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Abnormal endocrine profile among women with confirmed or presumed ovulation during long-term NORPLANT® use
CONTRACEPTION ABNORMAL ENDOCRINE PROFILE AMONG WOMEN WITH CONFIRMED OR PRESUMED OVULATION DURING LONG-TERM NORPLANT%USE Francisco Alvarez (l), Vivian Brache (11, Ana S. Tejada (11, Anibal Faundes (2)
1. PROFAMILIA P.O. Box 1053, Santo Domingo Dominican Republic 2. Departamento de Tocoginecologia Facultade de Ciincias Medicas Universidade Estadual de Campinas Campinas, S.P., Brazil
ABSTRACT were serially assayed LH, estradiol and progesterone during 8 cycles of six subjects using six subdermal implants releasing levonorgestrel (NORPLANT@)for a period of 2 to 6 years. All 8 cycles studied had a very low LH peak and a low or nonexistent FSH peak as compared to 8 control cycles. The mean LH peak for NORPLAN!l@users was 33.9 mIU/ml as compared to 142 mIU/ml in the control group; and FSH was 13.0 mIU/ml as compared to 31.3 mIU/ml in controls. A subsequent rise in progesterone was observed in the 8 cycles studied, but the mean mid-luteal levels were significantly lower than in controls (9.0 ng/ml vs. 15.6 ng/ml). No differences were observed in the estradiol curve. Two of the subjects using NORPLANT@had a laparotomy performed on days 17 and 20 of the cycle, for surgical sterilization purposes. A distinctive corpus luteum with a stigma was observed. Our results indicate that women under prolonged use of NORPLANT@do not have normal endocrine cycles, even though they may ovulate. It is doubtful however, that these ovulatory cycles can be fertile under the abnormal endocrine conditions found in our subjects. In addition to the possible effect of luteal insufficiency, the normal maturation of the oocyte may be impaired.
FSH,
* NORPLANe is the Population Council's registered trademark for contraceptive subdermalimplants. Submitted for publication October 11, 1985 Accepted for publication January 16, 1986 FEBRUARY 1986 VOL. 33 NO. 2
111
CONTRACEPTION
INTRODUCTION The six subdermal implant system currently in use under the trademark of NORPLANT@ implants, releases a daily dose of approximately 30 micrograms of levonorgestrel (1,2). This continuous low dose has proved very effective, even after prolonged use (2,3,4,5). In our experience, after two years of use about half the cycles show progesterone elevation over 4 ng/ml suggesting ovulation. In a previous study we found that progesterone levels in samples taken twice weekly in the second half of 49 cycles in women using NORPLANT@ implants were about half the values of normal controls in the same clinic (6). These results suggest either ovulation with deficient corpus luteum function or progesterone elevations not always corresponding to ovulation but to luteinization of unruptured follicles. In order to further understand the effect of this contraceptive method on the pituitary-ovarian axis, pituitary gonadotrophins (FSH 6 LH), estradiol and progesterone were assayed serially in subjects who had previously shown luteal activity during use of NORPLANT? MATERIAL AND METHODS Five subjects using NORPLANT@for a period of 27 to 79 months volunteered for this study. Four subjects were studied for one cycle each, and one of the subjects was studied for two cycles, 20 months apart, for a total of six cycles. All subjects had been menstruating regularly during the preceding months. In four cycles, blood samples were taken daily from day 10 through day 19 of the cycle, and every other day from then on until the onset of menses. For two cycles samples were taken daily from day 7 of the cycle until menses. Six subjects using barrier methods for contraception were included as controls and followed the same protocol as the first four treated subjects. Furthermore, two subjects who had been using the NORPLANT@ system for 74 and 76 months decided to undergo