Ahunces in Cmraception 5 (1989) 57-70 0 1989 Kluwer Academic Publishers, Printed in the Netherlands

Clinical evaluation of a new combined oral contraceptive desogrestrel- ethinylestradiol

J.A. YABUR, M. ALVARADO and V. BRITO

Gynecology and Human Reproduction Service, Yose &nacio Baldo’ Hospital, Caracas* Venezuela

Abstract

A clinical study was performed witb a new progestogen, desogestrel, in a 0.15 mg dose associated with 0.03 mg of ethinylestradiol and was administered cyclically during 21 days; 632 cycles were evaluated in 56 women.

Side-effects were scarce and generally of a mild nature. Monthly bleeding was normal and present in all cycles. Patients with irregular cycles were normalized to 28/29 days. The intermenstrual bleeding (spotting) was an isolated event in 16 cycles. Mastalgia, the most frequent symptom, disappeared spontaneously in the majority of patients. In only 2 cases was it necessary to stop medication because of side-effects.

The contraceptive effect was excellent; no pregnancies occurred. A progest- ative effect was evident in the cervical mucus and the endometrium. The patients who started treatment with acne improved noticeably. In the mild cases, acne disappeared completely. A discrete improvement in hirsutism was reported. The body-weight variation was not significant.

Biochemical studies revealed an increase in HDL-C and a decrease in the ratio LDL-C/HDL-C. Cholesterol and triglycerides did not show variations, which could indicate a lesser cardiovascular risk.

Introduction

Ever since the introduction of the first oral contraceptive (OC) by Pincus, a great number of studies have been done with new oral contraceptives, subsequently leading to the marketing of these new products. Likewise, researchers have conducted countless tests to evaluate the effects of these new OCs in humans. Efficacy has never been a problem, but side-effects and safety have been a cause for constant concern. This explains the periodic introduction of new progestogens and the reduction of the dosage, in an effort to diminish the risk of side-effects.

57

53 Yabur et aZ

Recent research [l-4] shows that the risk of severe side-effects of new OCs is relatively small, cardiovascular troubles being the chief cause for concern due to changes in the metabolism of the lipoproteins [5-91.

For this reason, desogestrel was introduced to the OC market. This is a completely new progestogen with a selective profile of activity, which binds preferably to the progesterone receptor [lo]. Papers published in 12 European countries have shown that the combination of 0.15 mg desogestrel with 0.03 mg ethinylestradiol* is an effective OC (pregnancy rate, 0.1 woman/year) and has negligible side-effects [l,ll-141.

Some researchers reported that this association of desogestrel with ethinyl- estradiol produces an increase of the HDL-C levels [4,1.5,16] and a decrease of the LDL-C levels [4,16], resulting in a reduced LDL-C/HDL-C ratio [4,16,17].

The objective of this paper is to study the effectiveness of the combination desogestrel-ethinylestradiol, its possible side-effects, and the behavior of the plasma lipoproteins.

Materials and methods

A total of 56 women between the ages of 18 and 33, with proven fertility (last childbirth less than one year prior to the date of beginning the treatment), and not smokers or smoking a maximum of 10 cigarettes a day, were selected for this clinical study. All of them were healthy and leading an active sexual life. None showed a contraindication to OC use. The product tested was a combination of 0,15 mg desogestrel associated with 0.003 mg ethinylestradiol, and the information collected covered a total of 632 cycles.

The method consisted of administering this combination of desogestrel and ethinylestradiol for 21 days, starting on the fifth day of the fust cycle, and, in a few instances, on the first day of menstruation during the initial treatment cycle, with a 7-day interruption between cycles. Each patient was programmed for 12 cycles. Clinical tests were made, as well as cytology for Papanicolaou and colposcopic tests. Women came back each month for consultation and their answers concerning their last menstruation were recorded on questionnaires, as were the results of the tests, and any abnormality noticed, or other data considered to be of interest.

One or two weeks prior to the beginning of the tests, at the time of the third, sixth and twelfth cycle, cholesterol, triglycerides, HDL-C and LDL-C values were determined in 10 patients selected at random. Hematology and glycemia tests were made before and after the research. During cycles 1,3,6 and 12 a study of the cervical mucus was made between days 11 and 13 of the cycle; functional vaginal cytology with the first sample taken between days 11 and 13 and a second one between days 20 and 21; and finally, along with a second cytology sample, an endometrial biopsy, in a significant number of patients. Arterial tension and body weight were controlled monthly.

