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Pharmacokinetic and pharmacodynamic studies of levonorgestrel-releasing intrauterine device
CONTRACEPTION
PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE Xiao Bilian, Zhou Liying, Zhang Xuling, Jia Mengchun National Research Institute for Family Planning Beijing, China Tapani Luukkainen Steroid Research Laboratory Department of Medical Chemistry, University of Helsinki Helsinki, Finland Hannu Allonen Leiras, Clinical Research Huhtamaki OY Pharmaceuticals, Helsinki, Finland ABSTRACT Intrauterine devices releasing 20 &g/day levonorgestrel were inserted in 10 women (ages 25-34). Bleeding and spotting patterns were recorded on a menstrual card during one year of follow-up. Blood samples were collected for radioimmunoassays of LH, estradiol (E2), progesterone (P) and levonorgestrel (LNG) and for sex hormone binding globulin (SHBG) 3 times a week during the 1st month of use, and twice a week during the 6th and 12th treatment months. Among the 10 women, two experienced irregular cycles with prolonged intermenstrual spotting, four had amenorrhea in the latter part of treatment months, while the other four had regular cycles. According to the serum levels of E2 and P, the hormone profiles were divided into four types of reaction: A) anovulatory, B) anovulatory but with high follicular activity, C) ovulatory but with luteal insufficiency, and D) ovulatory. Among the 29 treatment cycles, there were 10 D-type, 3 C-type, 13 B-type and 3 A-type of ovarian reactions: 44.8% of the cycles were ovulatory (C+D) and 55.2% were anovulatory (A+B). In general, serum levels of levonorgestrel were low in ovulatory cycles and were high in anovulatory cycles. The difference was statistically significant. There were marked individual differences. The decline of serum LNG from the 1st (492 pmol/l) to the 6th (320 pmol/l) treatment months was 34.9% on average. The amenorrheic cycles coincided mostly with the hormonal profile of ovulatory types, which indicated that the cause of amenorrhea is due to the local effect of levonorgestrel on the endometrium. The levonorgestrel levels were significantly correlated with serum SHBG, r=0.8856, p
for publication for publication
APRIL 1990 VOL. 41 NO. 4
September 25, 1989 December 13, 1989
353
CONTRACEPTION
INTRODUCTION Increase of menstrual blood loss after insertion of intrauterine device is the main concern among IUD users in China. In our national programme of contraceptive research, more efforts are being focused on the investigation and development of IUDs and other contraceptive devices that can reduce menstrual blood loss. Previous studies of levonorgestrel-releasing IUD (LNG-IUD) by Luukkainen et al.(l) showed decrease of menstrual blood loss and increase of hemoglobin. Similar results were observed by Gao et al.(Z) in a comparative study of Norplant- and LNG-IUD. As with all types of steroid contraceptives, changes in menstrual pattern were unavoidable and the main cause of removal. We have found in a pharmacokinetic and pharmacodynamic study of a levonorgestrel-releasing vaginal ring that more irregualr bleeding occurred in cases with anovulatory type of reaction (3). The purpose of the present study is to investigate the hormonal relationship between the bleeding pattern and the different types of ovarian function after using levonorgestrelreleasing IUDs. SUBJECTS AND METHODS Ten women ages 25-34, gravida 1-3, para 1, healthy and with regular menstrual cycles were recruited for this study. Before admission, no steroid contraceptives were used within 2 months, we required no births within one year, and return of at least two normal menstrual cycles after abortion; no endocrine disturbances were found. The LNG-IUDs used in this study were provided by the Leiras, Turku, Finland. It is Nova-T shaped, with levonorgestrel incorporated in a silastic polymer around the vertical arm of the IUD. The daily release rate of LNG is around 20 fig. It was inserted on the 5th-7th cycle day. There was only one removal at the 6th treatment month; the rest remained in the study for one year. Blood samples (8 ml) were collected 3 times a week during the 1st month of treatment and twice a week during the 6th and 12th treatment months for determination of estradiol (E2), progesterone (P) and LH. Levonorgestrel (LNG) was measured in the 1st and 6th month samples, and 12th month samples only in 2 cases. In each case, one sample was collected during the luteal phase (cycle day 21-23) of the pretreatment cycle for measurement of progesterone to verify luteal function. Radioimmunoassays of E2, P, LH and LNG were performed with WHO matched reagents and methods. Sex hormone binding globulin (SHBG) was measured in blood samples of the 1st and 6th treatment cycles using the method of Cekan et al. (4).
