CONTRACEPTION EFFECTS OF SEVEN LOW-DOSE COMBINED ORAL CONTRACEPTIVES ON SEX HORMONE BINDING GLOBULIN, CORTICOSTEROID BINDING GLOBULIN, TOTAL AND FREE TESTOSTERONE
N. van der Vange*, M.A. Blankenstein **, H.J. Kloosterboer*** A.A. Haspels* and J.H.H. Thijssen**
*
Department of Gynaecology, University Hospital of Utrecht, The Netherlands
**
Department of Clinical Endicrinology, University Hospital of Utrecht, The Netherlands
*** Organon Scientific Development Group, Oss, The Netherlands ABSTRACT The effect of seven low-dose oral contraceptive preparations on sex hormone . binding globulin (SHBG), cortical binding globulin (CBGl, total and absolute free testosterone were investigated in groups of 10 healthy volunteers. All preparations contained about the same amount of ethinylestradiol but they differed in type and/or dose of progestagen. The progestagens studied were: levonorgestrel (LNG; in mono- and triphasic preparations), norethisterone (NET; in monophasic preparation), desogestrel (DSG; in mono- and biphasic preparations) and gestodene (GSD; in triphasic preparation), all 19-nortestosterone derivatives, and the anti-androgen cyproterone acetate (CPA) in a monophasic preparation. Differences observed in SHBG level, which reflect the estrogen-androgen balance, can be attributed to the intrinsic androgenic (or anti-androgenic) properties of the progestagens, and were in agreement with the results of published receptor binding studies, performed in vitro. Based on our results the folowing ranking (high to low) can bexdewith respect to the androgenicity of the preparations: monophasic LNG ) monophasic NET = triphasic LNG b triphasic GSD = biphasic DSG = monophasic DSG > monophasic CPA. An anti-estrogenic effect of the 19-nortestosterone derived progestagens can be excluded by the effect on CBG, a marker for estrogenic activity. All preparations containing a 19-nortestosterone derived progestagen, independent of their type and dose, induce a similiar rise in CBG, whereas the preparation with cyproterone acetate induced an even higher CBG level. Irrespective of the effect on total testosterone, which varies between the preparations, the absolute free testosterone level decreased to a comparable degree for all preparations. We conclude that these preparations may be equally beneficial in women with androgenic phenomena like acne vulgaris. Reprint request to A.A. Haspels. Submitted for publication July 25, 1989 Accepted for publication December 26, 1989 APRIL 1990 VOL. 41 NO. 4
345
CONTRACEPTION INTRODUCTION Sex hormone binding globulin (SHBG) is the major carrier protein for testosterone (T), and to a lesser extent for estradiol (1). SHBG binding capacity determines the amount of absolute free T, which is considered as the biologically active fraction in blood. SHBG is synthesised in the liver and its rate of synthesis is influenced by hormones; estrogens and especially the synthetic ones, cause an increase in SHBG levels, whereas androgens reduce plasma SHBG levels (1, 2). Progesterone and the synthetic pregnane derivatives do not have an effect on SHBG levels, but synthetic progestagens derived from 19-nortestosterone (e.g. levonorgestrel and norethisterone), decrease plasma SHBG levels. The effect of these two synthetic progestagens was attributed to their intrinsic androgenicity (3). Therefore, the final effect of a combined oral contraceptive (OC) on SHBG level is determined by the dose and type of estrogen and progestagen, and is an expression of the estrogenic-androgenic balance (3-7). Corticosteriod binding globulin (CBG), the plasma binding protein for cortisol, is also synthesised in the liver but is induced only by estrogens (8). The magnitude of CBG increase may therefore be used as a measure for the degree of estrogenicity of OCs (9). Estimation of both SHBG and CBG in users of OCs may thus give an impression of the estrogenic and androgenic potency of an OC. Such estimations can be used in comparative studies to explain differences in effect of various OCs on changes in metabolic pathways, because SHBG levels are infuenced by OCs and consequently induce changes in the absolute amount of free T. This may be important in the view of androgen dependent phenomena such as acne vulgaris and hirsutism (10-13). In the present study the effects of 7 low-dose OC preparations on SHBG, CBG, total and absolute free T were estimated. All preparations contain approximately equal amounts of ethinylestradiol (EE) but differ in type and/or dose of the progestagen. MATERIALS AND METHODS Subjects and study design Seventy healthy female volunteers were selected according to the following criteria: age between 16 and 40 years, weight within 90-120 % of ideal body weight (62.5 f 7.1 kg), good general health, no use of other medications, regular menstrual cycle (26-35 days), and no oral contraceptive use for at least three months preceding the study. The women gave their written informed consent for participating in the study, which consisted of one pretreatment and six treatment cycles. The women were randomly allocated to one of 7 preparations (10 volunteers per group), of which the composition and intake regimen are presented in Table I. During the luteal phase of the control cycle (day 19-24) and on day 15 or 19 of the first, third and sixth treatment cycles,blood samples were taken. Consent of the local Ethical Committee was obtained for this study.