* Trade name: Marvelon (Organon International, Oss, Holland) (Organofl Venezolana, Caracas, Venezuela).

Clinical Evaluation of a New Combined Oral Contraceptive Desogestrel-Ethinylestradiol 59

Results

Age and parity

The study included only women with an active sexual life, proven fertility and those at the age of highest reproductive potential. The highest incidence (46 patients, 82.14%) was seen in women in their twenties (Figure 1). Data on parity and abortions are shown in Figure 2. No pregnancies occurred.

Cycle evolution

None of the patients reported amenorrhea. Bleeding appeared in all of the 632 cycles evaluated, during the period when treatment was interrupted. Of the cycles, 90.66% had a duration of 27 to 30 days, top limits being 22 and 33 days. By comparing these results with the duration of the pretreatment cycle, a tendency to reduction of the cycle to about 25-30 days may be observed (Figure 3).

During the use of the combination desogestrel-ethinylestradiol, monthly bleeding diminished in duration as well as in quantity, as compared with the last bleeding before treatment (Figure 4). No substantial abnormal bleeding was found; cycle changes and spotting were infrequent (Figure 5). Duration and quantity of bleeding became normal in ten patients who had previously reported hypermenorrhea. Another 19 patients with various degrees of dysmenorrhea before the test reported that the dysmenorrhea disappeared during the first six months of treatment (Table 1).

PATIENTS n=56

19 20-24 25-29 30-34

7 Figure 1 Patients: distribution by age AGE IN YEARS

60 I’abur et al

1

PATIENTS 25

n-56

1 2 3 4 5 6 7- 8 9 10 ABORTIONS

PARITY

Fiire 2 Patients: gestation

DURING TREATMENT BEFORE TREATMENT

NUMBER OF CYCLES h-632) NUMBER OF CYCLES (n-56) 350 28

D,,RlNG TREATMENT . . . . . . . . . . E- 28 DAYS

!i - 30 DAYS 300- -24

250- - 20

200- -16

150- - 12

100 - -8

50- -4 , , .

ol \; 1 1 I y 1 i l t 1 I y 1 1 --.y I()

21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

DAYS

Figure 3 Patients: cycle evolution

Clinical Evaluation of a New Combined OraI Contraceptive Desogestrel-Ethinylestradiol 61

DURATION MENSTRUAL BLEEDING DURING TREATMENT BEFORE TREATMEN

520

480

440

400

380

320

280

240

200

160

120

80

40

0

NUMBER CYCLES (n-632) NUMBER CYCLES h-56)

DURING TREATMENT +++++++ ?i - 3.0 DAYS

BEFORE TREATMENT *****-* y - 4.5 DAYS

30

25

20

15

10

*

t 1 JO 0 1 2 3 4 5 6 7 8 9 10

DAYS Figure 4 Patients: monthly bleeding

HYPOMENORRHEAPOLYMENORRHEA SPOTTING HYPERMENORRHEA

42 25 10 5

Fiire 5 Patients: cycle disturbances

62 Yabur et al

Table 1 Evolution of dysmenorrhea (n = 19)

Inten.@

First 3 months Moitths4-6 Months 7- 12

Light (n = 3) Moderate (n =S) Heavy (IZ = 11)

3 5 7 4

Table 2 Side-effects (n=56)

Inten@ QlfUF#ti~ Percent

Light 5 8.92 Moderate 2 3.58 Heavy 2 3.58 Asymptomatic 47 83.92

Total 56 100.00

Table 3 Side-effects type and intensity (n= 632 cycles)

Effect Ligh Moderate Heavy Total Percent

Mastalgia 27 7 3 37 5.85 Cephaigia 16 16 2.53 Mammary hypersensitivity 14 14 2.22 Insomnia 6 6 0.9.5 Nausea 2 1 3 0.47 Others 3 3 0.47

Total 12.48

Clinical Evaluation of a New Combined Oral Contraceptive Desogestrel-Ethinylestradiol 63

Tolerance and side-ej$ects

No major side-effects occurred and 47 patients (83.92%) had no side-effects at all (Table 2). According to type and intensity, the most frequent side-effects in the 632 cycles evaluated were mastalgia 5.85%, headaches 2.53% and mammary hypersensit- ivity 2.22%, giving a total of 12.48% of the women experiencing side-effects (Table 3).

