CONTRACEPTION
EFFECTS HORMONAL,
Arnaud
OF NOMEGESTROL ACETATE (5 mg/d) ON METABOLIC AND HEMOSTATIC PARAMETERS IN PREMENOPAUSAL WOMEN
BASDEVANTl.
Herve
DEGRELLE4.
Clara
PELISSIER’.
Thanh
T. GUYENE3
Jacqueline
. Jean-Louis
CONARI?. THOMAS'
1. Internal Medicine and Nutrition Department. Hemostasis Department, Obstetrics Department, HOTEL DIEU. Paris, France 2. Research and Clinical Development Department, Laboratoire Theramex. Bagnolet. France 3. Radioimmunology Department, BROUSSAIS hospital, Paris, France 4. Biochemical Laboratory, Faculty of Medicine, Paris, France
ABSTRACT The effects of nomegestrol acetate on circulating hormone levels, metabolic and hemostatic parameters and blood pressure were studied in 36 premenopausal women. The progestogen was administered from day 7 to 25 of the cycle during six cycles at a dosage (5 mg/d) known to inhibit ovulation. Analysis were performed before and in the third and sixth cycles. Estradiol and progesterone levels decreased significantly (p < 0.0011 during treatment. Body weight, fasting blood glucose and insulin, total HDL and LDL cholesterol. apolipoprotein B. fibrinogen and plasminogen did not change significantly. Triglycerides in the third cycle (p < 0.05) and apolipoprotein Al levels (p c 0.01) in both periods of sampling decreased significantly. There was a significant increase in antithrombin III (p -Z 0.01). These results indicate that nomegestrol acetate has no deleterious effect on blood glucose and lipids. The decrease in apolipoprotein Al and increase iri antithrombin III may be related either to the decrease in estradiol levels induced by the treatment or to the effect of the progestogen itself.
Reprint
Requests
:
Arnaud BASDEVANT, M.D. HOTEGDIEU 1 Place du Parvis Notre-Dame 75181 PARIS Cedex 04, France
Submitted for publication Accepted for publication
DECEMBER
: July 17, 1991 :
September
1991 VOL.44NO.6
3, 1991
699
CONTRACEPTION INTRODUCTION Progestogens include a variety of agents sharing a common biological to bind to the progesterone receptor. but effect, i.e. their ability differing one from another in term of specificity of their hormonal activity and their metabolic effects. On the one hand, progesteronerelated steroids are devoid of androgenicity and have little or no derivatives are On the other hand, nortestosterone metabolic effects. androgenic and induce major metabolic changes including alterations in cardiovascular risk factor such as a decrease in high density-lipoprotein (HDL) cholesterol (1). The aim of this study was to assess the biological effects of nomegestrol derivative with acetate CLUTENYL@lThCramex France). a 19-norprogesterone potent progestational activity and no androgenicity (2). Nomegestrol acetate was given discontinuously but for sufficient time in the cycle (19 dl at a dosage (5 mg/d) known to inhibit ovulation and cervical mucus production in normally menstruating women (3.4). METHODS Thirty-six regularly menstruating women gave their informed consent to participate in the study approved by an ethical committee. They were treated with nomegestrol acetate 5 mg once daily (one tablet of LUTENYL@) from day 7 to day 25 of the cycle for 6 consecutive cycles. Their mean age was 38.8 (range 18 - 49 years). mean body mass index (EM11 was 22.4 (range 19.1 - 29.8). Twenty-one (61%) of them were over the age of 36 years and six (17%) were overweight (BMI > 27). This progestational treatment was chosen for at least one of the following reasons : indication for a progestogen due to a benign disease endometrial of breast (n = 10) and/or uterus (fibroma:n = 9: hyperplasia:n = 3; endometriosis:n = 3: polyposis:n = 1; adenomyosis:n = 11. contraindication to the use of an intrauterine device (n = 61 or of a pill ccntaining ethinylestradiol (metabolic disorders under previous contraception:n = 13: 0tospongiosis:n = 1: varicose veins:n = 1: pregnancy-induced hypertension:n = 1). These clinical conditions explain Exclusion why most of the patients were over the age of 36 years. criteria were symptoms or history of thromboembolic and/or arterial diseases, diabetes. hyperlipidemia. more than 10 consumption of cigarettes per day and known or suspected cancer. Previous steroid treatment must have been stopped at least two months before the study. In fact 20 of the 36 women had not received hormonal therapy during the 2 years prior to the study. Women were investigated during the last untreated cycle and between days 18-25 of the third and sixth treatment cycles. On each occasion, a clinical control was performed including determination of body weight and blood presssure measured both with a sphygmomanometer by the physician and automatically by an oscillometric method (DINAMAP@). Fasting blood samples were also collected for determination of estradiol. progesterone, sex hormone binding globulin (SHBG). corticosteroid binding globulin (CBG). renin substrate. nomegestrol acetate, lipids (triglycerides. total cholesterol, HDL and LDL cholesterol. apolipoproteins Al and B). blood glucose and insulin and blood hemostasis parameters (antithrombin III. plasminogen and fibrinogen).
