose are in progress. 7. Summary Safe and individual administration of progestins can be obtained by using different progestins in minimum effective doses, by giving them 12-14 days every 1-3 months, or continuously. New alternatives of administration such as the transderreal patch and intrauterine device further decrease the side-effects. Still more experimental, clinical and epidemiological studies are needed on the effect of progestins on cardiovascular risk and on the risk of breast cancer.
References [I] Rutanen E-M, Nyman T, Lehtovirta P, ,~mm/il/i M, Pekonen F. Suppressed expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: a molecular mechanism associated endometrial cancer with its risk factors. Int J Cancer 1994; 59: 307-312. [2] M/ilk6nen M, Manninen V, Hirvonen E. Effect of danazoi and lynestrenol on serum lipoproteins in endometriosis. Clin Pharmacol Ther 1980; 28: 602-604. [3] Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E. Metabolic impact of adding medroXyprogesterone acetare to conjugated estrogen therapy in postmenopausal Women. Obstet Gynecol 1994; 84: 987-995. [4] Godsland IF, Crook D, Simpson R, Proudle T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V. The effects
S18
[5]
[6] [7]
[8]
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18 of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323: 1375-1381. Hirvonen E, Idanp/iin-Heikkil/i J. Cardiovascular death among women under 40 years of age using low estrogen oral contraceptives and intrauterine devices in Finland from 1975 to 1984. Am J Obstet Gynecol 1990; 163: 281-284. Portor JP, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987; 70: 29-32. Nabulsi AA, Folsom AR, White A, Patsch W, Heis G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069-1075. Ettinger B, Selby J, Citron JT, Vangessel A, Ettinger VM, Hendrickson MR. Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol 1994; 83: 693-700.
[9] Hirvonen E, Salmi T, Puolakka J et al. Can progestin be limited to every third month only in postmenopausal women taking estrogen? Maturitas 1995; 21: 39-44. [10] Staland B. Continuous treatment with a combination of estrogen and gestagen - - a way of avoiding endometrial stimulation. Acta Obstet Gynecol Scand 1985; (Suppl.) 130: 29-35. [l l] Archer DF, Pickar JH, Bottiglioni F. Bleeding pattern in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83: 686-692. [12] Andersson K, Mattson L-8f-, Rybo Get al. Intrauterine release of levonorgestrel - - a new way of adding progestogvn in hormone replacement therapy. Obstet Gynecol 1992; 79: 963-967. [13] Suhonen SP, Holmstrtm T, Allonen HO, Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy. Fertil Steril 1995; 63: 336-342.
ELSEVIER
Maturitas 23 Suppl. (1996) S13-S18
Progestins Erkki Hirvonen Departments of Obstetrics and Gynecology, Helsinki University Central Hospital Haartamanin-Kartin 2, 00290 HelsinkL Finland
Abstract The history of progesterone and hormone replacement therapy goes back to 1934 when Butenandt obtained crystalline progesterone and Kaufmann started to treat ovariectomized women with both estrogens and progesterone (Table 1). Today synthetic perorally active 19-nortestosterone and 17-a-hydroxyprogesterone derivatives are used in addition to contraception and hormone replacement therapy in a variety of gynecological disorders. In hormone replacement therapy progestin is added only to prevent development of hyperplasia of the endometrium and its consequences. However, because progestins may cause both subjective and metabolic adverse effects minimum effective antiproliferative doses are recommended. The duration of the progestin phase cannot be shortened to less than 10 days whereas the frequency of administration apparently can be reduced without increased risk of hyperplasia. Development of new modes of administration may further help in reduction of the doses. Keywords: Progestin; Estrogen; Hormone replacement therapy; Endometrium; Progestogenic side-effects; Cardiovas-
cular risk
1. Types of progestins There are three different types of progestins: 17alpha-hydroxy progestins, retrosteroids and 19nor-progestins (Table 2). Today natural progesterone is only one of the progestins. Perorally Table 1 Development of indications for progestins 1934 Substitution of ovariectomizedwomen (Kaufmann) 1937 Treatment of oligo- and hypomenorrhea(von Kehrer) 1938 Treatment of anovulation (Glauberg) 1953 Treatment of menorrhagia (Kaufmann) 1956 Contraception with norethynodrel (Pincus) 1960 Endometriosis (Kistner) 1970s Postmenopausal hormone replacement
administered effective transformation doses presented in Table 2 should better be called antiproliferative doses, ones that are shown to prevent development of hyperplasia. The other properties of progestins, such as androgenic and antiandrogenic activities, are mainly due to unspecific binding to steroid hormone receptors other than those of progesterone. Thus, progestins have different hormonal activities; most 19nortestosterone derivatives have some androgenic activity whereas cyproterone acetate is strongly antiandrogenic.
