Estetrol (E4): A Comprehensive Monograph on a Novel Native Estrogen

Executive Summary

Estetrol (E4) is a naturally occurring human estrogenic steroid hormone that represents a significant innovation in women's health therapeutics. Produced exclusively by the fetal liver during pregnancy, its unique biological origin formed the basis for its development as a pharmaceutical agent with a potentially superior safety profile.[1] Estetrol is the first compound to be classified as a Native Estrogen with Selective Tissue activity (NEST), a designation stemming from its unique pharmacological mechanism. This mechanism involves the differential modulation of estrogen receptors, specifically uncoupling the activation of nuclear estrogen receptor alpha (ERα), which mediates desired estrogenic effects, from the activation of membrane ERα, which is implicated in adverse effects in tissues such as the breast and liver.[2]

Its primary approved indication is for oral contraception, in a fixed-dose combination with the progestin drospirenone, marketed under brand names including Nextstellis® and Drovelis®.[6] This approval marks the introduction of the first new estrogen for contraceptive use in the United States in over 50 years, offering a novel alternative to formulations based on the long-standing synthetic estrogen, ethinylestradiol.[1]

The clinical profile of Estetrol is characterized by effective contraception, good cycle control, and a favorable safety and tolerability profile. Preclinical and clinical evidence strongly suggests that Estetrol has a minimal impact on hepatic parameters, including coagulation factors and lipid metabolism, providing a strong mechanistic rationale for a potentially lower risk of venous thromboembolism (VTE) compared to traditional estrogen-containing contraceptives.[9] Beyond contraception, Estetrol is under active investigation for menopausal hormone therapy and the treatment of hormone-sensitive cancers, highlighting its potential as a versatile therapeutic agent.

Section 1: Compound Profile and Chemical Properties

1.1. Identification and Nomenclature

To ensure precise identification, Estetrol is cataloged under several international and chemical database identifiers. A comprehensive list of its primary identifiers is provided in Table 1.

• Drug Name: Estetrol [1]
• DrugBank ID: DB12235 [1]
• CAS Number: 15183-37-6 [1]
• Systematic (IUPAC) Name: (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol. An alternative chemical name is Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol.[11]
• Common Synonyms: E4, Oestetrol, 15α-Hydroxyestriol.[2]
• Other Key Identifiers: For cross-referencing in pharmacological and chemical databases, it is also identified as UNII: ENB39R14VF, ChEBI: CHEBI:142773, ChEMBL: CHEMBL1230314, and KEGG: D11513.[1]

1.2. Molecular Structure and Physicochemical Characteristics

The biological activity and pharmacokinetic properties of Estetrol are a direct result of its unique molecular structure and physicochemical characteristics.

• Chemical Formula: C18​H24​O4​ [11]
• Molar Mass / Molecular Weight: The molecular weight is consistently reported as 304.38 to 304.39 g·mol⁻¹.[11]
• Structural Description: Estetrol is a 3-hydroxy steroid hormone derived from a hydride of an estrane core. Its structure is that of 17β-estradiol with two additional hydroxyl groups substituted at the 15α and 16α positions of the steroid D-ring.[1] This tetra-hydroxylated structure is fundamental to its distinct pharmacological properties compared to other natural estrogens like estrone (E1), estradiol (E2), and estriol (E3).
• Physical Properties: In its solid state, Estetrol appears as a white crystal or powder.[16] It has a defined melting point of 244 °C and a water solubility of approximately 1.4 g/L.[16]
• Druglikeness: Estetrol's physicochemical properties align well with established criteria for oral drug candidates. It adheres to Lipinski's Rule-of-Five, with zero rules broken, which predicts good oral absorption and bioavailability, a characteristic confirmed in clinical pharmacokinetic studies.[18]

1.3. Origin and Synthesis

Estetrol's journey from a biological curiosity to a globally approved pharmaceutical is a notable example of leveraging natural human biology for drug development.

• Natural Origin: Estetrol is a native estrogen produced exclusively by the human fetal liver during pregnancy.[1] It is detectable in both fetal and maternal circulation, with fetal plasma levels being significantly higher. After delivery, its levels rapidly become undetectable.[2] The specific physiological function of Estetrol during fetal development remains unknown, and attempts to use it as a marker for fetal well-being were unsuccessful due to high inter-individual variability.[2] The very presence of this hormone in high concentrations during the sensitive period of pregnancy formed the foundational hypothesis for its therapeutic development. The rationale was that a compound endogenous to human pregnancy would likely possess a favorable safety profile for broader human use.[20] This "biologically-informed" approach distinguishes Estetrol from many synthetic hormonal agents.
• Pharmaceutical Sourcing: While naturally occurring, obtaining Estetrol from human sources is not feasible for pharmaceutical production. For medicinal use, it is synthesized from a plant-based starting material, typically a soy-derived phytosterol.[6] The manufacturing process involves a multi-step chemical synthesis, a key reaction being the cis-hydroxylation of a double bond in the steroid D-ring using osmium tetroxide ( OsO4​) to introduce the characteristic 15α and 16α hydroxyl groups.[17] This scalable synthesis process was critical for its development and commercialization.

