Levonorgestrel-Releasing lntrauterine Device Tapani Luukkainen, Pekka Lahteenmaki and Juhani Toivonen An intrauterine contraceptive device releasing 20 pg levonorgestrel daily has been studied for 15 years. The international clinical experience covers over 8000 woman years. Main characteristics of the levonorgestrel-releasing intrauterine device are its great effectiveness in preventing unplanned pregnancies and a reduction in menstrual bleeding and pain as well as a low infection rate. Key words: intrauterine contraception; levonorgestrel.
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
(Annals of Medicine 22: 85-90,
1990)
Introduction The main reason for a woman stopping her use of a conventional intrauterine device (IUD) i s excessive bleeding. The inert as well as copper releasing IUDs increase the amount and the duration of bleeding. If the diet lacks iron or the IUD is used for many years, there could be adverse effects on a woman’s health even without excessive bleeding. Unnoticed anaemia is often associated with family planning programmes using IUD:s. Lev0norgest rel-releasi ng IUD (LNG-IUD) was developed to reduce menstrual bleeding. Studies over 15 years have shown that the use of LNG-IUD greatly reduces menstrual bleeding. This method also has very low pregnancy and infection rates. The main basic studies on LNG-IUD and some clinical ones are reviewed here.
trel to 20 pg (1). The recommended duration of use of the device is five years, and LNG-IUD should be removed during the sixth year of use; if necessary, a new device can be inserted immediately after removal. After studying the effects of various daily releases of LNG it was observed that the higher release rates had no merits over 20 pg per day and caused more hormonal side effects (2). The safety considerations for the longterm use resulted in the selection of a dose of 20 pg of LNG for daily release.
Device The plain plastic device, the same as is used to carry the copper wire i n the copper-releasing IUD Nova T (Leiras Pharmaceuticals, Turku, Finland), has a steroid reservoir around the vertical stem (Fig. 1). The reservoir consists of acylinder made of a mixture of levonorgestrel (LNG) and SilasticR, Medical Grade Elastomer, Dow Corning Corporation, Medical Product Division, Midland, Michigan, USA. This mixture, containing 50 YO steroid by weight, forms a sleeve around the vertical stem of the IUD and is covered by a SilasticR membrane which regulates the daily release of levonorgesFrom the Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Helsinki, Finland. Address and reprint requests: Tapani Luukkainen, M.D., Ph.D., Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Siltavuorenpenger 10 A, SF-00170 Helsinki , Fin land. Received: September 27, 1989.
Figure 1 . Levonorgestrel-releasing
IUD. Ann Med 22
Luukkainen
86
Lahteenmaki Toivonen
Mode of Action There is no single identifiable mechanism for the contraceptive action of LNG-IUD. The main findings are scanty cervical mucus and strong, reversible atrophy of the endometrium. A direct effect on sperm and on the process of fertilization cannot be ruled out. Interestingly, fertilized eggs have not been recovered from the reproductive tract of LNG-IUDusers (3). Here we review those studies carried out to discover the mode of action of LNG-IUD.
Table 1. Mean plasma estradiol (E,)and levonorgestrel (LNG) concentrations (pglmL) in menstruating and amenorrheic women using an LNG-IUD.
E2
N
LNG N
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
(5). Menstrual bleeding is not a predictor of ovarian function in LNG-IUD users: the analysis of plasma samples has shown that the average progesterone concentration is the same in those women who have regular but scanty bleedings and in those who have oligoamenorrhea. The incidence of ovulation is similar in both groups. Also, no difference has been found in plasma estradiol concentration between these two groups of women (6). After the first year of use most cycles are ovulatory (7). Recently, a comparative study between the LNGIUD and the Multiload 250 showed that after a year of use the incidence of ovulation is the same, as judged by plasma progesterone (8).Ovulatory cycles were seen in 85 O/O of women with either device. The avoidance of estrogen deficiency is an important prerequisite for a long acting contraceptive method in order to prevent osteoporosis. Table 1 shows the mean plasma estradiol and levonorgestrel concentrations in 86 women after one or two years of LNG-IUD use. The individual values for menstruating women fall into the range typical of normal menstrual cycles, and estradiol values in amenorrheic women fell within the same range. Furthermore, no individual menopausal estradiol values were found. Table 2 gives mean estradiol concentrations as a function of the length of time of LNG-IUD use. No changes were found in the mean concentrations between women using the device for one and seven years. The higher mean concentration after three months was owing to very high concentrations of up to 900 pglmL in five women. These high values were the result of follicular cyst formation, known to be associated with progestin only contraception (9).
