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Aspects of thyroid function during use of Norplant® implants
CONTRACEPTION
A S P E C T S O F T H Y R O I D FI~NCTION D U R I N G USE OF NORPLANT-IMPLANTS S. E. Olsson, L. Wide, V. Odlind
Departments of Obstetrics and Gynecology and Clinical Chemistry University of Uppsala, S-751 85 Uppsala, Sweden
ABSTRACT Plasma t h y r o x i n ( T 4 ) , t r i i o d o t h y r o n i n e ( T ~ ) , T ~ - u p t a k e and t h y r o i d stimulating hormone (TSH) were m e a s u r e d in 18 women u s i n g Norplant® implants or Norplant®-2 implants for six months. Free T 4 - i n d e x and free T 3 - i n d e x were also c a l c u l a t e d . All women had u s e d n o n - h o r m o n a l cont r a c e p t i v e s before insertion of the implants. T4 decreased and Ta-uptake increased, indicating a lower level of thyroid binding proteins during treatment. Free T4-index remained unchanged, indicating that the free concentration of thyroxin was unaltered. All women were euthyroid and TSH was unchanged. It is concluded that treatment with Norplant® implants does not result in a change in thyroid function.
Submitted for publication May 21, 1986 Accepted for publication December i , 1986
DECEMBER
1986 V O L . 34 N O . 6
583
CONTRACEPTION
INTRODUCTION It is well k n o w n t h a t t h e c o n c e n t r a t i o n s of c e r t a i n plasma p r o t e i n s c h a n g e d u r i n g t r e a t m e n t with s t e r o i d h o r m o n e s . T h e c o n c e n t r a t i o n of s e x h o r m o n e b i n d i n g g l o b u l i n ( S H B G ) i n c r e a s e s d u r i n g t r e a t m e n t with e s t r o g e n s a n d d e c r e a s e s d u r i n g t r e a t m e n t with a n d r o g e n s a n d c e r t a i n p r o g e s t o g e n s (1, 2 ) . T h e c o n c e n t r a t i o n of t h y r o x i n e b i n d i n g g l o b u l i n ( T B G ) i n c r e a s e s d u r i n g t r e a t m e n t with c o m b i n e d oral c o n t r a c e p t i v e s a n d d u r i n g p r e g n a n c y (3, 4). We h a v e p r e v i o u s l y r e p o r t e d t h a t t h e c o n c e n t r a t i o n of SHBG d e c r e a s e s d u r i n g u s e of Norplant® i m p l a n t s o r Norplant®-2 i m p l a n t s , b o t h of w h i c h r e l e a s e 30 - 60 p g / d a y of l e v o n o r g e s t r e l ( 5 ) . T h e p u r p o s e of t h e p r e s e n t s t u d y was to i n v e s t i g a t e t h y r o i d h o r m o n e p a r a m e t e r s d u r i n g u s e of Norplant® i m p l a n t s . MATERIAL AND METHODS T h e s t u d y was c a r r i e d o u t in 18 h e a l t h y v o l u n t e e r s u s i n g Norplant® i m p l a n t s d u r i n g six m o n t h s ( T a b l e I ) . T h e y h a d u s e d n o n - h o r m o n a l c o n t r a c e p t i v e m e t h o d s s u c h as b a r r i e r m e t h o d s o r IUCDs b e f o r e i n s e r t i o n of t h e i m p l a n t s . T e n of t h e 18 women u s e d t h e n e w i m p l a n t s y s tem, Norplant®-2, c o n s i s t i n g of only two i m p l a n t s (two r o d s made of Silastic® a n d l e v o n o r g e s t r e l c o v e r e d with a t h i n m e m b r a n e of Silastic®); t h e o t h e r 8 women u s e d t h e o r i g i n a l Norplant® s y s t e m w i t h s i x Silastic® c a p s u l e s c o n t a i n i n g l e v o n o r g e s t r e l . Both s y s t e m s h a v e b e e n s h o w n to h a v e t h e same r e l e a s e r a t e a n d to r e s u l t in i d e n t i c a l plasma l e v e l s of l e v o n o r g e s t r e l (6; u n p u b l i s h e d o b s e r v a t i o n s ) . A blood s a m p l e was t a k e n i m m e d i a t e l y p r i o r to i n s e r t i o n of t h e i m p l a n t s . T h e i m p l a n t s w e r e i n s e r t e d s u b d e r m a l l y on t h e a n t e r i o r a s p e c t of t h e f o r e a r m on o n e of t h e f i r s t f i v e d a y s of a normal m e n s t r u a t i o n . Blood s a m p l e s w e r e d r a w n a f t e r t h r e e a n d s i x m o n t h s of u s e from t h e c o n t r a l a t e r a l a r m . T h y r o x i n (T4) l e v e l s w e r e m e a s u r e d b y a solid p h a s e r a d i o i m m u n o a s s a y ( R I A ) ( 7 ) . NormaI v a l u e s w e r e 67 - 153 nmol/1. T r i i o d o t h y r o n i n e ( T a ) l e v e l s w e r e m e a s u r e d b y a solid p h a s e RIA ( 7 ) . Normal v a l u e s w e r e 1.2 - 2 . 8 n m o l / I . .