354
APRIL
1990 VOL. 41 NO. 4
CONTRACEPTION
Bleeding and spotting days were recorded on menstrual cards. The bleeding patterns were analyzed according to Snowden's parameters and compared with the data of normal menstrual cycles from the same population of women in Beijing (5). Geometric means of E2, P and LNG levels in different types of ovarian reaction were compared using Student's t test. Regression coefficients were used in the analysis of decline of levonorgestrel and its correlation with SHBG and E2. RESULTS
The bleeding patterns of each individual case during the 12 treatment months are shown in a schematic diagram (Fig. 1). There were 2 cases who experienced irregular bleeding and spotting, 4 cases of amenorrhea in the latter treatment months and 4 cases with regular cycles. Among the total treatment cycles, there were 13 regular cycles, 5 with prolonged spotting in the intermenstrual period and 11 with amenorrhea.
30
60
90
120
150
180
210
240
270
300
330
360 MYS
Fig. 1.
Bleeding patterns of individual cases during the 12-month follow-up after insertion of LNG-IUDs. +=insertion, +=removal, full bar=bleeding, half bar=spotting.
As the women in this study were recruited from the same population as in a previous study of normal menstrual pattern by Xiao et al. (5). their data were compared as shown in Table I. There were significant differences in the average length of episodes, longest episode and number of total spotting days in a reference period of 180 days. In the follow-up of 360 days after insertion of LNG-IUDs, there was a tendency to decreased bleeding days and increased interval days, though no statistically significant difference was found.
APRIL 1990 VOL. 41 NO. 4
355
CONTRACEPTION
Table I.
Comparison of bleeding patterns after LNG-IUD with normal menstrual cycles in a reference period of 180 & 360 days Normal cycle l-180 days (n=917)
No. of bleeding days No. of episodes Average length of episodes Longest episode Longest interval Average length of segments No. of spotting days
23.8k6.99 6.1kO.69 3.1k1.12 4.5k1.35 32.5k8.22 32.4+4.29 8.6k6.84
LNG-IUDs l-180 days 181-360 days (n=lO> (n=9) 28.2A16.77 4.7A2.12 5.6*1.71* 8.7f4.79" 62.3A47.71 53.9*47.18 38.4f28.00*
14.5k14.26 3.5k3.39 2.1+2.14++ 3.1?3.25+ 95.2k80.46 96.51t79.21 24.5k14.29
"pQl.05 (normal versus LNG-IUD l-180 days) +pco.o5, ++xO.Ol (LNG-IUD l-160 versus 180-360 days) According to the serum levels of estradiol and progesterone in the 29 treatment cycles of the 1st and 6th months, the ovarian reaction to levonorgestrel were divided into 4 types: low E2 and low P levels in 3 cycles (A:anovulatory); high E2 and low P levels in 13 cycles (B:anovulatory but with high follicular activity); normal E2 profile but comparatively low P levels in 3 cycles (C: ovulatory with luteal insufficiency); normal E2 and P profile in 10 cycles (D:ovulatory) as per Landgren et al. (6). The difference in mean E2 and mean P levels between the ovulatory (C+D) and the anovulatory cycles (A+B) was significant, pCO.001 (Table II). Table II. Comparison of geometric means of E2, P and LNG in ovulatory and anovulatory types of reaction after LNG-IUD insertion Type 132
P
(pmol/l) (nmol/l)
LNG (pmol/l)
n
Mean (+SD, -SD)
p value
A+B C+D
155 124
438 229
(1103, 174) ( 530, 99)
(0.001
A+B C+D
161 132
2.0 4.8
(4.0, 0.9) (20.1, 1.1)
(0.001
A+B C+D
110 97
460 332
(993, 213) (598, 187)
(0.001
APRIL
1990 VOL. 41 NO. 4
CONTRACEPTION
Serum levels of LNG were significantly higher in cycles where ovulation was suppressed (A+B) than in ovulatory cycles (C+D), their mean levels being 460 pmol/l and 332 pmol/l, respectively; the difference was statistically significant, p
Z.Y.E. S.Y.L. Z.S.F. W.H.L. L.G.Q. F.W.Y. J.S.Q. L.B.P. S.L.N. L.Y.J. MEAN
8
Fig. 2.
