Dienogest (DB09123): A Comprehensive Monograph on its Chemistry, Pharmacology, and Clinical Applications

I. Executive Summary

Dienogest is a fourth-generation, orally active synthetic progestin that has established a significant role in modern gynecological therapy. It is distinguished by a unique "hybrid" pharmacological profile that combines the potent endometrial effects characteristic of 19-nortestosterone derivatives with the favorable antiandrogenic properties of progesterone derivatives.[1] This profile is a direct result of its novel chemical structure, which features a 17α-cyanomethyl group in place of the more common 17α-ethinyl group, conferring high metabolic stability and a distinct spectrum of activity.[1]

The primary mechanism of action of dienogest is its function as a selective agonist of the progesterone receptor (PR). Despite a relatively weak in-vitro binding affinity, it exerts a powerful progestogenic effect in vivo, particularly on the endometrium, leading to tissue decidualization and subsequent atrophy of endometriotic lesions.[4] This is complemented by moderate antigonadotropic activity, which suppresses ovulation and modestly reduces endogenous estradiol levels, and a clinically validated antiandrogenic effect that is beneficial in treating conditions like acne.[2] Crucially, dienogest demonstrates high selectivity, with negligible activity at estrogen, glucocorticoid, or mineralocorticoid receptors, thereby minimizing off-target hormonal side effects.[8]

Dienogest's principal therapeutic applications are in the management of endometriosis, where it is used as a monotherapy (2 mg daily), and in hormonal contraception and the treatment of heavy menstrual bleeding (menorrhagia), where it is formulated in combination with estrogens.[4] Clinical evidence has firmly established its efficacy in reducing endometriosis-associated pelvic pain, with a performance non-inferior to that of gonadotropin-releasing hormone (GnRH) agonists.[3] However, its key advantage lies in a superior long-term safety and tolerability profile. By maintaining estradiol levels within a low-physiological "therapeutic window," dienogest avoids the severe hypoestrogenic side effects, such as significant bone mineral density loss, that limit the extended use of GnRH agonists.[5]

The safety profile of dienogest is well-characterized and generally favorable. The most common adverse effects include changes in menstrual bleeding patterns, headache, and breast tenderness, which are typically mild and diminish over time.[12] Clinicians must be aware of its metabolism via the cytochrome P450 3A4 (CYP3A4) enzyme, which creates a potential for significant drug-drug interactions with enzyme inducers and inhibitors.[6] The global regulatory landscape for dienogest is notably divergent, with approval as a standalone endometriosis treatment in Europe, Japan, and other regions, but availability in the United States is limited to combination oral contraceptive products.[4] This comprehensive report details the chemical, pharmacological, clinical, and regulatory aspects of dienogest, providing an exhaustive reference for healthcare professionals and researchers.

II. Chemical Profile and Formulation

A. Identification and Nomenclature

Dienogest is a well-characterized small molecule with a distinct steroid hormone structure. Its identity is defined by a comprehensive set of chemical names and identifiers that ensure its unambiguous recognition in scientific, clinical, and regulatory contexts.

• Chemical Name (IUPAC): The systematic IUPAC name for dienogest is 2-phenanthren-17-yl]acetonitrile.[4] Alternative systematic names, such as (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile, are also used and reflect its steroidal backbone.[16]
• Common Name: The universally accepted non-proprietary name is Dienogest.[4]
• Synonyms and Code Names: During its development and in various research contexts, dienogest has been referred to by several synonyms and code names, including STS 557, dienogestril, endometrion, M 18575, and ZK 37659.[1]
• Chemical Classification: Dienogest is classified as a fourth-generation, orally-active, semisynthetic progestogen.[5] It is structurally a derivative of 19-nortestosterone, but its unique 17α-cyanomethyl substituent gives it properties characteristic of 17α-hydroxyprogesterone derivatives as well.[1] This non-ethinylated structure distinguishes it from many other synthetic progestins and contributes to its unique metabolic and safety profile.[1]
• Key Identifiers: A consolidated list of key identifiers is presented in Table 1.

