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Climacteric symptoms and control of the cycle in women aged 35 years or older taking an oral contraceptive with 0.150 mg desogestrel and 0.020 mg ethinylestradiol
G.F. Trossarelli,* A. CovelliS
(G. Gennarelli,* C. Benedetto,* D. de Aloysio,+ M. Mauloni,+ G. Fanizza,* and
In a multicenter prospective trial, 58 healthy women aged between 35 and 49 years were studied for one year (639 cycles) while taking an oral contraceptive (OC) containing desogestrel 0.150 mg and ethinylestradiol (EE) 0.020 mg. Efficacy, control of the cycle, side effects, complaints, and climacteric symptoms were monitored after 3, 6, 9 and 12 cycles. No pregnancies occurred during the study period. Spotting gradually decreased from 29.3% in cycle 1 to 4.2% in cycle 12, while breakthrough bleeding (BTB) disappeared after cycle 7. One case of superficial thrombophlebitis and 3 cases of minor side effects were registered. With regard to the complaints, breast tenderness, headache, and depression gradually d#ecreased during the study (basal vs. 12-month data: 50.9% vs. 31.2%, 48.3% vs. 18.7%, 39.6% vs. 20.8%, respectively), while nausea disappeared after three months. A significant treatment-dependent reduction of climacteric symptoms was obtained after cycle 3 and this tendency WGIS maintained up to cycle 12. No changes were registered in body mass index (BMI) or blood pressure. CONTRACEPTION 1995;51: 13-18 WORDS: oral contraceptives, climacteric symptoms, 0.020 mg ethinylestradiol, desogestrel, cycle control, side effects
KEY
drome may arise and the risk of cardio- and cerebrovascular dysfunctions increases. However, after 35 years of age, women may experience some hormonal changes that can result in decreased fertility and an increase in the frequency of menstrual cycle disturbances. Nevertheless, the need for contraception is still present. Combined OCs could be a reliable choice but it is important to remember the possible link between OC use and thrombotic complications.’ Many studies have shown that the occurrence of cardiovascular dysfunctions is related to the estrogen content, and partly to the concentration and type of progestogens. S6 As a matter of fact, several progestogens exert androgenic effects. Desogestrel, because of its very weak androgenic and strong progestational activity, seems to display minimal, if any, metabolic changes. The purpose of this study was to assess efficacy, cycle control, side effects, and climacteric symptoms in a group of subjects older than 35 years during the intake of an OC containing 0.150 mg desogestrel and 0.020 mg EE.
Materials and Methods Introduction he climacteric: is a period of a woman’s life characterized by a waning of ovarian function, decreasing fertility, and manifestations of progressive tissue aging and atrophy. It begins at approximately 40 years of age, and it usually lasts until the age of 50. During this period the climacteric syn-
T
‘Deoaflment of Obst. and Gvn. (Chair A: A. Bocci)-Universitv of Turin. Italv: tDe~artment of Obstetrics andi dynecology, Univeisity of Bologna, Italy: *De: partment of Obstetrics and Gdnecology, University of Bari, Italy; and SPierre Fabre Medicament, Address for correspondent and reprint requests: Gian Franc0 Trossarelll, via Ventimlglia 3. 10126 Torino. Italy M D., lstituto di Ginecologla e
0 1995 Elsevier Science Inc. 655 Avenue of the Americas, New York,
NY 10010
This one-year study was performed as an open, longitudinal, multicenter trial. A total of 58 women were selected among the patients of the Menopausal Centers in the Academic Hospitals of Turin (n = 201, Bologna (n = 13) and Bari (n = 25). The study group fulfilled the following criteria: the subjects were between 35 and 49 years of age (mean age = 40.2 + 0.3 years), normal weight (mean body mass index (BMI) 22.1 + 0.3, range 18-29.3; 87.9% of women with a BMI < 25), healthy, nonsmokers, seeking fertility control, and none of them had any contraindication
for oral contraception
(Table 1). A Pap
smear was obtained from all subjects a maximum of 3 months before the beginning of the study. Most subISSN OOlO-7824/95/$9.50 SSDI 0010-7824(94)00009-L
14
Trossarelli
et al.
Contraception 1995;51:13-18
Table 1. Basal characteristics of subjects Age Groups (yrs)
35-39 No. (%)
40-44 No. (%)
45-50 No. (%)
Total No. (%)
Women’ Treatment Cycles Irregular Cycles
20 (34.5) 222 (34.7) 6/20 (30)
35 (60.3) 390 (61.0) 25/35 (71.4)
3 (5.2) 27 (4.3) o/3 (0)
58 (100) 639 (100) 31/58 (53.5)
‘58 women,
aged 40.2 5 0.3 years,
Table 2. Climacteric
healthy,
nonsmoking,
with
a BMI of 22 2 0.3 (mean
+
SE).
symptoms (% women)
Cycle No.
0
3
6
9
12
Hot Flushes Sweating Insomnia Chest Pain Arthralgia Palpitations Paresthesia Nervousness Fatigue Dizziness
41.4 50.0 34.5 15.5 32.8 50.0 39.7 44.8 31.0 25.9
6.9* 13.8$ 17.2* 5.2. 19.0’ 15.5* 24.127.6’ 17.213.8.
1.7* 1.7f 12.1* 3.5+ 17.2’ 14.8’ 13.8$ 20.7* 20.7 13.8.
0* 2.0* 12.2* 4.1. 16.3’ 12.2* 20.4+ 26.5. 14.3+ 14.3
0* 2.1* 12.5* 10.4 16.7. 10.4% 25.0. 25.0+ 14.6+ 12.5.
