Research
HJOG 2026, 25 (1), 34-42| doi: 10.33574/hjog.0613
Jeanette Michelle Choukrosimon, Sriwijaya, Irnawaty Bahar, Samrichard Rambulangi,
Fatmawati Madya, Nurbani Bangsawan
Department of Obstetrics and Gynecology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
Correspondence: Jeanette Michelle Choukrosimon, Department of Obstetrics and Gynecology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. E-mail: drjeanettechou@gmail.com
Abstract
Introduction: The use of hormonal contraceptives, such as progestin implants, is suspected to affect allopregnanolone levels and involved in mood regulation, potentially increasing depression risk. This study aimed to analyze the correlation between allopregnanolone levels and the duration of implant use on depression among implant acceptors compared to intrauterine device (IUD) users.
Material and methods: A cross-sectional study involved 90 women aged 20–35 years, divided into three groups: implant users <1 year (n=30) and ≥1 year (n=30), and IUD users (n=30). Allopregnanolone levels were measured using ELISA. Depression was assessed using the Hamilton Depression Rating Scale (HDRS). Data were analyzed using ANOVA, Kruskal-Wallis, and Spearman correlation tests.
Results: Allopregnanolone levels in implant users (<1 year: 2.33 ± 0.99 nmol/L; ≥1 year: 2.68 ± 1.19 nmol/L) were significantly lower than in IUD users (3.49 ± 1.40 nmol/L; p=0.001). However, no significant differences in depression scores were observed among the groups (p=0.204). Additionally, no significant correlation was found between allopregnanolone levels and depression scores in any group (p>0.05).
Conclusion: Progestin implant use is associated with reduced allopregnanolone levels but does not significantly increase depression risk compared to IUDs.
Keywords: Allopregnanolone, progestin implant, depression, hormonal contraception, IUD.
Introduction
Depression is a common mental disorder characterized by persistent sadness and a lack of interest in previously enjoyable activities [1]. Globally, the prevalence of major depression ranges from 5% to 17%. The incidence of depression in women is almost twice that of men [2]. Study on women aged 15 to 34 years, the incidence of depression in all users of hormonal contraception was 2.2 per 100 people per year, while in non-users of hormonal contraception it was 1.7 per 100 people per year [3]. The prevalence of depression due to the use of hormonal contraception ranges from 4.6-11.4% [4].
Allopregnanolone has been linked to mood disorders in women. Together, allopregnanolone can impact a woman’s psychological well-being [5]. Allopregnanolone can also modulate the action of gamma-aminobutyric acid (GABA), particularly at the GABA-A receptor. This activity has been linked to various psychiatric complaints related to the menstrual cycle and pregnancy in women [8]. Together with GABA, it is believed to work together to cause depressive symptoms and the interaction between these two compounds is mediated by allopregnanolone as a neurosteroid [6,7].
Depression can be measured using the Hamilton Depression Rating Scale (HDRS) questionnaire [8,9]. The incidence of depression reported in contraceptive implant users was 3.26% in women without Attention-Deficit/Hyperactivity Disorder (ADHD) and 8.68% in women with ADHD [10]. Another study reported a higher prevalence of depression in implant users, reaching 27.7% [11] This study aims to analyze the relationship between allopregnanolone levels and duration of implant use and the incidence of depression.
Material and methods
Study Design and Participants
This study is an observational analytical study with a cross-sectional design scheme conducted at the Polyclinic of a network hospital in Makassar and the Clinical Pathology Laboratory of Hasanuddin University Hospital during the period of July 2024 to May 2025. The study population was Implant and intrauterine device (IUD) acceptors aged 20-35 years and who used implants who were registered or came to the Obstetrics and Gynecology Polyclinic at a network hospital in Makassar City until the sample was fulfilled. The sample of this study was healthy women aged 20-35 years and were married. The sample inclusion criteria included women aged 20-35 years with regular menstrual cycles, first-time implant acceptors for at least 6 months, and were willing to participate in the study and had signed an informed consent. Exclusion criteria included having a history of previous depression, a history of hyperthyroidism, and a history of hormonal therapy use in the last 1 year.