B. Physicochemical Properties

The physical and chemical properties of dienogest dictate its stability, solubility, and suitability for oral formulation.

• Molecular Formula and Weight: The empirical formula of dienogest is C20​H25​NO2​, with a corresponding molecular weight of approximately 311.42 g/mol.[16]
• Physical State and Appearance: Under standard conditions, dienogest is a solid, appearing as a white to almost white crystalline powder.[16]
• Solubility: It is practically insoluble in water but demonstrates slight solubility in organic solvents such as methanol and acetone. It is soluble in dimethyl sulfoxide (DMSO) up to a concentration of 100 mM, making it suitable for in vitro experimental use.[16]
• Melting Point: The melting point of dienogest ranges from 213.0 °C to 217.0 °C.[16]
• Stability and Storage: Dienogest is a stable compound, with a shelf life of at least four years when stored under appropriate conditions.[8] It is considered heat-sensitive and should be stored under desiccating conditions.[16] For long-term preservation, refrigerated temperatures (0-10°C) or freezing (-20°C) are recommended.[16]

C. Available Formulations and Brand Names

Dienogest is available globally in several formulations, both as a single agent and in combination with estrogens, with availability varying by country and approved indication.

• Monotherapy for Endometriosis:
• The primary formulation for endometriosis is a 2 mg oral tablet intended for once-daily continuous use.[4]
• It is marketed internationally under the primary brand name Visanne. Other trade names include Dinagest, Visabelle, Alondra, Disven, and Visannette.[4] These monotherapy formulations are widely available in Europe, Japan, Australia, and Canada but are not approved or marketed in the United States.[4]
• Combination Oral Contraceptives (COCs):
• With Estradiol Valerate (Quadriphasic): This formulation is designed to mimic the natural menstrual cycle more closely. It is marketed as Natazia in the United States and Qlaira in Europe and Russia.[4] These products contain a 28-day regimen with tablets of varying doses of dienogest (2 mg or 3 mg) and estradiol valerate (1 mg, 2 mg, or 3 mg).[4]
• With Ethinylestradiol (Monophasic): A common formulation, particularly in Europe, combines 2 mg of dienogest with 30 µg of ethinylestradiol.[4] It is available under numerous brand names, including Valette, Jeanine, Sienima, Mistra, Diecyclen, and Paoletta.[4]
• Menopausal Hormone Therapy:
• In select countries, such as Germany and the Netherlands, dienogest is available in combination with 1 or 2 mg of estradiol valerate for the management of menopausal symptoms.[4]

Table 1: Key Identifiers and Physicochemical Properties of Dienogest

Category	Identifier / Property	Value / Description	Source(s)
Identifiers	DrugBank ID	DB09123	4
	CAS Number	65928-58-7	4
	UNII	46M3EV8HHE	4
	PubChem CID	68861	4
	IUPAC Name	2-phenanthren-17-yl]acetonitrile	4
Chemical Properties	Molecular Formula	C20​H25​NO2​	16
	Molecular Weight	311.42 g/mol	19
Physical Properties	Physical State	Solid	16
	Appearance	White to almost white powder or crystal	16
	Melting Point	213.0 – 217.0 °C	16
	Solubility	Insoluble in water; slightly soluble in methanol, acetone; soluble in DMSO	16
Storage	Recommended Conditions	Refrigerated (0-10°C) or frozen (-20°C); protect from heat; store under desiccating conditions	16

III. Comprehensive Pharmacological Profile

A. Pharmacodynamics: Mechanism of Action

The clinical utility of dienogest is rooted in its highly specific and multi-faceted pharmacodynamic profile. It acts as a selective progestin with a unique combination of activities that are particularly well-suited for the management of estrogen-dependent gynecological disorders.