2. Antiproliferative effect The antiproliferative effect is important both in
0378-5122/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PII S0378-5122(96)01005-5
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18
St4
Table 5 Determinants of progestogenic side-effects
Table 2 Different types and properties of progestins Progestin
17-a-OH-progestins Medroxyprogesterone acetate Megestrole acetate Cyproterone acetate
Anti- AntiAndro- Transforestro- andro- genie mation genie genic dose (rag/day)
+
-
-
5-10
+ +
+++
-
5 !
Retrosteroids Dydrogesterone
-
-
-
10-20
Progesterone (micronized)
-
-
-
300
19-Norprogestins Norethisterone Norethisterone acetate Levonorgestrel Desogestrel Gestodene Norgestimate
+ + ++ + ++ +
-
++ ++ ++ + + -
0.3-1 0.7 0.150 O. 150 0.075 0.250
• • • • •
Type and properties of progestin Unspecific binding to other hormone receptors Dose Non-receptor mediated effects Genetic factors
potent mitogens in endometrial cancer cells. Specific binding proteins modulate the biological action of IGFs. IGFBP-1 inhibits the receptor binding and mitogenic effects of IGFs in the endometrium. Stimulation of IGFBP-I mRNA by progesterone is important from the viewpoint of hormone replacement therapy. Recently, Rutanen et al. showed suppressed IGFBP-I expression in endometrial carcinoma cells [11 which may be a trigger of uncontrolled cell proliferation. The common factor among women with highest risk of endometrial carcinoma (obesity, hypertension, PCO) is insulin resistance. 3. Adverse effects
contraception and in hormone replacement therapy. It is composed of several different mechanisms, as presented in Table 3. The insulin-like growth factors (IGF) are mediators of steroid hormone actions in the endometrium. IGF-I and IGF-II are Table 3 Antiproliferative effect of progestins in the endometriurn • • • • •
Decrease of DNA synthesis Decrease of mitotic activity Down-regulation of estrogen receptors Activation of 17-#-hydroxysteroid-dehydrogenase Stimulation of IGEBP-1 gene expression
Table 4 Adverse effects of progestins Subjective side-effects
Metabolic side-effects
Headache Nervousness Depression Anxiety
Increase of LDL Decrease of HDL Hyperinsulinemia Deterioration of glucose tolerance
Subjective and metabolic side-effects (Table 4) are either receptor mediated or non-receptor mediated responses of progestins. Several factors determine the appearance of adverse effects (Table 5). Most women tolerate all progestins but for some 20% of women it is difficult to find any. 4. Effect of progestins on Hpoproteins
Progestins are known to affect lipoprotein and carbohydrate metabolism. When high doses of progestins are given to women in the treatment of endometriosis they not only suppress endogenous estrogen excretion but also have a direct effect on lipoprotein metabolism which is dose dependent [2]. The metabolic effect is also influenced by the properties of a progestin; 1 mg of cyproterone acetate and 0.25 mg of levonorgestrel are equivalent as for ovulation inhibition and the effect on the endometrium. When given together with 50 ttg of ethinylestradiol, cyproterone acetate is unable to oppose the ethinylestradiol-induced increase of HDL-cholesterol level but levonorgestrel reverses
E. Hirvonen/ Maturitas 23 Suppl. (1996) S13-S18
this effect. Comparative studies with different sequential estrogen/progestin treatment regimens have shown smaller differences between different progestins when equivalent doses needed for the transformation of the endometrium are used. Still the HDL-cholesterol decreasing effect is strongest with the use of 75 #g of levonorgestrel daily. In a recently published study, the impact of medroxyprogesterone acetate (MPA) on lipids and carbohydrate metabolism was studied [3]. All five treatment regimens contained 0.625 mg of conjugated estrogens (Premarin). Groups A and B were given continuous combined