346
APRlL1990VOL.41
NO.4
CONTRACEPTION Table I: Composition and intake regimen to the OC preparations
Days
Amount of ethinylestradiol (ug)
Progestagen Amount Type (119)
Group
Preparation
1
Monophasic LNG
21
30
150
levonorgestrel
2
Monophasic NET
21
35
1000
norethisterone
3
Monophasic DSG
21
30
150
desogestrel
4
Triphasic LNG
: 10
:oo 30
:: 125
levonorgestrel levonorgestrel levonorgestrel
5
Monophasic CPA
21
35
6
Triphasic GSD
5" 10
4": 30
:o" 100
gestodene gestodene gestodene
7
Biphasic DSG
1;
40 30
25 125
desogestrel desogestrel
2000
cyproterone acetate
Methods Total testosterone was estimated by radioimmunoassay, following ether extraction and using an antiserum developed by Pratt et al. (14). SHBG, CBG and % free testosterone were assayed by procedures dZ?cFTbed by Bergink et al. (151. The absolute amount of free testosterone was calculated using the sues for total testosterone and % free testosterone. Statistical analysis Differences in pretreatment values were analysed with an unpaired t test. Treatment effects were evaluated with the paired t test after differences in effect between log-transformation of values. The preparations on the variables were analysed by an analysis of covariance. Log-transformation was performed in order to meet better requirement for normal distribution. In the figures the geometric means, adjusted for difference in pretreatment values, are presented at the times of blood sampling.
APRlL199OVOL.41NO.4
347
CONTRACEPTION RESULTS Pretreatment values in the 7 groups, are shown in Table II. No statistically significant differences in pretreatment values were observed, except significant differences in CBG between groups 2 and 3 were found, and for free T between groups 1 and 7. These differences can purely be attributed to chance.
Table II:
Pretreatment values of SHBG, CBG and total and absolute free testosterone (T) in the seven groups; results are given as means f s.d.