1. Progesterone Receptor (PR) Selectivity and "Hybrid" Activity

Dienogest's primary molecular target is the progesterone receptor (PR), for which it is a selective agonist.[8] A notable characteristic is the apparent discrepancy between its in vitro receptor affinity and its in vivo potency. In human uterine tissue, its binding affinity for the PR is only about 10% of that of natural progesterone.[4] Despite this, it demonstrates exceptionally potent progestogenic effects in vivo, particularly on the endometrium.[4] This high oral potency is explained by its favorable pharmacokinetic profile, which allows for sustained, effective concentrations at the target tissue.[9]

The molecule is often described as a "hybrid progestin".[1] This term reflects its ability to combine the potent endometrial effects typical of 19-nortestosterone derivatives with the beneficial antiandrogenic properties more commonly associated with progesterone derivatives like cyproterone acetate.[1] This unique profile is largely attributed to a key structural modification: the presence of a C17α-cyanomethyl group instead of the 17α-ethinyl group found in many other synthetic progestins.[1] The ethinyl group is known to confer high oral activity but can also be associated with certain metabolic and toxicological liabilities; its absence in dienogest contributes to the drug's favorable tolerability.[2]

A cornerstone of its safety profile is its high receptor selectivity. Transactivation assays have confirmed that dienogest has negligible binding affinity for and no agonistic or antagonistic activity at estrogen receptors (ERα and ERβ), the glucocorticoid receptor (GR), or the mineralocorticoid receptor (MR).[4] This high degree of specificity ensures that its clinical effects are almost exclusively mediated through the PR and androgen receptor (AR), thereby minimizing the undesirable estrogenic, glucocorticoid, or mineralocorticoid side effects that can complicate therapy with less selective steroids.[2]

2. Antigonadotropic and Antiandrogenic Effects

Beyond its direct action on the endometrium, dienogest exerts systemic effects on the hypothalamic-pituitary-ovarian axis and on androgen signaling.

• Antigonadotropic Effects: Dienogest produces a moderate inhibition of gonadotropin secretion from the pituitary gland, leading to a modest reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.[3] This, in turn, suppresses ovarian follicle development and ovulation, and modestly lowers the endogenous production of estradiol.[10] A daily dose of 2 mg is sufficient to effectively suppress ovarian activity.[7] However, this suppression is not absolute. Estradiol levels are typically maintained within a low-physiological range, often cited as the "therapeutic window" of 30-50 pg/mL.[5] This is a critical distinction from GnRH agonists, which induce a state of profound hypoestrogenism. By avoiding complete estrogen deprivation, dienogest effectively manages the estrogen-dependent growth of endometriotic lesions without causing severe menopausal side effects, such as significant bone mineral density loss, making it suitable for long-term therapy.[5]
• Antiandrogenic Activity: Dienogest possesses clinically significant antiandrogenic activity, estimated to be about one-third as potent as that of the strong antiandrogen cyproterone acetate.[5] It functions as a direct antagonist at the androgen receptor (AR).[6] A key feature contributing to its favorable androgenic profile is its lack of binding to sex hormone-binding globulin (SHBG).[5] Some other progestins derived from 19-nortestosterone can displace testosterone from SHBG, thereby increasing the level of free, biologically active testosterone and causing androgenic side effects like acne and hirsutism. Dienogest does not do this, and its direct AR antagonism means it can actively improve such symptoms, a property leveraged in its use in combined oral contraceptives for the treatment of acne.[1]

3. Cellular and Molecular Effects on Endometrial Tissue

Dienogest exerts a multi-pronged attack on endometriotic tissue through direct cellular and molecular mechanisms.