600
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION and insulin levels were determined by Serum estradiol. progesterone nomegestrol acetate by HPLC radioimmunoassay (Coatria 's'. BioMerieux), SHBG and CBG by an electroimmunoassay on (unpublished method). was measured ready-to-use immunoplates (5). Renin substrate concentration I generation and expressed as ng of by a method based on angiotensin angiotensin I liberated per ml of plasma by an excess of renin (6). Serum triglycerides and glucose were measured using enzymatic cholesterol. procedures. HDL cholesterol was determined after precipitation of VLDL and LDL by phosphotungstate/manganese chloride and apolipoproteins by was estimated according nephelometric laser assays (7). LDL cholesterol to the Friedewald method (8). Antithrombin III determination was done by two methods : a radial immunodiffusion technique using Partigen" plates (Behring) and an amidolytic technique using ACA SX (Dupont de Nemours). Fibrinogen was measured according to Von Clauss (9) and plasminogen by an amidolytic method using ACA SX (DuPont de Nemours). Data were statistically paired t-test.
analyzed
by analysis
of variance
and
by Student's
RESULT8 The clinical tolerance of the treatment was good. Only one woman with a history of gastrointestinal intolerance to oral contraceptives withdrew intolerance. after a few days because of this from the study Modifications of the menstrual cycle were observed in 17 patients : amenorrhea in one case and spotting in the 16 others. Spotting was observed for more than one cycle only in B women. Age or prior hormonal therapy had no influence on the different basal measurements. Mean plasma estradiol and progesterone levels decreased significantly (p < No significant 0.001) in the third and sixth treatment cycles. CBG and renin substrate was observed variation of SHBG. levels (Table I).
Table
I. Plasma levels Cm f sem) of hormones. SHBG. CBG. renin substrate. before and during treatment with nomegestrol acetate (5 mg/d. 20 d/cycle)
Normal Estradiol
(pmol/l)
Progesterone SHBG
(nmol/l)
(pg/mll
CBG (pg/mll Renin
substrate
* p -z 0.001 estradiol
(rig/ml)
ranges
BASAL
250 - 800
418 + 51
10 - 75
14.6 + 2.5
3rd CYCLE
6th CYCLE
146 + 35*
98 + 13*
0.6 + D.D3*
0.6 + 0.03*
3 - 6
3.4 + 0.3
2.9 + 0.2
2.6 + 0.2
33 - 49
37.7 + 1.0
39.3 + 0.9
37.5 + 1.1
600 - 1500
as compared with basal 1 pmol/l = 0.27 pg/ml:
DECEMBER 1991 VOL. 44 NO. 6
1116.7 + 52.8 values progesterone
1125.8 + 47.4
:
1 nmol/l
1162.3 + 40.6
= 0.31
ng/ml
601
CONTRACEPTION The average nomegestrol acetate blood levels Mere 10.4 f 6.5 and 8.8 t during 3 and 6 cycles of treatment. 7.2 nglml. respectively, Mean values of metabolic parameters are shown in Table II. Body weight was not significantly modified by treatment. There was a significant decrease in triglycerides levels (p < 0.051 only in the third treatment cycle and in apolipoprotein Al (p < 0.05) in both periods. No significant LOL cholesterol, apolipoprotein B HOL and variation occurred in and apo AI/ape B ratio, blood glucose and insulin levels.