Significance
+p < 0.01, *p < 0.001.
vs. basal data: ‘p < 0.05;
jects (53 women: 91.4%) had at least one of the ten climacteric symptoms listed in Table 2. During the 6 months preceding the study, 31 subjects (53.5%) had oligo- and/or polymenorrhea (see below for definitions). In that subgroup of women, an ultrasound examination of internal genitalia and, when needed, an endometrial biopsy were performed in order to exclude any organic pathologies. None of the patients had received any hormonal treatment for at least three months before starting the study. Informed consent, according to the Declaration of Helsinki, was obtained from each subject. The OC was a monophasic combination containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol, administered as 1 tablet per day for 21 days followed by a 7-day tablet-free interval. The therapy started on the first day of a spontaneous menstruation. Before and after 3, 6, 9, and 12 treatment cycles, the patients underwent a clinical examination, including the measurement of blood pressure, body weight, and recording of any side effects. At the same time, the possible presence of climacteric
symptoms
was recorded
Table 3. Former complaints 1%)’ Cycle No. : 6 9 12
Breast Tenderness
Nausea
Headache
Depression
100 31 24.1 10.3 10.3
1000 0 0 0
100 60.7 46.4 46.4 46.4
100 43.5 43.5 21.7 21.7
‘Symptoms present in the pretreatment apy (cumulative percentages).
cycle and disappeared
during
ther-
Table 4. Newly emergent complaints (%)* Cycle No. 0 3 6 9 12
Breast Tenderness
Nausea
0 37.9 37.9 37.9 41.4
Headache
Depression
0
0
0
0 0 0 0
10 10 6.6 6.6
8.6 11.4 5.7 5.7
*Symptoms not present in the pretreatment apy (cumulative percentages].
cycle and registered
during
ther-
(Table 2).
Patients were given a record card to be completed daily, reporting data on pill intake, duration and amount of withdrawal bleeding, possible irregular bleedings, side effects, and climacteric symptoms. With respect to the last two variables, only the presence or absence of a specific symptom was registered without any grading of complaint intensity. The following definitions were used.
Oligomenorrhea: menstrual periods that occur more than 35 days apart. Polymenorrhea: menstrual cycles lasting less than 21 days. Irregular bleeding: bleeding beginning during tablet intake, including spotting (scanty bleeding that requires, at most, one sanitary pad per day) and breakthrough bleeding (more serious bleeding than spotting).
Contraception 1995;51:13-18
0.020 mg EE Pill in the Climacteric
Table 5. Withdrawal Cycle No.
15
bleeding (% womenl’ Women No.
Absence
Start Day 22
23-25
26-27
28
3 ;
58 58 49
fl 2.0
12 12.4 13.8
81 75.5 77.6
5.3 6.9 8.1
1.7 2.0 1.7
12
48
2.1
10.4
79.2
6.2
2.1
‘The
percentages
refer to the women
Table 6. Withdrawal No.
Women No.
0 3 6 9 12
58 58 58 49 48
Cycle
‘The
percentages
refer
under
treatment
in the cycle considered
bleeding (% women)*
to the women
Amount
under
Duration
Slight
Moderate
Heavy
l-2
3-5
93 Days
8.6 29.3 43.1 54.2 53.2
65.5 67.2 50.0 41.7 42.5
25.9 3.5 6.9 4.1 4.3
3.4 24.1 37.9 45.8 48.9
72.4 69 53.5 50 48.8
24.2 6.9 8.6 4.2 2.3
treatment
in the cycle considered
Withdrawal bleeding: bleeding occurring after the suspension of pill intake, and occasionally lasting over the first days of the next cycle of OC therapy. Climacteric symptoms: those present before and monitored during the: treatment (see Table 2). Former complaints: those present before the start of hormone therapy an possibly disappeared during OC (Table 3). Newly emergent complaints: those that occurred during OC in subjects who did not present them before starting the study (Table 4). All data are expressed as a percentage of the women under study for each cycle except for blood pressure and BMI for which mean (X) + standard error (SE) is shown. Statistical evaluation of the results was carried out by using one-way analysis of variance, as well as Bonferroni’s t-test for blood pressure and BMI and the Chi-square test for percentage data.
Taking into account the timing of the bleeding after the last tablet, we failed to observe any significant variations throughout the study period for each interval considered; most women (75.5-81%) had menstruations between days 23 and 25 of the cycle (Table 5). The amount and the duration of withdrawal bleeding (Table 6) showed a tendency toward a slight decrease during the treatment. In cycle 12, most women (95.7% ) reported slight to moderate bleeding and its duration was less than 5 days in 97.7% of the patients. Conversely, the percentage of women with heavy and long (>5 days] menstruations in the pretreatment cycle fell from 25.9 and 24.2% to 4.3 and 2.3%, respectively.
Results
Cycle No.
Table 7. Irregular bleeding (% women)
No The 58 women completed a total number of 639 treatment cycles. According to age and treatment cycles, the patients were divided as shown in Table 1. Efficacy No pregnancies occurred during the entire period of treatment with this low estrogen OC combination. Control of the Cycle Withdrawal bleeding occurred in 100% of patients in the first half of the tre/atment and in 98% afterwards. One case of amenorrhea from cycle 7 onward was noted (Table 5).
Women No.