therapy, group A received 2.5 mg of MPA daily and group B 5 mg. Groups C and D were treated with a sequential treatment regimen and Group E received unopposed Premarin. Thus, Groups A and C received 70 mg of MPA per month sequentially or continuously and B and D received 140 mg of MPA per month, respectively. All doses caused adequate transformation of the endometrium and gave good cycle control. All regimens decreased LDL-cholesterol level. Increase of total HDL-cholesterol level was blunted in all groups receiving MPA compared with the Premarin-only group but the effect on HDL2 cholesterol and the insulin response to glucose challenge was almost similar in all groups, indicating absence of adverse effect of MPA on lipoprotein and carbohydrate metabolism. Such large studies are not available from other progestins but lately Godsland et al. showed that even the modem oral contraceptives (OCs) cause changes in serum lipoproteins, glucose tolerance, insulin and C-peptide which, according to the investigators, correlate positively with the androgenic activity of a progestin [4]. However, the correlation of these findings with cardiovascular morbidity is unclear.
5. Epidemiological studies We studied cardiovascular mortality among Finnish women between 15 and 40 years of age during a 10-year period of low-estrogen oral contraceptive use and showed that there was no increased risk of death from cardiovascular diseases among OC users, except for a tendency to increas-
S15
Table 6 Cardiovascular deaths among women under 40 years of age using low-estrogen oral contraceptives in Finland from 1975 to 1984 [51 OC users Non-users RR P 95% CL value Deaths from pulmonary embolism Women-years Deaths from CHD Women-years Deaths from intracranial hemorrhage (years 1980, 1982, 1984)
4
11
1.2 0.78
0.37-3.68
0.2 0.01
0.05-0.70
1 585 000 5 107 000
2
33
1 585 000 5 107 000 9 73 0.3
0.03
0.18-0.70
ed risk from pulmonary embolism which, however, did not reach statistical significance (RR = 1.2, P = 0.78) [5], but which has been established in several other studies. The relative risk was 0.23 for death from myocardial infarction and 0.3 from intracranial haemorrhage (Table 6). Even though exclusion of women with cardiovascular risk factors and women over 35 who smoked might have greatly influenced these results they also strongly suggest that the doses of progestins used in modem OCs are no longer atherogenic. Similar results have been published by other investigators [6]. Estrogen therapy has been proposed to have
Table 7 Proposed mechanisms of estrogen and progestin action in reducing cardiovascular risk Mechanism
Estrogen
Progestin
LDL cholesterol HDL cholesterol TG Lp(a) Oxidation of LDL Insulin resistance Platel~t aggregation Prostacyclin synthesis EDRF(NO) Arterial blood flow
1 l I 1 ! .~ l ! l I
| .~ 1 l 1 ? ! .-. ? ? ? 1
S16
E. Hirvonen/ Maturitas 23 Suppl. (1996) S13-S18
several cardioprotective mechanisms (Table 7). Some of these have been shown to be attenuated by some progestins. In a cross-sectional study an association of hormone replacement therapy with various cardiovascular risk factors in postmenopausal women was investigated [7]. There was a total of 4145 postmenopausal women assigned to one of four groups; 853 were current unopposed estrogen users, 173 used an estrogen/ progestin combination and 3119 (63%) never used therapy. Current users had higher mean levels of highdensity-lipoprotein cholesterol, its subfraction HDL-2 and apolipoprotein A1 and lower mean levels of low-density-lipoprotein, apolipoprotein B and lipoprotein(a), fibrinogen, fasting glucose and insulin. After making certain assumptions, the authors estimated that the findings, if independent, additive and causal, would translate into a reduction of 42% in the risk of coronary heart disease in estrogen users. Women using estrogen with progestin would have an even better benefit.