Table
II. Metabolic parameters Cm 2 semi before and during nomegestrol acetate (5 mg/d. 20 d/cycle)
Normal Body weight
(kg)
Cholesterol
(mmol/ll
Triglycerides
Cmmol/ll
ranges
BASAL
treatment
3rd CYCLE
with
6th CYCLE
59.3 + 1.5
57.2 + 2.3
59.9 + 1.7
3.60
- 6.10
5.00 + 0.14
4.93 + 0.13
4.99 + 0.15
0.40
- 2.10
0.89 + 0.08
3.75 t 0.06*
3.83 + 0.05
HDL cholesterol
(mmol/l
0.80
- 2.10
1.13 + 0.03
1.15 + 0.04
1.12 f. 0.04
LOL cholesterol
(mmol/l
1.60
- 4.90
3.67 + 0.43
3.62 + 0.12
3.70 + 0.15
Apolipoprotein
Al (g/l)
1.00 - 2.00
1.56 + 0.04
1.41 + 0.04"
1.45 + 0.04*'
Apolipoprotein
B (g/l)
0.80
0.99 + 0.04
0.99 + 0.04
0.99 + 0.04
1.68 f. 0.07
1.55 + 0.11
1.54 + 0.07
4.82 + 0.08
4.92 + 0.07
4.77 + 0.08
11.5 + 0.8
11.4 + 0.6
11.8 + 0.6
Apo Al/Ape
B
>
Glucose
(mmol/l)
Insulin
(mUI/l)
-
1.60
1.40
3.80
- 6.10
10 - 15
* p < 0.05: l * p < 0.01 as compared with basal values. cholesterol 1 mm0171 = 0.38 g/l: triglycerides 1 mmol/l glucose 1 mmolll = 0.18 g/l Table
III. Hemostatic nomegestrol
parameters (m k sem) before and during acetate (5 mgld. 20 d/cycle)
Normal Antithrombin III (%I (immunodiffusion) Antithrombin (amidolytic
III
(%)
BASAL
ranges
g/l
treatment
3rd CYCLE
with
6th CYCLE
80 - 120
99 + 1
106 + l**
105 + 2**
80 - 120
99 + 1
106 + l**
104 + 2’
106 + 3
137 + 2
104 f. 2
3.2 + 0.1
3.4 + 0.1
3.2 + 0.1
method)
Plasminogen
(%I
70 - 130
Fibrinogen
(g/l)
2 - 4
* p < 0.01:
602
= 0.81
** p < 0.001
as compared
with
basal
values.
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
Antithrombin sixth and significant
III significantly treatment cycles. modification (Table
increased between and Plasminogen III).
5 and 7% in the third fibrinogen showed no
Mean systolic and diastolic blood pressure did not vary during treatment, There was a significant increase in when measured by the physician. automatically registered mean systolic blood pressure in the sixth cycle (basal values : 109 2 1.4 mmHg; third cycle : 112 + 1.7 mmHg: sixth There was no abnormal value nor 114 5 1.4 mmHG; p < 0.05). cycle: blood significant modification of automatically registered diastolic pressure.
DISCUSSION steroid administration may result in marked metabolic changes, such in lipoproteins metabolism, haemostatic changes and as alterations modification of the renin substrate which may respectively influence the thromboembolism and hypertension (1.13.18). risk of hyperlipidemia. Little is known about the metabolic effects of progestogen-only therapy. It has been shown that norethisterone derivatives induce a decrease in levels and are responsible for and triglycerides HDL cholesterol These effects have been related to the androgenic insulin-resistance. activity of these progestative compounds (1.13).
Sex
administered in normal study. nomegestrol acetate was In this at a dosage known to have a potent menstruating women once daily, inhibitory effect on gonadotropins when prescribed in a 20 days/cycle schedule (31. In fact, under treatment. plasma estradiol levels were markedly decreased whereas progesterone was undetectable. show that the administration of a derivative of 19These data norprogesterone. even at a dosage adequate to inhibit ovulation. results in no significant change in body weight and in fasting blood glucose and insulin. As far as lipoprotein metabolism is concerned, no change in HDL and LDL cholesterol, apolipoprotein B and apo Al/ape B ratio was observed. There was a significant decrease in apolipoprotein Al and a transient decrease in triglycerides levels. Thus, nomegestrol acetate induced only minor changes in lipoproteins metabolism as compared to the modifications observed with 19-nortestosterone derivatives. The latter are responsible for a decrease in HDL cholesterol, a parameter which is inversely correlated to the risk of cardiovascular disease, when they are given alone either to premenopausal women (10-13)) or to oophorectomized women (14). The decrease in apolipoprotein Al during nomegestrol acetate treatment is of the same magnitude as that observed during the administration of chlormadinone acetate and cyproterone acetate, when these progestogens are given in the same schedule as in the present study (15.161. In order to determine whether this effect is due to the progestogen itself or to the decrease in estradiol levels, studies