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levonorgestrel (Norplant)

✓ Approved

Takeda · PGR · Small Molecule

What is levonorgestrel?

levonorgestrel is a small molecule developed by Takeda. It is approved for therapeutic indications via surgical implantation.

Drug Profile

Brand NamesNorplant
CompanyTakeda
Drug ClassSmall Molecule
Molecular TargetPGR
RouteSurgical Implantation
StatusApproved
Sources: ClinicalTrials.gov, Takeda

Mechanism of Action

Molecular Targets

levonorgestrel acts on 1 molecular target:

PGRprogesterone receptor (NR3C3, PR)
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Related Research Articles

PubMedInternational journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group2026-11-09

Comparison of direct versus hysteroscopy-assisted levonorgestrel intrauterine system placement after high-intensity focused ultrasound ablation for adenomyosis: a retrospective cohort study.

Ding Kun K, Tian Chengzi C, Zhu Qiaoling Q, Sang Changmei C et al.

To compare LNG-IUS stability, clinical outcomes, and safety after direct versus hysteroscopy-assisted placement following high-intensity focused ultrasound (HIFU) ablation for adenomyosis. This single-center retrospective cohort study included 229 premenopausal patients with adenomyosis who underwent HIFU ablation and attempted LNG-IUS placement (direct, n = 135; hysteroscopy-assisted, n = 94). Post-placement outcomes were evaluated among patients with successful first-attempt placement and included LNG-IUS-related events, treatment continuation, symptom scores, lesion volume, and adverse events. Event-free survival was analyzed using Kaplan-Meier and Cox regression, with propensity score matching as a sensitivity analysis. First-attempt placement succeeded in 135 of 135 direct and 91 of 94 hysteroscopy-assisted patients. LNG-IUS-related events were less frequent with hysteroscopy-assisted placement (7.69% vs. 25.93%; p < 0.001), and treatment continuation at last follow-up was higher (92.31% vs. 74.07%; p < 0.001). Event risk remained lower with hysteroscopy-assisted placement before and after adjustment (HR = 0.393, 95% CI 0.173-0.891, p = 0.025; adjusted HR = 0.396, 95% CI 0.158-0.996, p = 0.049). Propensity score matching showed a similar but less precise association (HR = 0.265, 95% CI 0.070-1.002; p = 0.050). Symptom scores and lesion volume decreased in both groups, with no significant between-group difference in adverse events. Hysteroscopy-assisted LNG-IUS placement after HIFU may be associated with fewer displacement or expulsion events and a higher rate of treatment continuation than direct placement. Symptom improvement and recorded adverse events were similar between groups. It may be considered for selected patients with suspected residual intrauterine necrotic tissue or unfavorable uterine cavity conditions.

PMID 43000706
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PubMedResearch square2026-11-08

Safe Placement of a Micro-Electromechanical Systems (MEMS), Levonorgestrel Releasing Contraceptive: Cadaver and Porcine Studies.

Proos Elizabeth E, Kalish Jeffrey J, Carmine Brian J BJ, Pacelli Nicolas N et al.

In order to develop safe insertion criteria for future clinical studies of a levonorgestrel (LNG) releasing, wirelessly enabled micro-electromechanical system (MEMS)-based drug delivery device, we performed two pre-clinical studies in cadaver arms and pigs. Four female cadaver upper arms were dissected to assess the proposed insertion location, spatial orientation, and proximity to major muscle and neurovascular anatomy. Eight additional cadaver arms were dissected to assess insertion variables (incision depth, width, length, pocket creation). Twenty-four placebo MEMS devices were inserted sub-dermally into the backs of four miniature Yucatan pigs (6 devices per pig). Over a 2-to-4-month postoperative period, wound healing, device migration, and clinical observations were recorded. At removal, tissue capsule quality and tissue adhesions were evaluated. The target medial upper arm insertion site was 8-10 cm proximal to the medial epicondyle toward the axilla and 4-6 cm posterior to the brachial groove. Target insertion width (20 mm), depth (4 mm), and pocket length (51 mm) were defined. Porcine insertions were completed over 6-11 minutes with minimal bleeding. All sites healed well with no device migration over 2-4 months. After removal, tissue capsules were well formed and consistent with the expected normal healing response to a foreign body. These studies confirm the feasibility of safe insertion of the LNG MEMS device in the upper arm and a normal healing response to the device materials in live porcine tissue.

PMID 42996289
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PubMedOpen access journal of contraception2026-11-03

Impact of Hormonal Contraceptive Exposure on Pancreatic β-Cell Adaptation and Glucose Homeostasis: A Systematic Review.