Table 1: Key Chemical and Physical Identifiers for Estetrol

Property	Value	Source(s)
DrugBank ID	DB12235	1
CAS Number	15183-37-6	1
IUPAC Name	(8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol	11
Common Synonyms	E4, Oestetrol, 15α-Hydroxyestriol	2
UNII	ENB39R14VF	1
Chemical Formula	C18​H24​O4​	11
Molecular Weight	304.38 g·mol⁻¹	13
Appearance	White crystals or powder	16
Melting Point	244 °C	16
Water Solubility	1.4 g/L	16
Lipinski's Rules Broken	0	18

Section 2: Pharmacology and Mechanism of Action

The pharmacological profile of Estetrol is distinct from both natural and synthetic estrogens, underpinning its classification as a novel therapeutic agent. Its mechanism of action at the molecular level explains its unique tissue-selective effects and favorable safety profile.

2.1. Estrogen Receptor (ER) Binding and Selectivity

Estetrol exerts its effects by interacting with the primary biological targets of estrogens, the estrogen receptors.

• Receptor Agonism and Affinity: Estetrol is an agonist of both estrogen receptor-α (ERα) and estrogen receptor-β (ERβ).[6] It demonstrates a moderate binding affinity for these receptors. In vitro binding assays have determined its dissociation constants ( Ki​) to be 4.9 nM for ERα and 19 nM for ERβ, which indicates a 4- to 5-fold binding preference for ERα over ERβ.[2]
• Comparative Potency: The binding affinity of Estetrol for human ERs is significantly lower than that of the primary endogenous estrogen, estradiol (E2), estimated to be approximately 6.25% of E2's affinity.[11] When administered orally to women, Estetrol is approximately 10 to 20 times less potent than ethinylestradiol (EE), the most potent synthetic estrogen used in oral contraceptives.[11] This lower intrinsic potency at the receptor level is a key characteristic.
• High Receptor Selectivity: Estetrol is highly selective for estrogen receptors. At therapeutic concentrations, it shows minimal to no affinity for other steroid hormone receptors, including the androgen, progesterone, and glucocorticoid receptors. Furthermore, it demonstrated no significant interaction with a large panel of 124 other receptors and enzymes.[11] This high degree of selectivity predicts a low risk of undesirable off-target pharmacological effects and associated side effects.

2.2. The NEST Concept: A Unique Tissue-Selective Profile

The most innovative aspect of Estetrol's pharmacology is its tissue-selective activity, which has led to its classification as the first Native Estrogen with Selective Tissue activity (NEST).[2]

• SERM-like but Distinct Mechanism: Estetrol functions as a selective estrogen receptor modulator (SERM), exhibiting different effects in different tissues. However, its molecular mechanism is distinct from that of traditional SERMs like tamoxifen or raloxifene. While classical SERMs interact with the ERα ligand-binding domain in a unique way that recruits a different set of co-regulatory proteins, Estetrol recruits the same co-regulators as other estrogens, such as E2.[2]
• Tissue-Specific Actions:
• Agonist Activity: In tissues such as the vagina, uterus, endometrium, and bone, as well as in the cardiovascular and central nervous systems, Estetrol acts as a potent estrogen agonist.[2] This agonist activity is responsible for its therapeutic effects, including the inhibition of ovulation for contraception and the potential to alleviate menopausal symptoms like vaginal atrophy and prevent bone demineralization.[12]
• Neutral/Antagonistic Activity: In stark contrast, Estetrol demonstrates neutral or even antagonistic (anti-estrogenic) activity in breast tissue and has a minimal impact on the liver.[2] This is the cornerstone of its improved safety profile, as the adverse effects of traditional estrogens, such as increased VTE risk and potential breast cell proliferation, are largely driven by their strong agonistic effects in these tissues.

2.3. Molecular Mechanism: Uncoupling Nuclear and Membrane ERα Activation

The unique tissue-selective profile of Estetrol is explained by a distinctive mode of action at the molecular level, specifically in how it activates ERα.

• Nuclear ERα Activation: Like classical estrogens, Estetrol binds to and activates the ERα located in the cell nucleus. This interaction leads to the recruitment of coactivators (such as SRC3) and initiates gene transcription.[4] This nuclear pathway is responsible for the desired estrogenic effects observed in the uterus, bone, and vasculature. X-ray crystallography studies have confirmed that the overall conformation of the E4-ERα complex is very similar to that of the E2-ERα complex, explaining its ability to effectively activate this pathway.[25]
• Membrane ERα Antagonism/Neutrality: Estrogens also signal through a population of ERα located at the cell membrane, which mediates rapid, non-genomic effects. Unlike E2 and EE, which are strong agonists of both nuclear and membrane ERα, Estetrol induces very limited activity via the membrane ERα pathway in specific tissues, notably the breast. Furthermore, in the presence of estradiol, Estetrol can act as an antagonist of this membrane pathway.[2]
• The Uncoupling Effect: This uncoupling of nuclear (agonist) and membrane (antagonist/neutral) ERα activation is the core molecular mechanism that differentiates Estetrol from all other estrogens.[2] It allows Estetrol to deliver targeted estrogenic effects where they are therapeutically beneficial (via the nuclear pathway) while simultaneously avoiding or actively blocking the signaling pathways in other tissues that are associated with adverse effects. This elegant balance between agonist and antagonist actions across different cellular compartments and tissues resolves the apparent paradox of a "weaker" estrogen at the receptor level being a highly effective and safer clinical agent. It represents a shift from brute-force receptor activation to a more nuanced, precise modulation, achieving "potency with precision."

