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Fertility and Sterelity Vol. 65, No. 4, April 1996

Copyright ° 1996 American Society for Reproductive Medicine Printed on acid-five paper in U. S. A.

Effects of a single contraceptive Silastic implant containing nomegestrol acetate on ovarian function and cervical mucus producting during 2 years*

Ione Barbosa, M.D.if               Oladapo Ladipo, M.D.t

Elsimar Coutinho, M.D.t Sven-Eric Olsson, M.D.§

Cristina Hirsch, B.Sc.t               Ulf Ulmsten, M.D.§

Federal University of Bahia, Maternidade Climério de Oliveira, Salvador, Brazil, and University of Uppsala, Uppsala, Sweden

Objective: To study the mechanism of action of Uniplant (South to South Corporation in Reproductive Health, Salvador, Brazil), a single Silastic capsule containing nomegestrol acetate (Lutenyl, Theramex, France) in women during 2 years.

Design: Comparison between the hormonal levels, follicular development, cervical mucus (CM) production, and endometrial thickness in the menstrual cycle before implant insertion and at 1, 6, 12, 18, and 24 months after implant insertion.

Participants: A total of 15 women of reproductive age were enrolled for the 1st year of use. Twelve of these women continued for a 2nd year of Uniplant use.

Main Outcome Measures: Hormonal plasma levels were measured in control cycles and at 1, 6, 12, 18, and 24 months of Uniplant use. Cervical mucus, follicular development, and endometrial thickness also were evaluated.

Results: In this study, Uniplant blocks ovulation in 86% of cycles studied. Disturbances in follicular growth were observed also. Cervical mucus was scanty and viscous in all women during this study. Endometrial thickness was <8 mm in all cycles studied.

Conclusion: This study shows that Uniplant is a long-acting contraceptive that probably acts at the hypothalamic-pituitary levels, on the ovary, on CM production, and on the endometrium. These properties suggest the use of Uniplant as a contraceptive agent, especially if one considers the lack of androgenic and metabolic effects and the maintenance of periodic bleeding similar to menstruation. Fertil Steril 1996;65:724-9

Key Words: Nomegestrol acetate implants, ovarian function, cervical mucus, follicular devel-

opment, transvaginal sonography

Progestogen-only contraceptive methods were developed with the aim of avoiding certain side effects and risks associated with estrogen in combined oral contraceptives (OCs). Oral progestins (i.e., minipills) have a limited contraceptive efficacy that largely depends on the woman’s compliance with the pill regimen (1). Nomegestrol acetate (Lutenyl, Theramex, France), in the dose of 1.25, 2.5, and 5 mg orally, has been studied (2). The authors found that, concerning FSH and E2 levels, differences were observed between the effects of 2.5 or 5 mg/d and the effects of 1.25 mg/d. They found that the ovarian and pituitary blockade was similar with the two higher doses, and the very low E2 levels attested to the absence of follicular  maturation despite elevated plasma FSH. These observations may reflect a direct effect of nomegestrol acetate on the ovary, as proposed for other progestational agents (3). Olsson et al. (4) found that, despite regular menstruation in a group of women who had used Norplant-2 implants (Leiras Pharmaceuticals, Turku, Finland) for more than 3 years, 40% of them showed anovulation, 20% presence of unruptured luteinized follicles,  and 40%  apparently  normal  follicular growth and rupture. Barbosa et al. (5) found that the  levonorgestrel-releasing  intrauterine  device (IUD, Levo-Nova; Leiras, Turku, Finland)) exerted an effect on ovarian function that consisted of disturbances  in  follicular  growth  and  rupture, lower plasma levels of E2, LH, and P. They also found that in the regularly menstruating women, 8 out of 15 cycles had good cervical mucus (CM), according to the World Health Organization (WHO) criteria (6). Cervical mucus first attracted attention when the postcoital test was described by Sims (1868) (7). Coutinho et al. (8) reported that in a total of 1,085 women-months of use of a Silastic implant containing nomegestrol acetate, only one pregnancy occurred, resulting in a Pearl Index of 1.1. Nomegestrol acetate Silastic implant (Uniplant; South to South Cooperation in Reproductive Health, Salvador, Brazil) is a new, long-acting, nor-P derivative contraceptive. Hence, the aim of this study was to assess ovarian function with frequent transvaginal sonographic measurements of follicles and plasma determination of gonadotropins, E2, and P. Effects on CM and on endometrial thickness, sex hormone-binding globulin (SHBG) levels, and the effects of nomegestrol acetate on cervical cytology were evaluated also.