Ten out of 12 patients who began the treatment having acne were totally cured (83.33%) and the rest improved substantially (16.67%) (Table 4). Hirsutism shown by three patients improved by the end of the 12-cycle treatment.

Test-end hematology and glycemia controls showed no variation from fmdings obtained at the beginning of treatment.

For all of the ten patients (17.86%) who had varices of diiferent severity at the outset, no thrombophlebitis was reported.

Libido

The effects on libido are difficult to evaluate through questionnaires. Sexual activity may be reduced, owing to a feeling of guilt or fear about takmg OCs, or may be increased when the fear of pregnancy is relieved. Table 5 shows the changes reported by the patients.

Blood pressure

In monthly blood pressure measurements, few variations were found, all of them with- in a normal range. Practically no variations existed by the end of the test (Table 6).

Body weight

No significant changes were registered with respect to the patients’ body weight. Weight was recorded monthly and the initial weight of the patient was compared with the last weight recorded at the end of the study. Results showed an average increase of 0.56 kg (Table 7). A total of 29 women (51.79%) increased their weight, with a maximum of 3 kg in one case, and 9 of them (16.07%) showed weight losses, with a maximum of 2 kg in one case. There was no variation in the remaining 18 women.

64 Yabur et al

Table 4 Acne evolution (II= l2)

Disappearance

First 3 months Months 4 - 6 Month 7- 9 Months 10-12 Persists

Light (n = 9) Moderate (n) Heavy (n = 1)

6 1 1 1* 1 1

1*

* Major improvement Healed 83.33%; improvement 16.67%

Table 5 Libido (n = 632)

Qcles I-3 4-6 7-9 10-12 Total

Increased 5 (0.79%) 8 (1.27%) 6 (0.95%) 6 (0.9S%) 25 (3.96%) Decreased 2 (0.32%) 3 (0.47%) 3 (0.47%) 2 (0.32%) 10 (1.58%)

Table 6 Arterial pressure (mmHg)

Before assay After assay n = 56 n = 56

Systolic 113.57 ? 8.35 1lS.W ?I 8.23 Diastolic 63.75 2 5.24 64.02 25.08

Table 7 Body weigbt (kg)

Before assay (n = 56) f 53.88 2 7.06

After assay (n =56) x 54.41 2 6.89

Variation z 2 0.56

Clinical Evaluation of a New Combined Oral Contraceptive Desogestrei-Ethinylestradiol 65

Endomehium, cervical mucus and vaginal cytology

Between days 20 and 21 of each cycle, 52 endometrial biopsies were performed (8.23% of the total of cycles); 18 samples were taken during the fast cycle, 13 were taken in the third, 8 in the sixth, and 13 in the twelfth cycle. The histopathologic result was always the same, namely proliferative endometrium under progestational action.

Cervical mucus was taken in 124 samples and analyzed between days 11 and 13 of the cycle (19.42%), with a total of 116 taken between days 20 and 21 (18.35%); the mucus invariably showed the same pattern: it was viscous and scarce.

On evaluating functional vaginal cytology, 124 samples were taken in the inter- mediate phase of the cycles and 116 in the second one; average values for pyknosis were 32.21% and 31.28%, respectively (Table 8).

Lipids and lipoproteins

The results of cholesterol and triglyceride tests obtained before, during, and at the end of the treatment were within normal range. The values of HDL-C increased by an average 98 mg/dl. The LDL-C/HDL-C ratio fell by 0.83 (Table 9 and Figure 6).

Only 2 withdrawals (3.8%) due to side-effects occurred. One woman withdrew after 8 cycles of severe mastalgia and the other, a woman with a history of gastric ulcer, showed nausea, vomiting, dizziness and severe headache (Table 10).