1st mo.
6th mo.
% decline
p value
Tse
363.5
250.6 983.5 411.4 324.7 183.3 559.6 457.7 259.3 121.3 115.3
-13.8 -38.1 -25.2 -42.5 -47.1 -17.9 -22.3 -43.4 -30.6 -68.3
>0.050.05 <0.05 >0.05
D,D B,B D,A B,B D,D B,B C,D B,B B,B D,D
492.3
320.3
-34.9
(0.001
20
40
290.8
1589.6 549.8 564.7 346.7 682.3 588.9 458.4 176.8
la
220
DAYS
Decline of serum levonorgestrel levels from the 1st to the 6th treatment cycle.
APRIL 1990 VOL. 41 NO. 4
357
CONTRACEPTION
P
II
MOO-
---f 0
I -aIF--=
-G----T nom
_-y=
_------E 0
II
a 0
’
I
I
I
1 1000
6$b
200
D
1900 Estradiol (ml/f)
Fig. 3.
Correlation between the mean levels of levonorgestrel and estradiol during the 1st and 6th treatment cycles.
--r---l--44
20
&I
80
100
SHBC (nml/l)
Fig. 4.
Correlation between the mean levels of levonorgestrel and SHBG during the 1st and 6th treatment cycles.
APRIL 1990 VOL. 41 NO. 4
CONTRACEPTION
I
“,,.A’A\/A\ Jo
A-
A-A-A
mI D
Fig. 5.
Serum levels of E2, P and LNG during the lst, 6th and 12th treatmentmonths of LNG-IUD use in case no. 1 with regular menstrualcycles. The hormonal profile showed ovulatorypattern. The serum LNG was maintainedat relativelylow levels. o---o E2 pmolfl, o---o P nmol/l, a----OLNG pmol/l; double bar=bleeding,single bar-spotting.
APRIL 1990 VOL. 41 NO. 4
359
CONTRACEPTION
12 th month
Fig. 6.
360
Serum levels of E2, P and LNG during the lst, 6th and 12th treatment month of LNG-IUD use in case no. 2. The menstrual cycles were irregular, but the hormonal profile showed B type of ovarian reaction, with very high levels of E2 during the 1st and 6th treatment months and lower levels in the 12th month. P levels were suppressed but increased in the latter half of the 12th month. LNG was maintained at high levels. o---o E2, o---o P,b---* LNG; double bar=bleeding, single bar=spotting.
APRIL
1990VOL.
41 NO. 4
CONTRACEPTION
The mean value of SHBG in the pretreatment blood samples from the luteal phase was 62.09+23.9nmol/l. The mean SHBG level after insertion of LNG-IUD was 41.82~20.50nmo1/1. In each individual the mean levels of LNG and SHBG at one treatment cycle were calculated and their correlation analyzed. The correlation between LNG and SHBG the regression coefficient being was very significant (Fig. 4), The correlation between SHBG and y=153.54+15.337~, r=0.885, ~(0.01. 22 was insignificant (y=283.28+5.6022~, r=0.4086, pjO.05). The mean SHBG level of the anovulatory cycles (A+B) was higher than that of the ovulatory cycles (C+D), being 40.4nmol/l and 34.7nmol/l, respectively; the difference was significant p
APRIL
1990 VOL. 41 NO. 4
361
CONTRACEPTION ACKNOWLEDGEMENT We are grateful to UNFPA for the financial support of this study and to WHO Special Programme of Research, Development and Research Training in Human Reproduction for the provision of RIA reagents and consultant review of the study. REFERENCES 1.
