Multicentred clinical study of the metabolic effect of the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide 150 mg + estradiol enanthate 10 mg

MULTICENTRBD CLINICAL STUDY OF TBB NBTABOLIC EFFECT OF THE NOHTBLY INJBCTABLB CONTRACEPTIVE CONTAINING DIBYDROXYPROGBSTBI ACETCPEEIOIDE 150 MG + BSTRADIOL B NANTBATE 10 MG J.C.M. Wiemeyerl, C.L. Sagastalr2, J.M. Roncales Mateo3 A.C.M. Lavarello4, L.A. Angel de Toro, and R. Salas Diai6 1Farmerit S.A., Medical Department, J. Azurduy 1534, 1429-Buenos Aires, Argentina (Correspondence address) 'Present address: Europharma S.A., Madrid, Spain 3Servicio de Obstetricia y Ginecologia de la Ciudad Sanitaria N Miguel Servet, Zaragoza, Spain 4I Catedra de Ginecologia, Universidad de Buenos Aires, Argentina 'Profamilia Bogota, Colombia 6Clinica LoAdres, Mexico D.F., Mexico

Abstract metabolic effect of The the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enanthate (EEn) 10 mg was compared to that of other regularly used contraceptive methods (pills containing: ethinylestradiol (EE) 0.050 mg + levonorgestrel 0.250 EE 0.030 mg + LNG 0.150 mg; EE (WG) 0.030,0.040,0.0% 0.050/0.075/0.0125 mg; norethisterone enantmhgate+(NEEy200 mg i.m.; non-hormonal methods). Serum triglycerides, HDL/LDL-cholesterol, copper, ceruloplasmin, total and free cortisol, CBG, total and free testosterone and SHBG in chronic users were determined. A total of 237 women took part in this study. users of non-hormonal methods as Taking control, levels were higher, and total and free triglyceride testosterone levels were lower in women using DHPA 150 mg + EEn 10 mg and in those taking contraceptive pills (p co.05 Such modifications were slightly less in the group 0.01). using the injectable. The effects of DHPA 150 mg + EEn 10 mg on HDL/LDLceruloplasmin, CBG, total and free cholesterol, copper, cortisol and SHBG were rare or non-existent. Nevertheless, the contraceptive pills (even the low-dose formulations) correlate with modifications of all those variables, which were highly significant in comparison with the injectable (p ~0.01) and with non-hormonal methods (p cO.01); there were no differences between the last two methods. Submitted for publication December 5, 1989 Accepted for publication March 28, 1990

JULY 1900 VOL. 42 NO. 1

13

The results suggest that the metabolic effect of DHPA 150 mg + EEn 10 mg is not higher than that of the commonly On the other hand, they do not used oral contraceptives. suggest that the dose contained in this injectable is There is no evidence that it produces exaggerated. accumulation of effects in the organism. These findings should be taken into account when referring to the long-term safety of this injectable.

Introduction World Health Organization Experts from the have use of recently emphasized the injectable estrogenprogestogen combinations as a contraceptive option, which might be especially valid for the future, and encourage their development (1,2). The main advantage of estrogens in those preparations is that of improving the acceptability and tolerance of progestogens, thus contributing to causing similar the monthly female bleeding, to physiological bleeding (3). These combinations are expected to soon play an important role in many family planning programs all over the world (4). While other centers are investigating associations with estradiol valerate or cypionate at doses of 5 mg (5), we have been using a injectable monthly contraceptive containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enanthate (EEn) 10 mg (Perlutal/Topasele) for many years. A similar combination is marketed, at half doses, in Mexico. There are publications regarding the clinical use of DHPA 150 mg + EEn 10 mg for 5 or even 10 years (6,7), with satisfactory results. However, we have been especially interested in obtaining reliable data about the hormonal effects of this preparation, particularly as regards its estrogenic effect, taking into account that this fact may be related to its long-term safety. It has been experimentally pointed out that DHPA activity is barely l-2 times that of progesterone (8). More recently, based on studies with laboratory animals, Wiemeyer et al. proposed the experimental hypothesis that the estrogenic effect of EEn 10 mg i.m. in women could be similar or lower than that of ethinylestradiol (EE) commonly contained This extrapolation in 21-pill packagleaste;9). seemed to be confirmed when no significant differences were found ’
14