Niyomugabo Aime Patrick AP, Onaadepo Olufunke O, Ntakirutimana Leopold L, Birhanie Muluken Walle MW et al.

Hormonal contraceptives (HCs) modulate endocrine and metabolic function. Some formulations have been associated with reduced insulin sensitivity, increasing the functional demand on pancreatic β-cells. This systematic review synthesised evidence on pancreatic β-cell adaptation to HC exposure. In accordance with PRISMA 2020, PubMed, Scopus and Wiley Online Library were searched for records published from January 2000 to December 2025, combining terms for β-cell function and adaptation with terms for hormonal contraceptives and for glucose homeostasis and insulin resistance. Eligible studies were original investigations in humans and rodents examining β-cell structural, functional or signalling adaptation to HC exposure, with a comparison group or pre-exposure baseline. Risk of bias was assessed by design using RoB 2, NIH and Newcastle-Ottawa criteria, SYRCLE, and adapted in vitro indicators. Findings were synthesised thematically. Of 502 records identified, seven studies met the criteria: four human, two rodent in vivo and one isolated islet study. In women, ethinylestradiol with norgestimate improved insulin sensitivity in lean participants but reduced it in those with obesity; a drospirenone-containing pill raised HOMA-IR; an oral levonorgestrel preparation reduced insulin sensitivity more than an etonogestrel vaginal ring, with β-cell function unaltered by either; and androgenic formulations amplified postprandial glucose and insulin responses despite unchanged fasting values. In rodents, drospirenone-containing exposure produced hyperinsulinemia with preserved glucose tolerance, attributable to enhanced secretory activity and reduced insulin clearance; levonorgestrel impaired glucose tolerance and raised HOMA-IR, HOMA-β and circulating corticosterone. In isolated rat islets, gestodene metabolites increased insulin and glucokinase expression and glucose-stimulated insulin secretion via oestrogen receptor-dependent pathways. Effects of HC on glucose metabolism and β-cell function appear to depend on progestin composition, route of administration and pre-existing metabolic status. Longitudinal human studies using direct measures of secretory capacity are needed to establish whether compensatory capacity is sustained under continued exposure.

PMID 42974476
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PubMedResearch and practice in thrombosis and haemostasis2026-10-31

Signal of venous thromboembolism with ethinyl estradiol vs natural estrogens in oral contraceptives: analysis of the EudraVigilance and Food and Drug Administration Adverse Events Reporting System databases.

Raskin Lucie L, Didembourg Marie M, Locquet Médéa M, Morimont Laure L et al.

Disproportionality analyses in the Food and Drug Administration Adverse Events Reporting System (FAERS) and EudraVigilance reported lower reporting of venous thromboembolism (VTE) with natural estrogen-based combined oral contraceptives (COCs) than with ethinylestradiol/levonorgestrel. However, using ethinylestradiol/levonorgestrel as the reference showed reduced reporting only for natural estrogen-based products. We therefore reanalyzed both databases separately, using natural estrogen-based COCs as the reference. Previously extracted individual case safety report datasets and published disproportionality analyses were re-examined, using natural estrogen-based contraceptives as the comparator. Proportional reporting ratios (PRRs) were recalculated separately for each database. COCs were categorized as ethinylestradiol-based or natural estrogen-based formulations. Drospirenone-only pills were included for comparison. Analyses used pooled natural estrogen contraceptives, estetrol/drospirenone, or estradiol/dienogest as reference groups. Disproportionality was defined as PRR >2, at least 3 cases, and χ2 ≥ 4. Consistent patterns were observed in EudraVigilance and FAERS. Compared with natural estrogen-based COCs, ethinylestradiol-based COCs showed a disproportionate reporting of VTE (EudraVigilance: PRR, 5.10 [95% CI, 4.68-5.56]; FAERS: PRR, 4.21 [95% CI, 3.49-5.08]). In EudraVigilance, when using estetrol/drospirenone as the reference, all ethinylestradiol-based formulations showed disproportionality according to the conventional PRR threshold. A similar trend was noted in FAERS, though not statistically significant, with the drospirenone-only formulation comparable to estetrol/drospirenone. This analysis revealed a consistent and disproportionate reporting of VTE associated with ethinylestradiol-based COCs compared with natural estrogen-based alternatives across 2 pharmacovigilance databases. These results, together with prior biological and observational research, support further reevaluation of COC options given the estrogenic component's potential influence on VTE risk.

PMID 42965049
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PubMedReproductive health2026-10-31

Long-acting reversible contraceptive use in postpartum and postabortion adolescents: initiation, predictors, and continuation outcomes.