tubal ligation. They had blood samples taken daily from day 11 of their cycles until the day when the laparotomy was performed, on day 17 in one subject and on day 20 in the other. Two control subjects scheduled for surgical sterilization also volunteered for this protocol. At laparotomy both ovaries were inspected. Salpingectomy was performed on the side showing a ruptured follicle or a corpus luteum. The oviducts were flushed with Tyrode solution in an attempt to find an egg. The control subjects were followed by daily sampling of the cervical mucus. Serum samples were taken daily from the time the first signs of estrogen elevation appeared in the mucus until the day of laparotomy, which was scheduled soon after
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
clinical indications of ovulation. In the case of the two NORPLANT@implant users, the cervical mucus was totally altered and could not be taken as indicative of the day of ovulation. The time of laparotomy was chosen to give maximun chance of observing a released egg as guided by hormone assays taken during presumed midcycle. The age of the treated subjects at the time of the study ranged from 26 to 38 years, with a mean of 33.0 + 4.1. The age of the eight controls ranged from 24 to 36 wzth a mean of 30.0 + 4.1. These differences were not statistically significant. FSH, LH, estradiol and progesterone were measured by radioimmunoassay on all samples. FSH and LH assays were performed by a double antibody liquid phase I125 radioimmunoassay. The sensitivity was 1.2 mIU/ml and 2 mIU/ml, and the interassay coefficient of variation (CV) was 12.1% and 14.5%~ respectively. Estradiol and progesterone were assayed by a solid phase I125 radioimmunoassay with a sensitivity of 10 pg/ml and 0.05 ng/ml, and CV of 18.6% and 12.6%, respectively. The mean values of $he four hormones assayed were calculated for treated and control subjects, for each day before and after the LH peak. For the purpose of this paper, LH peak was simply the highest value found at midcycle, preceded or coinciding with an estradiol surge. The statistical significance of the differences between treated subjects and controls were estimated using Student's "t" test. In the case of progesterone, the values of days 5 to 10 after the LH peak were pooled for comparison of treated with control subjects. RESULTS Each of the 8 cycles of subjects receiving continuous low doses of levonorgestrel showed a characteristically low LH peak as well as a low or nonexistent FSH peak (Table I). The mean LH peak for NORPLANToimplant users was 33.9 mIU/ml (S. D. + 7.1; Range 28-50) as compared to 142 mIU/ml (S.D. + 93.1; Range 68-340) for controls. These differences are highly significant (p< 0.005) (Table II, Fig. 1). Four of the treated subjects had a small FSH peak (x = 17.8 + 3.21, and the remaining four showed no elevation. The mean FSH level at the day of the LH peak was 13.0 mIU/ml (S.D. + 5.6; Range 6.5-21.0) among users of the NORPLANT@ implants: and 31.3 mIU/ml (S.D. + 29.7; Range 24-105) among controls. Here, too, differences were highly significant (p < 0.025) (Table II, Fig. 2).
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1986 VOL. 33 NO. 2
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CONTRACEPTION
TABLE I.
INDIVIDUAL LH PEAKS AND CORRESPONDING PSH LEVELS FOR THE SAME DAY IN SUBJECTS USING NORPLANTOAND CONTROLS FSH mIU/ml NORPLANTW 1 CONTROLS
LH mIU/ml NORPLANTW 1 CONTROLS I
28.0 36.0 34.0 50.0 34.0 28.0 32.0 29.5
158.0 340.0 77.0 124.0 92.0 140.0 68.0 (67)*
9.1 7.6 14.2 19.8 21.0 6.5 16.0 10.0
24.9 105.0 25.5 37.0 27.5 25.5 23.0 (2o.0)* I
II
1 l
I
II
samples were Sample probably taken on day +l, because drawn every other day at the time, and value shown coincided with progeeterone of 2.1 ng/ml.
TABLE II. COMPARISON OF ENDOCRINE USERS AND CONTROLS
PROFILES
-NORPLANT@ S.D.
AMONG
;
NORPLANT@ CONTROLS S.D.