Irregular Bleeding’
Spotting”
BTB
1 2 3 4
58 58 58 58
70.7 79.3 82.8 84.5
22.4 17.2 15.5 13.8
6.9 3.5 1.7 1.7
i 7 ;
58 49 49
88.0 95.8 95.8
10.3 4.2 4.2
1.7 0 0
10 11 12
48 48 48
97.9 91.5 95.8
2:
‘Spotting and BTB never occurred together. The women under treatment in the cycle considered.
0 0 0
4.2 percentages
refer
to the
16 Trossarelli et al.
Contraception 1995;51:1%18
Table 8. Irregular bleeding (% women)* Women No.
l-5 Days
6-10 Days
11-15 Days
16-21 Days
1 2 3 4 2
17158 12158 lo/58 9158 8158 7/58
15.5 12.1 12.1 10.3 6.8 8.6
8.6 6.9 1.7 5.2 01.7
5.2 1.7 1.7 0 06.8
0 0 1.7 0 01.7
7
2149
4.1
0
0
; 10 11 12
2149 2/49 l/48 4148 2148
2.0 4.1 2.1 4.2 2.1
02.0 0 0 0
0 0 2.1 0
Cycle No.
‘The
percentages
refer
to the women
under
treatment
0 E 0 2.1 2.1
in the cycle considered
Table 8. Drop-outs (no. and % women)
The frequency of irregular bleeding gradually decreased from 29.3% in cycle 1 (spotting 22.4% and BTB 6.9%) to 4.2% in cycle 12 due to spotting alone (Table 7). Table 8 shows the percentage distribution (along the 21 days of tablet intake) of those women with irregular bleeding in the cycle considered: it should be noticed that after one year, BTB had completely disappeared and spotting, when present, clustered during the days just before and after the tablet-free period.
thrombosis that occurred between 6 and 9 months; after withdrawing from OC, that patient was treated with calcium-heparin and a NSAID. An additional 9 subjects dropped out of the study; two of them for reasons not related to the OC, including the desire to stop contraception or the need to move elsewhere. The remaining seven cases dropped out due to spotting (n = 4) and minor side effects (n = 3: right arm paresthesia, increased body weight, headache); those occurred between G and 9 months (Table 9). The frequency of newly emergent complaints such as breast tenderness, headache, and depression was unchanged throughout the study period, while nausea was not noted at all throughout the study (Table 4). On the other hand, OC intake strongly decreased those same symptoms when they were present before treatment (Table 3). In Tables 3 and 4, the cumulative percentages of former complaints and newly emergent complaints before and at 3, 6, 9, and 12 treatment cycles are shown. In Table 10, the total amount and relative percentages of complaints, for each cycle considered, are reported.
Tolerance The preparation was well tolerated by the majority of the women under study. Totally, we registered 10 dropouts (17.25%) (Table 9). No serious adverse effects occurred throughout the 639 cycles of pill intake, except for a single case of superficial vein
Climacteric Symptoms All symptoms were successfully controlled by the hormonal preparation, so that after 12 cycles, all but one (chest pain) were significantly decreased or disappeared (Table 2).
Cycle No.
Women No.
Spotting
Side Effects
Not Related to oc
3 6 9 12
58 58 49 48
-
-
-
4 (6.9) -
4 (6.9) -
1 (c72) 1 12)
Total
58
4 (6.9)
4 (6.9)
2 (3.45)
Table 10. Most Cycle No. : 6 9 12
common complaints (no. and %) Breast Tenderness 29157 21158 20158 14149 15148
36.2 50.9 34.5 28.6 31.2
Nausea 11/57 3158 Of58 o/49 O/48
19.3 5.2 0 0 0
Headache 28158 20158 16158 12149 9148
48.3 34.5 27.6 24.5 18.7
Depression 23158 14158 14/58 11149 10148
39.6 24.1 24.1 22.5 20.8
0.020 mg EE Pill in the Climacteric
Contraception 1995;51:13-18
Clinical Findings Neither blood pressure values nor BMI showed any significant variations before or during the OC intake (Table 11).
Discussion Fertility control during the climacteric years is highly recommended, especially in view of a significantly higher perinatal and maternal mortality after age 40.’ In spite of the low estrogen content (0.02 mg ethinylestradiol), the contraceptive efficacy of the compound used in this study was optimal, with no pregnancies occurring during the study that included 639 cycles. The excellent efficacy of the OC under investigation is confirmed by several European studies,‘-” thus showing this OC combination containing desogestrel 0.150 mg and EE 0.020 mg to be highly effective. Good cycle control is essential for an OC in order to maintain a satisfactory degree of patient compliance. In this trial, we registered only one woman with amenorhea and a lack of initiation of menstruation after pill interruption (Table 6). This result suggests that the very low estrogen content of this pill is able to induce good endometrial growth, but it is not in agreement with previously published data’-” showing an absence of withdrawal bleeding ranging from 2.3%8 to 15.6%” over twelve months. The reduction in the duration and amount of menstruations that we found during the treatment, especially for previously heavy and long bleeding (Table 6), must be regarded as a positive event: the incidence of irregular menses before OC administration was, in fact, high and typical of the climacteric. These findings agree with the literature.8-” With regard to the irregular bleeding (Tables 7 and 8), the incidence during the first cycle (29.3%) is similar to that reported for the majority of other OC combinations. 12-14 Afterwards, BTB was not registered in the second half of the study and spotting progressively decreased, occurring in 4.2% of the women in cycle 12 (Table 7). Similar results have been described Table (mean
11. Body mass index + SEI
Cycle No.