Plasma and Uterine Concentrations of LNG The local intrauterine release of LNG results in resorbtion of the steroid into the systemic circulation, reflected in quickly rising plasma concentrations after inser-
Ann Med 22
Arnenorrheic
103.9 66 175.2 62
132.7 20 179.9 20
Table 2. Mean plasma estradiol (E2)concentrations (pglmL) in women using an LNG-IUD.
Ovarian Function For complete ovulation inhibition a daily intrauterine release of 50 pg or over of LNG is needed (4). With the 20 pg release dose of LNG four different types of ovarian function can be found during the first year of the use: (I) anovulation with some inhibition in estradiol production; (11) anovulation with increased estradiol production; (Ill)normal proliferative phase with inadequate Meal phase; (IV) completely normal ovulatory cycles. It has been shown that types I and II are frequently seen in women with higher LNG plasma concentrations
Menstruating
Duration of use ~
E2
N
Three months
One year
Two years
Five years
Six years
Seven years
168.4 33
104.6 53
128.4 42
109.6 32
105.6 27
111.6 34
tion (10). The resorbtion takes place through the endometrium to the capillary network in the basal layer of the mucosa. LNG can be detected in plasma 15 minutes after insertion (10). The highest concentrations are reached during the first few hours. The individual plasma LNG concentrations are relatively stable, but there are great variations between individuals (Fig. 2). The mean plasma concentrations during the six year observation period show some decline (Fig. 3). In plasma levonorgestrel is mainly bound to sex hormone binding globulin (SHBG) ( I I ) , so there is a significant positive correlation between plasma LNG and SHBG concentrations. This is illustrated in Figure 4 , which depicts plasma concentrations of LNG and SHBG in ten women who have a LNG-IUD. The first studies to evaluate the tissue concentrations of LNG in the endometrium were made with an experimental model releasing 30 pg of LNG daily in women who were scheduled for hysterectomy after a diagnosis of adenomyosis or uterine fibroids (12). The hysterectomies were performed four to six weeks after insertion. At that time the endometrium was swollen. The determinations in the endometrium showed very high concentrations of LNG - from 470 to 1500 ng per gram of tissue wet weight (12). The calculations showed that the concentrations of the endometrial progesterone receptor were responsible for only a fraction of the bound steroid. The determination of the LNG concentration in endometrium of women who had used LNG-IUD for a longer time showed very much lower concentrations of LNG, but the amount still exceeded what could be bound by progesterone receptors (Fig. 5). The LNG concentrations in myometrial or fallopian tube tissue was very low and were similar regardless of the period of use of LNG-IUD. Oral administration of a dose ten times higher than the dose administered with LNG-IUD resulted in endometrial concentrations of LNG which did not differ from those in the adjacent tissues and the effects on endometrium were correspondingly much weaker (12). The high concentration of LNG in the endometrium of LNG-IUD users occurred during the period of en-
Levonorgest re 1-1 U D
LNG
-
20 pg LNG - IUD
pg/ml
I
200 -
A
150-
A.
@'%A-+.-.
k
I
q.pA'u o w-o.o.
9v . w d * ' i
; /
loo: 50
4
0
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
87
1
1
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I
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I
dometrial stimulation within four to eight weeks after insertion. This was followed by strong suppression and atrophy of the endometrium (13) the suppression being clinically reflected in scanty menstruation, and in some subjects oligoarnenorrhea. To evaluate the role of SHBG in high concentrations of the protein bound LNG in the endometrium after in-
LNG PS/ml 300 -
sert ion, we perf o rmed immu noperoxidase staining studies with two different highly specific monoclonal antibodies to SHBG (Wahlstrom et al., unpublished observations). Strong uptake of the stain occurred in the endometrium when the concentration of LNG in the tissue was high. The staining resembles that seen in the decidua of extrauterine pregnancies. Whether SHBG is synthesised in situ, or taken up by endometrial decidual cells, is not yet known. Nevertheless, the SHBG coiltent of decidual cells is increased by levonorgestrel for a few weeks after insertion.