Luukkainen T, Allonen H, Haukkamaa M,Lahteenmaki P, Nilsson CG, Toivonen .I. Five years experience with levonorgestrel-releasing IUDs. Contraception 1986; 33:139-148.
2.
Gao J, Wang SL, Wu SC, Sun BL. Comparison of the efficacy and acceptability of levonorgestrel-releasing IUD and Norplantin China. Contraception (in press).
3.
Xiao BL, Zhang XL, Feng DD. Pharmacokinetic and pharmacodynamic studies of vaginal rings releasing low-dose levonorgestrel. Contraception 1985; 32:455-471.
4.
Cekan SZ, Segersteen U, Jia MC. A simple, but reliable assay of sex hormone binding globulin. Analytical Letters 1985; 18(B3): 287-298.
5.
Xiao BL, Fan HM, Zheng SR, Wu YM, Zhang XL, XiaoS, Wu LR, Hong XN. Survey of menstrual cycle length and ovulation of healthy women in Beijing area. Chin J Obstet Gynecol 1988; 23:279-282.
6.
Landgren B-M, Diczfalusy E. Hormonal effects of the 300 ug norethisterone (NET) minipill. 1. Daily steroid levels in 43 subjects during a pretreatment cycle and during the second month of NET administration. Contraception 1980; 21:87-113.
7. Nilsson CG, Lahteenmaki P, Luukkainen T. Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steril 1984; 41:52-55. 8.
Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrelreleasing intrauterine devices. Int J Gynecol Path01 1986; 5:235-241
9.
The interaction Cekan SZ, Jia M, Landgren B-M, Diczfalusy E. between sex hormone binding globulin and levonorgestrel released from vaginal rings in women. Contraception 1984; 31:431-439.
APRIL 1990 VOL. 41 NO. 4
PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE Xiao Bilian, Zhou Liying, Zhang Xuling, Jia Mengchun National Research Institute for Family Planning Beijing, China Tapani Luukkainen Steroid Research Laboratory Department of Medical Chemistry, University of Helsinki Helsinki, Finland Hannu Allonen Leiras, Clinical Research Huhtamaki OY Pharmaceuticals, Helsinki, Finland ABSTRACT Intrauterine devices releasing 20 &g/day levonorgestrel were inserted in 10 women (ages 25-34). Bleeding and spotting patterns were recorded on a menstrual card during one year of follow-up. Blood samples were collected for radioimmunoassays of LH, estradiol (E2), progesterone (P) and levonorgestrel (LNG) and for sex hormone binding globulin (SHBG) 3 times a week during the 1st month of use, and twice a week during the 6th and 12th treatment months. Among the 10 women, two experienced irregular cycles with prolonged intermenstrual spotting, four had amenorrhea in the latter part of treatment months, while the other four had regular cycles. According to the serum levels of E2 and P, the hormone profiles were divided into four types of reaction: A) anovulatory, B) anovulatory but with high follicular activity, C) ovulatory but with luteal insufficiency, and D) ovulatory. Among the 29 treatment cycles, there were 10 D-type, 3 C-type, 13 B-type and 3 A-type of ovarian reactions: 44.8% of the cycles were ovulatory (C+D) and 55.2% were anovulatory (A+B). In general, serum levels of levonorgestrel were low in ovulatory cycles and were high in anovulatory cycles. The difference was statistically significant. There were marked individual differences. The decline of serum LNG from the 1st (492 pmol/l) to the 6th (320 pmol/l) treatment months was 34.9% on average. The amenorrheic cycles coincided mostly with the hormonal profile of ovulatory types, which indicated that the cause of amenorrhea is due to the local effect of levonorgestrel on the endometrium. The levonorgestrel levels were significantly correlated with serum SHBG, r=0.8856, p
for publication for publication
APRIL 1990 VOL. 41 NO. 4
September 25, 1989 December 13, 1989
353
CONTRACEPTION