Implant Insertion Technique
1. Position the patient supine on the examination table with the non-dominant arm flexed at the elbow and externally rotated.
2. Identify the insertion site.
3. The insertion site is located above the triceps muscle, 8 to 10 cm from the medial epicondyle and 3 to 5 cm below the groove (groove) between the biceps and triceps.
4. Mark the implant site.
5. Anesthesia.
6. Make a bump where the device needle will enter the skin and then infiltrate along the planned needle path.
7. Remove the sterile, pre-filled, disposable implant applicator containing the implant from the packaging.
8. Hold the applicator directly above the needle on a textured surface. Remove the clear protective cover by sliding it away from the needle.
9. Apply countertraction distal to the insertion site with your free hand.
10. Pierce the skin with the needle tip at a slightly less than 30-degree angle to the skin and insert it until the bevel is just under the skin.
11. Lower the applicator to a horizontal position and flex the skin by lifting it upward as the needle is fully advanced toward the guide mark.
12. Release the purple slider by pressing it down slightly.
13. The implant should now be in place, and the needle should be locked into the applicator. Remove the applicator [12]
Assessment
Data of Contraceptive use were obtained through patient interviews. All subjects were asked to complete the Hamilton Depression Rating Scale (HDRS) questionnaire and then calculate a total score. Serum allopregnenolone levels were measured using an ELISA test.
Ethical Clearance
Each action was carried out with the permission of the client or the client’s family through the signing of an informed consent form and was declared to have met the ethical requirements for conducting research from the Human Biometric Research Ethics Commission of the Faculty of Medicine, Hasanuddin University with a letter of recommendation for ethical approval and the Health Research Ethics Commission (KEPK) of RSPTN UH-RSWS, Number. 225/ UN4.6.4.5.3L/PP36l 2024.
Data Analysis
The data obtained were processed using a computerized data analysis program, then analyzed using SPSS version 25.0 software for Mac (IBM Corp., Armonk, NY, USA). Univariate analysis was used to describe the basic data characteristics in the form of frequency distribution, which was presented in tabular form. The Shapiro-Wilk normality test was performed to assess the distribution/normality of the data and the Levene test to assess the homogeneity of the data. A difference test was performed between two sample groups using the independent sample t-test for normally distributed data and the Mann-Whitney test for non-normally distributed data. The difference test for more than two sample groups was performed using the ANOVA test for normally distributed data and the Kruskal Wallis test for non-normally distributed data. Results were considered significant if p-value < 0.05
Results
This study involved 90 women, consisting of 30 women who used implants for <1 year, 30 women who used implants for ≥1 year, and 30 women who used IUDs who were registered or visited the Polyclinic of a network hospital in Makassar City. The subjects’ characteristics, including age, socioeconomic status, education, parity, and BMI, did not differ significantly between women who used implants for <1 year, women who used implants for ≥1 year, and women who used IUDs. Therefore, the three groups of women had homogeneous characteristics (Table 1).
There was a significant relationship between implant use for <1 year, implant use for ≥1 year, and IUD use with allopregnanolone levels (Table 2). The average allopregnanolone levels of IUD users were greater than those of implant users for more than or equal to 1 year, and the allopregnanolone levels of implant users for more than or equal to 1 year were greater than those of implant users for less than 1 year. In this study, demographic characteristics such as age, socioeconomic status, education, parity, and BMI were found to have no significant effect on allopregnanolone levels (P >0.05) (Figure 1). The average allopregnolone levels of implant users for less than 1 year were lower than those of implant users for more than or equal to 1 year, but this was not statistically significant. The average allopregnolone levels of implant users for less than 1 year were significantly lower than those of IUD users. The average allopregnolone levels of implant users for more than or equal to 1 year were significantly lower than those of IUD users.
