Effects of an implant of nomegestrol acetate, a 19-nor-progesterone derivative, on thyroid function

I.C. BARBOSA (1), E.M. COUTINHO (1), C. ATHAYDE (1), O.A. LADIPO (1), S.E. OLSSON (2) and U. ULMSTEN (2)

( 1) Maternidade Climerio de Oliveira, Federal University of Bahia, Rua do Limoeiro, No. 1, Salvador, 40.055-150, Bahia, Brazil

(2) Department of Obstetrics and Gynecology, Akademiska Sjukhuset, Uppsala, Sweden


This study was undertaken to assess tri-iodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), T3 uptake, free T3 and free T4 in nomegestrol acetate implant (Uniplant) users. A total of eighteen volunteers of reproductive age who wanted to avoid conception were enrolled in the study. All subjects were investigated before starting treatment. Blood samples for hormonal analysis were taken prior to insertion of the implant. Thereafter, blood samples were drawn at 3, 6, 12, 18 and 24 months of Uniplant use. All subjects had used non-hormonal contraceptives for at least 6 months prior to insertion of the implant.

The results observed in this study showed that there was no significant difference in tri-iodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) during two years of Uniplant use. No significant difference was found in free T3 levels during two years of Uniplant use. A significant decrease was observed in T3 uptake (p <0.05) in month 24 and in free T4 (p <0.05) in month 3 of Uniplant use. All changes observed in this study were inconsistent and all levels were within the normal range.


It is well known that administration of sex steroid hormones can change certain plasma proteins. The concentrations of sex hormone binding globulin (SHBG) increases during treatment with estrogens and decreases during treatment with androgens and certain progestogens [1,2]. Previous studies with Norplant have shown a significant decrease in SHBG levels [3]. The concentration of thyroxine binding globulin increases during pregnacy and during treatment with combined oral contraceptives [4,5]. Olsson et al. demonstrated that during six months of Norplant use, a significant decrease in T4 levels and a significant increase in T3 uptake occurred [6]. Nomegestrol acetate (Uniplant) is a 19-nor-progesterone derivative implant which provides effective contraception for one year [7] and has been ‘shown not to affect SHBG levels during one year of observation [8]. This is in accordance with previous studies with nomegestrol acetate 5 mg/d, orally, for six months [9]. The aim of this study was to evaluate the effect of a single Silastic implant containing acetate on thyroid function in women.


Following counselling, eighteen volunteers gave their informed consent to participate in this study. All women were in good health, had no systemic diseases, and no symptoms or signs of any condition that could contraindicate hormonal contra-

ception. All women had used non-hormonal contraception for at least six months prior to insertion of the implant. All women were investigated before starting treatment. The mean age of subjects enrolled in this study was 23.0 ± 0.9 years. Their mean height was 158.1 +1.2 cm. Their mean weight was 54.7 + 1.5 kg. The mean parity of subjects was 0.9 ±0.2 (Table 1). All values are means ± SE. All women were followed up for two years. At the end of one year, the capsules were removed and a new capsule was inserted in fifteen women who wanted to continue in the study. Three women did not complete the first year of this study.

The implants were hand made from medical-grade dimethylpolysiloxane (Silastic) tubing, catalogue number 602-265, made by Dow Corning, Midland, Michigan. Segments measuring 39 mm total length (35 mm filled length) and 2.4 mm in diameter were used to make the implants. The segments of Silastic tubing were filled with 55 mg (± 10%) of crystalline, finely-ground nomegestrol acetate (3,20-oxo-6-

methy1-17-a-acetoxy-19-norpregna-4,6-diene, Theramex, France) and sealed at both ends with Silastic medical-grade adhesive, type A. Steam sterilization, which had proved effective in previous studies with Silastic implants, was used [10]. In pilot studies, implants were analyzed before and after steam sterilization and it was confirmed that no alteration occurred in the steroid content of the implant during this procedure.

The technique of inserting Uniplant subcutaneously in the gluteal region and subsequent removal was as previously described [7].

