Int

The effects of subdermal hormonal contraceptive implant on health indices. A preliminary report.

Murad AZ, MOG*, Mokhtar A, MRCOG*, Sudesan R, MOG**, Lee SF, MRCOG**,Ghazali I, MOG**

Subdermal etonogestrel implant (Implanon®) is the newest, long term contraceptive implant which has recently been made available to Malaysian women. This prospective study was conducted to determine the effects on selected health indices among 42 women who had consented to Implanon® as their choice of contraception. Health indices were checked prior to Implanon® insertion and six months post insertion. Findings indicate a significant reduction in total cholesterol with a significant increase in total haemoglobin and BMI. However there was no significant change noted in the fasting blood sugar, glycosylated haemoglobin, systolic blood pressure and diastolic blood pressure.

In recent years, an important trend in contraceptive research had been the development of a range of contraceptive methods designed to meet the needs of individual users and fulfill the criteria of an ideal contraception. With the development of synthetic polymers, it became possible to develop a delivery system with a long duration of action which continuously released low amounts of hormones. Contraceptive implants were a successful system for long-term prevention of pregnancy¹. The advantages of this contraceptive method included greater efficacy, independence from user compliance and prompt return of fertility after removal

The development of such a system, in the form of a sub-dermal implant called Implanon®, based on selective progestogen etonogestrel, illustrates the ongoing search for innovative contraceptive methods. Implanon® was first introduced in Europe in 1999 and in Malaysia in 2002. Implanon® is a reversible, long acting, sub-dermal hormonal contraceptive of high efficacy with a Pearl Index of 0, 95% confidence interval 0.00-0.07².

Implanon® releases 3-keto-desogestrel which is the active metabolite of progestogen desogestrel. 3-keto-desogestrel has been given the international non-proprietary name of etonogestrel [ENG].

Desogestrol had been used in combined oral contraceptives for many years and therefore the pharmacological effects of desogestrol, and consequently those of etonogestrel, had been established. However, as Implanon® is subdermally administered and continuously releases etonogestrel into the bloodstream, the first-pass effect is avoided.

In comparison to other delivery systems which are made of silicone, Implanon® is based on an ethylenevinylacetate [EVA] carrier which consists of a single rod of 4 cm long and 2mm in diameter. The core of the implant contains 68 mg crystalline etonogestrel, dispersed in a matrix of ethylenevinylacetate copolymer surrounded by a 0.06 mm EVA membrane. The in vitro release rate profile of this implant is about 60-70 ug etonogestrel/day during week 5-6, decreasing to about 35-45 ug/day at the end of the first year, 30-40 ug/day at the end of the second year and 25-30 ug/day at the end of the third year².

Implanon® worked mainly by inhibiting ovulation. Even when ovulation did occur, it still had contraceptive effects because it suppressed sperm penetration by thickening the viscosity of the cervical mucus and altered the endometrium². It was also noted to have non-contraceptive effect on some health indices. This study was conducted to ascertain the non-contraceptive benefits of Implanon®.

The objective of the study was to determine the effects of Implanon® on selected health indices among women who had consented to a single rod subdermal etonogestrel implant as their choice of contraception. The selected health indices were body mass index (BMI), total lipid profile, blood sugar profile, blood pressure and haemoglobin.

This was a prospective observational study carried out at Hospital Tengku Ampuan Afzan (HTAA) and Family Planning Association (LPKN), Kuantan, Pahang, commencing from the 1^st June 2002 till 31^st May 2003.

Subjects recruited were women who consulted the family planning clinics for contraception. Informed consent was obtained from those who agreed to use Implanon®.

Women who participated in this study were of reproductive age and required a form of contraception. They had chosen Implanon® and consented to participate in the study.

Exclusion criteria were active venous thromboembolic disorder, progestogen dependent tumours, presence or history of severe hepatic disease with liver function value not returning to normal, known or suspected pregnancy, undiagnosed vaginal bleeding and hypersensitivity to any of the component of Implanon®.

Baseline data and blood tests for haemoglobin, fasting blood sugar and lipid profile were taken prior to insertion. These were repeated after 6 months of Implanon® insertion.

Values were recorded as mean ± SD. Statistical analysis was performed with SPSS version 11 using T-test and Wilcoxon Signed Ranks Test. A P-value of 0.05 was considered as significant.

During the period of 12 months, from 1^st. June 2002 to 31^st May 2003, a total of

1005 clients attended the family planning clinic for contraception. 744 were Malay (75%), 203 Chinese (20%), 14 Indians (1%) and 40 others (4%). (See Figure 4)

The majority of contraceptive users 614 (61%) were on Oral Contraceptive Pill (OCP), followed by 186 (19%) on Intra Uterine Contraceptive Device (IUCD), 79 (8%) used condoms, 73 (7%) on Depo Injection and 53 (5%) on Implanon®. (See Fig.5). 42 of the total Implanon® users consented to participate in this study.

