EN PT ES

Androgen Levels in Women Using a Single Implant of Nomegestrol Acetate

lone Barbosa,* Elsimar Coutinho,* Celia Athayde,* O.A. Ladipo,* Sven-Eric Olsson,t and Ulf Ulmstent.

This study was undertaken to evaluate the effects of a single implant containing nomegestrol acetate (Uniplant) on plasma levels of sex hormone-binding globulin (SHBG), testosterone, free testosterone, androstenedione and on blood pressure, body weight and the development of acne vulgaris. Plasma levels of sex hormone-binding globulin, testosterone, free testosterone and androstenedione were measured. Blood pressure and body weight were determined. The development of acne vulgaris was evaluated. Total testosterone and androstenedione decreased significantly during two years of Uniplant use but all levels were within the normal range. There were no significant differences in sex hormone-binding globulin and free testosterone during 24 months of Uniplant use. All changes observed in this study were within the normal range. SHBG was not affected by Uniplant use. No significant increase in androgen levels and in the development of acne vulgaris was observed in these women using nomegestrol acetate implant during two years. Based on these results, it is possible to conclude that Uniplant had no androgenic effect in women during this study. CONTRACEPTION 1996;53:37-40

KEY WORDS: Uniplant, SHBG, testosterone, free testosterone, androstenedione


INTRODUCTION

Plasma androgen concentrations have been reported both to increase as well as to decrease during use of progestogen-only contraceptives,¹⁻³ while a pronounced decrease in SHBG was observed in levonorgestrel-only users. ⁴⁻⁷ Women with severe acne also have been shown to have low levels of SHBG.⁸ Uniplant is an implant of nomegestrol acetate, a 19-nor-progesterone derivative, and a new contraceptive implant in the phase III stage of development. Therefore, the assessment of hormonal and metabolic parameters is highly important. The purpose of this study was to determine any changes in plasma testosterone, free testosterone, SHBG and androstenedione, body weight, blood pressure and in the development of acne vulgaris during Uniplant use.

Maternidade Climerio be Oliveira,  Federal University of Bahia, Rua do Limoeiro, No. 1, 40.055-150 Salvador, Bahia, Brazil and tDepartment of Obstetrics and Gynecology, Uppsala University, Uppsala, Sweden Name and address for correspondence: Dr. lone C. Barbosa, Maternidade Climério de Oliveira, Rua do Limoeiro, No. 1, Salvador, 40.055-150, Bahia, Brazil. Tel: (071) 243-0003. Fax: (071) 243-9153

Submitted for publication July 24, 1995

Revised October 2, 1995

Accepted for publication October 6, 1995

1996 Elsevier Science Inc. All rights reserved.

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MATERIALS AND METHODS

A total of 18 volunteers of reproductive age were enrolled in this study. All subjects were healthy women with no contraindications to hormonal contraception. All subjects had used non-hormonal contraception for at least six months prior to insertion of the implant. 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. All values are mean ± S.E. From a large clinical study in our center, 60 women were examined for the presence of acne vulgaris before and at one, three, six, 12, 18 and 24 months of Uniplant use.

The implants were handmade from medical grade dimethylpolysiloxane (Silastic) tubing, catalogue number 602-265, made by Dow Corning, Midland, MI. Segments measuring 39 mm total length 135 mm of 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 proved effective in previous studies with Silastic implants, was used.⁹ The technique of insertion and removal of Uniplant in these volunteers was as previously described.¹⁰ Fasting venous blood samples were drawn at 8:00-8:30 am, prior to insertion of the implant. After insertion of the implant, blood samples for hormone analysis were drawn at 3, 6 and 12 months. At the end of one year, the capsules were removed and a new capsule was inserted in ten subjects. After insertion of the new implant, fasting blood samples were taken every six months. Blood was collected into heparinized vials and plasma was recovered after centrifugation and kept frozen at -20°C until analyzed.

01

Hormone Determinations

SHBG capacity was determined using a time-resolved fluorimmunoassay kit from Pharmacia AB. The sensitivity was 0.8 nmo1/1 and the interassay coefficient of variation (CV) was 3.5%. Normal values were 16.0-120.0 nmol/1.

Total testosterone was determined by radioimmunoassay using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. The sensitivity was 0.1 nmo1/1 and the interassay coefficient of variation (CV) was 10.8%. Normal values were 0.2-3.0 nmo1/1.

Free testosterone was analyzed by radioimmunoassay using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. Normal serum levels for free testosterone with this method were 3.1 to 11.0 pmol/1. The sensitivity was 0.5 pmo1/1. The interassay coefficient of variation (CV) was 4.2%.

Androstenedione was determined by radioimmunoassay using a commercial kit from Diagnostic Products Corporation, Los Angeles, CA, USA. The sensitivity was 0.06 nmo1/1. The interassay coefficient of variation {CV) was 8.8%. Normal values of this method are 1.4-15.75 nmo1/1. Blood pressure and body weight were measured prior to blood sampling before implant insertion and thereafter in the 3rd, 6th, 12th, 18th and 24th month of Uniplant use. The development of acne vulgaris was evaluated by a physician before implant insertion and at three, six, 12, 18 and 24 months of Uniplant use. The women were also requested to report any development of acne vulgaris on their body during 24 months of Uniplant use.