comparing the effect of the progestogen given alone and combined with parental estradiol should be performed. Nomegestrol acetate had no significant fibrinogen and effect on plasminogen. but significantly increased antithrombin III. A similar increase has been previously shown with 17-hydroxyprogesterone derivatives prescribed discontinuously at high doses in premenopausal women (16.17). A few studies have been published on the effect on antithrombin III of the 19-nortestosterone derivatives used in the progestogen-only mini pill. There is no modification with most of them except for a decrease with lynestrenol (18). The mechanism by which
DECEMBER 1991 VOL. 44 NO. 6
603
CONTRACEPTION progestogen at high dose increases antithrombin III is not clear. Here again both the progestogen itself and its hypoestrogenic effect may play a role. According to the pharmacological data (2) and to the absence of significant change of SHBG levels in this study. it seems unlikely that the effect of nomegestrol acetate on antithrombin III is related to the same mechanism as that observed during administration of anabolic or androgenic steroids which results both in an increase in antithrombin III and in a decrease of SHBG (131. It should be reminded that a congenital deficit in antithrombin III. a physiological inhibitor of coagulation. is associated with some venous thromboses. Oral estrogens are responsible for a decrease in antithrombin III activity and for thrombosis (18). The induced increase in clinical consequence of a pharmacologically antithrombin III is not known. The levels of renin substrate did not change during treatment with acetate, neither did the diastolic blood pressure, as nomegestrol observed with other progestins (15.17.19). Although mild and only significant in the sixth cycle, the increase of automatically registered systolic blood pressure needs further studies since the results were contradictory to those observed by the physician. nomegestrol acetate, a Altogether. these results indicate that progestogen with little or no androgenic activity. has no deleterious levels and fasting blood influence on body weight, HDL cholesterol glucose. and avoids the effect of estrogen-progestogen association on coagulation.
ACKNOWLEDGEMENTS We would like to thank this study and Mrs M.R.
Dr A.S. POISSON-SALOMON for her participation LECOD and D. DESNAULT for technical assistance.
in
REFERENCES 1.
progestins on TIKKANEN H.J.. Effects of NIKKILA E-A.. KUUSI I. plasma lipoproteins and heparin releasable lipases. In: Progesterone and Progestins. C.W. Bardin Editor, E. Milgrom. P. Mauvais-Jarvis, Raven Press Publish, New-York, 1983 : 411 - 420.
2.
PARIS J.. THEVENOT R.. BONNET P.. GRANERO M. The pharmacological profile of TX 066 (17-alpha-acetoxy-6-methyl-l9-nor-4.6-pregna-diene-3,20Drug Res 1983; 33 : 710 715. dione),. a new oral progestative.
3.
BAZIN B.. PARIS J. Effect of nomegestrol THEVENOT R.. BURSAUX C.. acetate, a new 19-norprogesterone derivative on pituitary-ovarian function in women. Br J Obstet Gynaecol 1987; 94 : 1199 - 1204.
4.
CHRETIEN F.C.. DUBOIS R. Effect ferning and mesh dimension of 1991; 43 : 55 65.
5.
LORIC S.. DOMINGO M.. DEGRELLE H. EGLOFF H.. and CBG using the same standardized immunoassay clinical evaluation of oral contraceptives. Steroids
604
of nomeoestrol acetate on soinnabilitv. Cbntraceptibn cervical mucus. midcycle
:
Measurement of SBP application to the 1988; 52 : 401 402.
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION HENARO GUYENE T.T.. CORVOL P.. A., in plasma renin activity measurements. Am J
J. Methodologic Med 1976; 61 : 725
6.
DELORHE problems - 730.
7.
Clinical and laboratory LEWIS B. The hyperlipidemias. Scientific Publications. Ltd. Oxford. 1977: 383 - 419.
8.
LEVY R.I.. FREDRICKSON D.S. Estimation of FRIEDEWALD W.T.. concentration of low density lipoprotein cholesterol in plasma without of the preparative ultracentrifuge. Clin Chem 1972: 18 : 499 - 502.
9.
VON des
CLAUS'S A. Fibrinogens.
practice.
Gerinnungsphysiologische Schnellmethode Acta Haemat 1957; 17 : 237.
zur
Blackwell
Bestimmung
D-0.. WINGERD J.. 10. BRADLEY PETITTI 0.8.. KRAUSS Serum high-density-lipoprotein cholesterol in RAHCHARAN S. contraceptives. estrogens and using oral progestins. New Engl 1978: 299 : 17 - 20.