Table 8 Functional vaginal cytology

C+cle 1 3 6 12

Samples collected between days 11 - 13 (n = 124}

NO. of samples 32 33 30 29

% Pyknosis 35.53 2 3.98 32.79 ? 3.88 30.70 5 4.23 29.83 z 1.49

z32.21 2 2.54

Samples collected between days 20 -21 (n = 116)

NO. of samples 32 29 26 29

% Pyknosis 33.56 ? 4.43 31.24 2.80 2 30.38 k 2.94 29.93 k 2.05

x31.28 2 1.62

66 Yabur et al

Table 9 Cholesterol, triglyceride and lipoprotein values

Cycle 0 3 6 12 Variation

No. of women 14 14 11 10

CholesteroI 150-160 mg/dl

182.57 ? 52.36 171.21 2 3S.85 188.33 k 56.29 184.00 ? 32.29 +1.43

Triglyceride 10-199 mg/di

80.64 2 38SS 94.43 2 43.80 107.CKI ? 55.46 111.30 2 46,89 +30.66

HDL-C 33-75 mg/dl

45.70 z 13.48 48.00 ? 13.86 50.30 2 13.82 59.40 k 12.67 +13.70

LDL-C 60-178 mg/dl

120.40 2 43.W 106.20 2 31.38 119SO 2 37.78 110.60 2 29.62 -9.80

LDLX/HDLX 2.78 2 1.05 2.38 2 0.97 2.49 2 0.84 1.95 2 0.67 -0.83

Table 10 Patient withdrawals (II= 56)

Wthdrawak Quantiy Percent

Desires pregnancy 3 5.36 Side-effects 2 3.58 Completed studies 51 91.06

Total 56 100.00

Discussion

Gynecologic exams performed at the beginning and at the end of the test were normal. No pregnancy occurred during the study period. Cycle disturbances were not significant. The cycles, with an average duration of 30 days prior to the study, were shortened to an average of 28 days. Likewise, duration of bleeding dropped from an average 4.5 days to 3 days. In only 2 cases (3.58’7) 0 were side-effects so severe that medication was suspended. Of the patients 3.58% showed a symptomatology considered to be severe, while 83.92% suffered no side-effects. As reported by other authors [1,14], side-effects were found to be quite rare, mastalgia (.5.85%), headache (2.53%) and mammary hypersensitivity (2.22%) being the most frequent.

Clinieal Evaluation of a New Combined Oral Contraceptive Desogestrel-EthinylestradioI 67

Figure 6 LDL-C/HDLX ratio (B = 14)

In ten (83.33%) of the 12 women with acne at the beginning of the study, the acne had disappeared completely by the end of the study; in the others the acne improved considerably. Androgenic action is necessary for the development of acne [18,19], the skin being a tinal organ of androgenic activity [20]. The conversion of testosterone into 5dihydrotestosterone is 2 to 20 times higher in the acne areas [21,22] and women with acne often show high circulating androgen values. Palatzi er ul. [23] found abnormally high values of total and free testosterone in 57% of cases of severe acne, with a reduction of testosterone and increase of SHBG, following 6 months treatment with desogestrel and ethinylestradiol in the same doses used in this study.

Kuusi ef UL [9] found that administering desogestrel to menopausal patients reduced free-testosterone values in the plasma as a result of a moderate increase of the SHBG. A reduction of androgen production due to estrogenic effects 1241 and an increase of SHBG through desogestrel action [22,23,25] further decreases androgen circulation levels, thus reducing both acne and hirsutism as well [14,26]. In clinical practice, this results in the absence of androgenic side-effects because of reduced androgenic activity of desogestrel.

Blood pressure and body weight throughout the study remained withm normal limits. Endometrial changes were typical of those found with the use of OCs and were already reported in previous papers by de1 Real [27j and Yabur er ul. [28,29]. Cervical mucus continued to be viscous and scarce; vaginal cytology showed a low pyknotic index during the entire study, with average pyknosis of 32.21% and 31.28% in the first and second phases of the cycle, respectively.

HDL-C values increased from 45.7 ? 13.48 to 59,4 ? 12.67 mg/dl during the 12 cycles of desogestrel and ethinylestradiol treatment. This growth was due to lack of desogestrel interference ELI the increase of the HDL-C through estrogenic component action [7,9]. Progestogens with anti-estrogenic action tend to offset these increases of the HDL-C [9,13,30,31].

Epidemiologic studies have shown an inverse relation between the amount of HDL-C circulating in the blood plasma and ischemic heart disease [9]. Both increase of HDL-C and LDL-C decrease found as a result of our test agree with the results obtained by other authors [4,15-17,321.