• Antiproliferative Effects: It directly inhibits the proliferation of both eutopic (normal) and ectopic (endometriotic) endometrial cells.[1] Studies on human endometrial epithelial cell lines have shown that this effect is mediated, at least in part, by the significant downregulation of cyclin D1 gene expression, a key regulator of the cell cycle.[18] This suppression of cell division is fundamental to halting the growth of endometriotic lesions.
• Induction of Atrophy: Continuous administration of dienogest creates a local endocrine environment that is strongly progestogenic and moderately hypoestrogenic.[3] This hormonal milieu first induces a process called decidualization, a transformation of the endometrial tissue into a state resembling the uterine lining of pregnancy.[6] With sustained exposure, this decidualized tissue becomes metabolically unsupported and undergoes atrophy, leading to the shrinkage and regression of endometriotic lesions.[3]
• Anti-inflammatory and Anti-angiogenic Effects: Endometriosis is characterized by chronic inflammation and the formation of new blood vessels (angiogenesis) that supply the ectopic lesions. Dienogest has been shown to counteract these processes.[3] It modulates the expression of key enzymes involved in inflammation and estrogen production within the lesions, such as matrix metalloproteinases and aromatase.[3] Furthermore, one study has elucidated a novel mechanism whereby dienogest enhances autophagy (a cellular self-cleaning process) in endometriotic cells by impairing the activation of critical pro-survival signaling pathways, including AKT, ERK1/2, and mTOR.[22] This combination of effects—halting proliferation, starving lesions of their blood supply, reducing inflammation, and promoting cellular degradation—collectively contributes to its high efficacy in treating endometriosis.

B. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of dienogest is characterized by high oral bioavailability, rapid absorption, a short half-life that prevents accumulation, and efficient metabolism, all of which contribute to its clinical efficacy and favorable tolerability.

1. Absorption and Bioavailability

Dienogest is rapidly and almost completely absorbed following oral administration.[1] It demonstrates a very high absolute bioavailability of approximately 91%, which is superior to many other progestins.[6] This high bioavailability is attributed to its excellent metabolic stability and the absence of a significant first-pass effect in the liver, a common hurdle for orally administered steroid hormones.[1] Peak plasma concentrations (

Cmax​) are typically reached within 1.5 hours of ingestion.[6] The pharmacokinetics of dienogest are linear and dose-proportional within the clinically relevant range of 1–8 mg, meaning that an increase in dose results in a predictable and proportional increase in plasma concentration.[1]

2. Distribution

Once absorbed, dienogest is distributed throughout the body with an apparent volume of distribution (Vd​/F) of 40 L.[6] In the bloodstream, approximately 90% of circulating dienogest is non-specifically bound to serum albumin.[1] The remaining 10% circulates as a free, unbound steroid, which represents the biologically active fraction of the drug.[5] As previously noted, a critical feature of its distribution is its lack of binding to specific transport proteins like SHBG or corticoid-binding globulin (CBG).[5] This prevents the displacement of endogenous hormones like testosterone and cortisol from these carriers, further contributing to its clean side-effect profile.

3. Metabolism

Dienogest undergoes complete metabolism before excretion, primarily through pathways mediated by the cytochrome P450 3A4 (CYP3A4) isoenzyme in the liver.[5] The main metabolic reactions are hydroxylation and subsequent conjugation.[4] The resulting metabolites are pharmacologically inactive and are cleared rapidly from the plasma, meaning they do not contribute to the drug's therapeutic effect or its side effects.[6] The chemical stability of the 17α-cyanomethyl group is a key feature; unlike the 17α-ethinyl group of other progestins, it does not appear to form reactive intermediaries during metabolism, which may explain its excellent hepatic tolerability and lack of interference with certain liver enzyme functions.[1]

4. Excretion and Elimination Half-Life

Dienogest has a relatively short terminal elimination half-life, typically ranging from 7.5 to 12.2 hours depending on the study population.[1] This pharmacokinetic property is clinically advantageous as it prevents drug accumulation with once-daily dosing and ensures that the drug is well-controllable.[1] The inactive metabolites are excreted primarily via the kidneys into the urine, with a smaller fraction eliminated through the feces; the ratio of renal to fecal elimination is approximately 3:1.[6] The majority of an administered dose is excreted within the first 24 hours, consistent with its rapid metabolism and clearance.[7]