LH Peak * 33.9
7.1
142.7
93.1
13.0
5.6
38.3
28.7
Preovulatory Eatradio1 Peak W/ml
241.1
84.9
254.6
70.9
Mid-luteal Estradiol pg/ml
135.0
67.8
155.0
32.0
9.0
2.3
15.6
4.2
mIU/ml FSH Levels on Day of LH Peak l * mIU/ml
Mid-luteal Progesterone ng/ml
l
**
* Significant differences ** Significant differences *** Significant differences
114
PC 0.005 ~~0.025 pc.0.0005
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
cf
100
\ _
g
80-
& I A
1
I
0-O
NORPLANT”
M
CONTROLS
‘if S.E.
6o 4020i-+y==@ -2
0
2
4
6
8
IO
12
I4
DAYS FROM LH PEAK Fig. 1 : Mean LH levels during the menstrual cycle of using NORPLANT@and controls.
= E \
40
2
30
O-0
NORPLANT*
O-0
CONTROLS
1kS.E.
E -
20
iFI k
IO
women
-2
0
2
4
6
8
IO
12
14
DAYS FROM LH PEAK Fig. 2 : Mean FSH levels during the menstrual cycle of women using NORPLANT&and controls.
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1986 VOL. 33 NO. 2
115
CONTRACEPTION
In spite of the small gonadotropin peaks, a rise in progesterone was observed in all eight subjects. That rise was never greater than 14.5 ng/ml in samples taken every second day, and the mean value was about 40% lower and significantly different from that of the controls (p < 0.005) (Table II, Fig. 3). The estradiol curve showed no difference between treated subjects and controls, either in the pre-ovulatory surge or during the second phase of the cycle (Table II, Fig. 4). The two NORPLANT@implant users who were surgically sterilized had had LH peaks of only 32 and 29.5 mIU/nl. Both of them, however, showed a distinct corpus luteum. In one case, histology confirmed a corpus luteum in the 5th to 6th postovulation day. The histology of the other is unavailable. Oocytes were not recovered from the tubes in either of the two subjects.
o-0
CONTROLS
DAYS AFTER LH PEAK Fig. 3 : Mean progesterone levels during the menstrual cycle of women using NORPLANT@and controls.
116
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
@-O NORPLANT @ O-O
/
CONTROLS
1
-2
0
2
4
6
1
8
IO
12
14
DAYS FROM LH PEAK Fig. 4 : Mean estradiol levels during the menstrual cycle of women using NORPLANT@and controls.
DISCUSSION The presence of a subnormal progesterone rise during contraceptive treatment has been described with the use of progestagenm and GnRH analogs (7,S). It had been suggested that it may not correspond to ovulation but to luteinization of the follicle, The presence of only low LH and low or nonexistent FSH peaks in our patients, coinciding with below-normal progesterone levels, led us to believe that this low progesterone rise may not correspond to ovulation. The fiding of follicle rupture and corpus luteum formation in two of the patients with low LH peaks shows that ovulation may occur in some cases. Even though there were only two such cases, they show that follicle rupture does not require a very high LH peak, at least as determined by serum sampling at 24-hour intervals. Considering that these volunteers are under a pharmacologically induced condition, this observation is not necessarily situations. It does indicate applicable to physiological that women under prolonged continuous treatment with low doses of levonorgestrel do not have normal endocrine cycles, even though they may ovulate. Based on low pregnancy rate in implant users, it is doubtful that these ovulatory cycles are fertile. In view of the abnormal endocrine profiles found in our subjects, luteal insufficiency and impaired ma-
FEBRUARY
1986 VOL. 33 NO. 2
117
CONTRACEPTION