11.
the use
R.M.. women J Med
TIKKANEN H-J.. NIKKIIA E-A.. KUUSI 1.. SIPINEN S. Different effects high density lipoprotein (HDLZ) and of two progestins on plasma postheparin plasma hepatic lipase activity. Atherosclerosis 1981: 40 : 365369.
MANNINEN V.. HIRVONEN E. Effects of 12. HALKONEN M.. danazol lynestrenol on serum lipoproteins in endometriosis. Clin Pharmacol 1980: 28 : 602 - 606. 13. ELKIK F.. Contraception estradiol and
and Trer
BASDEVANT A.. JACKANICSZ T-H.. GUY-GRAND B. in hypertensive women using a vaginal ring delivering levonorgestrel. J Clin Endocr Metab 1986: 63 : 29 - 35.
14. SILFVERSTOLPE 6.. GUSTAFSON A.. SAMSIOE 6.. SVANBORG A. Lipid metabolic studies in oophorectomized women. Effects of three different progestogens. Acta Obstet Gynaecol Stand 1979: 88 (suppl) : 89 - 95. Etude 15. JAHIN C. acetate-estradiol 17 : 957 - 962.
de l'effet metabolique de l'association cyproterone 17 beta par voie percutanee. Contracept Fertil Sex 1989;
AIACH 16. JAHIN C.. cyproterone-estradiol 1987: 16 : 1007. 17.
H. Effet de l'association par voie cutanee sur l'antithrombine
acetate III. Presse
de Med
PELISSIER C.. BASDEVANT A., CONARD J.. EGLOFF M.. HUSSON T.. GUYENE T.T. Contraception progestative par l'acetate de chlormadinone femmes a vasculaire gyneco-endocrinienne. chez des risque (etude metabolique et vasculaire). Contracept Fertil Sex 1987: 15 : 45 - 54.
18. CONARD J.. SAHANA M. The effects of progestins on coagulation. Progesterone and Progestins. C.W. Editor, E. Milgrom. Bardin. Mauvais-Jarvis. Raven Press Publish, New-York, 1983 : 447 - 452. 19. BASOEVANT A.. CONARD J.. DENIS C.. T.T.. GUYENE DENYS I. Effets metaboliques et hormonaux de l'administration h de promegestone (RU 5020). Gynecologie 1989: 40 (suppl au 21.
DECEMBER 1991 VOL. 44 NO. 6
In: P.
EGLOFF N.. de 1 mg/24 no21 : 17 -
605
EFFECTS HORMONAL,
Arnaud
OF NOMEGESTROL ACETATE (5 mg/d) ON METABOLIC AND HEMOSTATIC PARAMETERS IN PREMENOPAUSAL WOMEN
BASDEVANTl.
Herve
DEGRELLE4.
Clara
PELISSIER’.
Thanh
T. GUYENE3
Jacqueline
. Jean-Louis
CONARI?. THOMAS'
1. Internal Medicine and Nutrition Department. Hemostasis Department, Obstetrics Department, HOTEL DIEU. Paris, France 2. Research and Clinical Development Department, Laboratoire Theramex. Bagnolet. France 3. Radioimmunology Department, BROUSSAIS hospital, Paris, France 4. Biochemical Laboratory, Faculty of Medicine, Paris, France
ABSTRACT The effects of nomegestrol acetate on circulating hormone levels, metabolic and hemostatic parameters and blood pressure were studied in 36 premenopausal women. The progestogen was administered from day 7 to 25 of the cycle during six cycles at a dosage (5 mg/d) known to inhibit ovulation. Analysis were performed before and in the third and sixth cycles. Estradiol and progesterone levels decreased significantly (p < 0.0011 during treatment. Body weight, fasting blood glucose and insulin, total HDL and LDL cholesterol. apolipoprotein B. fibrinogen and plasminogen did not change significantly. Triglycerides in the third cycle (p < 0.05) and apolipoprotein Al levels (p c 0.01) in both periods of sampling decreased significantly. There was a significant increase in antithrombin III (p -Z 0.01). These results indicate that nomegestrol acetate has no deleterious effect on blood glucose and lipids. The decrease in apolipoprotein Al and increase iri antithrombin III may be related either to the decrease in estradiol levels induced by the treatment or to the effect of the progestogen itself.