Table 2: Summary of Key Pharmacokinetic Parameters of Dienogest

Parameter	Value / Description	Source(s)
Bioavailability (Oral)	~91%	1
Time to Peak Plasma Concentration (Tmax​)	~1.5 hours	6
Peak Plasma Concentration (Cmax​)	47 ng/mL (after 2 mg single dose)	6
Elimination Half-life (t1/2​)	7.5 – 12.2 hours	1
Volume of Distribution (Vd​/F)	40 L	6
Plasma Protein Binding	~90% (to albumin); 10% free	1
	No binding to SHBG or CBG	5
Primary Metabolic Pathway	Hepatic hydroxylation and conjugation via CYP3A4	5
Primary Route of Excretion	Renal (~75%) and Fecal (~25%) as inactive metabolites	6

IV. Clinical Efficacy and Therapeutic Applications

A. Management of Endometriosis

Dienogest, administered as a 2 mg once-daily oral tablet, is a cornerstone of the medical management of endometriosis. Its efficacy has been rigorously established through extensive clinical development programs conducted primarily in Europe and Japan, which included dose-ranging, placebo-controlled, active comparator-controlled, and long-term extension studies.[10]

1. Pivotal Clinical Trials and Efficacy in Pain Reduction

The primary therapeutic goal in endometriosis management is the alleviation of pain. Consequently, the primary endpoint in modern pivotal trials for endometriosis treatments has shifted from the anatomical reduction of lesions to the clinically more relevant outcome of reducing endometriosis-associated pelvic pain (EAPP).[34] This is quantitatively assessed using a 100-mm Visual Analogue Scale (VAS), a validated and reliable tool for measuring subjective pain intensity.[3]

Placebo-controlled, randomized trials have consistently demonstrated the superiority of dienogest over placebo. In a pivotal 24-week study, women treated with dienogest 2 mg daily experienced a mean reduction in EAPP score that was significantly greater than that observed in the placebo group.[3] This finding is supported by other trials and a meta-analysis, which confirmed a statistically significant and clinically meaningful reduction in VAS scores for pelvic pain with dienogest compared to placebo.[10] A key secondary outcome in these trials was the intake of supportive analgesic medication (SAM), such as ibuprofen. Patients receiving dienogest showed a marked decrease in their need for SAM, whereas those on placebo reported a slight increase, further underscoring the analgesic efficacy of dienogest.[3]

2. Comparative Efficacy: Dienogest vs. GnRH Agonists

Gonadotropin-releasing hormone (GnRH) agonists have long been considered a reference standard for the medical treatment of endometriosis due to their profound suppression of ovarian estrogen production. Multiple head-to-head clinical trials have been conducted to compare the efficacy of dienogest with this established class of drugs. The consistent finding from these studies is that dienogest 2 mg daily is as effective as (non-inferior to) standard doses of GnRH agonists like leuprolide acetate, buserelin, and triptorelin in reducing EAPP.[3]

A landmark 24-week, randomized, open-label trial by Strowitzki et al. directly compared dienogest with depot leuprolide acetate.[3] The study demonstrated non-inferiority, with mean absolute reductions in VAS scores from baseline of 47.5 mm in the dienogest group and 46.0 mm in the leuprolide acetate group.[5] While the pain-relieving efficacy was equivalent, dienogest demonstrated a significantly more favorable safety and tolerability profile. The moderate suppression of estrogen by dienogest contrasts sharply with the severe hypoestrogenism induced by GnRH agonists, resulting in fewer and less severe menopausal side effects and, most importantly, a significantly smaller impact on bone mineral density (BMD).[3] This superior long-term safety profile makes dienogest a more suitable option for the chronic management of endometriosis.

3. Long-Term Treatment, Quality of Life, and Recurrence Prevention

Endometriosis is a chronic condition that requires long-term management. Clinical studies extending for up to 5 years have shown that the efficacy of dienogest is sustained over time.[12] It is effective in preventing the recurrence of both symptoms and endometriotic lesions after conservative surgery, a common challenge in endometriosis care.[12]

Beyond pain relief, treatment with dienogest leads to significant improvements in health-related quality of life (HRQoL). Patients report enhancements across multiple domains, including physical functioning, mental health, social engagement, and emotional well-being.[10] Studies have also documented improvements in sexual functioning, including a higher frequency of sexual intercourse, which can be severely impacted by endometriosis symptoms like dyspareunia.[12]