Table 2: Comparative Pharmacological Profile: Estetrol vs. Estradiol vs. Ethinylestradiol

Pharmacological Parameter	Estetrol (E4)	Estradiol (E2)	Ethinylestradiol (EE)
Relative ERα Affinity (Human)	~6.25% of E2	100% (Reference)	High
ERα/ERβ Selectivity	4- to 5-fold for ERα	Moderate	Varies
Nuclear ERα Activation	Agonist	Agonist	Agonist
Membrane ERα Activation	Neutral / Antagonist	Agonist	Agonist
Effect on Liver (e.g., SHBG Synthesis)	Minimal / Neutral	Moderate (Oral)	Strong
Effect on Breast Tissue	Neutral / Antagonist	Agonist (Proliferative)	Agonist (Proliferative)

Section 3: Pharmacokinetics and Metabolism (ADME)

The pharmacokinetic profile of Estetrol is a critical component of its clinical utility. Its absorption, distribution, metabolism, and elimination (ADME) characteristics are well-suited for a once-daily oral medication and contribute significantly to its favorable safety profile, particularly in how they interact with its pharmacodynamic properties.

3.1. Absorption and Bioavailability

Following oral administration, Estetrol is readily absorbed and becomes systemically available.

• Absorption: Estetrol is rapidly absorbed from the gastrointestinal tract.[1] The time to reach maximum plasma concentration (Tmax) is short, typically occurring between 0.5 and 2 hours after ingestion.[1] In the combination product with drospirenone, peak serum concentrations are achieved within 1 to 3 hours.[6]
• Bioavailability: It demonstrates high oral bioavailability, a key advantage over natural estradiol.[11] For the combination product, the absolute bioavailability is estimated to be between 76% and 85%.[1]
• Steady State: With once-daily dosing, steady-state plasma concentrations are reached within approximately 4 days, with some evidence of slight accumulation between the first dose and steady state.[1]

3.2. Distribution and Protein Binding

The distribution of Estetrol in the body is characterized by a uniquely favorable protein binding profile that distinguishes it from other estrogens.

• Volume of Distribution: Estetrol has demonstrated limited distribution into red blood cells.[1]
• Plasma Protein Binding: Estetrol is moderately bound to plasma proteins, with a bound fraction of 46-50%.[1] This binding is primarily to albumin (58.6%), with only low binding to alpha-1-acid glycoprotein (11.2%).[1]
• Lack of SHBG Binding: A crucial and defining pharmacokinetic feature is that Estetrol does not bind to Sex Hormone-Binding Globulin (SHBG).[1] This is a major point of differentiation from both estradiol and ethinylestradiol, which are extensively bound by SHBG.
• High Free Fraction: The lack of SHBG binding results in an exceptionally high proportion of unbound, pharmacologically active drug in the plasma. The free fraction of Estetrol is approximately 50%, which is dramatically higher than that of estradiol (~2%) and ethinylestradiol (~1%).[2] This high free fraction is a key factor in its clinical efficacy.

3.3. Metabolism

Estetrol's metabolic pathway is simple and avoids the complex and often problematic pathways of other estrogens.

• Primary Metabolic Pathway: Estetrol is primarily metabolized via Phase 2 conjugation reactions, forming glucuronide and sulfate conjugates.[1] These conjugated metabolites have negligible in-vitro estrogenic activity, meaning they are effectively inactive detoxification products.[1]
• Key Metabolizing Enzyme: In vitro studies have identified uridine 5'-diphospho-glucuronosyltransferase 2B7 (UGT2B7) as the dominant enzyme responsible for catalyzing the formation of E4-16-glucuronide, a major metabolite.[1]
• Minimal Cytochrome P450 Interaction: A significant safety advantage of Estetrol is its minimal interaction with the cytochrome P450 (CYP450) enzyme system. Unlike estradiol and ethinylestradiol, Estetrol does not inhibit the major CYP isozymes (including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) even at high concentrations.[11] This suggests a very low potential for clinically significant drug-drug interactions mediated by CYP inhibition.

3.4. Elimination and Half-Life

The elimination profile of Estetrol is characterized by a long half-life, which supports a convenient dosing schedule.