turation of the oocyte must be considered along with the progestational effects on the cervical mucus as reasons why NORPLANTeimplant users with regular cycles and apparent ovulation do not become pregnant. The consistency of the abnormal LH and FSH peaks found in the eight cycles described here indicates the need for further studies. The effect of abnormal FSH and LH at midcycle over oocyte maturation and corpus luteum function should be the elucidated before we can have a full understanding of contraceptive effect of NORPLANToimplants. ACKNOWLEDGEMENTS This study was undertaken as part of the contraceptive development programme sponsored and coordinated by the International Committee for Contraception Research of the Population Council Inc., New York, N.Y. The financial support provided by the International Development Research Center of Canada and the Swedish Medical Research Council, the Swedish Agency for Research and Cooperation with the Developing Countries (sAREC), the Ford Foundation, the Rockefeller Foundation and the George Hecht Fund is gratefully acknowledged. REFERENCES 1. Robertson, D.N., Sivin, I., Nash, H.A., Braun, J., Dinh, J. Release rates of levonorgestrel from silastice capsules, homogeneous rods and covered rods in humans. Contraception 27: 483-495 (1983). 2. Diaz, S., Pavez, M., Miranda P., Robertson, D.N., Sivin, I ., Croxatto, H.B. A five-year clinical trial of levonorgestrel silastic implants (NORPLANT@). Contraception 25: 447-456 (1982). 3. Diaz, S., Pavez, M., Robertson, D.N., Croxatto, H.B. A three-year clinical trial with levonorgestrel silastic implants. Contraception 19: 557-573 (1979). 4. Sivin, I., Alvarez-Sanchez, F., Diaz, S., Holma, P., Coutinho, E., McDonald, O., Robertson, D.N., Stern, J. Thsubdermal contraree-year experience with NORPLANT" ception. Fertil. Steril. 39: 799-808 (1983). 5. Sivin, I., Diaz, S., Holma, P., Alvarez-Sanchez, F., Roimbertson, D. A four-year clinical study of NORPLANI@ plants. Studies in Family Planning 14: 159-169 (1983).
118
FEBRUARY
1986VOL. 33N0.2
CONTRACEPTION
6. Bzache, V., FaGndes, A., Johansson, E., Alvarez, F. Anoluteal phase and poor sperm penevulation, inadequate tration in cervical mucus during prolonged use of NORimplants. Contraception 31: 261-272 (1985). PLANTR 7. Croxatto, deis, A. treatment docrinol.
H.B., Diaz, S., Pavez, M., Miranda, P., BranPlasma progesterone levels during long-term with levonorgestrel silastic implants. Acta En101: 307-311 (1982).
8. Bergquist, C., Nillius, S.J., Wide, L. Effect of a luteinizing hormone-releasing hormone agonist on luteal function in women. Contraception 22: 287-293 (1980).
FEBRUARY
1986VOL.33N0.2
119
1. PROFAMILIA P.O. Box 1053, Santo Domingo Dominican Republic 2. Departamento de Tocoginecologia Facultade de Ciincias Medicas Universidade Estadual de Campinas Campinas, S.P., Brazil
ABSTRACT were serially assayed LH, estradiol and progesterone during 8 cycles of six subjects using six subdermal implants releasing levonorgestrel (NORPLANT@)for a period of 2 to 6 years. All 8 cycles studied had a very low LH peak and a low or nonexistent FSH peak as compared to 8 control cycles. The mean LH peak for NORPLAN!l@users was 33.9 mIU/ml as compared to 142 mIU/ml in the control group; and FSH was 13.0 mIU/ml as compared to 31.3 mIU/ml in controls. A subsequent rise in progesterone was observed in the 8 cycles studied, but the mean mid-luteal levels were significantly lower than in controls (9.0 ng/ml vs. 15.6 ng/ml). No differences were observed in the estradiol curve. Two of the subjects using NORPLANT@had a laparotomy performed on days 17 and 20 of the cycle, for surgical sterilization purposes. A distinctive corpus luteum with a stigma was observed. Our results indicate that women under prolonged use of NORPLANT@do not have normal endocrine cycles, even though they may ovulate. It is doubtful however, that these ovulatory cycles can be fertile under the abnormal endocrine conditions found in our subjects. In addition to the possible effect of luteal insufficiency, the normal maturation of the oocyte may be impaired.