Group
1
SHBG
CBG
(nmol/l)
(nmol/l)
41.0 * 16.6
437 f 58
Total T
Abs. free T
(nmol/l)
(pmol/l)
1.43 * 0.48
48.9 f 19.2
2
50.9 f 22.8
476 i:53
1.51 f 0.41
54.6 f 15.4
3
42.9 f 16.5
395 f 96
1.43 f 0.35
53.4 f 13.8
4
48.0 f 19.4
453 f 51
1.45 f 0.36
56.3 * 19.1
5
49.4 f 17.4
445 j:78
1.69 f 0.42
62.8 f 19.0
6
53.6 It29.8
446 f 62
1.62 f 0.68
62.7 f 33.2
7
44.3 f 10.0
458 f 89
1.76 f 0.55
70.2 f 26.4
Figure 1 shows the effects of the seven low-dose OCs on SHBG (A) and CBG (9) levels. For all preparations,an increase in both SHBG and CBG levels during treatment is observed (P monophasic CPA. Receptor binding studies have shown that levonorgestrel and gestodene have a higher affinity for the androgen receptor than norethisterone and 3-ketodesogestrel, the active metabolite of desogestrel (15-171. Cyproterone acetate acts as an anti-androgen (18-201. (SHBG The discrepancies between the ranking found with in vivo quantification) and -in vitro (receptor studies1 results canbeamuted to the dose of the progestagens in the preparations. For example, the monophasic NET preparation becomes more androgenic than monophasic DSG due to a higher dose of norethisterone than desogestrel. As factors such as metabolism and pharmocokinetics play a role only in vivo, it is quite remarkable that -in vivo and in -- vitro results are in such a good agreement. The difference between preparations in SHBG levels could also be due to an anti-estrogenic effect of the progestagens (71. That anti-estrogenicity is not involved can be concluded from the finding that the effects on CBG induction is the same for all preparations containing progestagens derived from 1%nortestosterone (Figure 1B). The higher CBG values, found with monophasic CPA, can not be explained by other hormonal activities of cyproterone acetate. Barbosa -et al. found that other steroids with modifications in the A-ring induce an increase in CBG (21). Since all combined OC preparations in the present study induced an increase in SHBG levels, the distribution of free and bound fraction is influenced, as is shown in Figure 2 (A and Bl. The various preparations cause either an increase or a decrease in total T levels. Testosterone levels are determined by the rate of its synthesis and clearance. SHBG plays an important role in the latter mechanism.
350
APRIL199DVOL.41
NO.4
CONTRACEPTION Irrespective of the effect on total testosterone, the effect on the biologically active fraction (absolute free testosterone1 is far more important. Figure 2B shows that all preparations cause a decrease in absolute free testosterone. Though the effect of monophasic CPA on the free T fraction is not very marked compared to the other preparations, Aydinlik showed recently that this preparation has proven to be beneficial in the treatment of hirsutism and acne vulgaris, probably by a blockade of the androgen receptor (11). Dewis -et al. showed that monophasic DSG might be a suitable preparation for the treatment of hirsutism in women. In the present study, this preparation has an intermediate position with respect to absolute free T levels, compared to the other OC preparations (13). Hammond -et al. found that absolute free T values were lower after three months'treatment with monophasic DSG than with the monophasic LNG preparation (7). Our observations confirm this finding, however after 6 months treatment the free T levels with monophasic DSG are significantly higher than with monophasic LNG, showing the importance of prolonged observations. The present study indicates that preparations used or recommended for the treatment of acne or hirsutism can not be distinguished from the other OC preparations (including those with the most androgenic progestagens) as far as their effect on absolute free T levels is concerned. The latter preparations were contraindicated in women with clinical manifestation of androgenic hyperactivity (3,7). However, preparations containing progestagens with anti-androgenic properties like monophasic CPA may give an additional advantage by their action on the androgen receptor. We conclude from our study that the difference in effects on SHBG between preparations can well be explained by the dose and intrinsic androgenicity of the progestagens used in the OCs, and that all preparations induced a decrease in absolute free testosterone levels and may therefore be equally beneficial in women with androgen related syndromes such as acne. ACKNOWLEDGEMENT This study was supported by Cilag, Organon, Schering and Wyeth (The Netherlands). The contribution of Miss M. Zwinkels to the organisation of this study is greatly appreciated. The authors are indebted to Dr. F.J. Verbon for performing the statistical analysis. The authors thank Mrs. J. de Vreeden-Elbertse and Mrs. W. Veeman for skillful technical assistance, Dr. E.C. Firth for his editorial comments and Miss. H.G.F. Roodvoets for preparation of the manuscript. REFERENCES 1.
2. 3.
Lobl, T.J. Androgen transport proteins: physical properties, hormonal regulation, and possible mechanism of T, CBG and ABP action. Arch Androl 7: 133-151 (1981) Anderson, D.C. Sex hormone binding globulin. Clin Endocrinol 3: 69-96 Makhzangy, (1g741 M.N., Wynn, V., Lawrence, D.M. Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids. Clin Endocrinol 10: 39-45 (1979)
APRIL 1990 VOL. 41 NO. 4
351
CONTRACEPTION 4. 5. 6. 7.