• Route of Elimination: Estetrol and its metabolites are eliminated from the body primarily through the urine (approximately 69% of a dose) and, to a lesser extent, the feces (approximately 22%).[1] It is excreted as its sulfated and glucuronidated derivatives, with some unchanged drug found in the feces.[1]
• Elimination Half-Life: Pharmacokinetic studies have consistently shown that Estetrol has a long terminal elimination half-life, averaging approximately 24 to 28 hours, with a reported range of 19 to 40 hours.[1] This long half-life is a key property that makes it suitable for a once-daily oral dosing regimen.[24]

The pharmacokinetic profile of Estetrol is elegantly suited to its pharmacodynamic properties. While its intrinsic affinity for the estrogen receptor is lower than that of E2 or EE, its ADME characteristics ensure that a high and sustained concentration of active drug is available to interact with those receptors. The combination of high oral bioavailability, a long half-life that maintains stable plasma levels, and a uniquely high free fraction (due to the absence of SHBG binding) effectively compensates for its lower per-molecule potency. This interplay ensures robust and consistent target engagement over a 24-hour dosing interval, leading to reliable clinical efficacy.

Table 3: Summary of Pharmacokinetic Parameters of Estetrol

Parameter	Value	Source(s)
Bioavailability (Oral)	76 - 85% (in combination product)	1
Tmax (Time to Peak Concentration)	0.5 - 2 hours	1
Plasma Protein Binding	46 - 50% (primarily to albumin)	1
SHBG Binding	None	1
Free (Active) Fraction	~50%	2
Primary Metabolic Pathway	Phase 2 Glucuronidation and Sulfation	1
Key Metabolizing Enzyme	UGT2B7	1
Elimination Half-Life	~24 - 28 hours (Range: 19 - 40 hours)	1
Route of Elimination	~69% Urine, ~22% Feces	1

Section 4: Clinical Efficacy in Oral Contraception

The clinical utility of Estetrol has been most robustly established in the field of oral contraception. Its performance in large-scale clinical trials has confirmed its efficacy and characterized its impact on cycle control, leading to its global approval for this indication.

4.1. Pivotal Phase 3 Trials (E4 FREEDOM Program)

The foundation of Estetrol's approval for contraception rests on the results of two large, pivotal Phase 3 clinical trials, collectively known as the E4 FREEDOM program.[28] These were multicenter, open-label, single-arm studies designed to assess the efficacy, safety, and tolerability of a fixed-dose combination tablet containing 14.2 mg Estetrol (equivalent to 15 mg Estetrol monohydrate) and 3 mg drospirenone.

• NCT02817841 (US/Canada Study): This trial was conducted in the United States and Canada, enrolling 2,148 women between the ages of 16 and 50. The study followed participants for up to 13 consecutive 28-day cycles.[28]
• NCT02817828 (EU/Russia Study): This parallel trial was conducted across Europe and Russia, enrolling over 1,550 women aged 18 to 50, also for a duration of 13 cycles.[28]

The primary objective of these studies was to determine the contraceptive efficacy of the combination product, with key secondary objectives focused on evaluating the vaginal bleeding pattern (cycle control) and overall safety and user acceptability.[30]

4.2. Contraceptive Efficacy Analysis

Efficacy was primarily measured using the Pearl Index (PI), a standard metric in contraceptive trials that represents the number of on-treatment pregnancies per 100 woman-years of exposure.[30]

• Overall Efficacy: A pooled analysis of the two E4 FREEDOM trials, which included 3,027 participants in the efficacy cohort, demonstrated high contraceptive effectiveness. The overall pooled PI was 1.52 (95% confidence interval [CI] 1.04–2.16).[34] The corresponding 13-cycle life-table pregnancy rate was 1.28% (95% CI 0.83%–1.73%).[34] The results from the US/Canada study alone showed a PI of 2.65 (95% CI 1.73–3.88) in the subgroup of women aged 16 to 35.[31] These results are well within the range of efficacy expected for modern combined oral contraceptives (COCs).
• Efficacy by Subgroup: The pooled analysis provided important insights into efficacy across different patient populations:
• Body Mass Index (BMI): A key finding, reflected in the product's labeling, is the potential for reduced efficacy in females with a BMI ≥ 30 kg/m².[7] The pooled PI was 1.14 for women with a BMI <25 kg/m², rising to 2.19 for those with a BMI between 25 and 29.9 kg/m², and was higher still in the obese cohort.[34]
• Age: Efficacy was consistent across age groups, with a PI of 1.61 for women aged 16–25 and 1.43 for those aged 26–35.[34]
• Predictors of Contraceptive Failure: A multivariable analysis identified several factors associated with a higher risk of pregnancy. The strongest modifiable predictor was poor compliance (defined as taking <99% of expected pills), which increased the hazard of conception by over four-fold (Hazard Ratio 4.21). Non-modifiable predictors included a history of prior pregnancy (HR 3.61) and Black race (HR 4.61).[34]

These efficacy findings underscore the importance of patient counseling. While the overall effectiveness is high, clinicians must discuss the potential for reduced efficacy in women with a BMI of 30 or higher. Furthermore, the data powerfully reinforces the critical role of patient adherence, as imperfect compliance is the most significant and controllable factor contributing to contraceptive failure.