T h y r o i d s t i m u l a t i n g hormone ( T S H ) was m e a s u r e d b y a r a d i o i m m u n o s o r b e n t t e c h n i q u e ( 8 ) . Normal v a l u e s w e r e < 8 mU/1. T a - u p t a k e was m e a s u r e d b y P h a d e b a s T3U T e s t , S w e d e n . Normal v a l u e s w e r e 75 - 115 TBP%. F r e e T 4 - i n d e x was c a l c u l a t e d 67-153 a r b i t r a r y u n i t s .
as
Pharmacia, Uppsala,
T 4 X Ta-uptake/100.
Normal r a n g e was
F r e e ~ a - i n d e x was c a l c u l a t e d as T3 x T 3 - u p t a k e / 1 0 0 . Normal r a n g e was 1.2-2.8 arbitrary units. L e v o n o r g e s t r e l was m e a s u r e d b y a RIA d e s c r i b e d b y Weiner a n d : / o h a n s son
584
(9).
DECEMBER
1986 V O L . 34 N O . 6
CONTRACEPTION
S t a t i s t i c a l a n a l y s e s were d a n e by S t u d e n t ' s t - t e s t for p a i r e d samples. Table I.
C h a r a c t e r i s t i c s of t h e p a r t i c i p a n t s (mean + SE)
N Age, years Weight, kg
18 29.2
+ 1.4
61.0 + 2.1 167.0 + 1.5
H e i g h t , cm Pregnancies
I. 7
+_ 0.3
Parity
0.9
+ 0.3
RESULT~ T h y r o x i n levels d e c r e a s e d s i g n i f i c a n t l y d u r i n g t r e a t m e n t . T 3 - u p t a k e values (TBP%) i n c r e a s e d s i g n i f i c a n t l y d u r i n g t r e a t m e n t . TSH remained u n c h a n g e d as did T3. Free T 4 - i n d e x a n d f r e e T s - i n d e x r e m a i n e d u n c h a n g e d d u r i n g t r e a t m e n t . L e v o n o r g e s t r e l v a l u e s were as e x p e c t e d for women h a v i n g u s e d Norplant® implants f o r 3 to 6 m o n t h s . All women were clinically e u t h y r o i d d u r i n g t r e a t m e n t ( T a b l e I I ) . Table II. Levels of l e v o n o r g e s t r e l (LNG), t r i i o d o t h y r o n i n e ( T ~ ) , thyroxin (T4), T~-uptake test, T3-index, T4-index, thyroid stimulating hormone ( T S H ) b e f o r e and d u r i n g t r e a t m e n t with Norplant® implants Pre
3 months
6 months
N L N G (nmol/l) T s (nmol/l) T4 (nmol/l) Ts-uptake (%) T3-index
18 2.0 i 88:8 + 101.9+ 2.1 +
18 1.2 + 0.I 2.1 ± 0.I (n.s.) 78.4 +_ 2.1"* 1 0 7 . 2 +2.1" 2.3 + 0.1 ( n . s . )
18 I.i + 0.i 1.9 _+ 0.I (n.s.) 80.1 +_ 2.9* 110.9+ 2.7** 2.1 + 0.1 ( n . s . )
T4-index TSH (mU/1)
89.6 + 2.6 3.2 _+ 0.2
86.8 -+ 2.9 ( n . s . ) 3.4 + 0.2 ( n . s )
87.9 + 3.5 ( n . s . ) 3.4 +_ 0.2 ( n . s . )
0.I 3.6 2.2 0.1
Values are given as mean + SE. * = p<0.05, ** = p<0.01. DISCUSSION
The o b s e r v e d c h a n g e s in T4 a n d T s - u p t a k e t e s t d u r i n g t r e a t m e n t with Norplant® implants a r e compatible w i t h d e c r e a s e d p r o t e i n b i n d i n g of t h y r o x i n in s e r u m . T h e lower t h y r o x i n b i n d i n g c a p a c i t y is most l i k e l y a r e s u l t of d e c r e a s e d p r o d u c t i o n of TBG i n d u c e d b y l e v o n o r g e s t r e l . F r e e
DECEMBER
1986 V O L . 3 4 N O . 6
585
CONTRACEPTION