Table 3: Overview of Key Clinical Trials of Dienogest for Endometriosis

Trial Identifier / Reference	Phase & Design	Patient Population & Size (N)	Treatment Arms	Duration	Primary Endpoint	Key Efficacy Result
Strowitzki et al., 2010; NCT00225186 3	Phase III, Randomized, Open-Label, Active Comparator	Women with confirmed endometriosis (N=252)	Dienogest 2 mg/day vs. Leuprolide Acetate 3.75 mg depot q4w	24 weeks	Change in EAPP VAS score from baseline	Non-inferiority demonstrated. Mean VAS reduction: 47.5 mm (Dienogest) vs. 46.0 mm (Leuprolide Acetate).
Harada et al., 2009 3	Phase III, Randomized, Double-Blind, Active Comparator	Women with confirmed endometriosis (N=271)	Dienogest 2 mg/day vs. Buserelin Acetate 900 µg/day (nasal)	24 weeks	Change in symptom scores (e.g., pelvic pain, dysmenorrhea)	Dienogest showed comparable efficacy to buserelin in reducing symptoms, but with significantly less reduction in BMD.
Strowitzki et al., 2010; NCT01822080 3	Phase III, Randomized, Double-Blind, Placebo-Controlled	Women with confirmed endometriosis and EAPP ≥30 mm (N=198)	Dienogest 2 mg/day vs. Placebo	12 weeks	Change in EAPP VAS score from baseline	Dienogest was significantly superior to placebo in reducing EAPP (Mean difference: -12.5 mm).
Köhler et al., 2010; Pooled Analysis 13	Pooled analysis of four European RCTs	Women with confirmed endometriosis (N=332 on Dienogest)	Dienogest 2 mg/day vs. Placebo or LA	Up to 65 weeks	Safety and Tolerability	Confirmed favorable long-term safety profile; efficacy in pain reduction was sustained.

B. Hormonal Contraception (Combination Formulations)

Dienogest is a key component in modern combined oral contraceptives (COCs), where its potent progestogenic and antiandrogenic properties are highly valued.

• Quadriphasic Regimen (Natazia/Qlaira): In the United States and Europe, dienogest is combined with estradiol valerate, a pro-drug of natural estradiol, in a unique four-phasic dosing regimen.[4] Marketed as Natazia (U.S.) and Qlaira (Europe), this formulation was designed to provide effective contraception while improving cycle control and bleeding patterns compared to earlier estradiol-based pills.[28] The regimen features an estrogen step-down and a progestin step-up over 26 days of active tablets, followed by two placebo days.[28] It is approved by the FDA for the prevention of pregnancy.[4]
• Monophasic Regimen (Valette, etc.): In Europe, a more conventional monophasic COC combines 2 mg of dienogest with 30 µg of ethinylestradiol.[4] Marketed under numerous brand names such as Valette, this combination has been shown in clinical studies to be a highly reliable ovulation inhibitor, providing contraceptive efficacy comparable to other low-dose COCs while also offering benefits for skin and hair due to dienogest's antiandrogenic activity.[29]

C. Treatment of Heavy Menstrual Bleeding (Menorrhagia)

The combination of dienogest and estradiol valerate (Natazia) holds a specific FDA approval for the treatment of heavy menstrual bleeding (HMB) in women without underlying organic pathology who choose to use an oral contraceptive for birth control.[4] The potent progestogenic effect of dienogest on the endometrium leads to significant thinning and stabilization of the uterine lining, which in turn reduces the volume and duration of menstrual blood loss.[27] Patient reviews and clinical experience indicate a high degree of satisfaction with this treatment, with many users reporting a transformation from debilitatingly heavy periods to light, manageable, and less painful bleeding.[43]

D. Investigational and Off-Label Uses

The unique properties of dienogest have prompted investigation into its use for other gynecological conditions.