Figure 1. Comparison of allopregnanolone levels between study groups
Notes: LSD Test, Significant if p-value < 0.05.
There was no significant association between implant use for <1 year, implant use for ≥1 year, and IUD use with depression scores (Table 3). The mean depression score of IUD users was greater than that of implant users for more than or equal to 1 year, and the depression score of implant users for more than or equal to 1 year was greater than that of implant users for less than 1 year. The mean depression score of implant users for less than 1 year was lower than that of implant users for more than or equal to 1 year, but this was not statistically significant (Figure 2). The mean depression score of implant users for less than 1 year was lower than that of IUD users, but this was not statistically significant. The mean depression score of implant users for more than or equal to 1 year was lower than that of IUD users, but this was not statistically significant. There was no significant association between allopregnolone levels and depression scores in implant users for less than 1 year, implant users for ≥1 year, or IUD users (Table 4).
Figure 2. Comparison of depression scores between study groups
Description: Mann Whitney test, significant if p-value < 0.05
Discussion
The demographic profile of the participants in this study reflects the general characteristics of long-acting contraceptive users in urban Indonesia. Ninety women aged 20–35 years participated, with the majority coming from the upper-middle socioeconomic group (76.7–93.3%) and having a high school education (46.7–56.7%). This age range represents women in their reproductive years, which aligns with the target population for long-acting reversible contraceptive (LARC) users such as implants and IUDs [13]. The high proportion of primiparas (80–96.7%) is also in line with the trend of postpartum LARC use to space pregnancies, especially among women with one child [14]. The varying distribution of BMI (normal to obese) indicates diversity in participants’ metabolic health status, although no significant differences were found between groups. The predominance of participants from middle to upper socioeconomic groups may reflect limited access to free/affordable contraceptive information and services among women from low socioeconomic backgrounds. A study by Kassie et al. (2022) showed that discontinuation of implant use often occurs among women with financial constraints due to the cost of insertion or removal [15]. However, in this study, homogeneity in socioeconomic status reduced variability in the analysis of the relationship between contraception and depression. Relatively high levels of education (mostly high school graduates) may also have contributed to a better understanding of the benefits and side effects of contraception, as well as the ability to accurately report depressive symptoms [16].
However, demographic limitations of this study should be noted. The lack of socioeconomic diversity limits the generalizability of the findings to women from lower-income backgrounds, who may be more vulnerable to financial stress and its impact on mental health [15]. The absence of nulliparous (childless) participants limits understanding of implant/IUD use in this group, who may have different motivations, such as delaying a first pregnancy. Research by Worly et al. (2018) emphasizes the importance of considering contraceptive preferences based on parity, as the psychosocial needs of nulliparous and multiparous women may differ significantly [17]. For future recommendations, including a more diverse population, including women from rural areas, low-income backgrounds, and nulliparous women, would enhance the external validity of the findings. Longitudinal studies are also needed to monitor demographic changes and their impact on contraceptive satisfaction and mental health. A thorough understanding of the interactions between demographics, contraceptive choices, and mental health is essential for developing inclusive, evidence-based family planning programs.
The results of this study indicate that there were no cases of depression in implant use for less than 1 year, more than or equal to 1 year, and IUD use. The findings of this study are in line with the study by Rapkin et al (2019) which reported that although depression was a side effect in 1% of participants with sufficient severity to require implant removal, the insertion of progestin-only subdermal implant contraceptives was not reported to be associated with depression [18]. A meta-analysis study by Worly, Gur and Schaffir, 2018 also stated that no correlation between depression was found in five studies of progestin subdermal implants [16]. In contrast to this study, research by Aranosn et al (2016) on 5 women who used Norplant implants experienced major depression, two of whom also experienced obsessive-compulsive disorder and one of whom also experienced agoraphobia [19]. The woman had no prior psychiatric history but developed major depression within 1–3 months of Norplant insertion. Although there is a public perception of increased depression after starting progestin-only contraceptives, the evidence largely does not support an association based on validated measures (mostly level II-1 evidence, moderate quality, low risk of bias). Meanwhile, a study by Mu and Kulkarni (2022) reported that progestogen-only contraceptives are more likely to cause depressive disorders in vulnerable women [20].