LNG
ng/gww
200 gn52
1500
100 -
I1 1/4
I
I
I
I
2
1
3
I
I
4
0
5
6
Figure 3. Mean plasma levonorgestrel (LNG) levels over six years in women using a 20 pgld -releasing LNG-IUD.
1000
LNG
8001
500
v
20
40
60
80
100
120
140
160
180
200 SHBG
Figure 4. Correlation of plasma levonorgestrel (LNG) concen. tration (pglml) and sex hormone binding globulin (SHBG) con. centration (nmolll) i n ten LNG-IUD users.
Figure 5. Levonorgestrel (LNG) concentration of endometrium (nglg wet weight) in women who had used a LNG-IUD for two, nine and 78 months.
Ann Med 22
Luukkainen
88
Liihteenmaki Toivonen
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
Endometrial Morphology The endometrial samples were collected during or after LNG-IUD use by a vacuum endometrial sampler (VabraR). After a few weeks of use the endometrial glands atrophied and the stroma become decidual(l3,14). The mucosa was thin and the stromaswollen, while the endometrial glands were atrophic and the epithelium inactive. These histological changes were already uniform after one month’s use and there was no change in the histological picture during prolonged use of the LNG-IUD(13,14). The studies covered continuous use of LNG-IUD for more than seven years. Endometrial samples were taken from more than 100 women, mainly during years five, six or seven. There were no adverse findings nor reasons for concern. Endometrial biopsies were done on 62 women two to six months after the device was removed and there was a complete return of normal histology in samples from these patients (Liihteenmaki P, et al., unpublished observations). Resumption of fertility was not delayed after removal of LNG-IUD (15). Many women who discontinued the use of LNG-IUD for an intended pregnancy conceived during the first cycle after the removal. The pregnancies have been normal and uneventful.
Clinical Performance The striking positive features of LNG-IUD as compared with other IUD’s are reductions in the amount and duration of menstrual bleeding, high effectiveness and a reduction of menstrual pain. Even during the early studies with LNG-IUD it was observed that the duration and amount of bleeding lessened during use. The first quantitative determinations showed a significant fall in menstrual blood loss (MBL) when pre-and postinsertion MBL were compared (16). In comparative trials women kept menstrual records of spotting and bleeding days for up to two years. During the first two months the number of spotting days in LNG-IUD increased slightly compared with women with acopperreleasing IUD; thereafter the users of copper-releasing Nova-Tand LNG-IUD had the same number of spotting days over two years. The number of bleeding days fell sharply and the fall was significant after three months of use and continued to fall until the end of the first year. I f women who had oligoamenorrhea during the use of LNG-IUDare included in the statistics the reduction in the number of mean bleeding days is even more pronounced. In these studies the reduction in the amount and duration of bleeding is reftected by a significant increase of haemoglobin and ferritin levels. Recently, a well conducted randomised comparative study on the menstrual bleeding was carried out in Holland by comparing LNG-IUD and Multiload 250 IUD in 52 patients (8). The observation included quantitative determination of menstrual blood loss before and during the first year of use. Haemoglobin and ferritin determinations were also done. The mean number of bleeding days increased among users of Multiload and fell among those using LNG-IUD. The mean amount of bleeding increased from the pretreatment value by 20 ml in the
Ann Med 22
Multiload users during the first year and fell by 40 ml in those women using LNG-IUD. The different effects on bleeding were reflected in the haemoglobin and ferritin values (8). In Beijing a comparative study was performed on LNG-IUD and Norplant 2@,a subdermal implant releasing LNG. LNG-IUD significantly reduced the amount and duration of bleeding, and it also reduced MBL. This was not observed in Norplant 2@-users,even though they also had a significant increase i n hemoglobin levels (17). It seems that without exception the users of LNG-IUDexperience a sharp fall in the amount of menstrual bleeding and benefit from an increase in the haemoglobin and iron stores. The 5-year termination rates1100 woman years of a comparative randomized multicentre study (18) between LNG-IUDand copper-releasing Nova-Tare given in Table 3. The discontinuation of use was significantly less with LNG for accidental pregnancies, for bleeding and for PID, than with NovaT. The terminations for amenorrhea and for hormonal reasons were significantly higher with LNG-IUD.