• Adenomyosis: Several studies have explored the use of dienogest for adenomyosis, a condition where endometrial tissue grows into the uterine muscle wall. The available evidence suggests that dienogest is effective in alleviating the primary symptoms of adenomyosis, including pelvic pain and heavy menstrual bleeding, and may also reduce uterine volume.[47]
• Uterine Fibroids (Leiomyomas): The role of dienogest in managing uterine fibroids is complex and not well-established. The available evidence is conflicting and points to a need for caution. A clinical trial (NCT01738724) designed to evaluate its efficacy was initiated but subsequently terminated before completion.[49] While one study in premenopausal women suggested some clinical benefit in controlling bleeding and reducing uterine volume [51], a more recent and detailed retrospective analysis by Zhang et al. yielded concerning results. This study found that while dienogest was effective for treating co-existing endometriosis pain in patients who also had fibroids, its use was associated with a statistically significant increase in the maximum diameter and volume of the uterine fibroids over a 12-month period.[47]

This paradoxical effect underscores the principle of tissue-specific hormone receptor action. The pathophysiology of uterine fibroids involves both estrogen and progesterone receptors, and progesterone signaling is known to be a key driver of fibroid growth. Therefore, while the potent PR agonism of dienogest induces therapeutic atrophy in endometrial and endometriotic tissue, it may simultaneously act as a proliferative stimulus for PR-positive fibroid tissue. This finding suggests that the off-label use of dienogest in patients with known uterine fibroids, particularly where fibroid growth is a concern, is not advisable without further prospective, controlled data. This represents a critical nuance for prescribing clinicians, highlighting that a drug's effect cannot be generalized across different hormone-sensitive tissues, even within the same organ.

V. Safety and Tolerability Profile

Dienogest is generally well-tolerated, particularly in the context of long-term use for endometriosis, where its safety profile compares favorably to other hormonal therapies like GnRH agonists. Its adverse effects are primarily related to its progestogenic activity.

A. Adverse Drug Reactions (ADRs)

• Common ADRs (≥1% to <10%): The most frequently reported adverse drug reactions are consistent with the effects of progestogens on the endocrine system and target tissues. These include:
• Menstrual Irregularities: Changes in bleeding patterns are the most common side effect, especially during the first few months of therapy. This can manifest as spotting, breakthrough bleeding, amenorrhea, or irregular cycles.[4] While frequent, these changes are generally well-tolerated, with bleeding intensity and frequency tending to decrease over time, and very low rates of discontinuation due to bleeding events.[13]
• General and Neurological: Headache and migraine are common.[13]
• Reproductive System: Breast discomfort, pain, or tenderness are frequently reported.[4]
• Psychiatric: Depressed mood, nervousness, and loss of libido may occur.[12]
• Gastrointestinal and Metabolic: Nausea and weight gain are also common.[4]
• Dermatological: Acne can occur due to the hormonal shifts.[4]

These events are typically of mild-to-moderate intensity.12

• Serious ADRs (Rare): When dienogest is used in combination with an estrogen component, there is an established, albeit low, risk of serious cardiovascular events. These include venous and arterial thromboembolism (VTE and ATE), such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke.[26] The risk is significantly elevated in women with pre-existing risk factors, most notably in those who smoke and are over 35 years of age.[55] Rare but serious liver problems, including benign or malignant liver tumors and jaundice, are also associated with hormonal steroid use.[55]

Table 4: Common and Serious Adverse Drug Reactions Associated with Dienogest

System Organ Class	Common (≥1% to <10%)	Uncommon (≥0.1% to <1%)	Rare (<0.1%) / Serious
Nervous System	Headache, Migraine 14	Dizziness, Disturbance in attention 53	Stroke (ATE), Paresthesia 53
Psychiatric Disorders	Depressed mood, Sleep disorder, Nervousness, Loss of libido 14	Anxiety, Mood swings 56	-
Reproductive System & Breast	Breast discomfort/pain/tenderness, Menstrual irregularities (spotting, amenorrhea, metrorrhagia) 14	Ovarian cyst, Vulvovaginal dryness, Vaginal discharge 53	Breast cancer, Uterine cancer 4
Gastrointestinal	Nausea, Abdominal pain 53	Diarrhea, Constipation, Vomiting 53	-
Skin & Subcutaneous Tissue	Acne, Alopecia 14	Dry skin, Hyperhidrosis, Pruritus 53	Chloasma, Angioedema, Erythema nodosum 53
Metabolism & Nutrition	Weight increased 14	Edema, Weight decreased 53	-
Cardiovascular	-	Hypertension, Phlebitis 53	Venous Thromboembolism (DVT, PE), Arterial Thromboembolism (MI) 53
General Disorders	Asthenic conditions (fatigue) 53	Pyrexia, Peripheral edema 53	Malaise, Chest pain 53