8. 9. 10.
11. 12.
13. 14. 15.
16. 17. 18. 19. 20. 21.
van Kammen, E. Thijssen, J.H., Rademaker, B., Schwartz, F. The influence of hormonal contraceptives on sex hormone binding globulin (SHBG) capacity. Contraception 11: 53-59 (19741 Bowles, S.M., Mills, R.J. Sex hormone binding globulin: effect of synthetic steroids on the assay and effect of oral contraceptives. Ann Clin Biochem 18: 226-231 (1981) Bergink, E.W., Holma, P., Pydrlla. Effects of oral contraceptive combinations containing levonorgestrel or desogestrel on serum proteins and androgen binding. Stand J Clin Lab Invest 41: 663-668 (1981) Hammond, G.L., Langley, M.S., Robinson, P.A., Numni, P.S., Lund, L. Serum steroid binding protein concentrations, distribution of progestagens and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil Steril 42: 44-51 (1984) Brien, T.G. Human corticosteroid binding globulin. Clin Endocrinol 14: 193-212 (1981) Schwartz, U., Hammerstein, J. The oestrogenic potency of various contraceptive steroids as determined by their effect on transcortin binding capacity. Act Endocrinol 76: 159-171 (1974) Lawrence, D.M., Katz, M., Robinson, T.W.E., Newman, M.C., McGarrigle, H.H.G., Shaw, M., Lachelin, G.C. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clin Endocrinol 15: 87-91 (1981) Aydinlik, S., Lachnit-Fixson, U., Lehnert, J. Oestrogenreduzierter Ovulationshemmer zur Acnetherapie. Fortschritte der Medizin 104: 547-551 (1986). Palatsi, R., Hirvensalo, E., Liukko, P., Malmiharju, T., Mattila, L., Riihiluoma, P., Ylostalo, P. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Act Dermatol Venerol 64: 517-523 (1984) Dewis, P., Petsos, P., Newman, M., Anderson, D.C. The treatment of hirsutism with a combination of desogestrel and ethinylestradiol. Clin Endocrinol 22: 29-36 (1985) Pratt, J.J., Weigman, T., Lappl)hn,R.E. Estimation of plasma testosterone without extraction and chromatography. Clin Chim Act 59: 337-346 (1975) IBergink, E.W., Hamburger, A.D., de Jager, E., van der Vies, J. Binding of a contraceptive progestagen ORG 2969 and its metabolites to receptor proteins and human sex hormone globulin. J Ster Biochem 14: 175-183 (1981) Bergink, E-W., van Meel, F., Turpijn, E.W., van der Vies, J. Binding of progestagens to receptor proteins in MCF-7 cells. J Ster Biochem 1563-1570 (1983) IKloosterboer, H.J., Vonk-Noordegraaf, C.A., Turpijn, E.W. Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives. Contraception 38: 325-332 (19881 Hammerstein, J., Meckies, J., Leo-Rossberg, I., Mortz, L., Zielske, F. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism, and virilism. J Ster Biochem 6: 827-836 (1975) Ekoe, J.M., Burckhardt, P., Ruedi, B. Treatment of hirsutism, acne and alopecia with cyproterone acetate. Dermatologica 160: 398-404 (1980) Frey, H., Aakvaag, A. The treatment of essential hirsutism in women with cyproterone acetate and ethinyl estradiol. Act Obstet Stand 60: 295-300 (1981) Barbosa, J. Seal, U.S. Doe, R.P. Effects of anabolic steroids on hormone binding proteins, serum cortisol and serum non-protein bound cortisol. J Clin Endocrinol 32: 232-240 (1970)
352
APRIL 1990 VOL. 41 NO. 4
N. van der Vange*, M.A. Blankenstein **, H.J. Kloosterboer*** A.A. Haspels* and J.H.H. Thijssen**
*
Department of Gynaecology, University Hospital of Utrecht, The Netherlands
**
Department of Clinical Endicrinology, University Hospital of Utrecht, The Netherlands
*** Organon Scientific Development Group, Oss, The Netherlands ABSTRACT The effect of seven low-dose oral contraceptive preparations on sex hormone . binding globulin (SHBG), cortical binding globulin (CBGl, total and absolute free testosterone were investigated in groups of 10 healthy volunteers. All preparations contained about the same amount of ethinylestradiol but they differed in type and/or dose of progestagen. The progestagens studied were: levonorgestrel (LNG; in mono- and triphasic preparations), norethisterone (NET; in monophasic preparation), desogestrel (DSG; in mono- and biphasic preparations) and gestodene (GSD; in triphasic preparation), all 19-nortestosterone derivatives, and the anti-androgen cyproterone acetate (CPA) in a monophasic preparation. Differences observed in SHBG