Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel

CONTRACEPTION PLASMA HORMONE LEVELS IN WOMEN RECEIVING NEW ORAL CONTRACEPTIVES CONTAINING ETHINYL ESTRADIOL PLUS LEVONORGESTREL OR DESOGESTREL U.J. Gaspard*, M.A. Remus*, D. Gillain*, J. Duvivier**, E. DemeyPonsart *, and P. FranchimontO.

(*) Dept of Obstetrics and Gynecology, (**) Dept of Clinical Chemistry, (+) Dept of Internal Medicine and (0) Radioimmunoassay Laboratory, State University of Liege, Liege, Belgium

ABSTRACT

The changes in plasma hormone levels were evaluated in matched healthy female volunteers investigated before and af&er 6 months' use of three new oral contraceptives (OCs): Trigynon (n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) + levonorgestrel (LNg); MarvelonR (n = 14), a monophasic OC containing low doses of EE + desogestrel (DOG, a new progestogen derived from LNg); and Ovid01 R(n = lo), a sequential OC containing higher doses (50 erg) of EE + DOG. Serum levels of FSH, LH, estradiol and progesterone were decreased in all cases to levels incompatible with ovulation. Prolactin concentrations were unchanged. Sex hormone binding globulin (SHBG) and Transcortin (CBG) levels were significantly increased by all three OCs (Ovidol>Marvelon>Trigynon); free testosterone levels decreased significantly while free cortisol concentrations remained unchanged. Collectively, these data indicate that (a) all three OCs are effective ovulation inhibitors, (b) Ovid01 and Marvelon have greater estrogenic effects than Trigynon, (c) LNg is more effective than DOG in reducing the EE-induced increase in SHBG levels, and (d) free testosterone levels are equally well suppressed by all three Ocs. INTRODUCTION Epidemiological studies conducted in the past few years have indicated that increased frequency of vascular disease and hypertension in oral contraceptive (OC) users could be related not only to the estrogen (1) but also to the progestogen content (2) of the preparations used. In addition, laboratory findings concur to indicate that the doses of estrogens and progestogens contained in the OCs are correlated with alterations of blood coagulation factors, glucose and lipid metabolism (3), resulting in clinical problems for the user. Submitted for publication April 13, 1983 Accepted for publication May 31, 1983

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CONTRACEPTION It is therefore not surprising that new 0C.s with reduced doses of both estrogens and progestogens have been proposed. Moreover, it is now evident that the chemical structure of a progestogen deeply influences its biological properties (review in 4). Many studies (3,5,6) indicate that OCs may have considerably different endocrine and metabolic effects according to the nature of the progestogen they contain. Specifically, the metabolic alterations observed seem todepend on the estrogenic-androgenic balance of these OCs which most often contain a 19-nortestosterone-derived progestogen. These 19-norsteroids, particularly levonorgestrel (LNg), have been claimed to exert androgenic activities such as lowering HDL-cholesterol levels (7) and depressing sex hormone binding globulin (SHBG) synthesis (8),etc... Attempts have thus been made to develop OCs containing new progestogens, such as desogestrel (DOG), a 3-deoxo-11-methylene derivative of LNg, with less androgenic (9) and potentially less metabolic untoward effects than LNg (review in 10). In our study, we compared the influence of a triphasic OC containing particularly low doses of LNg, with a sequential and a monophasic preparations containing low doses of DOG (Table I), on various hormonal parameters. TABLE I

:

ORAL CONTRACEPTIVES

USED IN THIS STUDY

Nature of the preparations

TRIPHASIC

Trade Names

TRIGYNONR

Components

l.Ethinylestradiol(EE) 0.03mg + LNg 0.05mg

(days

OVIDOLR

7-11)

MONOPHASIC MARVELONR

l.EE 0.05mg (days l-7)

l-6)

2.EE 0.04mg t LNg 0.075mg

(days

SEQUENTIAL

EE O.O3mg+ DOG 0.150mg

(days

l-21)

2.EE 0.05mgt DOG 0.125mg

(days

8-21)