Sangvornrungsie Paparnin P, Panichyawat Nalinee N, Wongwananuruk Thanyarat T, Parkpinyo Nichamon N et al.

Adolescent pregnancy remains a significant global public health issue. Thailand enacted the Act on Prevention and Solution to the Adolescent Pregnancy Problem and implemented a public health policy that provides free long-acting reversible contraceptives (LARCs) access to adolescents. At our institution, a structured, adolescent-focused protocol was developed to improve contraceptive counselling and access for postpartum and postabortion adolescents. This study aimed to determine the LARC initiation rate following implementation of this practice. Continuation rates and factors associated with LARC initiation and early discontinuation were also analyzed. This retrospective study was conducted at a tertiary referral university hospital. Thai adolescents aged under 20 years at the time of delivery or abortion at our hospital were included. Demographic and clinical data were collected, including selected contraceptive method, LARC insertion and removal dates, and follow-up data for up to 36 months. Independent sample t-tests, Mann-Whitney U tests and chi-square tests were used as appropriated. The primary outcome was reported as frequency and percentages. Kaplan-Meier survival analysis assessed continuation rates, while logistic regression and Cox proportional hazards models identified factors associated with initiation and early discontinuation (defined as LARC removal before 3 years), respectively. Of 1,081 postpartum and post-abortion adolescents, 839 (77.6%) participants initiated LARC. Of these, 91.7% initiated LARC before hospital discharge. The most commonly chosen methods were the 2-rod levonorgestrel implant (44.2%) and the 1-rod etonogestrel implant (32.9%), while 0.6% chose the copper intrauterine device. Significant factors of LARC initiation included younger maternal age (adjusted odds ratio [aOR] 0.598; 95% CI: 0.518-0.691; p < 0.001), being employed (aOR 2.233; 95% CI: 1.050-4.751; p = 0.037), and younger partner age (aOR 0.966; 95% CI: 0.935-0.998; p = 0.035). The cumulative LARC continuation rates were 98.1% at 1 year, 93.0% at 2 years, and 79.7% at 3 years. The most commonly reasons for early removal were bleeding disturbances (40.7%), weight changes (18.5%) and desire for pregnancy (13.0%). Thailand's health policy of free LARC access, combined with a tailored structured adolescent protocol, resulted in high LARC initiation and continuation rates, demonstrating the effectiveness of integrated clinical and policy interventions in reducing adolescent pregnancy.

PMID 42963789
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PubMedAntimicrobial agents and chemotherapy2026-10-28

An open-label, Phase 1 study to evaluate the drug-drug interaction between ulonivirine and the combined oral contraceptive levonorgestrel/ethinyl estradiol in female participants without HIV.

Robinson Makeda M, Gillespie Gillian G, Kandala Bhargava B, Ankrom Wendy W et al.

Ulonivirine is a non-nucleoside reverse transcriptase inhibitor in development as an oral, once-weekly treatment for HIV-1 in combination with investigational islatravir. The effect of ulonivirine on the pharmacokinetics of an oral contraceptive, levonorgestrel (LNG)/ethinyl estradiol (EE) was evaluated in females without HIV. In this Phase 1 study (MK-8507-009), postmenopausal or oophorectomized females received a single dose of LNG/EE (0.1 mg/0.02 mg), followed by a 5-day washout period. Participants then received ulonivirine 400 mg once-weekly for 3 weeks, and LNG/EE was co-administered with the third dose. Blood samples were collected for pharmacokinetics analysis. Safety and tolerability were monitored by clinical and laboratory assessments. Twenty adults (90% White; 100% Hispanic or Latina) were enrolled (median age, 56 years; range, 47-66 years). Two participants discontinued for reasons considered unrelated to ulonivirine. The geometric mean ratios ([LNG/EE + ulonivirine]/[LNG/EE]; 90% CI) for plasma AUC0-inf of LNG and EE were 0.88 (0.84-0.93) and 0.85 (0.82-0.89). Maximum plasma concentration of LNG and EE decreased (26% and 20%, respectively) with LNG/EE + ulonivirine versus LNG/EE alone. Ulonivirine pharmacokinetics were similar for LNG/EE + ulonivirine and LNG/EE alone. Four participants (20%) experienced ≥1 adverse event: 2 (10%) after administration of LNG/EE alone and 2 (10.5%) after co-administration of LNG/EE + ulonivirine. All adverse events were mild and considered unrelated to study intervention. Co-administration of ulonivirine 400 mg once-weekly with a single dose of LNG/EE had no clinically meaningful effect on the pharmacokinetics of LNG or EE in females without HIV and was generally well tolerated.

PMID 42949629
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