T a - i n d e x was u n c h a n g e d i n d i c a t i n g t h a t t h e f r e e c o n c e n t r a t i o n of T4 was u n a l t e r e d . As t h e f r a c t i o n of T4 b o u n d t o TBG in blood is m u c h h i g h e r t h a n t h e f r a c t i o n of Ta b o u n d to TBG ( 1 0 ) , o n e would e x p e c t t h a t a d e c r e a s e in TBG s h o u l d i n d u c e a more s i g n i f i c a n t c h a n g e of total T4 t h a n of total Ta in b l o o d . T h i s is a most p r o b a b l e e x p l a n a t i o n to t h e f a c t t h a t a s i g n i f i c a n t d e c r e a s e was f o u n d fo r total T4 b u t n o t for total Ta in t h e p r e s e n t s t u d y . Previous studies have shown a marked decrease in SHBG levels as a result of treatment with levonorgestrel-only contraception (5). Women have higher levels than men of TBG as well as of SHBG ( 1 0 , 11). These differences in plasma proteins between men and women could be due to eil}:er high androgen levels in men or high estrogen levels in women. The ~ ~opehous estradiol levels in women using Norplant® implants are usually reported to be in the range found during the early to mid-follicular phase of the menstrual cycle and thus low estrogen levels are less likely to be the cause of any decrease in plasma proteins in Norplant® users (9). It could therefore be postulated that levonorgestrel as well as androgens could have an inhibitory effect on the production of these plasma proteins. Croxatto and Diaz studied levels of T4, T3 and TSH in two groups of women, one using levonorgestrel-releasing implants, and the other using a copper-IUD. They reported slightly lower levels of Ta in the Norplant@ implant group than in the IUD group (12). T4 or TSH levels did not differ significantly between the two groups. In another study on women using six covered rods, resulting in higher plasma concentrations of levonorgestrel than in the present study with only two covered rods, they found no difference between the IUD-group and the implant group with regard to T3, T4 or TSH (13). However, their sampling was done after 37 months of use (12) and after 20 or 65 months of use (13), cross-sectionally, whereas in the present study samples were collected longitudinally before and after 3 and 6 months of use. A longitudinal study with the pretreatment hormone levels serving as controls might be m o r e sensitive in detecting small changes. The changes found in "the present study were all within the normal range for these hormones. All w o m e n w e r e c l i n i c a l l y e u t h y r o i d a n d TSH was u n c h a n g e d . I t is c o n c l u d e d t h a t t h y r o i d f u n c t i o n is u h c h a n g e d d u r i n g u s e of Norplant® implants.
ACKNOWLEDGEMENTS This work was undertaken as part of the contraceptive development programme sponsored and coordinated by the International Committee for Contraception Research of the Population Council, N e w York, N e w York. The study was supported by M a u d and Birger Gustavsson s Fund for Medical Research, Stockholm, and the Swedish Medical Research Council~(grant no.3495) which is gratefully acknowledged.