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STATISTICS

Mean values and standard error for each variable at admission, 3, 6, 12, 18 and 24 months were obtained. Analysis of variables for repeated measures was used in order to detect significant differences throughout the study period.


RESULTS

Plasma concentration of SHBG did not change significantly during 24 months of Uniplant use (P=0.797).

(Figure 1). Before Uniplant insertion, plasma concentration was 69.2 ± 6.2 nmo1/1 (mean ± SE). After 24 months of use, the concentration was 59.8 ± 6.0 nmol/1 (mean ± SE).

Total testosterone decreased significantly from 1.9 ± 0.1 to 1.2 ± 0.1 nmol/ml (p<0.01) at 12 months of use and to 0.8 ± 0.1 nmo1/1 (p<0.01) at month 24 (Figure 2). Global analysis showed a significant decrease during the study period.

Plasma concentrations of free testosterone did not vary significantly during 24 months of use. The mean concentration before implant insertion was 2.6 ± 0.4 pmo1/1 and no significant variation was observed during the first 12 months of use. At month 18, the concentration increased to 4.2 ± 0.4 prno1/1 while at month 24 it was again 2.6 ± 0.4 pmol/l. Although a considerable increase was observed at month 18, global analysis did not detect any significant difference throughout the study period (p= 0.709).

Androstenedione decreased significantly from 8.7 ± 0.6 to 6.2 ± 0.9 nmol/l after six months of Uniplant use (p<0.05). The value after 12 months of observation was 4.8 ± 0.9 nmo1/1 (p<0.01). Plasma concentration decreased further to 3.3 ± 0.3 (p<0.01) at month 18 and to 3.2 ± 0.6 nmo1/1 (p<0.01) at month 24 (Figure 3). Global analysis showed a significant decrease throughout the 24 months of the study (p =0.029). Body weight increased from 54.7 ± 1.5 kg at admission to 55.3 ± 2.0 kg at 12 months of use {p<0.05) and to 56.0 ± 2.7 kg at 24 months of Uniplant use. A slight increase in both systolic and diastolic blood pressure was observed in month 12 {p<0:01). No other changes were observed during 24 months of Uniplant use. All values were within the normal range. No development of acne vulgaris was observed in the 18 women of this study, as well as in the 60 women participating in a large clinical study.


DISCUSSION

Little is known about the potential effects of nomegestrol acetate as a long-acting contraceptive on androgens, as well as on thyroid function and other hormonal and metabolic parameters. The significant decrease in androstenedione levels is consistent with reports on the effects of other progestins.¹¹ A significant part of androstenedione is of ovarian origin and produced as a result of follicular growth. Its production should, therefore, be expected to decrease during inhibition of ovulation. ¹²¸¹³ During use of Uniplant, around 80% of the women had anovulatory cycles.¹⁴ Hence, the decrease of androstenedione found in our study could be due to inhibition of ovulation. A single implant of nomegestrol acetate prevents conception in women for as long as one year. Only one pregnancy occurred in a total of 1,055 women-months of observation, resulting in a Pearl Index of 1.1.¹⁰

Previous studies have shown a significant decrease in SHBG in women using levonorgestrel implants. ¹⁵⁻¹⁷ In our study with nomegestrol acetate implant, no changes in SHBG levels were observed during two years of study. These results are in accordance with previous studies using 5 mg of nomegestrol acetate orally.¹⁸ Since testosterone is bound with high affinity to SHBG and since the binding capacity of SHBG is limited, no changes in free testosterone levels were expected as a result of an unchanged SHBG capacity. In this study, no significant changes in free testosterone levels were found during two years of Uniplant use. A significant decrease in total testosterone was observed during months six, 12, 18 and 24 of implant use but all levels were within the normal range. The metabolic clearance rate of testosterone, however, has been shown to increase with lower levels of SHBG,¹⁹ probably as a result of a higher proportion of total testosterone being free and easily available to metabolism, thereby rapidly restoring the balance between the free and protein-bound fractions of testosterone to a steady-state situation. The net result of this should be decreased total and unchanged free testosterone. The results by Olsson et al.¹¹ in Norplant® implants users is in accordance with this theory. In our study, despite no changes in SHBG levels, a significant decrease in total testosterone and no significant change in free testosterone was observed. This could be explained by the lack of changes in SHBG levels and by the high-frequency of anovulatory cycles¹⁴ and the significant decrease in LH levels. Previous studies have shown an overall increase of 21% in the frequency of acne during Norplant® implants use.¹¹

However, in the current study, using nomegestrol acetate implant, no development of acne vulgaris was observed and no woman complained of acne development during 24 months of Uniplant use. In conclusion, minor decreases in the levels of testosterone and androstenedione were found. No significant changes in free testosterone were observed during the 24 months of Uniplant use. All levels were within the normal range. SHBG levels were not affected during two years of Uniplant use. From these results, it may be possible to conclude that Uniplant has no androgenic effect in women during 24 months of treatment.

03


ACKNOWLEDGMENTS

This study was supported by the Rockefeller Foundation under the South-to-South Program and by the family planning program of the University of Uppsala, Uppsala, Sweden. The women were asked to report any development of acne vulgaris on their body during Uniplant use.


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