level, which reflect the estrogen-androgen balance, can be attributed to the intrinsic androgenic (or anti-androgenic) properties of the progestagens, and were in agreement with the results of published receptor binding studies, performed in vitro. Based on our results the folowing ranking (high to low) can bexdewith respect to the androgenicity of the preparations: monophasic LNG ) monophasic NET = triphasic LNG b triphasic GSD = biphasic DSG = monophasic DSG > monophasic CPA. An anti-estrogenic effect of the 19-nortestosterone derived progestagens can be excluded by the effect on CBG, a marker for estrogenic activity. All preparations containing a 19-nortestosterone derived progestagen, independent of their type and dose, induce a similiar rise in CBG, whereas the preparation with cyproterone acetate induced an even higher CBG level. Irrespective of the effect on total testosterone, which varies between the preparations, the absolute free testosterone level decreased to a comparable degree for all preparations. We conclude that these preparations may be equally beneficial in women with androgenic phenomena like acne vulgaris. Reprint request to A.A. Haspels. Submitted for publication July 25, 1989 Accepted for publication December 26, 1989 APRIL 1990 VOL. 41 NO. 4
345
CONTRACEPTION INTRODUCTION Sex hormone binding globulin (SHBG) is the major carrier protein for testosterone (T), and to a lesser extent for estradiol (1). SHBG binding capacity determines the amount of absolute free T, which is considered as the biologically active fraction in blood. SHBG is synthesised in the liver and its rate of synthesis is influenced by hormones; estrogens and especially the synthetic ones, cause an increase in SHBG levels, whereas androgens reduce plasma SHBG levels (1, 2). Progesterone and the synthetic pregnane derivatives do not have an effect on SHBG levels, but synthetic progestagens derived from 19-nortestosterone (e.g. levonorgestrel and norethisterone), decrease plasma SHBG levels. The effect of these two synthetic progestagens was attributed to their intrinsic androgenicity (3). Therefore, the final effect of a combined oral contraceptive (OC) on SHBG level is determined by the dose and type of estrogen and progestagen, and is an expression of the estrogenic-androgenic balance (3-7). Corticosteriod binding globulin (CBG), the plasma binding protein for cortisol, is also synthesised in the liver but is induced only by estrogens (8). The magnitude of CBG increase may therefore be used as a measure for the degree of estrogenicity of OCs (9). Estimation of both SHBG and CBG in users of OCs may thus give an impression of the estrogenic and androgenic potency of an OC. Such estimations can be used in comparative studies to explain differences in effect of various OCs on changes in metabolic pathways, because SHBG levels are infuenced by OCs and consequently induce changes in the absolute amount of free T. This may be important in the view of androgen dependent phenomena such as acne vulgaris and hirsutism (10-13). In the present study the effects of 7 low-dose OC preparations on SHBG, CBG, total and absolute free T were estimated. All preparations contain approximately equal amounts of ethinylestradiol (EE) but differ in type and/or dose of the progestagen. MATERIALS AND METHODS Subjects and study design Seventy healthy female volunteers were selected according to the following criteria: age between 16 and 40 years, weight within 90-120 % of ideal body weight (62.5 f 7.1 kg), good general health, no use of other medications, regular menstrual cycle (26-35 days), and no oral contraceptive use for at least three months preceding the study. The women gave their written informed consent for participating in the study, which consisted of one pretreatment and six treatment cycles. The women were randomly allocated to one of 7 preparations (10 volunteers per group), of which the composition and intake regimen are presented in Table I. During the luteal phase of the control cycle (day 19-24) and on day 15 or 19 of the first, third and sixth treatment cycles,blood samples were taken. Consent of the local Ethical Committee was obtained for this study.