FSH,
* NORPLANe is the Population Council's registered trademark for contraceptive subdermalimplants. Submitted for publication October 11, 1985 Accepted for publication January 16, 1986 FEBRUARY 1986 VOL. 33 NO. 2
111
CONTRACEPTION
INTRODUCTION The six subdermal implant system currently in use under the trademark of NORPLANT@ implants, releases a daily dose of approximately 30 micrograms of levonorgestrel (1,2). This continuous low dose has proved very effective, even after prolonged use (2,3,4,5). In our experience, after two years of use about half the cycles show progesterone elevation over 4 ng/ml suggesting ovulation. In a previous study we found that progesterone levels in samples taken twice weekly in the second half of 49 cycles in women using NORPLANT@ implants were about half the values of normal controls in the same clinic (6). These results suggest either ovulation with deficient corpus luteum function or progesterone elevations not always corresponding to ovulation but to luteinization of unruptured follicles. In order to further understand the effect of this contraceptive method on the pituitary-ovarian axis, pituitary gonadotrophins (FSH 6 LH), estradiol and progesterone were assayed serially in subjects who had previously shown luteal activity during use of NORPLANT? MATERIAL AND METHODS Five subjects using NORPLANT@for a period of 27 to 79 months volunteered for this study. Four subjects were studied for one cycle each, and one of the subjects was studied for two cycles, 20 months apart, for a total of six cycles. All subjects had been menstruating regularly during the preceding months. In four cycles, blood samples were taken daily from day 10 through day 19 of the cycle, and every other day from then on until the onset of menses. For two cycles samples were taken daily from day 7 of the cycle until menses. Six subjects using barrier methods for contraception were included as controls and followed the same protocol as the first four treated subjects. Furthermore, two subjects who had been using the NORPLANT@ system for 74 and 76 months decided to undergo tubal ligation. They had blood samples taken daily from day 11 of their cycles until the day when the laparotomy was performed, on day 17 in one subject and on day 20 in the other. Two control subjects scheduled for surgical sterilization also volunteered for this protocol. At laparotomy both ovaries were inspected. Salpingectomy was performed on the side showing a ruptured follicle or a corpus luteum. The oviducts were flushed with Tyrode solution in an attempt to find an egg. The control subjects were followed by daily sampling of the cervical mucus. Serum samples were taken daily from the time the first signs of estrogen elevation appeared in the mucus until the day of laparotomy, which was scheduled soon after
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
clinical indications of ovulation. In the case of the two NORPLANT@implant users, the cervical mucus was totally altered and could not be taken as indicative of the day of ovulation. The time of laparotomy was chosen to give maximun chance of observing a released egg as guided by hormone assays taken during presumed midcycle. The age of the treated subjects at the time of the study ranged from 26 to 38 years, with a mean of 33.0 + 4.1. The age of the eight controls ranged from 24 to 36 wzth a mean of 30.0 + 4.1. These differences were not statistically significant. FSH, LH, estradiol and progesterone were measured by radioimmunoassay on all samples. FSH and LH assays were performed by a double antibody liquid phase I125 radioimmunoassay. The sensitivity was 1.2 mIU/ml and 2 mIU/ml, and the interassay coefficient of variation (CV) was 12.1% and 14.5%~ respectively. Estradiol and progesterone were assayed by a solid phase I125 radioimmunoassay with a sensitivity of 10 pg/ml and 0.05 ng/ml, and CV of 18.6% and 12.6%, respectively. The mean values of $he four hormones assayed were calculated for treated and control subjects, for each day before and after the LH peak. For the purpose of this paper, LH peak was simply the highest value found at midcycle, preceded or coinciding with an estradiol surge. The statistical significance of the differences between treated subjects and controls were estimated using Student's "t" test. In the case of progesterone, the values of days 5 to 10 after the LH peak were pooled for comparison of treated with control subjects. RESULTS Each of the 8 cycles of subjects receiving continuous low doses of levonorgestrel showed a characteristically low LH peak as well as a low or nonexistent FSH peak (Table I). The mean LH peak for NORPLANToimplant users was 33.9 mIU/ml (S. D. + 7.1; Range 28-50) as compared to 142 mIU/ml (S.D. + 93.1; Range 68-340) for controls. These differences are highly significant (p< 0.005) (Table II, Fig. 1). Four of the treated subjects had a small FSH peak (x = 17.8 + 3.21, and the remaining four showed no elevation. The mean FSH level at the day of the LH peak was 13.0 mIU/ml (S.D. + 5.6; Range 6.5-21.0) among users of the NORPLANT@ implants: and 31.3 mIU/ml (S.D. + 29.7; Range 24-105) among controls. Here, too, differences were highly significant (p < 0.025) (Table II, Fig. 2).