4.3. Cycle Control and Bleeding Profile

For any COC, the bleeding profile is a critical determinant of patient satisfaction and continuation rates. The Estetrol/drospirenone combination was specifically selected for Phase 3 development based on its superior bleeding pattern in earlier dose-finding studies.[29]

• Scheduled Bleeding: The trials confirmed that the combination provides excellent cycle control, with the majority of users experiencing regular and predictable withdrawal bleeding.[3] In the US/Canada study, between 82.9% and 87.0% of women experienced scheduled bleeding in each cycle. The median duration of this bleeding was a consistent 4.5 days.[31]
• Unscheduled Bleeding (Breakthrough Bleeding and Spotting): Consistent with the experience of other COCs, the incidence of unscheduled bleeding was highest during the first cycle of use, reported by 30.3% of participants. This rate decreased substantially in subsequent cycles, stabilizing at a much lower rate of 15.5% to 19.2% from Cycle 5 onwards.[31] This predictable pattern of improvement is an important point for patient education to encourage persistence through the initial adaptation period.

Table 4: Efficacy Results from Phase 3 E4 FREEDOM Trials (Oral Contraception) - Pooled Analysis

Population / Subgroup	Pearl Index (95% CI)	Source(s)
Overall Population (Aged 16-35)	1.52 (1.04 - 2.16)	34
Age 16-25 Years	1.61 (0.94 - 2.57)	34
Age 26-35 Years	1.43 (0.78 - 2.40)	34
BMI <25 kg/m²	1.14 (0.64 - 1.88)	34
BMI 25 - 29.9 kg/m²	2.19 (1.05 - 4.03)	34
New Starters (No prior hormonal contraception)	1.88 (1.09 - 3.00)	34
Switchers (From prior hormonal contraception)	1.24 (0.68 - 2.08)	34

Section 5: Investigational and Future Therapeutic Applications

While approved for oral contraception, the unique pharmacological profile of Estetrol has prompted extensive investigation into other therapeutic areas, particularly where a safer estrogenic or SERM-like agent is needed. This research pipeline highlights a strategic leveraging of its core NEST mechanism to address unmet needs in women's health and oncology.

5.1. Menopausal Hormone Therapy (MHT)

Estetrol is in late-stage clinical development for the treatment of various symptoms associated with menopause, an indication where long-term safety is paramount.[2]

• Vasomotor Symptoms (VMS): Estetrol has been evaluated for the treatment of moderate to severe VMS, commonly known as hot flushes. Two large Phase 3 trials, the E4Comfort studies (NCT04090957 and NCT04209543), have assessed the efficacy of 15 mg and 20 mg daily doses of Estetrol.[24] The results from these studies have demonstrated that Estetrol significantly reduces both the frequency and severity of VMS compared to placebo.[37]
• Genitourinary Syndrome of Menopause (GSM): Estetrol's potent estrogenic agonist activity on vaginal tissue makes it a promising treatment for GSM, including symptoms like vaginal atrophy. Clinical studies have shown that Estetrol improves vaginal cytology and overall vaginal health, offering relief from this common and bothersome menopausal condition.[12]
• Bone Health and Osteoporosis Prevention: Estetrol has demonstrated clear bone-sparing activity. It has been shown to significantly decrease bone turnover markers, such as osteocalcin and type 1 collagen C-terminal telopeptide.[9] This suggests a potent anti-resorptive effect and a potential role in the prevention of postmenopausal osteoporosis.[12]

The rationale for Estetrol's use in MHT is compelling. Its profile of providing the desired estrogenic benefits for VMS, GSM, and bone health, while having a neutral or antagonistic effect on the breast and a minimal impact on the liver, directly addresses the primary safety concerns that have limited the use of traditional MHT.[12]

5.2. Oncology

Leveraging its SERM-like properties and particularly its anti-proliferative effects in specific tissues, high-dose Estetrol is being investigated as a treatment for hormone-sensitive cancers.

• Breast Cancer: Preclinical data have consistently shown that Estetrol has limited impact on normal breast tissue and can exert anti-proliferative, antagonistic effects on breast cancer cells.[2] Furthermore, studies have suggested that combining Estetrol with a progestogen for MHT or contraception is neutral with respect to breast cancer growth and metastasis.[39] This has led to its investigation for the treatment of advanced, estrogen receptor-positive breast cancer.[11]
• Prostate Cancer: Estetrol has also been studied in men. The Phase 2 PCombi study investigated its use in patients with advanced prostate cancer receiving androgen deprivation therapy (ADT). The study found that Estetrol was effective in preventing the debilitating hot flushes that are a common side effect of ADT, thereby improving patient quality of life.[12] High-dose Estetrol continues to be developed for this indication.[11]

5.3. Other Potential Indications

The therapeutic potential of Estetrol may extend to other areas of women's health.

• Female Sexual Arousal Disorder: A Phase 2 clinical trial (NCT06308614) is currently active and investigating the efficacy of Estetrol for the treatment of female sexual arousal disorder in postmenopausal women, suggesting a potential role in addressing hypoactive sexual desire disorder.[12]
• Neonatal Encephalopathy: Estetrol has received a positive orphan drug designation from the European Medicines Agency (EMA) for the treatment of neonatal encephalopathy.[1] This indication likely stems from its natural role as a fetal hormone, although the specific mechanism and development status are not fully detailed in the available information.