INTRODUCTION Increase of menstrual blood loss after insertion of intrauterine device is the main concern among IUD users in China. In our national programme of contraceptive research, more efforts are being focused on the investigation and development of IUDs and other contraceptive devices that can reduce menstrual blood loss. Previous studies of levonorgestrel-releasing IUD (LNG-IUD) by Luukkainen et al.(l) showed decrease of menstrual blood loss and increase of hemoglobin. Similar results were observed by Gao et al.(Z) in a comparative study of Norplant- and LNG-IUD. As with all types of steroid contraceptives, changes in menstrual pattern were unavoidable and the main cause of removal. We have found in a pharmacokinetic and pharmacodynamic study of a levonorgestrel-releasing vaginal ring that more irregualr bleeding occurred in cases with anovulatory type of reaction (3). The purpose of the present study is to investigate the hormonal relationship between the bleeding pattern and the different types of ovarian function after using levonorgestrelreleasing IUDs. SUBJECTS AND METHODS Ten women ages 25-34, gravida 1-3, para 1, healthy and with regular menstrual cycles were recruited for this study. Before admission, no steroid contraceptives were used within 2 months, we required no births within one year, and return of at least two normal menstrual cycles after abortion; no endocrine disturbances were found. The LNG-IUDs used in this study were provided by the Leiras, Turku, Finland. It is Nova-T shaped, with levonorgestrel incorporated in a silastic polymer around the vertical arm of the IUD. The daily release rate of LNG is around 20 fig. It was inserted on the 5th-7th cycle day. There was only one removal at the 6th treatment month; the rest remained in the study for one year. Blood samples (8 ml) were collected 3 times a week during the 1st month of treatment and twice a week during the 6th and 12th treatment months for determination of estradiol (E2), progesterone (P) and LH. Levonorgestrel (LNG) was measured in the 1st and 6th month samples, and 12th month samples only in 2 cases. In each case, one sample was collected during the luteal phase (cycle day 21-23) of the pretreatment cycle for measurement of progesterone to verify luteal function. Radioimmunoassays of E2, P, LH and LNG were performed with WHO matched reagents and methods. Sex hormone binding globulin (SHBG) was measured in blood samples of the 1st and 6th treatment cycles using the method of Cekan et al. (4).
354
APRIL
1990 VOL. 41 NO. 4
CONTRACEPTION
Bleeding and spotting days were recorded on menstrual cards. The bleeding patterns were analyzed according to Snowden's parameters and compared with the data of normal menstrual cycles from the same population of women in Beijing (5). Geometric means of E2, P and LNG levels in different types of ovarian reaction were compared using Student's t test. Regression coefficients were used in the analysis of decline of levonorgestrel and its correlation with SHBG and E2. RESULTS
The bleeding patterns of each individual case during the 12 treatment months are shown in a schematic diagram (Fig. 1). There were 2 cases who experienced irregular bleeding and spotting, 4 cases of amenorrhea in the latter treatment months and 4 cases with regular cycles. Among the total treatment cycles, there were 13 regular cycles, 5 with prolonged spotting in the intermenstrual period and 11 with amenorrhea.
30
60
90
120
150
180
210
240
270
300
330
360 MYS
Fig. 1.
Bleeding patterns of individual cases during the 12-month follow-up after insertion of LNG-IUDs. +=insertion, +=removal, full bar=bleeding, half bar=spotting.
As the women in this study were recruited from the same population as in a previous study of normal menstrual pattern by Xiao et al. (5). their data were compared as shown in Table I. There were significant differences in the average length of episodes, longest episode and number of total spotting days in a reference period of 180 days. In the follow-up of 360 days after insertion of LNG-IUDs, there was a tendency to decreased bleeding days and increased interval days, though no statistically significant difference was found.