BMI
0 3 6 9 12
22.1 22.3 22.4 22.5 23.6
k +k +k
(BMI) and blood pressure
Systolic BP (mmHg) 0.3 0.3 0.3 0.3 0.4
124 124 125 126 125
k k k k +
1.5 1.1 1.2 1.0 1.2
(BP)
Diastolic BP (mmHg) 81 80 79 79 81
+ k 2 k +
1.2 1.0 1.2 1.4 1.1
17
but we failed to find the signifiby other author&” cant incidence of BTB registered by some of those studies’,” after one year of OC intake. During the last six months, spotting occurred almost entirely at the beginning and at the end of the tablet intake period, which probably contributed to maintaining a high degree of compliance (Table 8). Results of another study that examined this issue reported that half of the irregular bleeding occurred between days 11 and 15 during cycle 12.” This apparent contradiction may be related to the large number of BTB observed in the previous study compared to the present results. Even taking into account that four women (6.9%) discontinued therapy for spotting (Table 9), the above described withdrawal bleeding patterns, obtained with the combination 0.150 mg desogestrel + 0.020 mg EE, are relevant and seem to show a very acceptable cycle control. The incidence of dropouts was low and similar to that in the literature (Table 9).s-11 With regard to the case of superficial thrombophlebitis, this condition may have been promoted by a reduction in blood flow related to a relatively high BMI (27.4) by the presence of varicose veins (vascular damage), and by aging and obesity themselves. 15-i7 Two additional subjects failed to finish the study due to conditions (right arm paresthesia and increased body weight) that were probably not related to the OC. In fact, there might be several reasons for the former and, concerning the latter, an increase in BMI is not normally associated with the use of the current OCs that contain new, more selective progestogens.“,i9 A third subject reported an increase in headache frequency and was also dropped from the study. Regarding newly emergent complaints (Table 41, headache and depression slightly decreased, whereas nausea was not noted at all, and the incidence of breast tenderness did not change throughout the study. Similar data are uncommon and quite unclear in the literature’ because newly emergent and former complaints are often pooled. However, the present results are somewhat higher than those reported previously; perhaps this finding was related to the fact that our percentages were calculated only on those women lacking the considered symptom before OC, instead of including the entire study group. With respect to former complaints (Table 3), we obtained, during the trial, a remarkable increase in the number of women free of the previous symptoms, particularly in the case of nausea and breast tenderness. The overall impression about these results seems to confirm the good clinical tolerance to this OC combination, especially taking into account the low rate (6.9% ) of dropouts due to side effects.
18
Trossarelli et al.
The contraceptive combination 0.150 mg desogestrel and 0.020 mg EE succeeded in controlling the climacteric symptoms (Table 2); at the end of the therapy, all symptoms except for chest pain were significantly decreased. This finding is particularly noteworthy considering that, in the premenopause, a hormonal contraceptive must combine a low estrogen dose together with good control of climacteric complaints. The unmodified values of BMI and blood pressure (Table 11) indirectly confirm the weak androgenic activity and the selective profile of desogestrel (low or absent peripheral resistance induced by the progestogen)“r21 and the advantage of low estrogen content (unmodified hepatic synthesis of angiotensinogen). It can be concluded that the combination of 0.150 mg desogestrel plus 0.020 mg EE, studied over 639 cycles in the climacteric age, seems to display good cycle control and very good tolerance. Furthermore, this combination of contraceptives is able to counteract the climacteric symptoms in a satisfactory manner.
Contraception 1995;51:13-18
10.
11. 12.
13. 14.
15. 16.
References 1. Jespersen J, Petersen KR, Skouby SO. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. Am J Obstet Gynecol 1990; 163:396-403. 2. Stadel BV. Oral contraceptives and cardiovascular disease (First of two parts). New Engl J Med 1981;305: 612-8. 3. Stadel BV. Oral contraceptives and cardiovascular disease (Second of two parts). New Engl J Med 1981;305: 672-7. 4. Stolley PD, Tonascia JA, Tockman MS, Sartwell PE, Rutledge AH, Jacobs MP. Thrombosis with lowestrogen oral contraceptives. Am J Epidemiol1975; 102: 197-208. 5. Mammen EF. Oral contraceptives and blood coagulation: A critical review. Am J Qbstet Gynecol 1982; 142: 781-90. 6. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-microgram oestrogen preparations. Br Med J 1980; 280:1157-61. 7. Beard RJ. Risks and problems for the older parent: Changing patterns of conception and fertility. London: Academic Press, 1979. 8. Nevimry-Stickel J. German trial of an oral contraceptive containing 0.150 mg desogestrel plus 0.020 mg ethinylestradiol. Acta Obstet Gynecol Stand 1987; Suppl 144:19-21. 9. Steffensen K. Evaluation of an oral contraceptive con-
17. 18.
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20.