MATERIALS AND METHODS

A total of 15 healthy women volunteers who had no previous history of gynecological or endocrine disorders were enrolled in this study. Their mean age was 23 ± 1.2 years (range, 18 to 33 years). Mean weight was 55.7 ± 2.6 kg (range, 40 to 72 kg). Mean parity of subjects was 1.1 (range, 0 to 4). Mean value for systolic blood pressure was 116 ± 1.6 mm Hg (range, 100 to 120 mm Hg). Mean value for diastolic blood pressure was 76 ± 1.6 mm Hg (range, 60 to 80 mm Hg). All values are means ± SE. They had not received any hormonal contraception for at least

6 months before the study. Implants were handmade from medical grade dimethylpolysiloxane (Silastic) tubing, catalog number 602 265, Dow Corning (Midland, MI). Segments measuring 39 mm of total length (35 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-methyl-17-a-acetoxy-19-norpregna-4,6-diene; Theramex, France) and sealed at both ends with Silastic, medical-grade ad-hesive, type A. Steam sterilization, which proved effective in previous studies with Silastic implants, was used (9). 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 insertion and removal of Uniplant in ‘ these volunteers was as previously described (8). Venous blood samples were drawn every other day

from day 8 of the cycle until sonographic evidence of  a 12-mm follicle and then every day until sonographic evidence of follicular rupture and thereafter every other day until the next menstrual bleeding. All blood samples mentioned above were taken before implant insertion (control cycle) and after 3, 6, and 12 months of Uniplant use. The capsules were removed at the end of 1 year of Uniplant use, and a new capsule was inserted in 12 subjects who desired to continue in the study. One subject wanted to have a new implant inserted but could not participate in the study. One subject wished to have another child, and another desired to change to OC use. The blood samples for hormonal analyses were taken after 18 and 24 months of Uniplant use in the 12 women who continued in the study.

Hormone Determinations

The SHBG capacity was determined using commercial kits from Diagnostic Products Corporation (Los Angeles, CA). The sensitivity was 0.04 nmol/L and the interassay coefficient of variation (CV) was 5.1%. Normal values were 16.0 to 120.0 nmol/L.

Progesterone was determined by RIA using commercial kits from Diagnostic Products Corporation.  The sensitivity was 0.02 ng/mL (0.09 nmol/L), and  the interassay CV was 6.4%. Normal values were 0.09 to 28 ng/mL (0.3 to 89 nmol/L). Estradiol was determined by RIA using a commercial kit from Diagnostic Products Corporation. The sensitivity was 0.28 pg/mL (5.3 pmol/L), and the interassay CV was 5.5%. Normal values were 38 to 400 pg/mL (146 to 1,468 pmol/L). Luteinizing hormone was analyzed by RIA using a commercial kit from Diagnostic Products Corporation. The sensitivity was 1.21 IU/L (conversion factor to SI unit, 1.00). The interassay CV was 8.3%. Normal values of this method are 15 to 90 IU/L.

Follicle-stimulating hormone was  analyzed by RIA using a commercial kit from Diagnostic Products Corporation. The sensitivity was 0.7 IU/L (conversion factor to SI unit, 1.00). The interassay CV was 5.6%. Normal values of this method are 5.9 to 16.4 IU/L.

Follicular Development

Follicular growth pattern was assessed in all volunteers by transvaginal sonography, scanning both ovaries, as described by Osmers (10) and Goswamy (11). The examinations started on day 8 of the cycle and were then performed on each day on which a blood sample was taken, as described above. Follicular rupture was diagnosed when the echo-negative structure disappeared or decreased its diameter by >50%. In the subjects who developed prolonged cycles or amenorrhea,  transvaginal  sonography  was  performed three times a week for at least 60 days. The endometrial thickness was measured from the proximal to the distal echogenic interface of the junction between the endometrium and the myometrium by electronic caliper built into the machine. Only the longitudinal section of the uterus was used for measurement of the uterine and endometrial thickness. To evaluate the ultrasonographic texture of the endometrium, the following parameters were used (12, 13): (1) the central linear echo representing the endometrial cavity often surrounded by two linear echoes representing the myometrial junctions, (2) the hypoechogenic layers surrounding the central linear echo representing the growing endometrium, and (3) the increasing echogenicity starting from the peripheral borders of the myoendometrial echoes representing differential changes of endometrial layers.