APRIL 1990 VOL. 41 NO. 4
355
CONTRACEPTION
Table I.
Comparison of bleeding patterns after LNG-IUD with normal menstrual cycles in a reference period of 180 & 360 days Normal cycle l-180 days (n=917)
No. of bleeding days No. of episodes Average length of episodes Longest episode Longest interval Average length of segments No. of spotting days
23.8k6.99 6.1kO.69 3.1k1.12 4.5k1.35 32.5k8.22 32.4+4.29 8.6k6.84
LNG-IUDs l-180 days 181-360 days (n=lO> (n=9) 28.2A16.77 4.7A2.12 5.6*1.71* 8.7f4.79" 62.3A47.71 53.9*47.18 38.4f28.00*
14.5k14.26 3.5k3.39 2.1+2.14++ 3.1?3.25+ 95.2k80.46 96.51t79.21 24.5k14.29
"pQl.05 (normal versus LNG-IUD l-180 days) +pco.o5, ++xO.Ol (LNG-IUD l-160 versus 180-360 days) According to the serum levels of estradiol and progesterone in the 29 treatment cycles of the 1st and 6th months, the ovarian reaction to levonorgestrel were divided into 4 types: low E2 and low P levels in 3 cycles (A:anovulatory); high E2 and low P levels in 13 cycles (B:anovulatory but with high follicular activity); normal E2 profile but comparatively low P levels in 3 cycles (C: ovulatory with luteal insufficiency); normal E2 and P profile in 10 cycles (D:ovulatory) as per Landgren et al. (6). The difference in mean E2 and mean P levels between the ovulatory (C+D) and the anovulatory cycles (A+B) was significant, pCO.001 (Table II). Table II. Comparison of geometric means of E2, P and LNG in ovulatory and anovulatory types of reaction after LNG-IUD insertion Type 132
P
(pmol/l) (nmol/l)
LNG (pmol/l)
n
Mean (+SD, -SD)
p value
A+B C+D
155 124
438 229
(1103, 174) ( 530, 99)
(0.001
A+B C+D
161 132
2.0 4.8
(4.0, 0.9) (20.1, 1.1)
(0.001
A+B C+D
110 97
460 332
(993, 213) (598, 187)
(0.001
APRIL
1990 VOL. 41 NO. 4
CONTRACEPTION
Serum levels of LNG were significantly higher in cycles where ovulation was suppressed (A+B) than in ovulatory cycles (C+D), their mean levels being 460 pmol/l and 332 pmol/l, respectively; the difference was statistically significant, p
Z.Y.E. S.Y.L. Z.S.F. W.H.L. L.G.Q. F.W.Y. J.S.Q. L.B.P. S.L.N. L.Y.J. MEAN
8
Fig. 2.
1st mo.
6th mo.
% decline
p value
Tse
363.5
250.6 983.5 411.4 324.7 183.3 559.6 457.7 259.3 121.3 115.3
-13.8 -38.1 -25.2 -42.5 -47.1 -17.9 -22.3 -43.4 -30.6 -68.3
>0.05
D,D B,B D,A B,B D,D B,B C,D B,B B,B D,D
492.3
320.3
-34.9
(0.001
20
40
290.8
1589.6 549.8 564.7 346.7 682.3 588.9 458.4 176.8
la
220
DAYS
Decline of serum levonorgestrel levels from the 1st to the 6th treatment cycle.
APRIL 1990 VOL. 41 NO. 4
357
CONTRACEPTION
P
II
MOO-
---f 0
I -aIF--=
-G----T nom
_-y=
_------E 0
II
a 0
’
I
I
I
1 1000
6$b
200
D
1900 Estradiol (ml/f)
Fig. 3.
Correlation between the mean levels of levonorgestrel and estradiol during the 1st and 6th treatment cycles.
--r---l--44
20
&I
80
100
SHBC (nml/l)
Fig. 4.
Correlation between the mean levels of levonorgestrel and SHBG during the 1st and 6th treatment cycles.