6. Reduction of progestogenic side-effects In reduction of progestogenic side-effects knowledge of the properties of different progestins, use of minimum effective dose, reducing the frequency of administration and the use of new alternatives of administration have to be considered. However, the duration of progestin phase per cycle cannot be shortened. Today it is generally accepted that the length of the progestin phase should be from 10 to 14 days per cycle which usually induces regular withdrawal bleedings and prevents the development of hyperplasia. 6.1. Three-month treatment regimens
In two recent studies the possibility to administer progestin less frequently was investigated [8,9]. Ettinger used 0.625 mg of conjugated estrogens for 91 days and MPA 10 mg per day during the last 14 days. We used 2 mg of E2V for 84 days and 20 mg of MPA during the last 14 days. This was followed by a 7-day drug-free period (Table 8). Continuation rates were high in both studies. Ettinger's patients changed without a washout period to the
Table 8 Three-monthcyclicestrogen/progestintherapy Ettinger et al. [8] Hirvonenet al. [9] Treatment
CE 0.625 rag 91 days + MPA 10 mg/day days 77-91 12 months
Duration of treatment Continuation 199/214 rate (93%) Incidenceof 1.5% hyperplasia
E2V 2 mg 84 days + MPA 20 mg/daydays 70-84 + 7-day drugfree interval 12 months 24 months 227/263 143/146 (86%) (98%) 0.5% --
quarterly regimen. Our patients had a washout period of at least 1 month. After 12 months the percentage of proliferative and secretory changes were almost similar in both studies. Among Ettinger's patients hyperplasia was present in I% of the initial samples and in 1.5% after 12 months. At baseline we had two cases out of 253 women with signs of hyperplasia, one simple and one adenomatous. Adenomatous features were present after 9 months of treatment and the patient was hysterectomized. In the other, hyperplastic changes were still present after 12 months of treatment but disappeared in 4 months after discontinuation of the therapy. These studies suggest that a 3-month treatment regimen is equally effective in prevention of hyperplasia as 1-month treatment regimens but it apparently is not able to reverse a hyperplastic endometrium to normal. It has been suggested that an incidence of 1-2% of hyperplasia has to be accepted. It may reflect the incidence of insulin resistance and an increase of the progestin dose is of no use. The bleeding pattern was acceptable but intermenstrual bleedings were more frequent than during the normal 1-month regimens. Analysis of these bleedings showed that they mainly occurred in women less than 3 years postmenopausal. As expected some of the women had heavier bleedings and in some they were associated with severe pains. In summary, 3-month treatment regimens are suitable for women more than 3 years postmenopausal with normal or scanty bleedings during 1-month treatment regimens.
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18
S17
6.2. Continuous combined treatment
6.3. New alternatives of progestin administration
A continuous combined treatment regimen has been developed for women who do not want to have bleedings at all. This is more common the more years since menopause have passed. Most widely used are a combination of 2 mg of micronized estradiol with 1 mg of norethisterone acetate and 0.625 mg of conjugated estrogens with 2.5-5 mg MPA daily. Estradiol valerate from 1 to 2 mg can be used as well. The first study concerning this kind of treatment is Staland's study with micronized estradiol and norethisterone acetate [10]. Amenorrhea was obtained in 56% in 4 months and in 90% in 12 months. In a large multicenter study with 1724 postmenopausal women treated with two continuous combined regimens (0.625 mg of conjugated estrogens/day combined with either 2.5 mg or 5 mg of MPA/day) amenorrhea was produced in 61.4% and 72.3%, respectively, of all evaluable cycles within 1 year [11]. Continuous combined treatment serves certain advantages such as absence of bleedings, atrophy of the endometrium, good effect in osteoporosis and better compliance among elderly women. It can be used also in hysterectomized women who have had stage I adenocarcinoma of the endometrium, a past history of pelvic endometriosis or endometrioid tumor of the ovary. Progestins decrease high triglyceride levels, particularly together with transdermal estrogen. Most disadvantages of continuous combined treatment are caused by progestin. Appearance of bleedings in a relatively high proportion of patients during the first 6 months decreases compliance and causes discontinuation of treatment. Breakthrough bleedings always require vaginal ultrasound examination or biopsy or both, which makes this kind of treatment more expensive. Androgenic progestins decrease HDL-cholesterol level and may increase the pulsatility index of arterial blood flow. Thus, they should not be prescribed to women with risk factors of coronary heart disease. The effect of continuous combined treatment on the risk of breast cancer is not known.