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Cervical Mucus

Cervical mucus was collected from the endocervix using a 20-mL syringe and a polyethylene catheter. Cervical mucus was evaluated according to WHO criteria (6). The maximum score for CM was 15. A score >  10 was indicative of good CM, favoring sperm penetration, and a score < 10 represented unfavorable CM. Cervical mucus was collected on the same day on which transvaginal sonography was performed, as described above. This technique was carried out as previously described (5).

STATISTICS

For statistical comparison, Student’s t-test for paired groups and Wilcoxon’s test (nonparametric test) were used. Values are shown as means ± SE.

RESULTS

All pretreatment cycles were ovulatory as judged by P, E2, LH, CM, endometrial thickness, and follicular growth and rupture. The observation time was 25 months. Plasma concentrations of E2 did not vary significantly during 24 months of Uniplant use. Although a considerable decrease was observed in month 24, no significant difference was detected using both Wilcoxon’s test (nonparametric test) and Student’s t-test for paired groups. Levels of LH were significantly lower than in the control cycles during the period of observation (Fig. 1). According to P levels, 86.56% of treated cycles were anovulatory (range, 80% to 93.3%). One subject had ovulatory cycles during the 24 months of Uniplant use.

According to transvaginal sonography, four different patterns of follicular development were found, as follows (Table 1): normal follicular growth and rupture, persistent follicle, follicular cysts, and no follicular growth. Follicular growth and rupture were observed in approximately 20% of the treated cycles. Presence of persistent follicles was observed in approximately 15% of the treated cycles. Follicular cysts were observed in 29% of the cycles studied during 24 months of Uniplant use. The cysts disappeared spontaneously within a maximum of 80 days. No follicular development was observed in approximately 36% of the cycles studied. These observations were maintained in more or less the same proportion during the periods of observation during 24 months of Uniplant use. All subjects had normal cervical cytology before starting treatment, after 12 months and after 24 months of Uniplant use. The maximum CM score for pretreatment cycles was 12.8 ± 0.4. In the 1st month of Uniplant use, CM was scanty and viscous as shown in Figure 2, and this effect was maintained during the 24 months of treatment with Uniplant. Endometrial thickness was <8 mm in all cycles studied including the few ovulatory cycles observed during 24 months of Uniplant use. One subject, who did not want to have another implant inserted after the 1st year of Uniplant because she desired to have another child, had a normal ovulatory cycle and a normal CM score of 11.0 in the 2nd month after Uniplant removal.

Bleeding Patterns During 24 Months of Uniplant use

Fifty-eight percent (7 of 12) of the women showed a normal menstrual cycle (26 to 32 days). Thirty-three percent (4 of 12) of the women experienced one or two episodes of amenorrhea (90 to 134 days), whereas 8.3% of women (1 of 12) experienced episodes of spotting, six times in a period of 24 months of Uniplant use (10 to 30 days). One of three women who were in this study for only 1 year showed one period of amenorrhea (90 days), whereas two of three women showed two episodes of prolonged bleeding  (16 to 20 days).

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Levels of SHBG

Plasma levels of SHBG did not change significantly during 24 months of Uniplant use when compared with the control cycle. Before Uniplant insertion, plasma concentration of SHBG was 72.3 ± 6.4 nmol/L (mean ± SE). After 24 months of Uniplant use, the concentration was 78.0 ± 9.0 nmol/L.