586
DECEMBER
1986 V O L .
34 N O . 6
CONTRACEPTION
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C e k a n S Z, Jia M, L a n d g r e n B-M, D i c z f a l u s y E: T h e i n t e r a c t i o n between sex hormone binding globulin and levonorgestrel released from v a g i n a l r i n g s in w o m e n . C o n t r a c e p t i o n 31: 431-439, 1985.
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R u d o r f f K H, H e r r m a n n :r, D i e t r i c h T , K r u s k e m p e r H L: E f f e c t of e s t r o g e n u p o n t h y r o i d m e t a b o l i s m . Med Klin. 73: 1109-13, 1978.
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O l s s o n S - E , O d l i n d V, J o h a n s s o n E D B: A n d r o g e n l e v e l s in women u s i n g N or pl a nt ® i m p l a n t s . C o n t r a c e p t i o n 34: 157-167, 1986.
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R o b e r t s o n D N, Sivin I , Nash H, B r a u n :[, D i n h J : R e l e a s e r a t e s of l e v o n o r g e s t r e l from S i l a s t i c c a p s u l e s , h o m o g e n o u s r o d s a n d c o v e r e d r o d s in h u m a n s . C o n t r a c e p t i o n 27: 483-495, 1983.
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Wide L: Use of p a r t i c u l a t e i m m u n o s o r b e n t s in r a d i o i m m u n o a s s a y . In: I m m u n o c h e m i c a l T e c h n i q u e s . ( V a n V u n a k i s H, L a n g o n e J 7, a d s ) . A c a d e m i c P r e s s , New Y o r k , vol B: 203-224, 1981.
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Wide L, D a h l b e r g P A. Q u a l i t y r e q u i r e m e n t s of b a s a l S - T S H a s s a y s in p r e d i c t i n g a S - T S H r e s p o n s e to T R H . S c a n d :[ Clin Lab I n v e s t ( S u p p l 155) 40: 101-110, 1980.
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Weiner E, J o h a n s s o n E D B: Plasma l e v e l s of d - n o r g e s t r e l , e s t r a diol, a n d progesterone during t r e a t m e n t with Silastic implants c o n t a i n i n g d - n o r g e s t r e l . C o n t r a c e p t i o n 14: 81-92, 1976.
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R o b b i n s J , Rail 7 E: T h e i o d i n e - c o n t a i n i n g h o r m o n e s . I n : H o r m o n e s in Blood. ( G r a y C H, Tames V H T, e d s ) , 3 r d e d . A c a d e m i c P r e s s , L o n d o n , vol 1: 576-688, 1979.
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A n d e r s o n D C: 69-96, 1974.
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C r o x a t t o H B, Diaz S, R o b e r t s o n D N, P a v e z M: Clinical c h e m i s t r y in women t r e a t e d w i t h l e v o n o r g e s t r e l i m p l a n t s ( N o r p l a n t ® ) o r a T C u 200 IUD. C o n t r a c e p t i o n 2 7 : 2 8 1 - 2 8 8 1983.
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Diaz S, C r o x a t t o H B, P a v e z M: Clinical c h e m i s t r y in women t r e a t e d with s i x l e v o n o r g e s t r e l c o v e r e d r o d s o r w i t h a c o p p e r IUD. C o n t r a c e p t i o n 31: 321-330, 1985.
DECEMBER
A p p l e t o n W G, Nicoloff J T: T h y r o x i n e t u r n o v e r p r e g n . ~ n c y . :l Clinical E n d o c r i n o l a n d Metabol 27:
Sex hormone b i n d i n g globulin.