3.EE 0.03mg t LNg 0.125mg

(days

12-21)

The different endocrine effects studied were:(a) inhibition of gonadal function as appreciated by alterations of the levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), 17~~ estradiol(E2) and Progesterone (P), (b) estrogenic effects as appreciated by alterations of serum concentrations of prolactin (PRL), cortisol binding globulin (CBG) and concomitant changes in total and free cortisol(F), (c) relative estrogenic-androgenic balance as determined by fluctuations of SHBG and concomitant

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CONTRACEPTION changes in total and free testosterone (T), and (d) potential influence on hydromineral balance and blood pressure as appreciated by changes in aldosterone (Aldo) concentrations and plasma renin activity (PRA). SUBJECTS

AND

METHODS

Subjects All women studied (n = 37) were healthy young medical students (mean age 22.75 yrs), who had never used oral contraception previously or had stopped OCs for at least 8 weeks prior to the study. In each individual, a fasting blood sample was obtained at 08:30a.m.seven days before menstruation during a spontaneous cycle (control cycle). After exclusion of any contraindication to OC use and following a normal gynecologic examination, three groups of,respectively,l3, 10 and 14 women were constituted at random. All subjects from group I received Trigynon for 6 cycles, beginning on day 1 of the first treatment cycle, with a Fday free interval between each treatment cycle. The subjects from group II were assigned to Ovid01 in a similar way and women from group III received Marvelon. A second blood sample was obtained during the last three days of the sixth cycle of OC use in each individual. Hormone determinations FSH and LH were measured by RIA according to Fanchimont et aZ.(U). PRL was determined by RIA according to Reuter et aZ.(12) and values were expressed in vU/ml (lmg hPRL Calbiochem = 39 U MRC 71/222 preparation). P, E2 and total T were measured by RIA according to Abraham (13) after chromatography on Sephadex LH-20 (14). Testosterone binding capacity and the apparent free T concentration were measured and calculated according to Vermeulen et aZ. (15). Total F was determined by direct RIA according to Sulon (16). Free F was measured by equilibrium dialysis (17) and Transcortin (CBG) was assayed by an immunochemical method (18). Plasma Aldo was measured by RIA according to the method of Ito et aL(19) and PRA was quantitated by RIA using a commercial kit (gamma coat CA 533) purchased from Clinical Assays. Statistical analyses bata was computerized and statistical analysis performed with a BMDP3D program (Health Sciences computing facility, UCLA). Paired Student's t test was used for comparing values obtained before and during the sixth treatment cycle in the same individuals

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CONTRACEPTION while nonpaired Student's t test was used for comparison of groups before and at 6 months of OC use. Only P values < 0.05 were considered as statistically significant. RESULTS No statistically significant the three groups of subjects parameters determined during These three groups were thus treatment was initiated.

difference could be observed between for any of the thirteen hormonal the control (pretreatment) cycle. fully comparable before the OC

Plasma FSH and hi’ ZeveZs fell by 38-46% and 28-55%, respectively, according to the treatment group concerned (Table II). However, mean FSH and LH levels, although low in each group after 6 months of OC use, were significantly depressed only in the Marvelon group. PRL ZeveZs were unchanged, irrespective of the OC treatment used. ~2 concentratians were significantly depressed in all women to values hardly compatible with incipient follicular growth, except in one subject during Marvelon therapy (440pg/ml). However, a low P level indicated that ovulation had apparently not occurred. All P va2ue.s were significantly inhibited, and were below 0.9ng/ml in all subjects during treatment, irrespective of the OC used. were distincly increased in all treatment groups and this elevation (Tables II and IV) was statistically greater during Marvelon and Ovid01 treatment than during Trigynon use. Concomitantly, a moderate but statistically significan decrease in total T ZeveZs was observed during Trigynon (- 33% from basal) and Marvelon therapy (- 28%) but not during Ovid01 treatment which had elicited the largest SHBG increase. In relation to SHBG increase, free T ZeveZs decreased significantly to very low levels in all treatment groups.