346
APRlL1990VOL.41
NO.4
CONTRACEPTION Table I: Composition and intake regimen to the OC preparations
Days
Amount of ethinylestradiol (ug)
Progestagen Amount Type (119)
Group
Preparation
1
Monophasic LNG
21
30
150
levonorgestrel
2
Monophasic NET
21
35
1000
norethisterone
3
Monophasic DSG
21
30
150
desogestrel
4
Triphasic LNG
: 10
:oo 30
:: 125
levonorgestrel levonorgestrel levonorgestrel
5
Monophasic CPA
21
35
6
Triphasic GSD
5" 10
4": 30
:o" 100
gestodene gestodene gestodene
7
Biphasic DSG
1;
40 30
25 125
desogestrel desogestrel
2000
cyproterone acetate
Methods Total testosterone was estimated by radioimmunoassay, following ether extraction and using an antiserum developed by Pratt et al. (14). SHBG, CBG and % free testosterone were assayed by procedures dZ?cFTbed by Bergink et al. (151. The absolute amount of free testosterone was calculated using the sues for total testosterone and % free testosterone. Statistical analysis Differences in pretreatment values were analysed with an unpaired t test. Treatment effects were evaluated with the paired t test after differences in effect between log-transformation of values. The preparations on the variables were analysed by an analysis of covariance. Log-transformation was performed in order to meet better requirement for normal distribution. In the figures the geometric means, adjusted for difference in pretreatment values, are presented at the times of blood sampling.
APRlL199OVOL.41NO.4
347
CONTRACEPTION RESULTS Pretreatment values in the 7 groups, are shown in Table II. No statistically significant differences in pretreatment values were observed, except significant differences in CBG between groups 2 and 3 were found, and for free T between groups 1 and 7. These differences can purely be attributed to chance.
Table II:
Pretreatment values of SHBG, CBG and total and absolute free testosterone (T) in the seven groups; results are given as means f s.d.
Group
1
SHBG
CBG
(nmol/l)
(nmol/l)
41.0 * 16.6
437 f 58
Total T
Abs. free T
(nmol/l)
(pmol/l)
1.43 * 0.48
48.9 f 19.2
2
50.9 f 22.8
476 i:53
1.51 f 0.41
54.6 f 15.4
3
42.9 f 16.5
395 f 96
1.43 f 0.35
53.4 f 13.8
4
48.0 f 19.4
453 f 51
1.45 f 0.36
56.3 * 19.1
5
49.4 f 17.4
445 j:78
1.69 f 0.42
62.8 f 19.0
6
53.6 It29.8
446 f 62
1.62 f 0.68
62.7 f 33.2
7
44.3 f 10.0
458 f 89
1.76 f 0.55
70.2 f 26.4
Figure 1 shows the effects of the seven low-dose OCs on SHBG (A) and CBG (9) levels. For all preparations,an increase in both SHBG and CBG levels during treatment is observed (P monophasic CPA. Receptor binding studies have shown that levonorgestrel and gestodene have a higher affinity for the androgen receptor than norethisterone and 3-ketodesogestrel, the active metabolite of desogestrel (15-171. Cyproterone acetate acts as an anti-androgen (18-201. (SHBG The discrepancies between the ranking found with in vivo quantification) and -in vitro (receptor studies1 results canbeamuted to the dose of the progestagens in the preparations. For example, the monophasic NET preparation becomes more androgenic than monophasic DSG due to a higher dose of norethisterone than desogestrel. As factors such as metabolism and pharmocokinetics play a role only in vivo, it is quite remarkable that -in vivo and in -- vitro results are in such a good agreement. The difference between preparations in SHBG levels could also be due to an anti-estrogenic effect of the progestagens (71. That anti-estrogenicity is not involved can be concluded from the finding that the effects on CBG induction is the same for all preparations containing progestagens derived from 1%nortestosterone (Figure 1B). The higher CBG values, found with monophasic CPA, can not be explained by other hormonal activities of cyproterone acetate. Barbosa -et al. found that other steroids with modifications in the A-ring induce an increase in CBG (21). Since all combined OC preparations in the present study induced an increase in SHBG levels, the distribution of free and bound fraction is influenced, as is shown in Figure 2 (A and Bl. The various preparations cause either an increase or a decrease in total T levels. Testosterone levels are determined by the rate of its synthesis and clearance. SHBG plays an important role in the latter mechanism.