APRIL 1990 VOL. 41 NO. 4
CONTRACEPTION
I
“,,.A’A\/A\ Jo
A-
A-A-A
mI D
Fig. 5.
Serum levels of E2, P and LNG during the lst, 6th and 12th treatmentmonths of LNG-IUD use in case no. 1 with regular menstrualcycles. The hormonal profile showed ovulatorypattern. The serum LNG was maintainedat relativelylow levels. o---o E2 pmolfl, o---o P nmol/l, a----OLNG pmol/l; double bar=bleeding,single bar-spotting.
APRIL 1990 VOL. 41 NO. 4
359
CONTRACEPTION
12 th month
Fig. 6.
360
Serum levels of E2, P and LNG during the lst, 6th and 12th treatment month of LNG-IUD use in case no. 2. The menstrual cycles were irregular, but the hormonal profile showed B type of ovarian reaction, with very high levels of E2 during the 1st and 6th treatment months and lower levels in the 12th month. P levels were suppressed but increased in the latter half of the 12th month. LNG was maintained at high levels. o---o E2, o---o P,b---* LNG; double bar=bleeding, single bar=spotting.
APRIL
1990VOL.
41 NO. 4
CONTRACEPTION
The mean value of SHBG in the pretreatment blood samples from the luteal phase was 62.09+23.9nmol/l. The mean SHBG level after insertion of LNG-IUD was 41.82~20.50nmo1/1. In each individual the mean levels of LNG and SHBG at one treatment cycle were calculated and their correlation analyzed. The correlation between LNG and SHBG the regression coefficient being was very significant (Fig. 4), The correlation between SHBG and y=153.54+15.337~, r=0.885, ~(0.01. 22 was insignificant (y=283.28+5.6022~, r=0.4086, pjO.05). The mean SHBG level of the anovulatory cycles (A+B) was higher than that of the ovulatory cycles (C+D), being 40.4nmol/l and 34.7nmol/l, respectively; the difference was significant p
APRIL
1990 VOL. 41 NO. 4
361
CONTRACEPTION ACKNOWLEDGEMENT We are grateful to UNFPA for the financial support of this study and to WHO Special Programme of Research, Development and Research Training in Human Reproduction for the provision of RIA reagents and consultant review of the study. REFERENCES 1.
Luukkainen T, Allonen H, Haukkamaa M,Lahteenmaki P, Nilsson CG, Toivonen .I. Five years experience with levonorgestrel-releasing IUDs. Contraception 1986; 33:139-148.
2.
Gao J, Wang SL, Wu SC, Sun BL. Comparison of the efficacy and acceptability of levonorgestrel-releasing IUD and Norplantin China. Contraception (in press).
3.
Xiao BL, Zhang XL, Feng DD. Pharmacokinetic and pharmacodynamic studies of vaginal rings releasing low-dose levonorgestrel. Contraception 1985; 32:455-471.
4.
Cekan SZ, Segersteen U, Jia MC. A simple, but reliable assay of sex hormone binding globulin. Analytical Letters 1985; 18(B3): 287-298.
5.
Xiao BL, Fan HM, Zheng SR, Wu YM, Zhang XL, XiaoS, Wu LR, Hong XN. Survey of menstrual cycle length and ovulation of healthy women in Beijing area. Chin J Obstet Gynecol 1988; 23:279-282.
6.
Landgren B-M, Diczfalusy E. Hormonal effects of the 300 ug norethisterone (NET) minipill. 1. Daily steroid levels in 43 subjects during a pretreatment cycle and during the second month of NET administration. Contraception 1980; 21:87-113.
7. Nilsson CG, Lahteenmaki P, Luukkainen T. Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steril 1984; 41:52-55. 8.
Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrelreleasing intrauterine devices. Int J Gynecol Path01 1986; 5:235-241
9.
The interaction Cekan SZ, Jia M, Landgren B-M, Diczfalusy E. between sex hormone binding globulin and levonorgestrel released from vaginal rings in women. Contraception 1984; 31:431-439.
APRIL 1990 VOL. 41 NO. 4