Section 6: Comprehensive Safety and Tolerability Profile

The safety profile of Estetrol is a central element of its value proposition, with a mechanistic basis for potential advantages over existing estrogens, particularly ethinylestradiol. Clinical trial data have established its general tolerability, while ongoing research aims to confirm its long-term safety benefits.

6.1. Common Adverse Events

In the large Phase 3 trials for oral contraception, the adverse events reported for the Estetrol/drospirenone combination were generally consistent with those known for other COCs.[41]

• Most Frequent Reactions: The most commonly reported adverse events (AEs) include:
• Irregular bleeding (metrorrhagia/spotting)
• Mood disturbance
• Headache
• Breast symptoms (pain, tenderness, discomfort)
• Dysmenorrhea (painful periods)
• Acne
• Weight gain
• Decreased libido [7]
• Discontinuation Rates: The overall rate of discontinuation due to AEs was low. In the US/Canada study, 7.1% of women discontinued early for an AE. The most common specific reasons for discontinuation were bleeding irregularities like metrorrhagia (0.9%) and menorrhagia (0.8%).[31]

6.2. In-Depth Risk Profile Analysis

Beyond common side effects, the evaluation of Estetrol has focused on serious risks associated with hormonal therapy.

• Venous Thromboembolism (VTE): VTE is the most serious risk associated with COC use. The increased risk is largely attributed to the potent hepatic effects of ethinylestradiol, which alters the balance of pro-coagulant and anti-coagulant factors, creating a pro-thrombotic state.[9] Estetrol offers a compelling mechanistic rationale for a lower VTE risk:
• Minimal Hepatic Impact: As established, Estetrol has a minimal impact on the liver. It causes significantly less pronounced changes in hepatic proteins, including coagulation factors, SHBG, and angiotensinogen, compared to EE-containing products.[2] This reduced effect on the hemostatic system is expected to translate into a lower VTE risk.[10] No thromboembolic events were reported during the US/Canada Phase 3 trial.[31]
• Ongoing Surveillance: While the mechanistic data is strong, definitive clinical confirmation requires large-scale epidemiological data. The International Active Surveillance Study: Safety of Estrogen Estetrol (INAS-SEECS) is a major ongoing prospective study designed to compare the real-world VTE risk of Estetrol/drospirenone with that of standard EE/levonorgestrel COCs. The study aims to enroll approximately 101,000 women and is powered to demonstrate non-inferiority, which will be crucial in establishing Estetrol's long-term safety profile.[47]
• Metabolic and Hepatic Profile: Estetrol/drospirenone has demonstrated a favorable metabolic profile. It has a limited effect on lipid profiles, with minimal impact on triglycerides, and no effect on carbohydrate metabolism or glucose tolerance.[3] This contrasts with EE, which can have more significant metabolic effects.[48]
• Effects on Breast Tissue: The unique NEST mechanism of Estetrol, involving antagonism of membrane ERα, suggests a superior breast safety profile. Preclinical data indicate neutral or even anti-proliferative effects on breast tissue, which is a significant departure from the known proliferative effects of E2 and EE.[2]
• Hyperkalemia: The drospirenone component of the combination product is a spironolactone analogue with anti-mineralocorticoid properties, which can lead to potassium retention. This creates a risk of hyperkalemia, particularly in patients with renal impairment or those taking other medications that can increase serum potassium (e.g., ACE inhibitors, NSAIDs). Therefore, monitoring of serum potassium is recommended for at-risk individuals during the first treatment cycle.[7]

The development of Estetrol represents a fundamental shift in the strategy for improving hormonal contraceptive safety. For decades, the primary approach was to incrementally lower the dose of the potent, non-selective estrogen, ethinylestradiol. Estetrol's introduction reflects a move toward "molecular redesign"—replacing EE with a novel molecule that is inherently designed, through its tissue-selective mechanism, to be less impactful on the physiological systems (hepatic, hemostatic) that mediate the most serious adverse events. The results of the INAS-SEECS study will be the ultimate test of whether this innovative, mechanism-based approach translates into a clinically meaningful reduction in real-world VTE risk.

6.3. Contraindications, Warnings, and Precautions

The Estetrol/drospirenone combination shares many of the contraindications and warnings applicable to all combined hormonal contraceptives (CHCs).

• Boxed Warning: The product carries an FDA boxed warning regarding cigarette smoking and serious cardiovascular events. It is contraindicated in females over 35 years of age who smoke.[7]
• Absolute Contraindications: Use is contraindicated in individuals with:
• A high risk of, or existing, arterial or venous thrombotic/thromboembolic diseases (e.g., history of DVT, pulmonary embolism, stroke, myocardial infarction).[42]
• Known or suspected hormone-sensitive malignancies, such as breast cancer.[49]
• Severe liver disease or liver tumors (benign or malignant).[49]
• Undiagnosed abnormal uterine bleeding.[7]
• Renal impairment or adrenal insufficiency (due to the drospirenone component).[7]
• Warnings and Precautions: Other significant warnings include the risk of hypertension, new or worsening migraine with aura, gallbladder disease, hypertriglyceridemia, and depression.[7]