Our intention in this study was to provide new elements may allow the comparison of the effect of DHPA 150

JULY 1990VOL. 42 NO. 1

CONTRACEPTION EEn 10 mg + contraceptives.

mg

with

that

of

other

commonly

used

Variations as regards higher or lower serum or plasma levels of triglycerides, HDL/LDL-cholesterol, sex hormone binding globulin (SHBG), transcortin (cortisol binding globulin, cortisol, ceruloplasmin, CX), copper, testosterone, etc., correlate with higher or lower estrogenic and progestogenic effects of different hormonal contraceptives (11-14). The effects of estrogens and progestogens on each parameter and the time of treatment needed to induce a new steady-state are summarized in the following scheme:

PARAMETER ----_----

EFFECT

ESTROGENIC _______-----------

TRIGLYCERIDES

t

13

-

HDL-CHOLESTEROL LDL-CHOLESTEROL

+

(1

MONTHI

CERULOPLASMIN

*

COPPER

‘f

id

MONTHSi

CBG

+

( 1 IIONTH)

+

il

hONTH,

9

(1

MONTH)

+

(3

-

44

(1

MONTH)

TOTAL FREE

CORTISOL CORTISOL

SHBG TOT&L FREE

TESTOSTERONE TESTOSTERONE

b

MONTHS)

PROGESTOGEN

EFFECT

+I+

N

6

MONTHS1

This research was based on the comparison of the changes the different methods produce on these parameters. Materials

and Methods

Two-hundred-and-thirty-seven women selected from four centers participated in this study on a voluntary basis. The above-mentioned centers were: Centro de Orientation Familiar, in Zaragoza, Spain; Clinica Londres, in Mexico D-F., Mexico; Hospital de Clinicas Jose de San Martin, in

JULY 1990VOL. 42 NO. 1

15

CONTRACEPTION Aires, Buenos Colombia.

Argentina:

and

Profamilia,

in

Bogota,

Women were selected at each center when they came for routine consultation, and they were grouped according to the contraceptive method each of them had been using for the last months, as shown in the following schedule:

NUHSEROF HOtlENWHO PARTICIPATED

~__________~_____~__~~~~____~__________________ CONTRACEPTIVE tiETHOD USED tlEXIC0 ARGENTINA SPnIN COLOHSIn Tom ___~~________~______~~~~~~~~~__________________________~~~~~_~_~_~_~_______________________________ a.

DI~YDROXYPROGESIERONE ACETOPHENIDE 150 mg t ESTRADIOLENANTHATE10 mg

13

10

II

15

49

12

10

IO

15

47

13

10

10

14

41

t LEWNORGESTREL0.050/0.075/0.125 #g

11

10

10

__

31

NORETHISTERONE ENANTHATE200 rg

12

5

__

__

17

NON-HORffONAL CONTRACEPTIVES

12

IO

10

14

46

73

55

51

58

237

0.050 rg t b. ElHINYLESlRADIOL t LEVONORGESTREL 0.250 rg ETHINYLESIRADIOL 0.030 figt t LEVONORGESTREL 0.150 mg ETHINYLESTRRDIOL 0.030/0.040/0.030 mg

ToTnLs

device pill, injection or was No especially manufactured for this study. All users had been purchasing them at the drug stores or receiving them from the family planning centers under normal conditions. It was taken into account that in some countries a certain group of women might not exist when, at the time of this study, the corresponding treatment was not available. Non-hormonal methods included periodic abstinence, coitus interruptus, condoms or diaphragms without jellies or other substances, and inert IUDs. In order to be accepted in the study, every woman had to meet the following criteria for inclusion: a) use of the same contraceptive method for at least the 6 previous months, b) absence of signs or symptoms of illness, c) 20-30 years of age, d) white race, and e) body weight ranging between 90 and 104% of that corresponding to the age and height.