LNG-IUD during Lactation Hormonal contraception is contraindicated in breast feeding women because steroids are transferred into milk. Furthermore, combined oral contraceptives reduce the amount of milk produced (19). Since LNG-IUD gives lower concentrations of circulating LNG in blood than is the case after oral contraception, puerperal insertion of LNG-IUDwas studied, the device was inserted in 70 breast-feeding amenorrheic women six weeks after delivery. Milk and plasma samples were collected for 12 weeks, and the concentrations of LNG were determined by radioimmunoassay. Small but measurable amounts of LNG were detected in breast milk (20). The plasma to milk ratio of LNG was 100:25. The results showed that even with a low maternal steroid dose of 10 to 30 pgld of LNG, suckling infants are exposed to progestin. This small dose, however, was only 0.1 OO/ of the maternal daily dose and has no harmful effects on the infants (21). The weight gain of infants, their blood chemistry, and the time of breast feeding were not significantly affected when the children of mothers with a copper-releasing IUD were compared with those of mothers using LNG-IUDs (21). Thus the negligible amounts of progestins ingested in breast milk should have no detectable effects on child health. Accordingly, the LNG-IUDcan be used while a mother is breast feeding but bleeding patterns are more satisfactory during the first three months i n women using copper-releasing IUD.
Therapeutic Possibilities LNG-IUD has been used for contraception in women with menorrhagia with good clinical results. Two studies have recently been performed, to assess the value of LNG-IUD in the treatment of menorrhagia, both entailing quantitative measurements of MBL. In the first study (Andersson and Rybo, unpublished obser-
Levonorgestrel-l UD
89
Table 3. 5-year termination ratesllO0 woman years with Nova T and LNG-IUD. Nova T N Pregnancy Expulsion Bleeding problems Amenorrhea Pain Hormonal PID Other medical Planning pregnancy Other personal
31 47 133 0 33 9 13 60 91 24
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
Women enrolled Terminations Woman-mon ths
937 461 29 446
vations) only women who had MBL over 80 ml per period during two consecutive cycles and who had a normal sized or slightly enlarged uterus with no sign of pelvic pathology were included into the study. A significant reduction in bleeding at three months was found in every woman and the effect was more pronounced at 12 months when the mean bleeding was 10 OO/ of that during the preinsertion cycles. This convincing study also demonstrated a significant increase in the women’s haemoglobin concentration after six months of use (P< 0.001). Scholten et al. (22) demonstrated a significant reduction in the MBLof 11 patients 7 t o 12 months after the insertion. The mean reduction was from 119 ml to 17 ml and there was also significant increases in haemoglobin concentration and serum ferritin (P
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
(Annals of Medicine 22: 85-90,
1990)
Introduction The main reason for a woman stopping her use of a conventional intrauterine device (IUD) i s excessive bleeding. The inert as well as copper releasing IUDs increase the amount and the duration of bleeding. If the diet lacks iron or the IUD is used for many years, there could be adverse effects on a woman’s health even without excessive bleeding. Unnoticed anaemia is often associated with family planning programmes using IUD:s. Lev0norgest rel-releasi ng IUD (LNG-IUD) was developed to reduce menstrual bleeding. Studies over 15 years have shown that the use of LNG-IUD greatly reduces menstrual bleeding. This method also has very low pregnancy and infection rates. The main basic studies on LNG-IUD and some clinical ones are reviewed here.
trel to 20 pg (1). The recommended duration of use of the device is five years, and LNG-IUD should be removed during the sixth year of use; if necessary, a new device can be inserted immediately after removal. After studying the effects of various daily releases of LNG it was observed that the higher release rates had no merits over 20 pg per day and caused more hormonal side effects (2). The safety considerations for the longterm use resulted in the selection of a dose of 20 pg of LNG for daily release.
Device The plain plastic device, the same as is used to carry the copper wire i n the copper-releasing IUD Nova T (Leiras Pharmaceuticals, Turku, Finland), has a steroid reservoir around the vertical stem (Fig. 1). The reservoir consists of acylinder made of a mixture of levonorgestrel (LNG) and SilasticR, Medical Grade Elastomer, Dow Corning Corporation, Medical Product Division, Midland, Michigan, USA. This mixture, containing 50 YO steroid by weight, forms a sleeve around the vertical stem of the IUD and is covered by a SilasticR membrane which regulates the daily release of levonorgesFrom the Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Helsinki, Finland. Address and reprint requests: Tapani Luukkainen, M.D., Ph.D., Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, Siltavuorenpenger 10 A, SF-00170 Helsinki , Fin land. Received: September 27, 1989.