21.
taining 0.150 mg desogestrel and 0.020 mg ethinylestradiol in women aged 30 years or older. Acta Obstet Gynecol Stand 1987;Suppl I44:23-7. Tuimala R, Saranen M, Alapiessa U. A clinical comparison in Finland of two oral contraceptives containing 0.150 mg desogestrel in combination with 0.020 mg or 0.030 mg ethinylestradiol. Acta Obstet Gynecol Stand 1987;Suppl 144:7-12. van Kets HE. Belgian trial of an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. Acta Obstet Gynecol Stand 19137~Suppl144:13-7. Wallin M. A multicenter efficacy and safety study of an oral contraceptive containing I50 mcg desogestrel and 30 mcg ethinylestradiol. Contraception 1992;46:31326. Reekers H. Multicenter trial of a monophasic oral contraceptive containing ethinylestradiol and desogestrel. Acta Obstet Gynecol Stand 1988;67:1714. Masson S, Franssen E, Hilditch JR, Powell MG. A clinical comparison of two triphasic oral contraceptives with levonorgestrel or norethindrone: a prospective, randomized, single-blind study. Contraception I993j 47:43-54. Hamsten A. Hypertriglyceridemia, triglyceride-rich lipoproteins and coronary heart disease. Bailliere’s Clin End Metab. 1990;4:895-922. Gelmini G, Coiro V, Manotti C, Delsignore R, Passeri M. Effect of diet and weight loss on whole blood filterability and plasma fibrinogen values in hypertensive and obese postmenopausal women. Acta Diabetol Lat 1989;26:329-35. Meade TV, Vickers GJ, Thompson SG, Stirling Y, Haines AP, Miller GJ. Epidemiological characteristics of platelet aggregability. Br Med J 1985j290:42831. Trossarelli GF, Bordon R, Gennarelli G, Carta Q. An open prospective study on the effects on carbohydrate metabolism of an oral monophasic contraceptive containing gestodene (WL-70). Contraception I99Oj43: 423-33. Trossarelli GF, Benedetto C, Bordon R, et al. Clotting and lipid systems during the use of an oral contraceptive with 20 mcg ethinylestradiol. In: Genazzani AR, Petraglia F, Baselli F, Segre A, Genazzani AD, D’Ambrogio G, ed. Current Research in Gynecology and Obstetrics. Casterton Hall, Camforth: The Parthenon Publishing Group, 1991:419-23. Trossarelli GF, Bordon R, Meriggi E, et al. Effect of a monophasic oral contraceptive with desogestrel on beta-cell function. In: Gennazzani AR, Facchinetti F, Petraglia F, Volpe A, Facchinetti F, ed. Recent Research on Gynecological Endocrinology, ~012. Casterton Hall, Carnforth: The Parthenon Publishing Group, 1988: 12530. Luycks AS, Gaspard UJ, Romus MA, Grigorescu F, De Meyts P, Lefebvre P. Carbohydrate metabolism in women who used oral contraceptives containing levonorgestrel or desogestrel: a six-month prospective study. Fertil Steril 1986;45:635.
(G. Gennarelli,* C. Benedetto,* D. de Aloysio,+ M. Mauloni,+ G. Fanizza,* and
In a multicenter prospective trial, 58 healthy women aged between 35 and 49 years were studied for one year (639 cycles) while taking an oral contraceptive (OC) containing desogestrel 0.150 mg and ethinylestradiol (EE) 0.020 mg. Efficacy, control of the cycle, side effects, complaints, and climacteric symptoms were monitored after 3, 6, 9 and 12 cycles. No pregnancies occurred during the study period. Spotting gradually decreased from 29.3% in cycle 1 to 4.2% in cycle 12, while breakthrough bleeding (BTB) disappeared after cycle 7. One case of superficial thrombophlebitis and 3 cases of minor side effects were registered. With regard to the complaints, breast tenderness, headache, and depression gradually d#ecreased during the study (basal vs. 12-month data: 50.9% vs. 31.2%, 48.3% vs. 18.7%, 39.6% vs. 20.8%, respectively), while nausea disappeared after three months. A significant treatment-dependent reduction of climacteric symptoms was obtained after cycle 3 and this tendency WGIS maintained up to cycle 12. No changes were registered in body mass index (BMI) or blood pressure. CONTRACEPTION 1995;51: 13-18 WORDS: oral contraceptives, climacteric symptoms, 0.020 mg ethinylestradiol, desogestrel, cycle control, side effects
KEY
drome may arise and the risk of cardio- and cerebrovascular dysfunctions increases. However, after 35 years of age, women may experience some hormonal changes that can result in decreased fertility and an increase in the frequency of menstrual cycle disturbances. Nevertheless, the need for contraception is still present. Combined OCs could be a reliable choice but it is important to remember the possible link between OC use and thrombotic complications.’ Many studies have shown that the occurrence of cardiovascular dysfunctions is related to the estrogen content, and partly to the concentration and type of progestogens. S6 As a matter of fact, several progestogens exert androgenic effects. Desogestrel, because of its very weak androgenic and strong progestational activity, seems to display minimal, if any, metabolic changes. The purpose of this study was to assess efficacy, cycle control, side effects, and climacteric symptoms in a group of subjects older than 35 years during the intake of an OC containing 0.150 mg desogestrel and 0.020 mg EE.
Materials and Methods Introduction he climacteric: is a period of a woman’s life characterized by a waning of ovarian function, decreasing fertility, and manifestations of progressive tissue aging and atrophy. It begins at approximately 40 years of age, and it usually lasts until the age of 50. During this period the climacteric syn-
T
‘Deoaflment of Obst. and Gvn. (Chair A: A. Bocci)-Universitv of Turin. Italv: tDe~artment of Obstetrics andi dynecology, Univeisity of Bologna, Italy: *De: partment of Obstetrics and Gdnecology, University of Bari, Italy; and SPierre Fabre Medicament, Address for correspondent and reprint requests: Gian Franc0 Trossarelll, via Ventimlglia 3. 10126 Torino. Italy M D., lstituto di Ginecologla e
0 1995 Elsevier Science Inc. 655 Avenue of the Americas, New York,
NY 10010
This one-year study was performed as an open, longitudinal, multicenter trial. A total of 58 women were selected among the patients of the Menopausal Centers in the Academic Hospitals of Turin (n = 201, Bologna (n = 13) and Bari (n = 25). The study group fulfilled the following criteria: the subjects were between 35 and 49 years of age (mean age = 40.2 + 0.3 years), normal weight (mean body mass index (BMI) 22.1 + 0.3, range 18-29.3; 87.9% of women with a BMI < 25), healthy, nonsmokers, seeking fertility control, and none of them had any contraindication
for oral contraception
(Table 1). A Pap
smear was obtained from all subjects a maximum of 3 months before the beginning of the study. Most subISSN OOlO-7824/95/$9.50 SSDI 0010-7824(94)00009-L
14
Trossarelli
et al.