The age of participants of this study ranged from 23 to 45 years with a mean age of 32.17 and a median of 32.00 years (Figure 6). The standard deviation was calculated as 5.805. Except for a few participants at the extreme age groups, most were in their 30’s.

During the 6 month period, 61% (26) of the patients had an increase in body weight with only 21% (9) of them having gained more than 10%. The increase in body-weight noted in implant users was largely attributed to a normal increase over the time period and therefore partially attributable to implant use. In the study there was a significant weight gain over the first 6 months in Implanon® users.

BMI

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

23.692

5.0042

0.034

Post insertion

24.146

5.1810

There was a significant reduction in serum total cholesterol level despite the significant increase in BMI of participants.

Cholesterol

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

5.5481

1.0297

0.000

Post insertion

5.1198

0.8911

There was a statistically significant overall increase in mean Hb of participants in the sample.

Haemoglobin

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

12.79

1.130

0.001

Post insertion

13.32

1.3307

There was a slight raise in the FBS and HbA_1C, but were statistically not significant.

(HbA_1C)

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

4.836

0.9596

0.179

Post insertion

4.976

0.7210

FBS

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

5.364

1.1018

0.201

Post insertion

5.967

1.7990

E) Effect of Implanon® on Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP).

There was a small mean decrease in both systolic and diastolic pressure after insertion of Implanon® which was statistically insignificant.

SBP

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

112.86

11.106

0.314

Post insertion

111.52

11.644

DBP

Mean

Std.Deviation

Sig.(2-tailed)

Pre insertion

74.52

7.392

0.113

Post insertion

72.67

7.267

Implanon® is the newest contraceptive implant which was recently made available to Malaysian women. It had been proven to be effective in preventing pregnancy with a Pearl Index of 0².

Implanon® is a progestogen-only system and is suitable for a wide category of women. Implanon® makes family planning possible throughout reproductive life as it provides reversible, long term contraception. Since Implanon® did not contain estrogen, it could also be used in women in whom combined oral contraceptives were to be avoided⁴. There are a number of non-contraceptive benefits of using Implanon® as seen in the findings of this study, especially on total cholesterol and haemoglobin levels.

The acceptability of hormonal contraception depended mainly upon the degree of subjective side-effects and its effect on vaginal bleeding pattern⁵.The women studied were predominantly Malays where vaginal bleeding pattern was an important factor for consideration before offering any form of contraception. Implanon® was associated with initial irregular prolonged frequent bleeding-spotting episode followed by amenorrhoea which may finally lead to significant increase in the serum haemoglobin as observed in this study. However, the bleeding pattern was not assessed in this sample and published data on a significant increase of serum haemoglobin while on Implanon® were limited.

Some patients erroneously regard to menstrual flow as a process where the body ‘cleanse itself’. Hence amenorrhoea was sometimes considered unhealthy because the ‘dirty blood’ was retained in the body. Particular attention should be given when counselling women about the likelihood of irregular bleeding during Implanon® use as this could lead to early removal of Implanon®^6,7,8. It was also important that counselling include the partner as with his support, this would further enhance her confidence to continue with Implanon®.

Increased risk of coronary heart disease (CHD) was associated epidemiologically with elevated concentrations of plasma total cholesterol (TC) and low density lipoprotein (LDL), decreased plasma concentration of high density lipoprotein (HDL) and, in some circumstances, high levels of total triglycerides⁹. Given this relationship, and with clinical data showing that estrogen, progestins and androgens influenced lipoprotein metabolism, the study of the effects of steroidal contraceptives on lipid metabolism had generated intense interest. However, most of these studies only involved small samples size and the published results were limited.

This study showed significant beneficial reduction of total cholesterol level even though we did not look into the other components of the lipid profile. The beneficial effects need to be further confirmed on a larger sample by expanding this study to three years when the other components of the lipid profile are also examined. Any positive effects must be analysed in further details taking into consideration the dietary habit of the study participants.

The body mass index (BMI) increased significantly after Implanon® insertion compared to pre insertion. The BMI indirectly reflected changes in body weight which may have a negative impact on potential Implanon® users.Weight gain was one of the factors against accepting hormonal contraceptive by women. However, Funk S et al. concluded that the use of Implanon® had no clinical significant effect on body mass index on their 330 women studied over 2 years¹⁰.

The larger number of patients with weight gain in this observational study may be contributed by other factors. A sample size of 42 is too small, the type of diet consumed by the patients were not scrutinised and shorter study duration of 6 months only were aspects requiring further verification. In contrast to weight gain being directly proportional to increase in total cholesterol, this study showed an inverse proportional relation.