Figure 1 . Levonorgestrel-releasing
IUD. Ann Med 22
Luukkainen
86
Lahteenmaki Toivonen
Mode of Action There is no single identifiable mechanism for the contraceptive action of LNG-IUD. The main findings are scanty cervical mucus and strong, reversible atrophy of the endometrium. A direct effect on sperm and on the process of fertilization cannot be ruled out. Interestingly, fertilized eggs have not been recovered from the reproductive tract of LNG-IUDusers (3). Here we review those studies carried out to discover the mode of action of LNG-IUD.
Table 1. Mean plasma estradiol (E,)and levonorgestrel (LNG) concentrations (pglmL) in menstruating and amenorrheic women using an LNG-IUD.
E2
N
LNG N
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
(5). Menstrual bleeding is not a predictor of ovarian function in LNG-IUD users: the analysis of plasma samples has shown that the average progesterone concentration is the same in those women who have regular but scanty bleedings and in those who have oligoamenorrhea. The incidence of ovulation is similar in both groups. Also, no difference has been found in plasma estradiol concentration between these two groups of women (6). After the first year of use most cycles are ovulatory (7). Recently, a comparative study between the LNGIUD and the Multiload 250 showed that after a year of use the incidence of ovulation is the same, as judged by plasma progesterone (8).Ovulatory cycles were seen in 85 O/O of women with either device. The avoidance of estrogen deficiency is an important prerequisite for a long acting contraceptive method in order to prevent osteoporosis. Table 1 shows the mean plasma estradiol and levonorgestrel concentrations in 86 women after one or two years of LNG-IUD use. The individual values for menstruating women fall into the range typical of normal menstrual cycles, and estradiol values in amenorrheic women fell within the same range. Furthermore, no individual menopausal estradiol values were found. Table 2 gives mean estradiol concentrations as a function of the length of time of LNG-IUD use. No changes were found in the mean concentrations between women using the device for one and seven years. The higher mean concentration after three months was owing to very high concentrations of up to 900 pglmL in five women. These high values were the result of follicular cyst formation, known to be associated with progestin only contraception (9).
Plasma and Uterine Concentrations of LNG The local intrauterine release of LNG results in resorbtion of the steroid into the systemic circulation, reflected in quickly rising plasma concentrations after inser-
Ann Med 22
Arnenorrheic
103.9 66 175.2 62
132.7 20 179.9 20
Table 2. Mean plasma estradiol (E2)concentrations (pglmL) in women using an LNG-IUD.
Ovarian Function For complete ovulation inhibition a daily intrauterine release of 50 pg or over of LNG is needed (4). With the 20 pg release dose of LNG four different types of ovarian function can be found during the first year of the use: (I) anovulation with some inhibition in estradiol production; (11) anovulation with increased estradiol production; (Ill)normal proliferative phase with inadequate Meal phase; (IV) completely normal ovulatory cycles. It has been shown that types I and II are frequently seen in women with higher LNG plasma concentrations
Menstruating
Duration of use ~
E2
N
Three months
One year
Two years
Five years
Six years
Seven years
168.4 33
104.6 53
128.4 42
109.6 32
105.6 27
111.6 34
tion (10). The resorbtion takes place through the endometrium to the capillary network in the basal layer of the mucosa. LNG can be detected in plasma 15 minutes after insertion (10). The highest concentrations are reached during the first few hours. The individual plasma LNG concentrations are relatively stable, but there are great variations between individuals (Fig. 2). The mean plasma concentrations during the six year observation period show some decline (Fig. 3). In plasma levonorgestrel is mainly bound to sex hormone binding globulin (SHBG) ( I I ) , so there is a significant positive correlation between plasma LNG and SHBG concentrations. This is illustrated in Figure 4 , which depicts plasma concentrations of LNG and SHBG in ten women who have a LNG-IUD. The first studies to evaluate the tissue concentrations of LNG in the endometrium were made with an experimental model releasing 30 pg of LNG daily in women who were scheduled for hysterectomy after a diagnosis of adenomyosis or uterine fibroids (12). The hysterectomies were performed four to six weeks after insertion. At that time the endometrium was swollen. The determinations in the endometrium showed very high concentrations of LNG - from 470 to 1500 ng per gram of tissue wet weight (12). The calculations showed that the concentrations of the endometrial progesterone receptor were responsible for only a fraction of the bound steroid. The determination of the LNG concentration in endometrium of women who had used LNG-IUD for a longer time showed very much lower concentrations of LNG, but the amount still exceeded what could be bound by progesterone receptors (Fig. 5). The LNG concentrations in myometrial or fallopian tube tissue was very low and were similar regardless of the period of use of LNG-IUD. Oral administration of a dose ten times higher than the dose administered with LNG-IUD resulted in endometrial concentrations of LNG which did not differ from those in the adjacent tissues and the effects on endometrium were correspondingly much weaker (12). The high concentration of LNG in the endometrium of LNG-IUD users occurred during the period of en-
Levonorgest re 1-1 U D
LNG
-
20 pg LNG - IUD
pg/ml
I
200 -
A
150-
A.