SHBGconcentrations

CBG ZeveZs increased quite significantly during Marvelon and Trigynon therapy, and even more so during Ovid01 use (Tables II and IV). This increase in CBG was abided by a significant rise in tota F ZeveZs (109 to 165 % over basal values) in all treatment groups. In spite of this impressive total F increase, free F concentrations increased only to a small extent and the fluctuations observed did not reach the level of statistical significance.

580

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1983 VOL. 27 NO. 6

hormones

G z

kz

5 o\

r

_r 1.06

_r 2.6

43.4

2.10

_r 0.30

248 t 31

+ 1.0

11.7

193 + 10

84 + 14

5.08

486 2 34

IiS

f?2 0 CT.000 241 t 59 iS 4.38 t 1.07

80.1

34 Y-5 0.006 0.44 t 0.15 0.01 324 t 50 0.02 1.90 + 0.31 0.002 191 t 25 Loo0 405 t 34 b. 000 13.1 + 1.7

152 + 29

+ 1.64

428 771

8.10

Pretreatment

OVIDOL

t 0.67 t 1.32

ES

y1.58 0.01

6.15

2.06 + 0.29

220 + 28

94.5 TS4 5 0. o;lo 274 t 29

33 Y7 6.02 0,17 t 0.02 CT.006 393 t 49 LTLS 1.60 t 0.22 5.002 348 t 37 b. 000 460 t 37 0.000 15.7 t 1.8

442 ?63

5.30

2.84

6th month

(n = 10)

40.8 + 1.7

10.5 + 1.1

173 -f 12

70 2 7

5.99 t 1.36

507 + 64

6.61 + 1.40

124 -f 27

430 + 68

2.65 _r0.57 (*) 4.14 _r0.62 NS (**I 4.81 + 1.08 9.30 f 3.66

6th month

(n = 13)

463 + 111

6.61 + 0.93

4.23 + 0.67

Pretreatment

TRIGYNON

+ 1.35

t 0.48

+ 2.33

+ 1.47

t 2.6

t 1.2

3.05

t 1.58

240 t 40

40.8

10.6

176 t 11

59 t 8

4.90

429 t 66

9.59

163 -f 24

482 t 99

6.84

3.60

Pretreatment

MARVELON

NS

NS

3.51Nf

0.77

t 2.6 0:ooo 304 t 43

83.7

267 t 22 or000 393 + 24 0:ooo 14.2 t 2.4

or005

57 t 30 or02 0.20 t 0.04 or001 312 t 46 or07 1.50 t 0.20

NS

1.97 t 0.35 or001 3.09 t 0.45 or01 320 t 81

6th month

(n = 14)

: INFLUENCE OF ORAL CONTRACEPTIVES ON PLASMA HORMONE LEVELS BEFORE AND AFTER 6 MONTHS OF USE

(*) Mean t SEM (wt) Paired Student's 5 test for comparison of pretreatment and 6th month values; NS = not tignificant

ng/ml/hr

%rfl' n Mel/l Total F ng/mI Free F ng/mI CBG w/I Aldo $mI

ng/ml Total T pg/mI Free T

p/ml

FSH mIU/ml LH mIU/ml PRL d/ml E2

Plasma

3

d -2

TABLE II

2

9

NS

NS

NS

NS

NS

PRL

E2

P

Total T

Free

NS

Free

0.005

NS

NS

CBG

Aldo

PRA

F

NS

Total F

SHBG

T

0.003

NS

NS

LH

NS

NS

NS

NS

NS

0.032

NS

NS

NS

NS

NS

NS

NS

Plasma hormones

FSH

OF TRFATMENT

NS

NS

0.04

NS

NS

0.059 (NS)

NS

NS

NS

NS

NS

NS

NS

Ovidol/Marvelon

ORAl COWPTIVFS ON PlASMA HORMQNF 1 FVFlS AFTFBSU( (Student's 5 test for comparison oftwo groups)

: COMPARATIVE INFLUENCF OF THRE Trigynon/Marvelon

III

Trigynon/Ovidol

TABLE

M(INWS_

H

21

g

P

3

0

0

CONTRACEPTION

+

P

w

cu

t4 +

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::

0 0 II 0.