16

JULY 196OVOL. 42 NO. 1

Criteria for exclusion were: a) present pregnancy, b) pregnancy, parturition, abortion or lactation during the 6 of absolute or relative previous months, c) presence contraindications to use of hormonal contraceptives, d) habit of smoking, e) alcoholism (weekly consumption over 140 treatments during g ethanol), and f) other pharmacological the 3 previous months. Criteria for inclusion and exclusion were verified in selected, and good was every woman health confirmed clinically and by the usual complementary analysis in the The following biochemical studies were different centers. 1) carried out, each center using the same methodology: serum triglycerides (completely enzymatic method, U.V. test, HDL-cholesterol/LDL-cholesterol, Boehringer-Mannheim); 2) based on cholesterol (enzymatic calorimetric method, CHODPAP, Boehringer-Mannheim) and HDL-cholesterol (precipitation + CHOD-PAP, Boehringer-Mannheim) determinations and the LDL-cholesterol = cholesterol following calculation: HDL-cholesterol; 3) triglycerides/5 serum copper bathocuproin with deproteinization, (calorimetric method, serum ceruloplasmin Boehringer-Mannheim); 4) (radial Behring); 5) immunodiffusion, Partigen, serum total testosterone (RIA, Maia, Serono); 6) serum free testosterone (calculated according to Pearlman(;;~G)Cre&;A(15)): 7) serum sex hormone binding globulin (NH4)2 S04, Serono); 8) serum total cortisol (RIA, Mai;, Serono); 9) serum free cortisol (calculated according to Chader and (CBG) Westphal (16)) ; 10) serum cortisol binding globulin (disk assay, according to Rossner et al. (17)). these biochemical analyses, venous blood was For extracted between the 25th and 28th day of the menstrual In women whose cycles were habitually shorter than cycle. 28 days, blood extraction was performed during one of the 3 days prior to the expected menstruation. were Women requested to fast for 12-14 h prior to blood collection. Results obtained for each of the biochemical parameters studied were statistically assessed as follows: 1) users of non-hormonal methods were considered as control: 2) control groups from different countries were compared by analysis of variance: 3) when differences between control groups were from significant, results all the countries were not accumulated: 4) when differences between control groups were significant, the arithmetic mean of the control from each country was considered to be 100, all the results being arithmetic mean of the expressed as relative to the we corresponding country; 5) with data so transformed, proceeded as in [3]; 6) based on data from [3], a comparison of the effects of the different treatments was performed by analysis of variance: 7) when differences between treatments treatments were compared against the significant, were

JULY 199OVOL. 42 NO. 1

17

control group and DHPA 150 described by Huitson (18).

mg

+

EEn

10

mg

by

the

test

Results Women using DHPA 150 mg + EEn 10 mg were doing so for 21.7 + 2.5 months S.E.); (mean + those taking the contraceptive pills were consuming them for 24.8 + 3 months (EE 0.050 mg + LNG 0.250 mg), 22.5 + 2.9 months (EE 0.030 mg + LNG 0.150 mg), and 13.9 + 1.1 months (EE + LNG triphasic); those receiving NEE, for 14.3 + 1.2 months; those using nonhormonal contraceptive methods, 35.8 f. 3.5 months. Table I shows the results (mean It standard error) of the biochemical studies carried out in the different groups of Spanish women. Table II presents the values found in Mexican women, Table III those for Argentine women, and Table IV those for Colombian women. Figure illustrates the mean The value of each biochemical parameter studied, taking into account all the women and the contraceptive method used. Tendencies shown by the results from the different countries were compatible and allow the global assessment of the results beyond interindividual variations and changes among centers, which, even though having used the same methods, may be due to ethnic, diet, seasonal, etc., and especially to the fact that biochemical differences, tests were not performed in only one laboratory. The triglyceridemia did not show significant differences among treatments when considering each separate Accumulation of results, however, center. shows higher values in groups receiving estrogens, either orally or parenterally, than in the control group. This increase was higher in women treated with pills containing EE 0.050 mg (p ~0.01) than in those using low-dose pills or DHPA 150 mg + EEn 10 mg (p c0.05). There were no significant differences between these last two groups. Likewise, groups receiving monophasic pills showed a decrease in the HDL/LDL-cholesterol relationship, clearly distinguishing those women from the ones treated with the combined injectable (p ~0.05) and from those using nonhormonal methods (p
18