Table 5: Summary of Common Adverse Events (≥2% incidence) from Clinical Trials

Adverse Event	Incidence Rate (%)	Source(s)
Metrorrhagia (Irregular Bleeding)	4.6%	31
Headache	5.0%	31
Breast Symptoms (Pain, Tenderness, etc.)	>2% (not specified)	7
Dysmenorrhea (Painful Periods)	>2% (not specified)	7
Acne	>2% (not specified)	7
Weight Increased	>2% (not specified)	7
Libido Decreased	>2% (not specified)	7
Mood Disturbance	>2% (not specified)	7

Section 7: Drug-Drug Interactions

The potential for drug-drug interactions with the Estetrol/drospirenone combination is an important consideration for safe prescribing. The majority of clinically significant interactions are driven by the well-characterized pharmacokinetic and pharmacodynamic properties of the drospirenone component, rather than the novel Estetrol component.

7.1. Pharmacokinetic Interactions

These interactions primarily affect the plasma concentrations of the contraceptive hormones, which can impact efficacy and safety.

• Interactions Affecting the Drospirenone Component: Drospirenone is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme.[27]
• CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g., anticonvulsants like carbamazepine and phenytoin; antibiotics like rifampin; and the herbal supplement St. John's wort) can significantly increase the metabolism of drospirenone. This leads to lower plasma concentrations of the progestin and potentially Estetrol, which can result in decreased contraceptive efficacy and an increased risk of breakthrough bleeding. Co-administration should be avoided, or a reliable back-up, non-hormonal contraceptive method should be used during and for 28 days after discontinuation of the inducer.[7]
• CYP3A4 Inhibitors: Strong CYP3A4 inhibitors (e.g., azole antifungals like ketoconazole; protease inhibitors like ritonavir) may decrease the metabolism of drospirenone, leading to increased systemic exposure and a potentially higher risk of adverse effects.[27]
• Interactions Affecting the Estetrol Component: As noted previously, Estetrol has a very low potential for pharmacokinetic interactions because it is not significantly metabolized by the CYP450 system.[11] Its metabolism is primarily via UGT enzymes, and while interactions are theoretically possible, they are less clinically prominent than the CYP3A4-mediated interactions involving drospirenone.

7.2. Pharmacodynamic Interactions

These interactions involve the combined physiological effects of the drugs rather than changes in their concentrations.

• Drugs that Increase Serum Potassium: This is the most significant pharmacodynamic interaction. Due to the anti-mineralocorticoid activity of drospirenone, there is an increased risk of developing hyperkalemia when the contraceptive is co-administered with other drugs that can also raise serum potassium levels. This includes:
• ACE inhibitors (e.g., lisinopril)
• Angiotensin-II receptor antagonists (ARBs, e.g., losartan)
• Potassium-sparing diuretics (e.g., spironolactone)
• Non-steroidal anti-inflammatory drugs (NSAIDs) used long-term
• Heparin
• Aldosterone antagonists.[6]

For women at increased risk of hyperkalemia, monitoring of serum potassium during the first treatment cycle is recommended.7

• Other Clinically Relevant Interactions:
• Antidiabetic Agents: The estrogen component may cause a degree of glucose intolerance. Therefore, women with diabetes may require increased monitoring of their blood glucose levels and potential adjustment of their antidiabetic medication dosage.[27]
• Thyroid Hormone Replacement Therapy: Estrogens can increase the serum concentration of thyroxine-binding globulin (TBG). Women on thyroid hormone replacement therapy may require an increased dose of their medication to maintain therapeutic free thyroxine levels.[27]

The interaction profile of the combination product is largely predictable based on the known properties of drospirenone. The novel estrogen, Estetrol, contributes minimally to the risk of drug-drug interactions due to its favorable metabolic profile. This allows clinicians to apply their existing knowledge of drospirenone-related interactions when prescribing this new contraceptive option.

Table 6: Major Drug-Drug Interactions for the Estetrol/Drospirenone Combination

Interacting Drug Class / Agent	Potential Outcome	Clinical Management Recommendation
Strong CYP3A4 Inducers (e.g., Carbamazepine, Rifampin, St. John's Wort)	Decreased contraceptive efficacy; Increased breakthrough bleeding	Avoid concomitant use. If unavoidable, use a back-up non-hormonal contraceptive method during and for 28 days after discontinuation.
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Itraconazole)	Increased drospirenone exposure and potential for adverse effects	Use with caution.
Potassium-Increasing Agents (e.g., ACE inhibitors, ARBs, NSAIDs, Potassium-sparing diuretics)	Increased risk of hyperkalemia	Monitor serum potassium during the first treatment cycle in at-risk patients.
Antidiabetic Drugs (e.g., Metformin, Insulin)	Potential for reduced efficacy of antidiabetic drug	Monitor blood glucose levels more frequently, especially during initiation. Adjust antidiabetic drug dosage as needed.
Thyroid Hormone Replacement (e.g., Levothyroxine)	Increased requirement for thyroid hormone	Monitor thyroid function. Increase thyroid hormone replacement dose as needed.