Such action of sexual steroids on HDL-C is probably by means of an enzyme, hepatic endothelial lipase (HL) [33,34], which is stimulated by the progestogens. The greater the anti-estrogenic effect, the higher the HL-production will be [33,34].

Conclusions

The combination of 0.15 mg desogestrel with 0.03 ethinylestradiol acts as an efficient oral contraceptive, as shown by the absence of pregnancy in the series under review. Patients with dysmenorrhea, acne or hirsutism responded positively to the treatment. Blood pressure and body weight showed no significant variations. Changes produced in the cervical mucus and on the endometrial level support the contraceptive action of this OC combination.

Desogestrel exerts a protective action on the skm as it substantially relieves acne and hirsutism by increasing SHBG and reducing the free-testosterone values in the blood plasma. Desogestrel has no androgenic side-effects as a result of little or no androgenic activity.

With an increase of HDL-C values and a decrease of LDL-C values in the blood plasma, there is a reduced risk of coronary disease.

References

1. 2. 3. 4. 5. 6. 1. 8. 9. 10. 11.

12.

13.

14.

Weijem, M.J. (1982). Cht. Ther., 4, 3.59 Graham, S. and Fraser, IS. (1982). Cantracepfion, 26,373 Fotherby, K. (1985). Contrucepzion, 31,367 Fotherby, K. (1985). Br. I. Fam, Plunn., 11,86 Stadel, B.W. (1981). N. En& .I, Med., 305,612 Kay, C.R (1984). Obster. GynecoZ., 11,759 Meade, W., Greenberg, G. and Thompson, S.G. (1980). Er. Med. T, 380,1157 Vessey, M.P. (1980). J. Fam. Pfunn., Suppl6,l Kuusi. T.. Nikkila. EA.. Tikkanen. M.J. and Sipinin, S. (1985). A~hmoscZff~si~, %L2Sl Information Organon

.

Bergink, E.W., Hamburger, A.D., de Jaeger, E. and Van der Bies, J. (1981). J. Steroid Biochem., 14, 175 - Aznar-Ramos, R, Giner-Velazquez, J., Lara-Ricalde, R and Martinez-Manauton, J. (1969). Am. .7. Obstet. Gynechl., iOS,ll44 - Powell, M.G., Hedlin, A.M., Cerkus, I., Kakis, G., Prudham, D. and Rosenrot, P. (1984). Obstet Gynecol, ~ 63,764 Ruutiainen, K (1986). Inf. J. Gynecol. Obstef., 24,361

Chnical Evaluation of a New Combined Oral Contraceptive Desogestrel-Ethinylestradiol 69

15. 16. 17. 18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28.

29.

30. 31. 32.

33.

34.

Bergink, E.W., Borglin, N.E., Klottrup, P. and Liukko, P. (1982). C~rr&uceptio~, 25,477 Gaspard, U.J., Buret, J., Gillain, D., Remus, M.A. and Lambotte, R (1985). Co~&~cepti~~, 31,395 Samsioe, G. (1982). Cdn&zcepti~rr, 25,487 B&h, B. (1931). Br. J. DermutoZ., 43,61 Hamilton, J.B. (1941). J. CZin. EndocrinoZ., 1, S70 Bonne, C., Saurat, J.H., Chivot, M., Lenucet, D. and Raynaud, J.R (1977). DermutoZogy, 97,501 Sansone, G. and Reisner, RM. (1971). I. Invesr. DermuroZ., 56,356 Berg& E.W., Holma, P. and Pyorala, T. (1981). Scund. J. CZin. Lub. Invesf., 41,663 Palatsi, R, Hirvensalo, E., Liukko, P., Malmiharju, T., Mattila, L., Riihiluotna, P. and Ylostalo, P. (1984). Acta DermutoZ. VenereoZ. (Stockh,), 64,517 Pocchi, P.E. (1982). Arch. Dermutol., 118,803 Hammond, G.L., Langley, M.S., Robinson, P.H., Nummi, S. and Lund, L. (1984). Fertil. SteriZ., 42,44 Dewis, P., Petsos, P., Newman, M. and Anderson, D.C. (1985). CZin. EndocrinoZ., 22,29 Del Real Nestler, E.A. (1966). Rev. Obstet. GinecoZ. Venez., 26,357 Yabur, JA. and Villarroel, J.S. (1969). Simposio Esteroides Saules. Bogota 1968, p. 153, Saladruk-Berlin Yabur, J.A. and Villarroel, J.S. (1972). II Reunih Latinoameticano SH 90999 C MT&O, 1970, p. 76, Saladruk-Berlin Fahraeus, L., Larsson-Cohn, U. and Wallentin, L. (1983). Eur. J. CZin. Invest., 13,447 Tikkanen, M.J., Nikkila, E.A., Kuusi, T. and Sipinen, S. (1981). Adzeroschosis, 40,365 Wiseman, A., Bowie, J., Cogswell, D., Dewsbury, J., Hamilton, M., Hutchinson, F., Kirkman, R, Loudon, N., Lincoln, R., Lyons, M., Pullen, D. and Wilson, E. (1984). Br. J, Fum. PZunn., 10 (Suppl), 38 Nikkila, EA., Kuusi, T., Hamo, T., Tikkanen, K. and Taskinert, M.R (1980). AthoscZerosis V, Springer-Verlag, New York, p. 387 Kuusi, T., Nikkila, EA., Tikkanen, M.J., Taskinen, M.R and Ehnholm, C. (1983). AtheroscZerosis W, Springer-Verlag, New York, p. 628