Depression scores were higher in implant users than in IUD users, possibly due to both systemic effects of the implant and local effects of the IUD. Levonorgestrel (LNG) IUDs were not associated with depression [21]. Meanwhile, the implant has been reported to influence depression [22]. Implanon affects mood and may be associated with depression. Implanon is an implant containing etonogestrel. Each implanon rod consists of an ethylene vinylacetate (EVA) copolymer core containing 68 mg of the synthetic progestin etonogestrel (ENG), surrounded by an EVA copolymer shell [23] It can affects mood because progestogen-only agents, such as etonogestrel in Implanon, can affect neurotransmitter pathways like serotonin, which are important in mood regulation. Furthermore, Implanon can affect the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response. The development of anxiety and mood disorders may be associated with HPA axis dysregulation. The hormonal effects of the implant may also affect neuroendocrine pathways and potentially exacerbate psychiatric symptoms [22].
In this study, allopregnolone levels in implant users, whether implanted for less than 1 year or more than or equal to 1 year, were significantly lower than those using an IUD. Meanwhile, allopregnolone levels in implant users for less than 1 year were lower than those using an implant for more than 1 year, but not significant. These results indicate that the duration of implant use does not affect allopregnolone levels, but implant use results in lower allopregnolone levels than those using an IUD. The mechanism of action of allopregnanolone is not only related to GABA A receptors but also includes effects on neurogenesis and the regulation of the HPA system. Other neurotransmitter systems are also involved. Serotonin, a key neurotransmitter involved in mood regulation, has been shown to modulate the antidepressant effects of allopregnanolone, as well as dopamine and several neurosteroidogenic enzymes [24]. In this study, the decrease in allopregnolone due to the use of implants or IUDs did not affect depression because allopregnolone levels were within normal limits. Normal levels in healthy women across various reproductive cycles are reported to be around 0.5-4.5 nmol/L [24]. In this study, allopregnolone levels in implant users for less than 1 year were 2.33 ± 0.99 nmol/L, in implant users for more than or equal to 1 year were 2.68 ± 1.19 nmol/L and in IUD users were 3.49 ± 1.40 nmol/L.
The main strength of this study lies in its novelty, specifically examining the relationship between duration of contraceptive implant use, allopregnanolone levels, and depressive symptoms. These findings provide an important foundation for understanding the impact of long-term hormonal contraception on neurosteroids and mental health. However, this study has several limitations. The cross-sectional design does not allow for causal conclusions. Confounding factors such as daily stress were not controlled for in the analysis. Furthermore, the findings have limited generalizability because the sample was drawn from only one health service area. This study did not control for environmental and psychosocial factors such as stress, socioeconomic status, and family support, which are known to influence mood and the risk of depression. Therefore, the results may be influenced by unmeasured confounding variables. Future research requires a longitudinal design with a larger sample size and broader coverage, as well as an in-depth study of the mechanisms by which allopregnanolone influences mood.
Conclusion
There was no significant association between allopregnanolone levels and duration of implant use and the incidence of depression. Contraceptive implants and IUDs can be considered safe long-term contraceptive options for women of reproductive age without risk factors for depression, given that no significant differences in depression scores were found between user groups. Future research is recommended to expand the sample size with multi-center recruitment, use a longitudinal design with an adequate follow-up period, consider serial measurements of allopregnanolone levels, and control for potential confounding variables such as stress and sleep disturbances.
Conflict of Interest
The authors declares no conflict of interest.
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