FEBRUARY
1986 VOL. 33 NO. 2
113
CONTRACEPTION
TABLE I.
INDIVIDUAL LH PEAKS AND CORRESPONDING PSH LEVELS FOR THE SAME DAY IN SUBJECTS USING NORPLANTOAND CONTROLS FSH mIU/ml NORPLANTW 1 CONTROLS
LH mIU/ml NORPLANTW 1 CONTROLS I
28.0 36.0 34.0 50.0 34.0 28.0 32.0 29.5
158.0 340.0 77.0 124.0 92.0 140.0 68.0 (67)*
9.1 7.6 14.2 19.8 21.0 6.5 16.0 10.0
24.9 105.0 25.5 37.0 27.5 25.5 23.0 (2o.0)* I
II
1 l
I
II
samples were Sample probably taken on day +l, because drawn every other day at the time, and value shown coincided with progeeterone of 2.1 ng/ml.
TABLE II. COMPARISON OF ENDOCRINE USERS AND CONTROLS
PROFILES
-NORPLANT@ S.D.
AMONG
;
NORPLANT@ CONTROLS S.D.
LH Peak * 33.9
7.1
142.7
93.1
13.0
5.6
38.3
28.7
Preovulatory Eatradio1 Peak W/ml
241.1
84.9
254.6
70.9
Mid-luteal Estradiol pg/ml
135.0
67.8
155.0
32.0
9.0
2.3
15.6
4.2
mIU/ml FSH Levels on Day of LH Peak l * mIU/ml
Mid-luteal Progesterone ng/ml
l
**
* Significant differences ** Significant differences *** Significant differences
114
PC 0.005 ~~0.025 pc.0.0005
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
cf
100
\ _
g
80-
& I A
1
I
0-O
NORPLANT”
M
CONTROLS
‘if S.E.
6o 4020i-+y==@ -2
0
2
4
6
8
IO
12
I4
DAYS FROM LH PEAK Fig. 1 : Mean LH levels during the menstrual cycle of using NORPLANT@and controls.
= E \
40
2
30
O-0
NORPLANT*
O-0
CONTROLS
1kS.E.
E -
20
iFI k
IO
women
-2
0
2
4
6
8
IO
12
14
DAYS FROM LH PEAK Fig. 2 : Mean FSH levels during the menstrual cycle of women using NORPLANT&and controls.
FEBRUARY
1986 VOL. 33 NO. 2
115
CONTRACEPTION
In spite of the small gonadotropin peaks, a rise in progesterone was observed in all eight subjects. That rise was never greater than 14.5 ng/ml in samples taken every second day, and the mean value was about 40% lower and significantly different from that of the controls (p < 0.005) (Table II, Fig. 3). The estradiol curve showed no difference between treated subjects and controls, either in the pre-ovulatory surge or during the second phase of the cycle (Table II, Fig. 4). The two NORPLANT@implant users who were surgically sterilized had had LH peaks of only 32 and 29.5 mIU/nl. Both of them, however, showed a distinct corpus luteum. In one case, histology confirmed a corpus luteum in the 5th to 6th postovulation day. The histology of the other is unavailable. Oocytes were not recovered from the tubes in either of the two subjects.
o-0
CONTROLS
DAYS AFTER LH PEAK Fig. 3 : Mean progesterone levels during the menstrual cycle of women using NORPLANT@and controls.
116
FEBRUARY
1986 VOL. 33 NO. 2
CONTRACEPTION
@-O NORPLANT @ O-O
/
CONTROLS
1
-2
0
2
4
6
1
8
IO
12
14
DAYS FROM LH PEAK Fig. 4 : Mean estradiol levels during the menstrual cycle of women using NORPLANT@and controls.