Contraception 1995;51:13-18
Table 1. Basal characteristics of subjects Age Groups (yrs)
35-39 No. (%)
40-44 No. (%)
45-50 No. (%)
Total No. (%)
Women’ Treatment Cycles Irregular Cycles
20 (34.5) 222 (34.7) 6/20 (30)
35 (60.3) 390 (61.0) 25/35 (71.4)
3 (5.2) 27 (4.3) o/3 (0)
58 (100) 639 (100) 31/58 (53.5)
‘58 women,
aged 40.2 5 0.3 years,
Table 2. Climacteric
healthy,
nonsmoking,
with
a BMI of 22 2 0.3 (mean
+
SE).
symptoms (% women)
Cycle No.
0
3
6
9
12
Hot Flushes Sweating Insomnia Chest Pain Arthralgia Palpitations Paresthesia Nervousness Fatigue Dizziness
41.4 50.0 34.5 15.5 32.8 50.0 39.7 44.8 31.0 25.9
6.9* 13.8$ 17.2* 5.2. 19.0’ 15.5* 24.127.6’ 17.213.8.
1.7* 1.7f 12.1* 3.5+ 17.2’ 14.8’ 13.8$ 20.7* 20.7 13.8.
0* 2.0* 12.2* 4.1. 16.3’ 12.2* 20.4+ 26.5. 14.3+ 14.3
0* 2.1* 12.5* 10.4 16.7. 10.4% 25.0. 25.0+ 14.6+ 12.5.
Significance
+p < 0.01, *p < 0.001.
vs. basal data: ‘p < 0.05;
jects (53 women: 91.4%) had at least one of the ten climacteric symptoms listed in Table 2. During the 6 months preceding the study, 31 subjects (53.5%) had oligo- and/or polymenorrhea (see below for definitions). In that subgroup of women, an ultrasound examination of internal genitalia and, when needed, an endometrial biopsy were performed in order to exclude any organic pathologies. None of the patients had received any hormonal treatment for at least three months before starting the study. Informed consent, according to the Declaration of Helsinki, was obtained from each subject. The OC was a monophasic combination containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol, administered as 1 tablet per day for 21 days followed by a 7-day tablet-free interval. The therapy started on the first day of a spontaneous menstruation. Before and after 3, 6, 9, and 12 treatment cycles, the patients underwent a clinical examination, including the measurement of blood pressure, body weight, and recording of any side effects. At the same time, the possible presence of climacteric
symptoms
was recorded
Table 3. Former complaints 1%)’ Cycle No. : 6 9 12
Breast Tenderness
Nausea
Headache
Depression
100 31 24.1 10.3 10.3
1000 0 0 0
100 60.7 46.4 46.4 46.4
100 43.5 43.5 21.7 21.7
‘Symptoms present in the pretreatment apy (cumulative percentages).
cycle and disappeared
during
ther-
Table 4. Newly emergent complaints (%)* Cycle No. 0 3 6 9 12
Breast Tenderness
Nausea
0 37.9 37.9 37.9 41.4
Headache
Depression
0
0
0
0 0 0 0
10 10 6.6 6.6
8.6 11.4 5.7 5.7
*Symptoms not present in the pretreatment apy (cumulative percentages].
cycle and registered
during
ther-
(Table 2).
Patients were given a record card to be completed daily, reporting data on pill intake, duration and amount of withdrawal bleeding, possible irregular bleedings, side effects, and climacteric symptoms. With respect to the last two variables, only the presence or absence of a specific symptom was registered without any grading of complaint intensity. The following definitions were used.
Oligomenorrhea: menstrual periods that occur more than 35 days apart. Polymenorrhea: menstrual cycles lasting less than 21 days. Irregular bleeding: bleeding beginning during tablet intake, including spotting (scanty bleeding that requires, at most, one sanitary pad per day) and breakthrough bleeding (more serious bleeding than spotting).
Contraception 1995;51:13-18
0.020 mg EE Pill in the Climacteric
Table 5. Withdrawal Cycle No.
15
bleeding (% womenl’ Women No.
Absence
Start Day 22
23-25
26-27
28
3 ;
58 58 49
fl 2.0
12 12.4 13.8
81 75.5 77.6
5.3 6.9 8.1
1.7 2.0 1.7
12
48
2.1
10.4
79.2
6.2
2.1
‘The
percentages
refer to the women
Table 6. Withdrawal No.
Women No.