1986 V O L .
34 N O . 6
C l i n E n d o c r i n o l 3:
587
A S P E C T S O F T H Y R O I D FI~NCTION D U R I N G USE OF NORPLANT-IMPLANTS S. E. Olsson, L. Wide, V. Odlind
Departments of Obstetrics and Gynecology and Clinical Chemistry University of Uppsala, S-751 85 Uppsala, Sweden
ABSTRACT Plasma t h y r o x i n ( T 4 ) , t r i i o d o t h y r o n i n e ( T ~ ) , T ~ - u p t a k e and t h y r o i d stimulating hormone (TSH) were m e a s u r e d in 18 women u s i n g Norplant® implants or Norplant®-2 implants for six months. Free T 4 - i n d e x and free T 3 - i n d e x were also c a l c u l a t e d . All women had u s e d n o n - h o r m o n a l cont r a c e p t i v e s before insertion of the implants. T4 decreased and Ta-uptake increased, indicating a lower level of thyroid binding proteins during treatment. Free T4-index remained unchanged, indicating that the free concentration of thyroxin was unaltered. All women were euthyroid and TSH was unchanged. It is concluded that treatment with Norplant® implants does not result in a change in thyroid function.
Submitted for publication May 21, 1986 Accepted for publication December i , 1986
DECEMBER
1986 V O L . 34 N O . 6
583
CONTRACEPTION
INTRODUCTION It is well k n o w n t h a t t h e c o n c e n t r a t i o n s of c e r t a i n plasma p r o t e i n s c h a n g e d u r i n g t r e a t m e n t with s t e r o i d h o r m o n e s . T h e c o n c e n t r a t i o n of s e x h o r m o n e b i n d i n g g l o b u l i n ( S H B G ) i n c r e a s e s d u r i n g t r e a t m e n t with e s t r o g e n s a n d d e c r e a s e s d u r i n g t r e a t m e n t with a n d r o g e n s a n d c e r t a i n p r o g e s t o g e n s (1, 2 ) . T h e c o n c e n t r a t i o n of t h y r o x i n e b i n d i n g g l o b u l i n ( T B G ) i n c r e a s e s d u r i n g t r e a t m e n t with c o m b i n e d oral c o n t r a c e p t i v e s a n d d u r i n g p r e g n a n c y (3, 4). We h a v e p r e v i o u s l y r e p o r t e d t h a t t h e c o n c e n t r a t i o n of SHBG d e c r e a s e s d u r i n g u s e of Norplant® i m p l a n t s o r Norplant®-2 i m p l a n t s , b o t h of w h i c h r e l e a s e 30 - 60 p g / d a y of l e v o n o r g e s t r e l ( 5 ) . T h e p u r p o s e of t h e p r e s e n t s t u d y was to i n v e s t i g a t e t h y r o i d h o r m o n e p a r a m e t e r s d u r i n g u s e of Norplant® i m p l a n t s . MATERIAL AND METHODS T h e s t u d y was c a r r i e d o u t in 18 h e a l t h y v o l u n t e e r s u s i n g Norplant® i m p l a n t s d u r i n g six m o n t h s ( T a b l e I ) . T h e y h a d u s e d n o n - h o r m o n a l c o n t r a c e p t i v e m e t h o d s s u c h as b a r r i e r m e t h o d s o r IUCDs b e f o r e i n s e r t i o n of t h e i m p l a n t s . T e n of t h e 18 women u s e d t h e n e w i m p l a n t s y s tem, Norplant®-2, c o n s i s t i n g of only two i m p l a n t s (two r o d s made of Silastic® a n d l e v o n o r g e s t r e l c o v e r e d with a t h i n m e m b r a n e of Silastic®); t h e o t h e r 8 women u s e d t h e o r i g i n a l Norplant® s y s t e m w i t h s i x Silastic® c a p s u l e s c o n t a i n i n g l e v o n o r g e s t r e l . Both s y s t e m s h a v e b e e n s h o w n to h a v e t h e same r e l e a s e r a t e a n d to r e s u l t in i d e n t i c a l plasma l e v e l s of l e v o n o r g e s t r e l (6; u n p u b l i s h e d o b s e r v a t i o n s ) . A blood s a m p l e was t a k e n i m m e d i a t e l y p r i o r to i n s e r t i o n of t h e i m p l a n t s . T h e i m p l a n t s w e r e i n s e r t e d s u b d e r m a l l y on t h e a n t e r i o r a s p e c t of t h e f o r e a r m on o n e of t h e f i r s t f i v e d a y s of a normal m e n s t r u a t i o n . Blood s a m p l e s w e r e d r a w n a f t e r t h r e e a n d s i x m o n t h s of u s e from t h e c o n t r a l a t e r a l a r m . T h y r o x i n (T4) l e v e l s w e r e m e a s u r e d b y a solid p h a s e r a d i o i m m u n o a s s a y ( R I A ) ( 7 ) . NormaI v a l u e s w e r e 67 - 153 nmol/1. T r i i o d o t h y r o n i n e ( T a ) l e v e l s w e r e m e a s u r e d b y a solid p h a s e RIA ( 7 ) . Normal v a l u e s w e r e 1.2 - 2 . 8 n m o l / I . .