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CONTRACEPTION ZeveZs did not vary significantly in any treatment group. In contrast, PRA was distinctly increased in all groups and this increase was statistically significant during Ovid01 therapy.

- Atdo

- When the three groups of volunteers are compared at six months of treatment, it can be clearly seen from Table III that there are only small differences in the action of the three OC regimens tested on the concentrations of endogenous hormones. The differences bear only on the carrier protein levels. The increase in SHBG levels is significantly greater with Ovid01 and Marvelon than with Trigynon therapy; CBG concentrations are significantly higher during Ovid01 than during Trigynon and Marvelon treatment. DISCUSSION As judged by their mean age, ideal body weight and endocrine results collected during a control cycle, our three groups of female volunteers were homogeneous and comparable. However, it is noteworthy that this population of active young medical students was characterized by normal E2 levels whereas total T and free T concentrations were at the upper limit of the normal range, and associated - as is frequently the case - with P levels in the low normal range (20). The use-effectiveness pregnancy rate calculated for each of the three OCs under investigation has been reported to be very low (0.06 to 0.1) (Zl-23), indicating similar and excellent contraceptive efficacy, even in the case of Trigynon which contains the absolutely lowest doses of estrogen t progestogen in a three-phase combination. Endocrine levels reported in this study are in agreement with the above-mentioned contraceptive efficacy. Inhibition of mid-cycle peak and low circulating levels of gonadotrophins have been documented by sequential determinations performed during cycles treated by these three OCs (24-26). In our study, serum FSH and LH levels are also inhibited after 6 months of OC use; however, this decrease is only significant during Marvelon treatment, as in the study of Mall-Haefeli et aZ. (27). Two reasons can explain this discrepancy of action between the three OCs: (i) the progestogen content is greater in Marvelon than in the two other OCs; (ii) DOG (the progestogen contained in Marvelon) acts as a stronger hypothalamic-pituitary inhibitor than LNg, even when given in identical amounts (28).

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CONTRACEPTION

In concordance with the decrease in gonadotropin levels, inhibition of gonadal function is effectively achieved in each individual during administration of the three OCs. All serum E2 values except one, are in the range of early follicular maturation and all P levels are far below the ovulatory range. These observations are in keeping with the results obtained by other authors for each of the OCs studied (25-27). PRL secretion can be increased by the estrogen component of OCs, particularly if daily doses over 0.050mg are used. However, owing to the episodic nature of PRL release, the increase in PRL levels is more distinctly delineated if the mean of frequent samplings is taken into consideration (29). With OCs containing a daily dose of 0.050mg EE or less, we did not observe any rise of PRL levels after 6 months of use, and these results corroborated other studies (26,27,30). However, a PRL-facilitated secretory response to different stimuli during low-dose OC treatment cannot be ruled out, even in spite of unchanged serum PRL levels, as Taubert et al. (30) have observed an augmented PRL response to thyrotropin releasing hormone (TRH), during Trigynon administration. There is now strong evidence that SHBG levels are increased by estrogens and decreased by androgens and 19-nortestosterone-derived progestogens,particularly LNg (8). In OCs c.ontaining different amounts of EE + LNg, SHBG levels will increase only if the EE/LNg ratios increase. Determinations of SHBG concentrations are thus considered to give an estimate, in km, of relative estrogenicity of OCs (31). In our study, the favorable EE/LNg ratio of Trigynon is abided by a significant increase in SHBG capacity (Table IV), indicating estrogen dominance of the triphasic combination. This observation corroborated similar results of Larsson-Cohn et aZ.(31), Vermeulen and Thiery (32) and Cullberg et aZ. (33). DOG has been estimated to have less androgenic activity than LNg as determined by studies of comparative binding affinity for androgen receptors (9), although this was not confirmed by more recent studies (34,35). Nevertheless,our results clearly show that the combination of DOG with EE in Marvelon and Ovid01 is accompanied by a significantly greater increase in SHBG than is the case for Trigynon. The maximum increase is observed during treatment with Ovidol, a distinctly more estrogenic preparation than the two others. These results confirm recent data from Cullberg et aZ. (33) and Bergink et aZ. (36). Owing to the simultaneous increase in SHBG capacity, the drop of total T concentrations in relation with the inhibitory action of these three OCs on gonadotropin secretion and gonadal function is less than anticipated. Accordingly, total T levels are not significantly decreased during Ovid01 treatment, i.e. during maximal increase in SHBG levels. In contrast, free T levels, in all cases, were significantly depressed. These results are in agreement with other reports (27,32).