Reprint
Requests
:
Arnaud BASDEVANT, M.D. HOTEGDIEU 1 Place du Parvis Notre-Dame 75181 PARIS Cedex 04, France
Submitted for publication Accepted for publication
DECEMBER
: July 17, 1991 :
September
1991 VOL.44NO.6
3, 1991
699
CONTRACEPTION INTRODUCTION Progestogens include a variety of agents sharing a common biological to bind to the progesterone receptor. but effect, i.e. their ability differing one from another in term of specificity of their hormonal activity and their metabolic effects. On the one hand, progesteronerelated steroids are devoid of androgenicity and have little or no derivatives are On the other hand, nortestosterone metabolic effects. androgenic and induce major metabolic changes including alterations in cardiovascular risk factor such as a decrease in high density-lipoprotein (HDL) cholesterol (1). The aim of this study was to assess the biological effects of nomegestrol derivative with acetate CLUTENYL@lThCramex France). a 19-norprogesterone potent progestational activity and no androgenicity (2). Nomegestrol acetate was given discontinuously but for sufficient time in the cycle (19 dl at a dosage (5 mg/d) known to inhibit ovulation and cervical mucus production in normally menstruating women (3.4). METHODS Thirty-six regularly menstruating women gave their informed consent to participate in the study approved by an ethical committee. They were treated with nomegestrol acetate 5 mg once daily (one tablet of LUTENYL@) from day 7 to day 25 of the cycle for 6 consecutive cycles. Their mean age was 38.8 (range 18 - 49 years). mean body mass index (EM11 was 22.4 (range 19.1 - 29.8). Twenty-one (61%) of them were over the age of 36 years and six (17%) were overweight (BMI > 27). This progestational treatment was chosen for at least one of the following reasons : indication for a progestogen due to a benign disease endometrial of breast (n = 10) and/or uterus (fibroma:n = 9: hyperplasia:n = 3; endometriosis:n = 3: polyposis:n = 1; adenomyosis:n = 11. contraindication to the use of an intrauterine device (n = 61 or of a pill ccntaining ethinylestradiol (metabolic disorders under previous contraception:n = 13: 0tospongiosis:n = 1: varicose veins:n = 1: pregnancy-induced hypertension:n = 1). These clinical conditions explain Exclusion why most of the patients were over the age of 36 years. criteria were symptoms or history of thromboembolic and/or arterial diseases, diabetes. hyperlipidemia. more than 10 consumption of cigarettes per day and known or suspected cancer. Previous steroid treatment must have been stopped at least two months before the study. In fact 20 of the 36 women had not received hormonal therapy during the 2 years prior to the study. Women were investigated during the last untreated cycle and between days 18-25 of the third and sixth treatment cycles. On each occasion, a clinical control was performed including determination of body weight and blood presssure measured both with a sphygmomanometer by the physician and automatically by an oscillometric method (DINAMAP@). Fasting blood samples were also collected for determination of estradiol. progesterone, sex hormone binding globulin (SHBG). corticosteroid binding globulin (CBG). renin substrate. nomegestrol acetate, lipids (triglycerides. total cholesterol, HDL and LDL cholesterol. apolipoproteins Al and B). blood glucose and insulin and blood hemostasis parameters (antithrombin III. plasminogen and fibrinogen).
600
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION and insulin levels were determined by Serum estradiol. progesterone nomegestrol acetate by HPLC radioimmunoassay (Coatria 's'. BioMerieux), SHBG and CBG by an electroimmunoassay on (unpublished method). was measured ready-to-use immunoplates (5). Renin substrate concentration I generation and expressed as ng of by a method based on angiotensin angiotensin I liberated per ml of plasma by an excess of renin (6). Serum triglycerides and glucose were measured using enzymatic cholesterol. procedures. HDL cholesterol was determined after precipitation of VLDL and LDL by phosphotungstate/manganese chloride and apolipoproteins by was estimated according nephelometric laser assays (7). LDL cholesterol to the Friedewald method (8). Antithrombin III determination was done by two methods : a radial immunodiffusion technique using Partigen" plates (Behring) and an amidolytic technique using ACA SX (Dupont de Nemours). Fibrinogen was measured according to Von Clauss (9) and plasminogen by an amidolytic method using ACA SX (DuPont de Nemours). Data were statistically paired t-test.
analyzed
by analysis
of variance
and
by Student's
RESULT8 The clinical tolerance of the treatment was good. Only one woman with a history of gastrointestinal intolerance to oral contraceptives withdrew intolerance. after a few days because of this from the study Modifications of the menstrual cycle were observed in 17 patients : amenorrhea in one case and spotting in the 16 others. Spotting was observed for more than one cycle only in B women. Age or prior hormonal therapy had no influence on the different basal measurements. Mean plasma estradiol and progesterone levels decreased significantly (p < No significant 0.001) in the third and sixth treatment cycles. CBG and renin substrate was observed variation of SHBG. levels (Table I).