JULY 1990 VOL. 42 NO. 1

DHPA 150 t EEn 10 (a) EE 50 + LN6 250 (b)

EE 30 + LNS 150 (c)

EE t LN6 TRIPHASIC (d)

X t_ SE anova

0.29

t

0.01 0.31

?

0.01

0.32

f

0.006

0.31

i

0.006

0.31

!

0.01

3.02

k t SE anova

FREE

28.54

0.35

I.96

148.77

j

a.79

?

?

3.50

0.03

_t 0.19

10)

41.0&

0.50

1.8b

153.83

?

.!

t

i iOOi

4.62

0.05

0.33

8.5b

32.23

0.42

2.09

152.08

8.02

0.05

_+ 4.11

t

_t 0.16

t (00)

19.36

0.30

2.93

140.00

t

t

3.07

0.04

t 0.30 iDOh

_t 8.55

b0.83

0.58

1.13

125.17

i

?

f

i

9.71

0.08

0.17

6.29

44.67

0.49

1.48

lob.75

29.31

0.31

86.83

2.15

0.46

f

t

t

7.04

0.07

O.ib

t 5.05 ($1

t

t. 0.01

f

I

X ! SE anova

94.31

t

12.14

137.08

t

12.66

173.23 (00)

f

13.89 i**)

174.55 _t 14.44 (00) (‘$)

CORTISOL X ? SE 16.80 f 3.86 14.90 ! 2.77 13.81 ! 1.19 14.13 ! 2.64 (nnol/l) anova ________________________________________~________~____~_____~__~_~~~~~---------------------------~-----------~---------------------~----

iREE

(n9lrl

TOTAL CORTISOL

11.51

95.33

!

!

0.89

11.91

11.89

01.42

4.17

t_ (1.91

!

& _______________________________________________________________________~_____~________~_______________________~~~~~_ c 8 i; x _tSE 40.lb _t 3.76 70.58 f 0.37 79.62 t 3.69 07.52 f 7.94 49.03 r 6.56 39.13 r 1.25 anova (00) (*‘I (00) (“) I mcglrl) (0) (‘I

KSTOSTEROIIE ipt!OL/ll

t

X ! SE anova

(ng/nl

TOTAL TESTOSTEROlvE

x t SE anova

SHBG (rcg DHTjiOO

81)

x ! SE anova

COPPER (acg/loO li)

CERULOPLASHIN X t SE 37.52 t. I.84 51.52 t 3.12 53.35 t 2.0 52.05 _t 2.82 38.59 t 5.11 (eg/1OOeli anova (00) (00) (‘) (00) ___________________________________________________________________________________________________________~~~~~~~~~_~~__~_~_______~~___

HDL/LDL CHOLESTEROL

NON-HORHONAL

(f) (n : 12) ___________________^__________ : 12)

(e)

NEE 200

X j SE 99.15 ! 9.33 109.42 ? 7.92 101.00 ? 9.60 95.55 ? 8.10 88.00 ! TRIGLYCERIDES (rg/10011) anova ________________________.__._______________________________________“____________________________________________________________________

___________________________“____!~_~_!~~_*________!~_~_!~!__________!~_~_!~~__________!~_~_!!~___________!n

DETERtlINATION

fror 73 Spanish Women Using Different Contraceptive nethods (for footnotes see Table IV) _________________________________________________________________~_________________________________________~____~_~~__~_~~~~~~_~~~~_~~~~

Table I: Results Obtained

CONTRACEPTION

20

JULY 1990 VOL. 42 NO. 1

0.53

TOTAL TESTOSTERONE

0.20

2.49

109.20

85.00

t

3.20 96.20

j

3.09

0.30

_t 9.62

f

45.40

2.80

2.41

135.20

f

!