T h y r o i d s t i m u l a t i n g hormone ( T S H ) was m e a s u r e d b y a r a d i o i m m u n o s o r b e n t t e c h n i q u e ( 8 ) . Normal v a l u e s w e r e < 8 mU/1. T a - u p t a k e was m e a s u r e d b y P h a d e b a s T3U T e s t , S w e d e n . Normal v a l u e s w e r e 75 - 115 TBP%. F r e e T 4 - i n d e x was c a l c u l a t e d 67-153 a r b i t r a r y u n i t s .
as
Pharmacia, Uppsala,
T 4 X Ta-uptake/100.
Normal r a n g e was
F r e e ~ a - i n d e x was c a l c u l a t e d as T3 x T 3 - u p t a k e / 1 0 0 . Normal r a n g e was 1.2-2.8 arbitrary units. L e v o n o r g e s t r e l was m e a s u r e d b y a RIA d e s c r i b e d b y Weiner a n d : / o h a n s son
584
(9).
DECEMBER
1986 V O L . 34 N O . 6
CONTRACEPTION
S t a t i s t i c a l a n a l y s e s were d a n e by S t u d e n t ' s t - t e s t for p a i r e d samples. Table I.
C h a r a c t e r i s t i c s of t h e p a r t i c i p a n t s (mean + SE)
N Age, years Weight, kg
18 29.2
+ 1.4
61.0 + 2.1 167.0 + 1.5
H e i g h t , cm Pregnancies
I. 7
+_ 0.3
Parity
0.9
+ 0.3
RESULT~ T h y r o x i n levels d e c r e a s e d s i g n i f i c a n t l y d u r i n g t r e a t m e n t . T 3 - u p t a k e values (TBP%) i n c r e a s e d s i g n i f i c a n t l y d u r i n g t r e a t m e n t . TSH remained u n c h a n g e d as did T3. Free T 4 - i n d e x a n d f r e e T s - i n d e x r e m a i n e d u n c h a n g e d d u r i n g t r e a t m e n t . L e v o n o r g e s t r e l v a l u e s were as e x p e c t e d for women h a v i n g u s e d Norplant® implants f o r 3 to 6 m o n t h s . All women were clinically e u t h y r o i d d u r i n g t r e a t m e n t ( T a b l e I I ) . Table II. Levels of l e v o n o r g e s t r e l (LNG), t r i i o d o t h y r o n i n e ( T ~ ) , thyroxin (T4), T~-uptake test, T3-index, T4-index, thyroid stimulating hormone ( T S H ) b e f o r e and d u r i n g t r e a t m e n t with Norplant® implants Pre
3 months
6 months
N L N G (nmol/l) T s (nmol/l) T4 (nmol/l) Ts-uptake (%) T3-index
18 2.0 i 88:8 + 101.9+ 2.1 +
18 1.2 + 0.I 2.1 ± 0.I (n.s.) 78.4 +_ 2.1"* 1 0 7 . 2 +2.1" 2.3 + 0.1 ( n . s . )
18 I.i + 0.i 1.9 _+ 0.I (n.s.) 80.1 +_ 2.9* 110.9+ 2.7** 2.1 + 0.1 ( n . s . )
T4-index TSH (mU/1)
89.6 + 2.6 3.2 _+ 0.2
86.8 -+ 2.9 ( n . s . ) 3.4 + 0.2 ( n . s )
87.9 + 3.5 ( n . s . ) 3.4 +_ 0.2 ( n . s . )
0.I 3.6 2.2 0.1
Values are given as mean + SE. * = p<0.05, ** = p<0.01. DISCUSSION
The o b s e r v e d c h a n g e s in T4 a n d T s - u p t a k e t e s t d u r i n g t r e a t m e n t with Norplant® implants a r e compatible w i t h d e c r e a s e d p r o t e i n b i n d i n g of t h y r o x i n in s e r u m . T h e lower t h y r o x i n b i n d i n g c a p a c i t y is most l i k e l y a r e s u l t of d e c r e a s e d p r o d u c t i o n of TBG i n d u c e d b y l e v o n o r g e s t r e l . F r e e
DECEMBER
1986 V O L . 3 4 N O . 6
585
CONTRACEPTION