Table
I. Plasma levels Cm f sem) of hormones. SHBG. CBG. renin substrate. before and during treatment with nomegestrol acetate (5 mg/d. 20 d/cycle)
Normal Estradiol
(pmol/l)
Progesterone SHBG
(nmol/l)
(pg/mll
CBG (pg/mll Renin
substrate
* p -z 0.001 estradiol
(rig/ml)
ranges
BASAL
250 - 800
418 + 51
10 - 75
14.6 + 2.5
3rd CYCLE
6th CYCLE
146 + 35*
98 + 13*
0.6 + D.D3*
0.6 + 0.03*
3 - 6
3.4 + 0.3
2.9 + 0.2
2.6 + 0.2
33 - 49
37.7 + 1.0
39.3 + 0.9
37.5 + 1.1
600 - 1500
as compared with basal 1 pmol/l = 0.27 pg/ml:
DECEMBER 1991 VOL. 44 NO. 6
1116.7 + 52.8 values progesterone
1125.8 + 47.4
:
1 nmol/l
1162.3 + 40.6
= 0.31
ng/ml
601
CONTRACEPTION The average nomegestrol acetate blood levels Mere 10.4 f 6.5 and 8.8 t during 3 and 6 cycles of treatment. 7.2 nglml. respectively, Mean values of metabolic parameters are shown in Table II. Body weight was not significantly modified by treatment. There was a significant decrease in triglycerides levels (p < 0.051 only in the third treatment cycle and in apolipoprotein Al (p < 0.05) in both periods. No significant LOL cholesterol, apolipoprotein B HOL and variation occurred in and apo AI/ape B ratio, blood glucose and insulin levels.
Table
II. Metabolic parameters Cm 2 semi before and during nomegestrol acetate (5 mg/d. 20 d/cycle)
Normal Body weight
(kg)
Cholesterol
(mmol/ll
Triglycerides
Cmmol/ll
ranges
BASAL
treatment
3rd CYCLE
with
6th CYCLE
59.3 + 1.5
57.2 + 2.3
59.9 + 1.7
3.60
- 6.10
5.00 + 0.14
4.93 + 0.13
4.99 + 0.15
0.40
- 2.10
0.89 + 0.08
3.75 t 0.06*
3.83 + 0.05
HDL cholesterol
(mmol/l
0.80
- 2.10
1.13 + 0.03
1.15 + 0.04
1.12 f. 0.04
LOL cholesterol
(mmol/l
1.60
- 4.90
3.67 + 0.43
3.62 + 0.12
3.70 + 0.15
Apolipoprotein
Al (g/l)
1.00 - 2.00
1.56 + 0.04
1.41 + 0.04"
1.45 + 0.04*'
Apolipoprotein
B (g/l)
0.80
0.99 + 0.04
0.99 + 0.04
0.99 + 0.04
1.68 f. 0.07
1.55 + 0.11
1.54 + 0.07
4.82 + 0.08
4.92 + 0.07
4.77 + 0.08
11.5 + 0.8
11.4 + 0.6
11.8 + 0.6
Apo Al/Ape
B
>
Glucose
(mmol/l)
Insulin
(mUI/l)
-
1.60
1.40
3.80
- 6.10
10 - 15
* p < 0.05: l * p < 0.01 as compared with basal values. cholesterol 1 mm0171 = 0.38 g/l: triglycerides 1 mmol/l glucose 1 mmolll = 0.18 g/l Table
III. Hemostatic nomegestrol
parameters (m k sem) before and during acetate (5 mgld. 20 d/cycle)
Normal Antithrombin III (%I (immunodiffusion) Antithrombin (amidolytic
III
(%)
BASAL
ranges
g/l
treatment
3rd CYCLE
with
6th CYCLE
80 - 120
99 + 1
106 + l**
105 + 2**
80 - 120
99 + 1
106 + l**
104 + 2’
106 + 3
137 + 2
104 f. 2
3.2 + 0.1
3.4 + 0.1
3.2 + 0.1
method)
Plasminogen
(%I
70 - 130
Fibrinogen
(g/l)
2 - 4
* p < 0.01:
602
= 0.81
** p < 0.001
as compared
with
basal
values.