Venous blood samples were drawn prior to insertion of the implant between 8.00 and 8.30 a.m. Thereafter, blood samples for hormonal analysis were drawn after 3, 6, 12, 18 and 24 months of Uniplant use. Blood was collected into vacutainer tubes and serum was recovered after centrifugation and kept frozen at —20°C until analyzed.




Hormone determinations

Tri-iodothyronine (T3) and thyroxine (T4) were determined by a solid-phase radio-

immunoassay (RIA), using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. The sensitivity was 8.0 ng/dl and 0.31.1g/d1 and the interassay coefficient of variation was 3.4% and 6.1%, respectively. Normal values were 90-210 ng/dl for T3 and 4.5-12.5 ng/dl for T4. Thyroid stimulating hormone (TSH) and T3 uptake were measured by a solid-phase RIA, using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. The interassay coefficients of variation were 4.8% and 3.8%, respectively. Normal values were 0-4.0 [tIU/L and 25-37%, respectively. Free T4 and free T3 were measured by a solid-phase RIA, using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. The sensitivity was <0.01 ng/dl and 0.2 pg/ml and the interassay coefficient of variation was 8% and 3.8%, respectively. Normal values were 0.8-2.0 ng/dl for free T4 and 1.4-4.4 pg/ml for free T3.


For statistical comparison, Student’s 1-test for paired groups was used. Values are shown in means + SE.





There was no significant difference in tri-iodothyronine (T3) and thyroxine (T4) during two years of Uniplant use (Figure 1). No significant difference in TSH levels was observed during 24 months of Uniplant use (Figure 2). No significant difference was observed in free T3 levels during 24 months of Uniplant use. A significant decrease in free T4 (p <0.05) was observed only in the third month of Uniplant use (Figure 3). A significant decrease in T3 uptake (p <0.05) was observed only in the twenty-fourth month of use (Figure 4). All levels were within the normal range. All women were euthyroid during the period of observation.


Little is known about the hormonal and metabolic effects of progestogen-only therapy. It has been shown that levonorgestrel implants significantly decrease SHBG [3] and thyroxine [6] and significantly increase T3 uptake [6]. Basdevant et al. have shown the effects of nomegestrol acetate (5 mg/d) on sex steroid hormones, SHBG, cortisol-binding globulin (CBG), carbohydrate metabolism and on serum lipids [9]. They reported a significant decrease in triglycerides in the third cycle and also a significant decrease in apolipoprotein Ai levels, estradiol and progesterone during six months of study. All the other parameters studied remained unchanged. No data have been available up to now on the effects of long-acting nomegestrol acetate on thyroid function, androgens and other parameters. We have found that nomegestrol acetate implant does not affect SHBG levels [8]. This study shows that Uniplant does not affect thyroid function during two years of use. However, a transitory decrease in free T4 was observed in the third month only, with no demonstrable clinical effect. T3 and T4 are present in the circulation, either free or bound to TBG, TBPA or albumin, but, according to the free hormone hypothesis, only the free hormones are physiologically active. In this study, free T4 and free T3 were measured to achieve a better estimation of thyroid function and only a transient isolated change in free T4 was observed. All changes observed in this study were transient and all levels were within the normal range. All subjects remained euthyroid and it is concluded that thyroid function is unimpaired during two years of Uniplant use.


Financial support from the Rockefeller Foundation under the South to South Program and from the family planning unit of the University of Uppsala, Sweden, is gratefully acknowledged.


1. Van Kammen R, Thijssen JHH, Rademaker B, Schwartz F. The influence of hormonal contraceptives on sex hormone binding globulin capacity. Contraception. 1974;11:53.

2. Cekan SZ, Jia M, Landgren BM, Diczfalusy E. The interaction between sex hormone binding globulin and levonorgestrel released from vaginal rings in women. Contraception. 1985;31:431-9.

3. Olsson SE, Odlind V, Johansson EDB, Androgen levels in women using Norplant implants. Contraception. 1986;34:157-67.

4. Dowling JT, Appleton WG, Nicoloff JT. Thyroxine turnover during human pregnancy. J Clin Endocrinol Metabol. 1967;27:1749.