350
APRIL199DVOL.41
NO.4
CONTRACEPTION Irrespective of the effect on total testosterone, the effect on the biologically active fraction (absolute free testosterone1 is far more important. Figure 2B shows that all preparations cause a decrease in absolute free testosterone. Though the effect of monophasic CPA on the free T fraction is not very marked compared to the other preparations, Aydinlik showed recently that this preparation has proven to be beneficial in the treatment of hirsutism and acne vulgaris, probably by a blockade of the androgen receptor (11). Dewis -et al. showed that monophasic DSG might be a suitable preparation for the treatment of hirsutism in women. In the present study, this preparation has an intermediate position with respect to absolute free T levels, compared to the other OC preparations (13). Hammond -et al. found that absolute free T values were lower after three months'treatment with monophasic DSG than with the monophasic LNG preparation (7). Our observations confirm this finding, however after 6 months treatment the free T levels with monophasic DSG are significantly higher than with monophasic LNG, showing the importance of prolonged observations. The present study indicates that preparations used or recommended for the treatment of acne or hirsutism can not be distinguished from the other OC preparations (including those with the most androgenic progestagens) as far as their effect on absolute free T levels is concerned. The latter preparations were contraindicated in women with clinical manifestation of androgenic hyperactivity (3,7). However, preparations containing progestagens with anti-androgenic properties like monophasic CPA may give an additional advantage by their action on the androgen receptor. We conclude from our study that the difference in effects on SHBG between preparations can well be explained by the dose and intrinsic androgenicity of the progestagens used in the OCs, and that all preparations induced a decrease in absolute free testosterone levels and may therefore be equally beneficial in women with androgen related syndromes such as acne. ACKNOWLEDGEMENT This study was supported by Cilag, Organon, Schering and Wyeth (The Netherlands). The contribution of Miss M. Zwinkels to the organisation of this study is greatly appreciated. The authors are indebted to Dr. F.J. Verbon for performing the statistical analysis. The authors thank Mrs. J. de Vreeden-Elbertse and Mrs. W. Veeman for skillful technical assistance, Dr. E.C. Firth for his editorial comments and Miss. H.G.F. Roodvoets for preparation of the manuscript. REFERENCES 1.
2. 3.
Lobl, T.J. Androgen transport proteins: physical properties, hormonal regulation, and possible mechanism of T, CBG and ABP action. Arch Androl 7: 133-151 (1981) Anderson, D.C. Sex hormone binding globulin. Clin Endocrinol 3: 69-96 Makhzangy, (1g741 M.N., Wynn, V., Lawrence, D.M. Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids. Clin Endocrinol 10: 39-45 (1979)
APRIL 1990 VOL. 41 NO. 4
351
CONTRACEPTION 4. 5. 6. 7.
8. 9. 10.
11. 12.
13. 14. 15.
16. 17. 18. 19. 20. 21.
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