DISCUSSION The presence of a subnormal progesterone rise during contraceptive treatment has been described with the use of progestagenm and GnRH analogs (7,S). It had been suggested that it may not correspond to ovulation but to luteinization of the follicle, The presence of only low LH and low or nonexistent FSH peaks in our patients, coinciding with below-normal progesterone levels, led us to believe that this low progesterone rise may not correspond to ovulation. The fiding of follicle rupture and corpus luteum formation in two of the patients with low LH peaks shows that ovulation may occur in some cases. Even though there were only two such cases, they show that follicle rupture does not require a very high LH peak, at least as determined by serum sampling at 24-hour intervals. Considering that these volunteers are under a pharmacologically induced condition, this observation is not necessarily situations. It does indicate applicable to physiological that women under prolonged continuous treatment with low doses of levonorgestrel do not have normal endocrine cycles, even though they may ovulate. Based on low pregnancy rate in implant users, it is doubtful that these ovulatory cycles are fertile. In view of the abnormal endocrine profiles found in our subjects, luteal insufficiency and impaired ma-
FEBRUARY
1986 VOL. 33 NO. 2
117
CONTRACEPTION
turation of the oocyte must be considered along with the progestational effects on the cervical mucus as reasons why NORPLANTeimplant users with regular cycles and apparent ovulation do not become pregnant. The consistency of the abnormal LH and FSH peaks found in the eight cycles described here indicates the need for further studies. The effect of abnormal FSH and LH at midcycle over oocyte maturation and corpus luteum function should be the elucidated before we can have a full understanding of contraceptive effect of NORPLANToimplants. ACKNOWLEDGEMENTS This study was undertaken as part of the contraceptive development programme sponsored and coordinated by the International Committee for Contraception Research of the Population Council Inc., New York, N.Y. The financial support provided by the International Development Research Center of Canada and the Swedish Medical Research Council, the Swedish Agency for Research and Cooperation with the Developing Countries (sAREC), the Ford Foundation, the Rockefeller Foundation and the George Hecht Fund is gratefully acknowledged. REFERENCES 1. Robertson, D.N., Sivin, I., Nash, H.A., Braun, J., Dinh, J. Release rates of levonorgestrel from silastice capsules, homogeneous rods and covered rods in humans. Contraception 27: 483-495 (1983). 2. Diaz, S., Pavez, M., Miranda P., Robertson, D.N., Sivin, I ., Croxatto, H.B. A five-year clinical trial of levonorgestrel silastic implants (NORPLANT@). Contraception 25: 447-456 (1982). 3. Diaz, S., Pavez, M., Robertson, D.N., Croxatto, H.B. A three-year clinical trial with levonorgestrel silastic implants. Contraception 19: 557-573 (1979). 4. Sivin, I., Alvarez-Sanchez, F., Diaz, S., Holma, P., Coutinho, E., McDonald, O., Robertson, D.N., Stern, J. Thsubdermal contraree-year experience with NORPLANT" ception. Fertil. Steril. 39: 799-808 (1983). 5. Sivin, I., Diaz, S., Holma, P., Alvarez-Sanchez, F., Roimbertson, D. A four-year clinical study of NORPLANI@ plants. Studies in Family Planning 14: 159-169 (1983).
118
FEBRUARY
1986VOL. 33N0.2
CONTRACEPTION
6. Bzache, V., FaGndes, A., Johansson, E., Alvarez, F. Anoluteal phase and poor sperm penevulation, inadequate tration in cervical mucus during prolonged use of NORimplants. Contraception 31: 261-272 (1985). PLANTR 7. Croxatto, deis, A. treatment docrinol.
H.B., Diaz, S., Pavez, M., Miranda, P., BranPlasma progesterone levels during long-term with levonorgestrel silastic implants. Acta En101: 307-311 (1982).
8. Bergquist, C., Nillius, S.J., Wide, L. Effect of a luteinizing hormone-releasing hormone agonist on luteal function in women. Contraception 22: 287-293 (1980).
FEBRUARY
1986VOL.33N0.2
119