5. Rudorff KH, Herrmann J, Dietrich T, Kruskemper HL. Effect of estrogen upon thyroid metabolism. Med Klin. 1978;73:1109-13.

6. Olsson SE, Wide L, Odlind V. Aspects of thyroid function during use of Norplant implants. Contraception. 1986;36(6):583-7.

7. Coutinho EM. One year contraception with a single subdermal implant containing nomegestrol acetate (Uniplant). Contraception. 1993;47:97-105.

8. Barbosa IC, Coutinho EM, Hirsch C, Ladipo OA, Olsson SE, Ulmsten U. Effects of a single contraceptive Silastic implant containing nomegestrol acetate on ovarian function and cervical mucus production during two years. Fertil Steril. 1995.

9. Basdevant A, Pelissier C, Conrad J, Degrelle H, Guyene TT, Thomas IL. Effects of nomegestrol acetate (5 mg/d) on hormonal metabolic and hemostatic parameters in premenopausal women. Contraception. 1991;44(6):599-602.

10. Coutinho EM. Clinical experience with implant contraception. Contraception. 1978;18:411-27.

MS received 24 Apr. 95.

Accepted for publication 9 May 95



Cette etude a ete entreprise pour evaluer, chez les utilisatrices d’implants d’acetate de nomegestrel (UNIPLANT), la triiodothyronine (T3), la thyroxine (T4), la thyreostirnuline (TSH), l’adsorption de T3, la T3 libre et la T4 libre. Dix-huit volontaires en age de procreer qui souhaitaient eviter une grossesse, ont ete inscrites pour participer a l’etude. Toutes les participantes ont ete examinees avant le debut du traitement. Des prelevements sanguins ont ete effectues avant le traitement aux fins d’analyse hormonale. Ensuite, des prelevements sanguins ont ete effectues apres 3, 6, 12, 18 et 24 mois d’utilisation d’UNIPLANT. Tous les sujets avaient utilise des contraceptifs non hormonaux pendant au moins 6 mois avant ]’insertion de l’implant. Les resultats observes dans cette etude ont montre qu´il n’y avait pas de difference significative au niveau des triiodothyronine (T3), thyroxine (T4) et thyreostimuline (TSH) pendant les deux annees d’utilisation d’UNIPLANT. Aucune difference significative n’a ete constatee dans les taux de T3 libre pendant les deux annees. Une diminution significative est apparue dans l’adsorption de T3 (p <0,05) au cours des 24 mois et de T4 (p <0,05) au troisieme mois d’utilisation d’UNIPLANT Tous les changements observes lors de cette etude etaient insignifiants et tons les taux sont restes dans les limites normales.


Este estudio se realize a los efectos de evaluar la triiodotironina (T3), tiroxina (T4), hormona de estimulacion tiroidea (TSH), captaciOn de T3, T3 libre y T4 libre en usuarias de implantes de acetato de nomegestrol (UNIPLANT). Participaron en el estudio, en total, dieciocho voluntarias de edad fertil que deseaban evitar la concepcien. Todas fueron examinadas antes de iniciarse el tratamiento. Se extrajeron muestras de sangre para realizar analisis hormonales antes de colocar el implante. Posteriormente se extrajeron muestras de sangre a los 3, 6, 12, 18 y 24 meses de uso de Uniplant. Todas las mujeres habian utilizado anticonceptivos no hormonales durante al menos 6 meses antes de la colocacien del implante.

Los resultados observados en este estudio indicaron que no hubo ninguna diferencia significativa en la triiodotironina (T3), tiroxina (T4) y hormona de estimulacien tiroidea (TSH) durante dos altos de uso de UNIPLANT. No se determine ninguna diferencia significativa en los niveles de T3 libre durante dos afios de uso de UNIPLANT. Se observe. una disminucien significativa en la captacien de T3 (p <0,05) en el vigesimo cuarto mes y en T4 libre (p <0,05) al tercer mes de uso de Uniplant. Todos los cambios observados en este estudio seiialaban una falta de coherencia y todos los niveles estaban comprendidos dentro de la gama normal.


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