0 3 6 9 12
58 58 58 49 48
Cycle
‘The
percentages
refer
under
treatment
in the cycle considered
bleeding (% women)*
to the women
Amount
under
Duration
Slight
Moderate
Heavy
l-2
3-5
93 Days
8.6 29.3 43.1 54.2 53.2
65.5 67.2 50.0 41.7 42.5
25.9 3.5 6.9 4.1 4.3
3.4 24.1 37.9 45.8 48.9
72.4 69 53.5 50 48.8
24.2 6.9 8.6 4.2 2.3
treatment
in the cycle considered
Withdrawal bleeding: bleeding occurring after the suspension of pill intake, and occasionally lasting over the first days of the next cycle of OC therapy. Climacteric symptoms: those present before and monitored during the: treatment (see Table 2). Former complaints: those present before the start of hormone therapy an possibly disappeared during OC (Table 3). Newly emergent complaints: those that occurred during OC in subjects who did not present them before starting the study (Table 4). All data are expressed as a percentage of the women under study for each cycle except for blood pressure and BMI for which mean (X) + standard error (SE) is shown. Statistical evaluation of the results was carried out by using one-way analysis of variance, as well as Bonferroni’s t-test for blood pressure and BMI and the Chi-square test for percentage data.
Taking into account the timing of the bleeding after the last tablet, we failed to observe any significant variations throughout the study period for each interval considered; most women (75.5-81%) had menstruations between days 23 and 25 of the cycle (Table 5). The amount and the duration of withdrawal bleeding (Table 6) showed a tendency toward a slight decrease during the treatment. In cycle 12, most women (95.7% ) reported slight to moderate bleeding and its duration was less than 5 days in 97.7% of the patients. Conversely, the percentage of women with heavy and long (>5 days] menstruations in the pretreatment cycle fell from 25.9 and 24.2% to 4.3 and 2.3%, respectively.
Results
Cycle No.
Table 7. Irregular bleeding (% women)
No The 58 women completed a total number of 639 treatment cycles. According to age and treatment cycles, the patients were divided as shown in Table 1. Efficacy No pregnancies occurred during the entire period of treatment with this low estrogen OC combination. Control of the Cycle Withdrawal bleeding occurred in 100% of patients in the first half of the tre/atment and in 98% afterwards. One case of amenorrhea from cycle 7 onward was noted (Table 5).
Women No.
Irregular Bleeding’
Spotting”
BTB
1 2 3 4
58 58 58 58
70.7 79.3 82.8 84.5
22.4 17.2 15.5 13.8
6.9 3.5 1.7 1.7
i 7 ;
58 49 49
88.0 95.8 95.8
10.3 4.2 4.2
1.7 0 0
10 11 12
48 48 48
97.9 91.5 95.8
2:
‘Spotting and BTB never occurred together. The women under treatment in the cycle considered.
0 0 0
4.2 percentages
refer
to the
16 Trossarelli et al.
Contraception 1995;51:1%18
Table 8. Irregular bleeding (% women)* Women No.
l-5 Days
6-10 Days
11-15 Days
16-21 Days
1 2 3 4 2
17158 12158 lo/58 9158 8158 7/58
15.5 12.1 12.1 10.3 6.8 8.6
8.6 6.9 1.7 5.2 01.7
5.2 1.7 1.7 0 06.8
0 0 1.7 0 01.7
7
2149
4.1
0
0
; 10 11 12
2149 2/49 l/48 4148 2148
2.0 4.1 2.1 4.2 2.1
02.0 0 0 0
0 0 2.1 0
Cycle No.
‘The
percentages
refer
to the women
under
treatment
0 E 0 2.1 2.1
in the cycle considered
Table 8. Drop-outs (no. and % women)
The frequency of irregular bleeding gradually decreased from 29.3% in cycle 1 (spotting 22.4% and BTB 6.9%) to 4.2% in cycle 12 due to spotting alone (Table 7). Table 8 shows the percentage distribution (along the 21 days of tablet intake) of those women with irregular bleeding in the cycle considered: it should be noticed that after one year, BTB had completely disappeared and spotting, when present, clustered during the days just before and after the tablet-free period.
thrombosis that occurred between 6 and 9 months; after withdrawing from OC, that patient was treated with calcium-heparin and a NSAID. An additional 9 subjects dropped out of the study; two of them for reasons not related to the OC, including the desire to stop contraception or the need to move elsewhere. The remaining seven cases dropped out due to spotting (n = 4) and minor side effects (n = 3: right arm paresthesia, increased body weight, headache); those occurred between G and 9 months (Table 9). The frequency of newly emergent complaints such as breast tenderness, headache, and depression was unchanged throughout the study period, while nausea was not noted at all throughout the study (Table 4). On the other hand, OC intake strongly decreased those same symptoms when they were present before treatment (Table 3). In Tables 3 and 4, the cumulative percentages of former complaints and newly emergent complaints before and at 3, 6, 9, and 12 treatment cycles are shown. In Table 10, the total amount and relative percentages of complaints, for each cycle considered, are reported.
Tolerance The preparation was well tolerated by the majority of the women under study. Totally, we registered 10 dropouts (17.25%) (Table 9). No serious adverse effects occurred throughout the 639 cycles of pill intake, except for a single case of superficial vein
Climacteric Symptoms All symptoms were successfully controlled by the hormonal preparation, so that after 12 cycles, all but one (chest pain) were significantly decreased or disappeared (Table 2).
Cycle No.
Women No.
Spotting
Side Effects
Not Related to oc
3 6 9 12
58 58 49 48
-
-
-
4 (6.9) -
4 (6.9) -
1 (c72) 1 12)
Total
58
4 (6.9)
4 (6.9)
2 (3.45)
Table 10. Most Cycle No. : 6 9 12
common complaints (no. and %) Breast Tenderness 29157 21158 20158 14149 15148
36.2 50.9 34.5 28.6 31.2
Nausea 11/57 3158 Of58 o/49 O/48
19.3 5.2 0 0 0
Headache 28158 20158 16158 12149 9148
48.3 34.5 27.6 24.5 18.7
Depression 23158 14158 14/58 11149 10148
39.6 24.1 24.1 22.5 20.8
0.020 mg EE Pill in the Climacteric
Contraception 1995;51:13-18
Clinical Findings Neither blood pressure values nor BMI showed any significant variations before or during the OC intake (Table 11).