T a - i n d e x was u n c h a n g e d i n d i c a t i n g t h a t t h e f r e e c o n c e n t r a t i o n of T4 was u n a l t e r e d . As t h e f r a c t i o n of T4 b o u n d t o TBG in blood is m u c h h i g h e r t h a n t h e f r a c t i o n of Ta b o u n d to TBG ( 1 0 ) , o n e would e x p e c t t h a t a d e c r e a s e in TBG s h o u l d i n d u c e a more s i g n i f i c a n t c h a n g e of total T4 t h a n of total Ta in b l o o d . T h i s is a most p r o b a b l e e x p l a n a t i o n to t h e f a c t t h a t a s i g n i f i c a n t d e c r e a s e was f o u n d fo r total T4 b u t n o t for total Ta in t h e p r e s e n t s t u d y . Previous studies have shown a marked decrease in SHBG levels as a result of treatment with levonorgestrel-only contraception (5). Women have higher levels than men of TBG as well as of SHBG ( 1 0 , 11). These differences in plasma proteins between men and women could be due to eil}:er high androgen levels in men or high estrogen levels in women. The ~ ~opehous estradiol levels in women using Norplant® implants are usually reported to be in the range found during the early to mid-follicular phase of the menstrual cycle and thus low estrogen levels are less likely to be the cause of any decrease in plasma proteins in Norplant® users (9). It could therefore be postulated that levonorgestrel as well as androgens could have an inhibitory effect on the production of these plasma proteins. Croxatto and Diaz studied levels of T4, T3 and TSH in two groups of women, one using levonorgestrel-releasing implants, and the other using a copper-IUD. They reported slightly lower levels of Ta in the Norplant@ implant group than in the IUD group (12). T4 or TSH levels did not differ significantly between the two groups. In another study on women using six covered rods, resulting in higher plasma concentrations of levonorgestrel than in the present study with only two covered rods, they found no difference between the IUD-group and the implant group with regard to T3, T4 or TSH (13). However, their sampling was done after 37 months of use (12) and after 20 or 65 months of use (13), cross-sectionally, whereas in the present study samples were collected longitudinally before and after 3 and 6 months of use. A longitudinal study with the pretreatment hormone levels serving as controls might be m o r e sensitive in detecting small changes. The changes found in "the present study were all within the normal range for these hormones. All w o m e n w e r e c l i n i c a l l y e u t h y r o i d a n d TSH was u n c h a n g e d . I t is c o n c l u d e d t h a t t h y r o i d f u n c t i o n is u h c h a n g e d d u r i n g u s e of Norplant® implants.
ACKNOWLEDGEMENTS This work was undertaken as part of the contraceptive development programme sponsored and coordinated by the International Committee for Contraception Research of the Population Council, N e w York, N e w York. The study was supported by M a u d and Birger Gustavsson s Fund for Medical Research, Stockholm, and the Swedish Medical Research Council~(grant no.3495) which is gratefully acknowledged.
586
DECEMBER
1986 V O L .
34 N O . 6
CONTRACEPTION
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A p p l e t o n W G, Nicoloff J T: T h y r o x i n e t u r n o v e r p r e g n . ~ n c y . :l Clinical E n d o c r i n o l a n d Metabol 27:
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C l i n E n d o c r i n o l 3:
587