Section 8: Regulatory and Development History

The journey of Estetrol from its discovery as a fetal hormone to its approval as a component of a modern contraceptive is a testament to long-term vision in pharmaceutical development. Its regulatory approvals across the globe mark a significant milestone in women's health.

8.1. Timeline of Development

• Discovery (1965): Estetrol was first identified as a natural human estrogen present in the urine of pregnant women by the endocrinologist Egon Diczfalusy at the Karolinska Institute in Stockholm.[3] For decades, it remained a biological curiosity with no known physiological function.
• Modern Development (2000-Present): The therapeutic potential of Estetrol was first seriously explored at the turn of the millennium. In 2000, Herjan Coelingh Bennink founded the biotechnology company Pantarhei Bioscience with the specific goal of developing this fetal estrogen for clinical use in oral contraception and menopausal hormone therapy.[20] The company conducted the initial preclinical and Phase 1/2 clinical studies that characterized its unique properties. In 2015, the Estetrol portfolio was acquired by Mithra Pharmaceuticals, a Belgian biotech company, which undertook the final, large-scale Phase 3 development and spearheaded the global commercialization efforts.[8]

8.2. Global Regulatory Approvals

The year 2021 was pivotal for Estetrol, with near-simultaneous approvals from major regulatory agencies worldwide. This rapid succession of approvals underscores the strength and consistency of the clinical data package from the E4 FREEDOM program.

• Significance: The approval of the Estetrol/drospirenone combination represents the first introduction of a new estrogen in the United States in over 50 years and the first approved Estetrol-containing product anywhere in the world.[1]
• Health Canada: Canada was the first country to grant approval. The combination was approved in March 2021 under the brand name Nextstellis.[1]
• U.S. Food and Drug Administration (FDA): The FDA approved the combination in April 2021, also under the brand name Nextstellis.[1]
• European Medicines Agency (EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in March 2021, the European Commission granted marketing authorization in May 2021. In Europe, it is marketed under brand names including Drovelis® and Lydisilka®.[20]
• Australian Therapeutic Goods Administration (TGA): The TGA approved the combination in November 2021 under the brand name Nextstellis.[53] The TGA's decision was based on a comprehensive review of quality, nonclinical, and clinical data, which concluded a favorable benefit-risk profile. As part of its approval, the TGA mandated post-marketing safety monitoring, including inclusion in the Black Triangle Scheme for five years to encourage reporting of any adverse events.[56]

This coordinated global launch reflects a broad international regulatory consensus on the drug's efficacy and acceptable safety profile, establishing it as a new therapeutic option for women worldwide.

Section 9: Expert Analysis and Conclusion

9.1. Synthesis of Evidence

Estetrol (E4) is a novel therapeutic agent that represents a significant and thoughtfully designed advancement in the field of hormonal therapy. Its development was predicated on a sound biological hypothesis: that a natural estrogen produced by the human fetus during pregnancy would possess an inherently favorable safety profile. The evidence accumulated to date largely supports this premise.

The defining characteristic of Estetrol is its unique pharmacology as a Native Estrogen with Selective Tissue activity (NEST). At the molecular level, this is driven by its ability to uncouple nuclear and membrane ERα activation, allowing it to exert desired estrogenic effects in target tissues (e.g., suppressing ovulation) while remaining neutral or even antagonistic in tissues associated with adverse outcomes, such as the breast and liver. This tissue selectivity is the foundation of its improved benefit-risk profile.

This unique pharmacodynamic profile is complemented by a near-ideal pharmacokinetic profile for an oral drug. Its long elimination half-life, high oral bioavailability, and, most critically, its lack of binding to SHBG result in a high and sustained level of free, active drug. This ensures robust clinical efficacy, as demonstrated in the large-scale E4 FREEDOM trials, which confirmed high contraceptive effectiveness and good cycle control.

9.2. Positioning and Future Outlook

The introduction of the Estetrol/drospirenone combination marks an evolution in contraceptive development. It moves beyond the decades-long strategy of simply reducing the dose of ethinylestradiol and instead introduces a fundamentally different estrogen molecule designed for greater safety. It offers women and clinicians a new, effective, and well-tolerated option for oral contraception that has a demonstrably lower impact on metabolic and hemostatic parameters compared to EE-containing products.

The ultimate place of Estetrol in the therapeutic armamentarium will be determined by long-term, real-world safety data. The ongoing INAS-SEECS post-marketing surveillance study is of paramount importance. If this large-scale study confirms the mechanistic promise of a clinically significant reduction in VTE risk compared to standard COCs, Estetrol could justifiably become the estrogen of choice for first-line hormonal contraception.

Beyond contraception, the future for Estetrol appears bright. Its investigational pipeline in menopausal hormone therapy and oncology is a logical extension of its core pharmacology. It has the potential to become a versatile platform molecule, addressing unmet needs in various areas of women's health and beyond where a safer, tissue-selective estrogenic or anti-estrogenic agent is required. In conclusion, Estetrol is not merely a new drug, but a new class of estrogen, whose full therapeutic potential is only beginning to be realized.

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