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CONTRACEPTION Transcortin (CBG) levels are partly estrogen-dependent, but contrary with SHBG regulation - CBG levels seem independent of androgen and progestogen influence (review in 37). Accordingly, as previously demonstrated (32-33), CBG levels are equally and statistically increased by Trigynon and Marvelon treatment, in relation with the equivalent amount of estrogens contained in both these preparations. CBG levels are significantly more elevated during Ovid01 therapy, due to the higher estrogenic content of this formulation. Concurrently to true CBG concentration increase, total F is significantly elevated. Owing to the negative feedback mechanism of F control, free F levels remain rather stable during treatment with all three OCs. A slight tendency of free F levels to increase, particularly during Ovid01 therapy,is however notstatistically significant. One such unexplained tendency has already been delineated during other OC use (37) and during human pregnancy (38). Activation of the renin-angiotensin-aldosterone (RAA) system during OC treatment is a rapidly occurring and estrogen-related phenomenon (3,39). Elevation of plasma renin substrate through enhanced hepatic synthesis is considered to be the primary effect of estrogens on the RAA system, while increases in PRA, angiotensin II and aldosterone excretion rate may be somewhat blunted by a fall in plasma renin concentration (39). Our results are in agreement with these observations and demonstrate a distinct increase in PRA within six months of OC use. A significant rise of 200% over basal values is observed during Ovid01 treatment. Concomitantly, plasma Aldo concentrations, although tending to increase during Ovid01 and Marvelon treatment, do not fluctuate significantly. It is noteworthy that both in Briggs and Briggs'study (3) and in ours, no woman became hypertensive despite large changes in the RAA system. CONCLUSION This study demonstrates that all three OCs under investigation, namely Trigynon, Ovid01 and Marvelon, inhibit pituitary gonadotropin secretion and gonadal function, as evidenced by low levels of FSH, LH, E2 and P in all the cases studied. All three OCs also exert dominant estrogenic effects, as exemplified by marked and significant increases in the carrier proteins SHBG and CBG. Ovid01 is clearly the most estrogenic preparation tested (greatest increase in SHBG, CBG and PRA), owing essentially to its daily dosage of 0.050mg EE and its sequential formulation, responsible for a high EE/DOG ratio. Although Marvelon contains lower EE doses and higher progestogen amounts than Trigynon, it behaves as a definitely more estrogenic OC than the latter preparation.

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CONTRACEPTION This is due to the lower antiestrogenic activity of DOG versus LNg, best exemplified in our study by a significantly greater rise in SHBG during Marvelon treatment. Increased SHBG and CBG concentrations during treatment with these three estrogen-dominant OCs are abided by elevated levels of total F. Free F levels are however not statistically increased, while, in contrast, free T levels are markedly decreased in all the cases studied, a potential beneficial effect in the treatment of clinica manifestations of androgen excess in women. ACKNOWLEDGEMENTS We wish to thank Mr. J. Sulon, Ph.D.(Dept of Internal Medicine, laboratory of steroid biochemistry, Univ. of Liege, Belgium), for his collaboration to the steroid assays, Mrs. A.M. VerlySmolnik for her secretarial assistance, and Mr. P. Le Noach for help in the translation of the manuscript. Financial support of Schering Pharma, Belgium, is gratefully acknowledged. REFERENCES 1. Inman, W.H.W., Vessey, M.P., Westerholm, B. and Engerlund, A. Thromboembolic disease and steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 2 : 203-209 (1970).