Discussion Fertility control during the climacteric years is highly recommended, especially in view of a significantly higher perinatal and maternal mortality after age 40.’ In spite of the low estrogen content (0.02 mg ethinylestradiol), the contraceptive efficacy of the compound used in this study was optimal, with no pregnancies occurring during the study that included 639 cycles. The excellent efficacy of the OC under investigation is confirmed by several European studies,‘-” thus showing this OC combination containing desogestrel 0.150 mg and EE 0.020 mg to be highly effective. Good cycle control is essential for an OC in order to maintain a satisfactory degree of patient compliance. In this trial, we registered only one woman with amenorhea and a lack of initiation of menstruation after pill interruption (Table 6). This result suggests that the very low estrogen content of this pill is able to induce good endometrial growth, but it is not in agreement with previously published data’-” showing an absence of withdrawal bleeding ranging from 2.3%8 to 15.6%” over twelve months. The reduction in the duration and amount of menstruations that we found during the treatment, especially for previously heavy and long bleeding (Table 6), must be regarded as a positive event: the incidence of irregular menses before OC administration was, in fact, high and typical of the climacteric. These findings agree with the literature.8-” With regard to the irregular bleeding (Tables 7 and 8), the incidence during the first cycle (29.3%) is similar to that reported for the majority of other OC combinations. 12-14 Afterwards, BTB was not registered in the second half of the study and spotting progressively decreased, occurring in 4.2% of the women in cycle 12 (Table 7). Similar results have been described Table (mean
11. Body mass index + SEI
Cycle No.
BMI
0 3 6 9 12
22.1 22.3 22.4 22.5 23.6
k +k +k
(BMI) and blood pressure
Systolic BP (mmHg) 0.3 0.3 0.3 0.3 0.4
124 124 125 126 125
k k k k +
1.5 1.1 1.2 1.0 1.2
(BP)
Diastolic BP (mmHg) 81 80 79 79 81
+ k 2 k +
1.2 1.0 1.2 1.4 1.1
17
but we failed to find the signifiby other author&” cant incidence of BTB registered by some of those studies’,” after one year of OC intake. During the last six months, spotting occurred almost entirely at the beginning and at the end of the tablet intake period, which probably contributed to maintaining a high degree of compliance (Table 8). Results of another study that examined this issue reported that half of the irregular bleeding occurred between days 11 and 15 during cycle 12.” This apparent contradiction may be related to the large number of BTB observed in the previous study compared to the present results. Even taking into account that four women (6.9%) discontinued therapy for spotting (Table 9), the above described withdrawal bleeding patterns, obtained with the combination 0.150 mg desogestrel + 0.020 mg EE, are relevant and seem to show a very acceptable cycle control. The incidence of dropouts was low and similar to that in the literature (Table 9).s-11 With regard to the case of superficial thrombophlebitis, this condition may have been promoted by a reduction in blood flow related to a relatively high BMI (27.4) by the presence of varicose veins (vascular damage), and by aging and obesity themselves. 15-i7 Two additional subjects failed to finish the study due to conditions (right arm paresthesia and increased body weight) that were probably not related to the OC. In fact, there might be several reasons for the former and, concerning the latter, an increase in BMI is not normally associated with the use of the current OCs that contain new, more selective progestogens.“,i9 A third subject reported an increase in headache frequency and was also dropped from the study. Regarding newly emergent complaints (Table 41, headache and depression slightly decreased, whereas nausea was not noted at all, and the incidence of breast tenderness did not change throughout the study. Similar data are uncommon and quite unclear in the literature’ because newly emergent and former complaints are often pooled. However, the present results are somewhat higher than those reported previously; perhaps this finding was related to the fact that our percentages were calculated only on those women lacking the considered symptom before OC, instead of including the entire study group. With respect to former complaints (Table 3), we obtained, during the trial, a remarkable increase in the number of women free of the previous symptoms, particularly in the case of nausea and breast tenderness. The overall impression about these results seems to confirm the good clinical tolerance to this OC combination, especially taking into account the low rate (6.9% ) of dropouts due to side effects.
18
Trossarelli et al.
The contraceptive combination 0.150 mg desogestrel and 0.020 mg EE succeeded in controlling the climacteric symptoms (Table 2); at the end of the therapy, all symptoms except for chest pain were significantly decreased. This finding is particularly noteworthy considering that, in the premenopause, a hormonal contraceptive must combine a low estrogen dose together with good control of climacteric complaints. The unmodified values of BMI and blood pressure (Table 11) indirectly confirm the weak androgenic activity and the selective profile of desogestrel (low or absent peripheral resistance induced by the progestogen)“r21 and the advantage of low estrogen content (unmodified hepatic synthesis of angiotensinogen). It can be concluded that the combination of 0.150 mg desogestrel plus 0.020 mg EE, studied over 639 cycles in the climacteric age, seems to display good cycle control and very good tolerance. Furthermore, this combination of contraceptives is able to counteract the climacteric symptoms in a satisfactory manner.
Contraception 1995;51:13-18
10.
11. 12.
13. 14.
15. 16.
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