@'%A-+.-.
k
I
q.pA'u o w-o.o.
9v . w d * ' i
; /
loo: 50
4
0
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
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1
1
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I
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I
dometrial stimulation within four to eight weeks after insertion. This was followed by strong suppression and atrophy of the endometrium (13) the suppression being clinically reflected in scanty menstruation, and in some subjects oligoarnenorrhea. To evaluate the role of SHBG in high concentrations of the protein bound LNG in the endometrium after in-
LNG PS/ml 300 -
sert ion, we perf o rmed immu noperoxidase staining studies with two different highly specific monoclonal antibodies to SHBG (Wahlstrom et al., unpublished observations). Strong uptake of the stain occurred in the endometrium when the concentration of LNG in the tissue was high. The staining resembles that seen in the decidua of extrauterine pregnancies. Whether SHBG is synthesised in situ, or taken up by endometrial decidual cells, is not yet known. Nevertheless, the SHBG coiltent of decidual cells is increased by levonorgestrel for a few weeks after insertion.
LNG
ng/gww
200 gn52
1500
100 -
I1 1/4
I
I
I
I
2
1
3
I
I
4
0
5
6
Figure 3. Mean plasma levonorgestrel (LNG) levels over six years in women using a 20 pgld -releasing LNG-IUD.
1000
LNG
8001
500
v
20
40
60
80
100
120
140
160
180
200 SHBG
Figure 4. Correlation of plasma levonorgestrel (LNG) concen. tration (pglml) and sex hormone binding globulin (SHBG) con. centration (nmolll) i n ten LNG-IUD users.
Figure 5. Levonorgestrel (LNG) concentration of endometrium (nglg wet weight) in women who had used a LNG-IUD for two, nine and 78 months.
Ann Med 22
Luukkainen
88
Liihteenmaki Toivonen
Ann Med Downloaded from informahealthcare.com by University of Otago on 01/12/15 For personal use only.
Endometrial Morphology The endometrial samples were collected during or after LNG-IUD use by a vacuum endometrial sampler (VabraR). After a few weeks of use the endometrial glands atrophied and the stroma become decidual(l3,14). The mucosa was thin and the stromaswollen, while the endometrial glands were atrophic and the epithelium inactive. These histological changes were already uniform after one month’s use and there was no change in the histological picture during prolonged use of the LNG-IUD(13,14). The studies covered continuous use of LNG-IUD for more than seven years. Endometrial samples were taken from more than 100 women, mainly during years five, six or seven. There were no adverse findings nor reasons for concern. Endometrial biopsies were done on 62 women two to six months after the device was removed and there was a complete return of normal histology in samples from these patients (Liihteenmaki P, et al., unpublished observations). Resumption of fertility was not delayed after removal of LNG-IUD (15). Many women who discontinued the use of LNG-IUD for an intended pregnancy conceived during the first cycle after the removal. The pregnancies have been normal and uneventful.