0.14

8.16

103.90

6.05 __________

!

_t 0.07 0.58

t

0.08 0.33

.!

0.04 0.36

_t 0.03

TESTOSTERONE

X t SE

42.82

t

7.47 45.10

!

7.06

104.40

22.95

CORTISOL

X _t SE

21.07

f

f

2.00

11.76

29.29

319.70

t

0.05

t

(“)

110.10 t 4.70 44.90 f 3.29 (00) (6s) ____________________________~~~~~~~~~~~~~

5.87

t 3.13 19.40 t 1.83 51.40 f 4.90 (0) (00) ____________________~~~~__~~~~~~~~~~~~~~~~~-----

0.69

f

5.46

43.63

5.98

41.15

f

5.15

23.50

t

5.05 (*) ____________________~~~~_________~_~~_~~~~~~~~~~

+

f 60.22 438.00 ! 37.82 444.00 f 37.13 134.10 i 15.05 (0) (1) (OO) (“) (00) (“) _______________________________________________~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~----

132.73

anova Intlol/l) __________________________________________________________~_~~~~~~~~~~

anova (ng/rU ____________________-------FREE CORTISOL X r SE

TOTllL

anova (00) (00) (“) (rc9lrlI ________________________________________________________________~_~~~~~~~~~~~

anova (PWl) __________________________________________________________~~~~~~~~~~~~ C B 6 X _t SE 42.18 _t 2.48 94.10 t 14.33

FREE

anova (00) (00) (ng/el) ____________________________________________________________________________________~~~~________~_~~_~~~~~~~~~~-~-----

X f SE

3.55 t 0.15 2.17 ?I 0.19 (001 (“) (rcg DHT/lOO rl) anova ____________________________________________________________________________~_~~~~~~~~~~_____~~~~~~~~~~~~~~~~--~---~--

f

2.06

7.16

5.76

0.09

8.23

(00) (“) (00) 01) (a*) ____________________________________________~_~~~~~~~~~~~~~~-

158.50 _t 6.65 (00) (“) _________________________________________________~_~~~~~~~~~~~~~~~~------------

!

105.64

COPPER X f SE anova (rcg/lOO rl) _____________________________ SHE6 X f SE

j ?

82.90

anova (rg/lOOel) (00) ____________~_________~_~~~~~_____~_~~~~~~~~~~~~~-~~-----

_t 5.49

CERULOPLASHIN

49.91

f

HDL/LDL X ! SE 0.54 r 0.05 0.42 f 0.03 0.47 _( 0.06 0.44 1 0.05 0.61 anova CHOLESTEROL ____________________________________________________________________________________~~~~____~~~~~~~~~~~~~~~~--~-------

X ! SE

!

NON-NORttONbL EE 50 t EE 30 t EE t LN6 DHPR 150 + TRIPHASIC (d) LN6 250 (b) LN6 150 (c) EEn 10 (a) (f) (n : 11) (n : IO) (n : IO) (n : ID) (n : 10) ___________________________________________________________~_____________~_~~~~~~~~~~~~-~-

Contraceptive liethods ifor footnotes see Table IV) ______^____________________~~~~~~~~~~~~~~

70.73 f 7.14 79.30 _t 9.06 63.10 ? 9.28 78.60 ! 4.36 65.60 (r9/100al) anova ______________________________________________________~__~~______________~_~~~~~~~~~~~~-~~~~~~~~~~--------------------

____________________________ TRIGLYCERIDES X f SE

DETERHINRTION

Table III: Results Obtained from 51 Argentine Woren Using Different ___________________________________________________~_~~~~~~~~~~~-~~----------

d

?

z

k

B

X i SE

128.80

i

16.43

DHPA 150 + EEn 10 (a) (n : 13) 133.67

LNG

+

11.23

230 (b) (n : IS)

EE 30 t

141.71

!