High progesterone levels during the luteal phase or exogenously administered progesterone had been associated with a deterioration of glucose tolerance and a decrease in insulin sensitivity. Biswas A et al. found a significant but minimal rise of HbA1c in their sample of 80 implant acceptors after 24 months on Implanon®¹¹. However there was no significant change in fasting blood sugar. They concluded that even though Implanon® induced mild insulin resistance, there was no significant change in serum glucose level. Dorflinger LJ concluded that the metabolic effect as a whole was minimal, within normal range and therefore unlikely to be of clinical significance especially in a young healthy population like in the sample studied¹². Similar findings of a slight increase in sugar profile, fasting and glycosylated haemoglobin were seen but not statistically significant.

This minimal rise in sugar profile could be attributed again to the diet as Malays, who constituted the majority of recruits usually consumed carbohydrate rich diet. We need to take into account the pre and post insertion dietary habits of future participants to explain whether diet influenced these results thus reducing any bias.

Meyer et al. found that Implanon® users were associated with increased insulin resistance especially in polycystic ovarian syndrome (PCOS) patients but in this study no patient with PCOS was recruited¹³.

The slight reduction in both systolic and diastolic blood pressure 6 months after Implanon® insertion was encouraging although it was not statistically significant. Again published data on this finding was very limited. Funk S et al. found no clinical significant effect on blood pressure after 2 years on Implanon® in 330 sample size¹⁰.

Implanon® accounted for a mere 5% of total contraceptive acceptors in the family planning clinic. The acceptability rate was low due to the fear of the unknown and its higher cost. Patients paid RM 300.00 per insertion, up front although after a three year period it worked out to be almost RM 9 per month (the cost during this study period at Family Planning Association Kuantan).

Sub dermal etonogestrel single rod implant, Implanon® for contraception had shown to have additional beneficial non-contraceptive effects especially on total cholesterol and haemoglobin levels. There were negative effects on BMI, blood sugar profile and blood pressure. These findings over an initial six months period follow up need further confirmation through perhaps a three year longitudinal study with 300 to 400 recruits. It was possible that the type of diet influenced non-contraceptive benefits of Implanon®. Future studies over three years should include not only a larger number of women with more biochemical indices, but also the type of diet consumed before definitive conclusions could be established for Malaysian women.

We wish to acknowledge Ms Ng FK from Family Planning Association (FPA) Kuantan for her assistance with subject recruitment in this study.

1. Varney, Susan J, Julian F. Relative cost effectiveness of depo provera, implanon and mirena in reversible long-term hormonal contraceptive in the UK. Pharmacoeconomics 2004; 22(17): 1141-51.

2. Croxatto HB, Makarainen L. The pharmacodynamics and efficacy of Implanon®; an overview of the data. Contraception 1998; 58 suppl 6: 91S.

3. Mascarenhas L. Insertion and removal of Implanon®. Contraception Supplement 1998; 58: vol. 6 : 79-85.

4. WHO scientific Group on Cardiovascular Disease and Steroid Hormone Contraception: Cardiovascular Disease and Steroid Hormone Contraception: Report of the WHO Scientific Group. WHO Technical Report 877: i-vii; 1-89. Geneva, Switzerland, 1998.

5. Affandi B. An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon®. Contraception 1998; 58: VOL.6: 99S-107S.

6. Agrawal A, Robinson C. An assessment of the first 3 years’ use of Implanon in Luton. J Fam Plann Reprod Health Care 2005; 31(4): 310-2.

7. Chaovisitsaree S, Piyamongkol W, Pongsatha S, Morakote N, Noium S, Soonthornlimsiri N. One year study of Implanon on the adverse events and discontinuation. J Med Assoc Thai 2005; 88(3): 314-7.

8. Bitzer J, Tschudin S, Alder J. Acceptability and side-effects of implanon in Switzerland: Swiss Implanon study group. Eur J Contracept Reprod Health Care 2004; 9(4): 278-84.

9. Biswas A, Viegas OA, Roy AC. Effect of Implanon® and Norplant® subdermal contraceptive implants on serum lipids-a randomised comparative study. Contraception 2003; 68(3): 189-93.

10. Funk S, Miller MM, Mishell DR Jr et al. Safety and efficacy of implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 2005; 71(5): 319-26.

11. Biswas A, Viegas OA, Coeling Bennink HJ, Korver T, Ratnam SS. Implanon® contraceptive implants: effects on carbohydrate metabolism.Contraception 2001; 63(3): 137-41.

12. Dorflinger LJ. Metabolic effects of implantable steroid contraceptive for women. Contraception 2002; 65(1): 47-62.

13. Meyer C, Talbot M, Teede H. Effect of Implanon on insulin resistance in women with Polycystic Ovarian Syndrome. Aus N Z J Obstet Gynaecol 2005; 45(2): 155-158.