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CONTRACEPTION 7. Bradley, D.D., Wyngerd, J., Petitti, D.B., Krauss, R.M., and Serum high density lipoprotein cholesterol in Ramcharan, S. women using oral contraceptives, estrogens and progestins. N Engl J Med 299 : 17-20 (1978). Rademaker, B. and Schwartz, 8. Van Kammen, E., Thijssen, J.J.H., F. The influence of hormonal contraceptives on sex hormone binding globulin (SHBG) capacity. Contraception 11 : 53-56 (1974). 9. Bergink, E.W., Hamburger, A.D., De Jager, E. and Van der Vies, J. Binding of a contraceptive progestogen Org 2969 and its metabolites to receptor proteins and human sex hormone binding globulin. J Steroid Biochem 14 : 175-183 (1981). 10. Gaspard, U. Le desogestrel: nouveau progestatif en contraception orale. Med et Hyg 40 : 2758-2765 (1982). 11. Franchimont, P., Hendrick, J.C., Reuter, A.M. and Burger, H.G. In: Radioimmunoassay and Related Procedures in Medicine. International Atomic Energy Agency, Vienna, 1974, vol. I, p. 195-211. 12. Reuter, A.M., Kennes, F., Gevaert, Y. and Franchimont, P. Homologous radioimmunoassay for human prolactin. Int J Nucl Med Biol 3 : 21-28 (1976). 13. Abraham, G.E. In: Radioimmunoassay and Related Procedures in Medicine. International Atomic Energy Agency, Vienna, 1974, vol. II, p. 3-28. 14. Germeau, P. and Duvivier, J. Chromatographie des steroides gonadiques sur Sephadex LH-20. J Chromatog 129 : 471-472 (1976). 15. Vermeulen, A., Stoica, T. and Verdonck, L. The apparent free testosterone concentration, an index of androgenicity. J Clin Endocrinol Metab 33 : 759-767 (1971). 16. Sulon, J. Dosage radioimmunologique des principaux corticosteroides synthetises par la zone fasciculee du cortex surrenalien humain. Ph D Thesis, Univ of Liege, Belgium, 1982, p. 98-118. 17. Demey-Ponsart, E., Foidart, J.M., Hendrick, J.C. and Sodoyez, J.C. Effect of serum dilution on binding of cortisol to thermolabile and thermostable serum proteins. J Steroid Biochem 8: 1091-1095 (1977).

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CONTRACEPTION 28. Rijmmler, A., Baumgarten, S., Schwartz, U. and Hammerstein, J. Anti-estrogenic effects of contraceptive progestins on the dynamics of oonadotrooin release. Contraception 25 : 619-627

(i982).

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(1981). etabolic effects of the triphasic oral contraceptive Trigynon !! . Contraception 26 : 505-513 (1982).

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33. Cullberg, G., On the use of bolic effects Gynecol Stand

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34. Spona, J. In: Aktuelle Aspekte der hormonalen Kontrazeption (Hammerstein,J, editor). Excerpta Medica, Amsterdam, 1982, p 45-54. 35. Briggs, M.H. and Briggs, M. Metabolic comparative data of Levonorgestrel versus Desogestrel. Proc. Symp. 17 October 1982, San Francisco. Excerpta Medica, Amsterdam, in press (1983). 36. Bergink, E.W., Holma, P. and PyorllX, T. Effects of oral contraceptive combinations containing levonorgestrel or desogestrel on serum protin and androgen binding. Stand J Clin Lab Invest 41 : 663-668 (1981). 37. Brien, T.G. Free cortisol in human plasma. Horm Metab Res 12 : 643-650 (1980). 38. Demey-Ponsart, E., Foidart, J.M., Sulon, J. and Sodoyez, J.C. Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Biochem 16 : 165-169 (1982).

W., Bliimel, A., SchtineshUfer, M., Schwartz, IJ. and Hammerstein, J. Effects of ethinylestradiol on the reninangiotensin-aldosterone system and on plasma transcortin in women and men. J Clin Endocrinol Metab 43 : 1036-1040 (1976).

39. Oelkers,

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