19.39

I50 (c) (n = 14)

EE 30 + LNG

X f SE

0.59

f

0.07 0.46

f

0.03

0.43

!

0.06

anova

X + SE

30.40

_t 2.32 (001

78.60

! (‘“)

4.82 (00)

77.64 I”)

_t 4.06

X + SE

2.29

t

0.23 4.71

t_ 0.25

4.99

f

0.30

TESTOSTERONE

TESTOSTERONE

(n9lel)

X _t SE

anova

X ! SE

24.33

0.33

t

3.39

_t 0.03

18.20

0.40

t

t

2.82

0.06

7.14

0.17

f

f

(00)

SORTISOL

X r SE

167.80

24.80

t

_t

8.07

1.09

379.40

t_ 26.17

337.07

(_ 32.62

1.27

0.04

CORTISOL

(nHol/l)

anova

X 2 SE

60.18

t

4.80 (00)

167.62

!.

20.76 (‘$)

_____________________________________________________________________________________________-_____

FREE

147.01 (00)

!

24.81 (“)

(00) (**) (00) I**) ___________________________________________________________________~~~~~~~~_~_~~_~-~~-~~~----------

TOTAL

X i SE

anova cpn0Lil) (01 _______.____________________________________________!~~!______________~~~!_______________!~~_______

FREE

TOTAL

lrcg DHi/iOO 111 anova 100) (“) (00) (**) _____________________________________________~~~~~_______~_________~~~~~~~~~~~~~~~~~~~~~~----------

SHE6

X r SE 118.40 t 3.34 227.43 f 12.96 233.33 + 10.81 anova (ecg/lOO rl) (00) (**) (00) ($1) ___________________________________________________________________~~~~~_________~~~~~~~~--~~-~~--~

COPPER

(eg/ lOOel)

CERULOPLAStlIN

CHOLESTEROL anova __________________________________________________________________________________~_~~___~~~~~~~~~~

HDLiLDL

(Dg/looel) anova __________________________________________________________________________________~___~__~~~~~~~~~~

TRIGLYCERIDES

DETEMINATION

Table IV: Results Obtained fror 38 ColombianYoren Using Different Contraceptive _____________________________________________~_~_________________________________________~~~~~~~~~_

37.32

138.14

43.00

0.59

t

f

+

i

6.41

11.13

7.34

0.09

t 0.20

2.11

2.03

0.11

17.64

_t 3.19

f

f

t

122.37

44.29

0.70

96.79

(f) (n = 14)

NON-HORI(ONRL

tlethods

vs. vs. vs. vs.

*) p ( 0.03 **) p ( 0.01

Non-horeonal

0) p ( 0.03 00) p ( 0.01

t;

e) Noretisterone I injection

orally,

enanthate everv

DHPA DHPA

130 130

non-horeonal non-horronal t EEn + EEn

10 10

200 rg, 2-3 eonths

rg + 0.050/0.073/0.123 per ronth.

t levonorgestrel:

contraceptives

1.1.

0.030/0.040/0.030 orally, 21 pills

d) Ethinylestradiol

orally,

t levonorgestrel:

0.030 rg t 0.130 rg, 21 pills per ronth.

c) Ethinylestradiol

acetophenide 130 rg t 10 rg, ronth.

t levonorgestrel:

enanthate: 1.1. per

0.030 rg + 0.230 rg, 21 pills per ronth.

b) Ethmylestradlol

estradiol 1 injection

a) Dihydroxyprogesterone

FOOTNOTES:

+

ag,

CONTRACEPTION

ERULOPLASMIN

!IGLYCERIDES

I ri I I 3I1 0

I

-I

00

d

e

3 .