MS received 9 ~Uuy 89. Accepted forpublicution 24 June 89.

Resum&

Au tours d’une etude clinique effectuee avec un nouveau progestogene, un melange de O,l5 mg de desogestrel et de 0,03 mg d’ethinylestradiol a et.5 administre cycliquement pendant 21 jours; 632 cycles ont ete &alues chew 56 femmes,

Les effets secondaires constates ont ete peu frequents et en general b&ins. Les pertes sanguines mensuelles etaient normales et presentes dans tous les cycles. Chez les patientes dont les cycles menstruels etaient irr&uliers, ceux-ci se sont normal&% a 28/29 jours. On a constate quelques cas isolt% d’ecoulement sanguin intermenstruel (traces) pour 16 cycles. Le symptome le plus frequent, la mastose, a disparu spontanement chew la plupatt des patientes. Dans 2 cas seulement il a et.5 necessaire d’interrompre le traitement en raison d’effets secondaires.

Leffet contraceptif s’est aver.5 excellent: aucune grossesse ne s’est produite. On a retrouve une action progestative evidente dans le mucus cervical et l’endometre. Les patientes qui souffraient d’acne en debut de traitement ont constate une amelioration sensible. Dans les cas b&ins, l’acne a disparu completement. On a egalement constate une asset bonne amelioration de l’hirsutisme. Les variations pond&ales n’ont pas atteint des proportions significatives.

Les examens biochimiques ont r&t% une augmentation de HDLX et une diminution du rapport LDL-C/HDLC. Aucune variation du cholesterol et des triglycerides n’est apparue, ce qui pourrait indiquer un moindre risque cardiovasculaire.

Resumen

Se efectuo un estudio clinico con un nuevo progestageno: 0,lS mg de desogestrol asociado con 0,03 mg de etinilestradiol, administrado cfclicamente durante 21 dfas; fueron evaluados 632 ciclos en 56 mujeres.

Los efectos colaterales fueron escasos y, generalmente, moderados. El sangrado mensual fue normal y ocurrio en todos 10s ciclos. Las pacientes con ciclos irregulares se normalizaron en 28 a 29 dfas. En 16

70 Yabur et al

ciclos el sangrado intermenstrual (manchado) fue un episodio aislado. El sintoma mas frecuente, la mastalgia, desaparecio espontaneamente en la mayorfa de las pacientes. Solamente en dos cases hubo necesidad de suspender la medication debido a 10s efectos colaterales.

El efecto anticonceptivo fut5 excelente: no hubo ningun embarazo. El efecto progestacional fue evidente en el moco cervical y en al endometrio. Las pacientes con acne que iniciaron el tratamiento mejoraron notablemente. En 10s cases moderados el acne desaparecio completamente. Se not6 una discreta mejoria en el hirsutismo. Las variaciones en peso no fueron significativas.

Ektudios bioquimicos revelaron un aumento en HDL-C y una disminucion en la relation LDL-C/HDIA. El colesterol y 10s trigliceridos no mostraron variaciones lo que podria indicar menor riesgo cardiovascular.