Progestogenic side-effects can further be diminished by reducing the doses to the minimal effective and by new routes of administration, of which transdermal is already in practice. During the use of Estra-Comb, norethisterone levels correspond to those obtained after 0.75 mg of norethisterone given perorally. Risk of hyperplasia is reported to be 2%. Intrauterine administration of progestin in combination with orally or transdermally administered estrogen has aroused interest because the systemic effects are believed to be minimized. According to Swedish and Finnish studies amenorrhea is achieved in 1 year and the continuation rate is high [12,13]. Development of new levonorgestrel releasing IUDs of smaller size and lower dose are in progress. 7. Summary Safe and individual administration of progestins can be obtained by using different progestins in minimum effective doses, by giving them 12-14 days every 1-3 months, or continuously. New alternatives of administration such as the transderreal patch and intrauterine device further decrease the side-effects. Still more experimental, clinical and epidemiological studies are needed on the effect of progestins on cardiovascular risk and on the risk of breast cancer.
References [I] Rutanen E-M, Nyman T, Lehtovirta P, ,~mm/il/i M, Pekonen F. Suppressed expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: a molecular mechanism associated endometrial cancer with its risk factors. Int J Cancer 1994; 59: 307-312. [2] M/ilk6nen M, Manninen V, Hirvonen E. Effect of danazoi and lynestrenol on serum lipoproteins in endometriosis. Clin Pharmacol Ther 1980; 28: 602-604. [3] Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E. Metabolic impact of adding medroXyprogesterone acetare to conjugated estrogen therapy in postmenopausal Women. Obstet Gynecol 1994; 84: 987-995. [4] Godsland IF, Crook D, Simpson R, Proudle T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V. The effects
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[5]
[6] [7]
[8]
E. Hirvonen / Maturitas 23 Suppl. (1996) S13-S18 of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323: 1375-1381. Hirvonen E, Idanp/iin-Heikkil/i J. Cardiovascular death among women under 40 years of age using low estrogen oral contraceptives and intrauterine devices in Finland from 1975 to 1984. Am J Obstet Gynecol 1990; 163: 281-284. Portor JP, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987; 70: 29-32. Nabulsi AA, Folsom AR, White A, Patsch W, Heis G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069-1075. Ettinger B, Selby J, Citron JT, Vangessel A, Ettinger VM, Hendrickson MR. Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol 1994; 83: 693-700.
[9] Hirvonen E, Salmi T, Puolakka J et al. Can progestin be limited to every third month only in postmenopausal women taking estrogen? Maturitas 1995; 21: 39-44. [10] Staland B. Continuous treatment with a combination of estrogen and gestagen - - a way of avoiding endometrial stimulation. Acta Obstet Gynecol Scand 1985; (Suppl.) 130: 29-35. [l l] Archer DF, Pickar JH, Bottiglioni F. Bleeding pattern in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83: 686-692. [12] Andersson K, Mattson L-8f-, Rybo Get al. Intrauterine release of levonorgestrel - - a new way of adding progestogvn in hormone replacement therapy. Obstet Gynecol 1992; 79: 963-967. [13] Suhonen SP, Holmstrtm T, Allonen HO, Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy. Fertil Steril 1995; 63: 336-342.