HDL/LDL 1

L

COPPER

CHOLESTEROL

I

*

*

I

1

b

b

c

(cont.)

FIGURE

:

COMPARISON DETERMINED CEPTIVE

JULY 1990 VOL. 42 NO. 1

OF BIOCHEMICAL PARAMETERS (mean -?r SE) IN CHRONIC USERS OF DIFFERENT CONTRO-

METHODS

(non-hormonal

methods

=

100

t

SE).

23

CONTRACEPTION

CSG

SHBG

I...;:

h (a 1 I

II a

TOTAL

1

i

CORTISOL

e

f

-

a

e

I

OTCIL

l!

TESTOSTERONE

-l

I 00

2

**

00 **

t

I

I h1 a

FREE

L

C

CORTISOL

REE

TESTOSTERONE I

FIGURE

24

(cont.)

For

footnotes

see

Table

IV.

JULY 1990 VOL. 42 NO. 1

CONTRACEPTION The same changes were seen when comparing total and levels: values of and CBG serum mean free cortisol contraceptive pill users were twice those of the control There were no significant differences, group (p
We have seen that serum levels of ceruloplasmin, consistently and SHBG, CBG and cortisol change copper, receiving pills with EE + significantly in women levonorgestrel (LNG), even at low doses, in comparison with non-hormonal those those women using methods and with receiving the monthly injection containing DHPA 150 mg + EEn The same change occurs when assessing triglycerides 10 mg. and HDL/LDL-cholesterol globally. Changes observed in women treated with the studied monthly injection were not higher than those confirmed in with treatment the usual low-dose oral women under On the contrary, most of the contraceptives in any case. injectable use of the corresponded with time, the significantly lower changes and/or with values similar to those of the group not receiving hormones. Recio et al. reported the absence of effect of DHPA + EEn on HLD-cholesterol levels and judged that this might be due to the fact that the actions of DHPA and EEn on this Our results agree indicator are opposed and balanced (19). In this with those of Recio et al. and complement them. parameters which may be modified by study we included estrogenic substances but are virtually not affected by and such as ceruloplasmin CBG progestogens, copper, These parameters changed as expected in women (13,14,20). receiving BE + LNG but not in those using DHPA + EEn. So, the estrogenic activity of EEn 10 mg seems to be low rather than balanced by DHPA. It is worthwhile to comment that women using DHPA 150 mg + EEn 10 mg had been doing so for 21.7 months (average)

JULY 1990 VOL. 42 NO. 1

25

We point this out because Schiavon et prior to the study. al. found estrone levels which were temporarily high in 7 women using this method for a long time (21). The clinical and metabolic consequences of this slight increase remained Now, our results show, no additional but, to be elucidated. fewer metabolic consequences than those found with other hormonal methods of contraception. of this trial does not allow Although the design verification of each one of the possible long-term side effects of the different methods, it must be kept in mind of estrogenic that high estrogenic activity, accumulation the organism and changes of the studied effects in parameters have been directly correlated with many delayed, undesirable effects of hormonal contraceptives. We have not evidence indicating that the estrogenic observed any activity of DHPA 150 mg + EEn IO mg is exaggerated, or that it causes accumulation of estrogenic effects. Metabolic changes induced by it seem to be similar or very much lower than those corresponding to oral low-dose contraceptives. so, this might suggest that its long-term safety might be lower than that of the commonly used oral contraceptives. If these data are also valid for other monthly injectable contraceptives, containing other progestogens and other estradiol esters at different doses, remains to be confirmed. As regards the injectable containing norethisterone enanthate 200 mg, the low number of women seen while using this method, and its lack of availability in two centers (Argentina and Colombia) resulted in a small sample size (n = 17). Therefore, although we do not disregard the results, we cannot comment on them.