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DISCUSSION

Nomegestrol acetate is a 19-nor-P derivative with a potent progestational activity and no androgenicity(14). Nomegestrol acetate, given orally in a dose of 1.25, 2.5, and 5.0 mg/d, exerts a potent antiovulatory effect that probably acts at the hypothalamic-pituitary levels but also on the ovary (2).In this study, 55 mg of nomegestrol acetate was used in a single Silastic capsule. The release through such Silastic membranes gives a very stable release throughout the time of use. Fifteen healthy women with a rigorously normal menstrual cycle were recruited for this study. The study showed that nomegestrol acetate blocks ovulation in approximately 86% of the cycles studied during 2 years. Nomegestrol acetate also exerted an effect on ovarian function, which consisted of disturbances in follicular growth, rupture, and lower plasma levels of P. Levels of LH and FSH were also significantly lower than the controls, which probably indicates an effect on the hypothalamus-pituitary level. The presence of elevated levels of E2 and the absence of gonadotropin surge during the follicular phase indicates that the positive feedback of E2 on gonadotropins is disrupted. This mechanism previously was reported for ST-1435 and other progestogens (15-17). These findings are in accordance with our results, in which we found elevated levels of E2 and absence of LH surge in the great majority of cycles. Folliculogenesis inhibition is associated with a decrease in LH and FSH ratio, which mainly depends on LH-RH pulse frequency (18). In our study, LH and FSH ratio was >2:1 in 44.4% of the cycles studied in the 1st year of Uniplant use and in 31.8% of the cycles in the 2nd year of Uniplant use. These results could be explained by the follicular activity observed by ultrasonography in the majority (68%) of the cycles studied during 2 years. Normal follicular development and rupture was observed in 15.5% of the cycles studied in the 1st year of Uniplant use and in 13.6% of the cycles in the 2nd year of Uniplant use. This study shows that a single Silastic capsule of nomegestrol acetate exerts a potent antiovulatory effect in women. Disturbances in follicular growth and rupture, such as no follicular growth and rupture, persistent follicles, and follicular cysts, were observed. All cysts disappeared spontaneously within 80 days. The disturbances in follicular growth and rupture also were reported in previous studies with levonorgestrel implants  and  in levonorgestrel-releasing  IUDs (4, 5, 19). This study shows that Uniplant has no effect on SHBG levels. No androgenic effect was observed during 2 years of observation. This is in accordance with previous studies with oral nomegestrol acetate (20). Cervical cytology was performed before and after the 1st and 2nd year of Uniplant use. No effect in cervical cytology has been observed during Uniplant use. Uniplant has a potent effect on CM production. Cervical mucus was scanty and viscous in all women during 24 months of Uniplant use. This is in accordance with previous findings with low continuous progestogen (norgestrienone) (21). Cervical mucus was scanty and viscous even in ovulatory cycles. No differences could be observed concerning CM production, endometrial thickness, and E2 levels when ovulatory cycles were compared with anovulatory cycles. Plasma levels of P, LH, and FSH in these ovulatory cycles were lower than in the control cycles. This may explain the contraceptive effect of Uniplant in ovulatory cycles.   Endometrial thickness in treated cycles was below 8.0 mm in all women during 2 years, even in the cycles with very high E2 levels. This finding may be explained by a direct effect of nomegestrol acetate on the endometrium. Bakos et al. (22) found that only one thin echogenic line was seen from menstruation to day 7. From days 6 to 1, a change from one to three thin lines was observed, together with an increasing hypoechogenic  texture between the lines. These changes corresponded to the increasing serum concentration of E2 and increasing thickness of the endometrium. It may be concluded that Uniplant has several contraceptive mechanisms of action. The first mechanism involves a suppressive effect on follicular development,  causing anovulation in the majority of women.  The  second mechanism involves  disturbances in follicular growth and rupture, such as persistent follicles and follicular cysts. The third mechanism involves suppression of endometrial growth, as seen by transvaginal sonography, which accounts for the reduction in the amount of menstrual flow and, in some cases, amenorrhea. The fourth mechanism involves a profound reduction in the production and changes in the chemical and physical CM in all cycles studied. It also may explain the very low pregnancy rate, resulting in a Pearl Index of 1.1 (8). Taken all together, the results of this study show that Uniplant is a long-acting contraceptive that probably acts at the hypothalamic-pituitary levels but also on the ovary, on CM production, and on the endometrium. These properties suggest the use of Uniplant as a contraceptive agent, especially if one considers the lack of androgenic and metabolic side effects.


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