DECEMBER 1991 VOL. 44 NO. 6
CONTRACEPTION
Antithrombin sixth and significant
III significantly treatment cycles. modification (Table
increased between and Plasminogen III).
5 and 7% in the third fibrinogen showed no
Mean systolic and diastolic blood pressure did not vary during treatment, There was a significant increase in when measured by the physician. automatically registered mean systolic blood pressure in the sixth cycle (basal values : 109 2 1.4 mmHg; third cycle : 112 + 1.7 mmHg: sixth There was no abnormal value nor 114 5 1.4 mmHG; p < 0.05). cycle: blood significant modification of automatically registered diastolic pressure.
DISCUSSION steroid administration may result in marked metabolic changes, such in lipoproteins metabolism, haemostatic changes and as alterations modification of the renin substrate which may respectively influence the thromboembolism and hypertension (1.13.18). risk of hyperlipidemia. Little is known about the metabolic effects of progestogen-only therapy. It has been shown that norethisterone derivatives induce a decrease in levels and are responsible for and triglycerides HDL cholesterol These effects have been related to the androgenic insulin-resistance. activity of these progestative compounds (1.13).
Sex
administered in normal study. nomegestrol acetate was In this at a dosage known to have a potent menstruating women once daily, inhibitory effect on gonadotropins when prescribed in a 20 days/cycle schedule (31. In fact, under treatment. plasma estradiol levels were markedly decreased whereas progesterone was undetectable. show that the administration of a derivative of 19These data norprogesterone. even at a dosage adequate to inhibit ovulation. results in no significant change in body weight and in fasting blood glucose and insulin. As far as lipoprotein metabolism is concerned, no change in HDL and LDL cholesterol, apolipoprotein B and apo Al/ape B ratio was observed. There was a significant decrease in apolipoprotein Al and a transient decrease in triglycerides levels. Thus, nomegestrol acetate induced only minor changes in lipoproteins metabolism as compared to the modifications observed with 19-nortestosterone derivatives. The latter are responsible for a decrease in HDL cholesterol, a parameter which is inversely correlated to the risk of cardiovascular disease, when they are given alone either to premenopausal women (10-13)) or to oophorectomized women (14). The decrease in apolipoprotein Al during nomegestrol acetate treatment is of the same magnitude as that observed during the administration of chlormadinone acetate and cyproterone acetate, when these progestogens are given in the same schedule as in the present study (15.161. In order to determine whether this effect is due to the progestogen itself or to the decrease in estradiol levels, studies comparing the effect of the progestogen given alone and combined with parental estradiol should be performed. Nomegestrol acetate had no significant fibrinogen and effect on plasminogen. but significantly increased antithrombin III. A similar increase has been previously shown with 17-hydroxyprogesterone derivatives prescribed discontinuously at high doses in premenopausal women (16.17). A few studies have been published on the effect on antithrombin III of the 19-nortestosterone derivatives used in the progestogen-only mini pill. There is no modification with most of them except for a decrease with lynestrenol (18). The mechanism by which
DECEMBER 1991 VOL. 44 NO. 6
603
CONTRACEPTION progestogen at high dose increases antithrombin III is not clear. Here again both the progestogen itself and its hypoestrogenic effect may play a role. According to the pharmacological data (2) and to the absence of significant change of SHBG levels in this study. it seems unlikely that the effect of nomegestrol acetate on antithrombin III is related to the same mechanism as that observed during administration of anabolic or androgenic steroids which results both in an increase in antithrombin III and in a decrease of SHBG (131. It should be reminded that a congenital deficit in antithrombin III. a physiological inhibitor of coagulation. is associated with some venous thromboses. Oral estrogens are responsible for a decrease in antithrombin III activity and for thrombosis (18). The induced increase in clinical consequence of a pharmacologically antithrombin III is not known. The levels of renin substrate did not change during treatment with acetate, neither did the diastolic blood pressure, as nomegestrol observed with other progestins (15.17.19). Although mild and only significant in the sixth cycle, the increase of automatically registered systolic blood pressure needs further studies since the results were contradictory to those observed by the physician. nomegestrol acetate, a Altogether. these results indicate that progestogen with little or no androgenic activity. has no deleterious levels and fasting blood influence on body weight, HDL cholesterol glucose. and avoids the effect of estrogen-progestogen association on coagulation.
ACKNOWLEDGEMENTS We would like to thank this study and Mrs M.R.
Dr A.S. POISSON-SALOMON for her participation LECOD and D. DESNAULT for technical assistance.
in
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