Acknowledgements The authors with to thank Dr. J .M. Gomez Calatayud and in Dr. A. Minano Navarro in Spain and Dr. A. Michelini Argentina for their help in volunteer recruitment. We acknowledge the biochemical and statistical assistance of Dr. S. Dainilano, Dr. J. Tessler and Mr. J. Labrador in Buenos Aires, Dr. P. Bellod Gimenez in Madrid and Dr. Ruth de Estrada in Bogota. We are also grateful to Ms. M.R. Pulido for her excellent secretarial help. References 1. 2.

26

Diczfalusy E. Fertility regulation - The present and the future. Contraception 1985;32:1-22. Diczfalusy E. New developments in oral, injectable and implantable contraceptives, rings vaginal and intrauterine devices A review. Contraception 1986;33:7-19.

JULY 1990 VOL. 42 NO. 1

3.

4. 5.

6.

7.

8.

9.

10.

11.

12.

13. 14.

15.

16.

Diczfalusy E. WHO Special Programme of Research, Development and Research Training in Human Reproduction. The first fifteen years: A review. Contraception 1986;34:2-119. Hall PE. Anticonceptivos inyectables de dosis mensual. Bol Fled IPPF 1987;21:1-2. WHO Task Force on Long-Acting Systemic Agents for A multicentred phase III Fertility Regulation. contraceptive comparative study of two hormonal intramuscular preparations given once-a-month by injection. I. Contraceptive efficacy and side effects. Contraception 1988;37:1-20. Roncales Mateo JM, Minano Navarro A, Gomez Calatayud JM. Experiencia clinica con anticonceptivos hormonales administrados por via inyectable. Toko-Ginecologia Practica 1982;41:63-73. Rustrian AA. Investigation clinica sobre diez anos de anticoncepcion inyectable mensual. Invest Med Int 1980;7:27-31. Lerner IJ, Brennan DM, DePhillipo M, Yiacas E. Comparison of biological activities of progesterone, norethisterone and the acetophenone derivative of 16-a, 17-a-dihydroxyprogesterone. Fed Proc 1961;20:200. Wiemeyer JCM, Guerreiro RB, Fernandez M, Sagasta CL. Experimental findings on the estrogenic activity of estradiol enanthate. Arzneim Forsch/Drug Res 1986;36:1667-70. Moguilevsky JA, Wiemeyer JCM, Sagasta CL, Leiderman S. Estrogenic activities of estradiol enanthate and ethinylestradiol compared at a clinical level. Arzneim Forsch/Drug Res 1986;36:1671-74. Bradley DD, Wingerd J, Pettiti DB, Kraus RM, Ramcharan S. Serum high density lipoprotein cholesterol in women using oral contraceptive estrogens and progestins. N Engl J Med 1978;299;17-20. Larson-Cohn U, Fahraeus L, Wallentin L, Zador G. Lipoprotein changes may be minimized by proper composition of a combined oral contraceptive. Fertil Steril 1981;35:172-79. Vermeulen A, Thiery M. Metabolic effects of the triphasic oral contraceptive Trigynon. Contraception 1982;26:505-12. Gaspard UJ, Romus MA, Guillain F, Duvivier J, DemeyPlasma hormone levels in Ponsart E, Franchimont P. women receiving new oral contraceptives containing ethinylestradiol plus levonorgestrel or desogestrel. Contraception 1983;27:577-90. Pearlman WH, Crepy 0. Steroid-protein interaction with particular reference to testosterone binding by human serum. J Biol Chem 1967;242:182-89. Steroid protein interactions. Chader GJ, Westphal U. J Biol Chem 1968;243:928-39.

JULY 199OVOL. 42 NO. 1

27

CONTRACEPTION 17.

18. 19.

Rosner W, Beers PC, Awan T, Khan S. Identification of corticosteroid-binding globulin in human milk: with a filter disk J measurement assay. Clin Endocrinol Metab 1976;42:1064-73. Huitson A. The analysis of variance. Griffin, London, 1966. Garza-Flores J, Recio R, Schiavon R, et al. assessment of Pharmacodynamic dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly Contraception 1986;33:579injectable contraceptive. 89.

JULY 1990VOL. 42 NO. 1