Clinical Performance The striking positive features of LNG-IUD as compared with other IUD’s are reductions in the amount and duration of menstrual bleeding, high effectiveness and a reduction of menstrual pain. Even during the early studies with LNG-IUD it was observed that the duration and amount of bleeding lessened during use. The first quantitative determinations showed a significant fall in menstrual blood loss (MBL) when pre-and postinsertion MBL were compared (16). In comparative trials women kept menstrual records of spotting and bleeding days for up to two years. During the first two months the number of spotting days in LNG-IUD increased slightly compared with women with acopperreleasing IUD; thereafter the users of copper-releasing Nova-Tand LNG-IUD had the same number of spotting days over two years. The number of bleeding days fell sharply and the fall was significant after three months of use and continued to fall until the end of the first year. I f women who had oligoamenorrhea during the use of LNG-IUDare included in the statistics the reduction in the number of mean bleeding days is even more pronounced. In these studies the reduction in the amount and duration of bleeding is reftected by a significant increase of haemoglobin and ferritin levels. Recently, a well conducted randomised comparative study on the menstrual bleeding was carried out in Holland by comparing LNG-IUD and Multiload 250 IUD in 52 patients (8). The observation included quantitative determination of menstrual blood loss before and during the first year of use. Haemoglobin and ferritin determinations were also done. The mean number of bleeding days increased among users of Multiload and fell among those using LNG-IUD. The mean amount of bleeding increased from the pretreatment value by 20 ml in the
Ann Med 22
Multiload users during the first year and fell by 40 ml in those women using LNG-IUD. The different effects on bleeding were reflected in the haemoglobin and ferritin values (8). In Beijing a comparative study was performed on LNG-IUD and Norplant 2@,a subdermal implant releasing LNG. LNG-IUD significantly reduced the amount and duration of bleeding, and it also reduced MBL. This was not observed in Norplant 2@-users,even though they also had a significant increase i n hemoglobin levels (17). It seems that without exception the users of LNG-IUDexperience a sharp fall in the amount of menstrual bleeding and benefit from an increase in the haemoglobin and iron stores. The 5-year termination rates1100 woman years of a comparative randomized multicentre study (18) between LNG-IUDand copper-releasing Nova-Tare given in Table 3. The discontinuation of use was significantly less with LNG for accidental pregnancies, for bleeding and for PID, than with NovaT. The terminations for amenorrhea and for hormonal reasons were significantly higher with LNG-IUD.
LNG-IUD during Lactation Hormonal contraception is contraindicated in breast feeding women because steroids are transferred into milk. Furthermore, combined oral contraceptives reduce the amount of milk produced (19). Since LNG-IUD gives lower concentrations of circulating LNG in blood than is the case after oral contraception, puerperal insertion of LNG-IUDwas studied, the device was inserted in 70 breast-feeding amenorrheic women six weeks after delivery. Milk and plasma samples were collected for 12 weeks, and the concentrations of LNG were determined by radioimmunoassay. Small but measurable amounts of LNG were detected in breast milk (20). The plasma to milk ratio of LNG was 100:25. The results showed that even with a low maternal steroid dose of 10 to 30 pgld of LNG, suckling infants are exposed to progestin. This small dose, however, was only 0.1 OO/ of the maternal daily dose and has no harmful effects on the infants (21). The weight gain of infants, their blood chemistry, and the time of breast feeding were not significantly affected when the children of mothers with a copper-releasing IUD were compared with those of mothers using LNG-IUDs (21). Thus the negligible amounts of progestins ingested in breast milk should have no detectable effects on child health. Accordingly, the LNG-IUDcan be used while a mother is breast feeding but bleeding patterns are more satisfactory during the first three months i n women using copper-releasing IUD.
Therapeutic Possibilities LNG-IUD has been used for contraception in women with menorrhagia with good clinical results. Two studies have recently been performed, to assess the value of LNG-IUD in the treatment of menorrhagia, both entailing quantitative measurements of MBL. In the first study (Andersson and Rybo, unpublished obser-
Levonorgestrel-l UD
89
Table 3. 5-year termination ratesllO0 woman years with Nova T and LNG-IUD. Nova T N Pregnancy Expulsion Bleeding problems Amenorrhea Pain Hormonal PID Other medical Planning pregnancy Other personal
31 47 133 0 33 9 13 60 91 24
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Women enrolled Terminations Woman-mon ths
937 461 29 446
vations) only women who had MBL over 80 ml per period during two consecutive cycles and who had a normal sized or slightly enlarged uterus with no sign of pelvic pathology were included into the study. A significant reduction in bleeding at three months was found in every woman and the effect was more pronounced at 12 months when the mean bleeding was 10 OO/ of that during the preinsertion cycles. This convincing study also demonstrated a significant increase in the women’s haemoglobin concentration after six months of use (P< 0.001). Scholten et al. (22) demonstrated a significant reduction in the MBLof 11 patients 7 t o 12 months after the insertion. The mean reduction was from 119 ml to 17 ml and there was also significant increases in haemoglobin concentration and serum ferritin (P