B. Contraindications and High-Risk Populations

The use of dienogest is contraindicated in certain patient populations where the risks are deemed to outweigh the potential benefits.

• Absolute Contraindications: These include active venous thromboembolic disorder; a history of arterial or cardiovascular disease (e.g., myocardial infarction, stroke); diabetes mellitus with vascular complications; presence or history of severe hepatic disease or liver tumors; known or suspected hormone-dependent malignancies (e.g., breast cancer); and undiagnosed abnormal vaginal bleeding.[4] Dienogest is also contraindicated in known or suspected pregnancy and during lactation.[58]
• High-Risk Populations: Caution should be exercised when prescribing dienogest to women with a history of depression, as mood changes are a known side effect.[26] Patients with controlled hypertension, dyslipidemia, gallbladder disease, or obesity should also be monitored closely, as these conditions may be exacerbated.[43] The risk of serious cardiovascular events with combination products is substantially increased in women over 35 who smoke, and this combination of risk factors is a strong relative contraindication.[55]

C. Warnings and Precautions

• Bone Mineral Density (BMD) in Adolescents: A significant precaution relates to the use of dienogest in adolescents (ages 12-18). Treatment has been associated with a loss or plateauing of BMD.[14] Since adolescence is a critical period for bone mass accretion, this effect is of particular concern. The bone loss may not be completely reversible after discontinuation of treatment.[14] Therefore, the decision to use dienogest in this population requires a careful risk-benefit assessment for each individual patient, weighing the severity of endometriosis symptoms against the potential long-term impact on peak bone mass and future osteoporosis risk.[12]
• Depression: Patients with a history of depression should be carefully monitored. If significant depression recurs, the drug should be discontinued.[14]
• Liver Function: As with other steroid hormones, treatment should be discontinued if jaundice or other signs of severe liver dysfunction develop.[55]
• GHS Hazard Classification: In non-clinical settings (e.g., research, manufacturing), dienogest is classified under the Globally Harmonized System (GHS) with hazard codes such as H361 ("Suspected of damaging fertility or the unborn child"), corresponding to Reproductive Toxicity Category 2.[11]

D. Drug and Food Interactions

Dienogest's metabolism via CYP3A4 makes it susceptible to clinically significant drug and food interactions.

• CYP3A4 Inducers: Co-administration with strong inducers of the CYP3A4 enzyme can dramatically accelerate the metabolism of dienogest, leading to lower plasma concentrations and potentially diminished efficacy.[14] This can result in treatment failure, manifesting as a return of endometriosis pain or, in the case of COCs, breakthrough bleeding and unintended pregnancy. Clinically important inducers include certain anticonvulsants (e.g., phenytoin, carbamazepine, primidone), the antibiotic rifampicin, and the herbal supplement St. John's wort ( Hypericum perforatum).[14] The interaction can be profound; for example, co-administration with rifampicin was shown to decrease the systemic exposure (AUC) of dienogest at steady state by 83%.[14] Concomitant use with strong inducers should be avoided, or alternative/additional non-hormonal methods of contraception should be used.[14]
• CYP3A4 Inhibitors: Conversely, strong inhibitors of CYP3A4 can decrease the metabolic clearance of dienogest, leading to higher plasma concentrations and an increased risk of side effects.[31] Examples include azole antifungals (e.g., ketoconazole, itraconazole), some HIV protease inhibitors, and macrolide antibiotics like erythromycin.[31]
• Other Interactions: For combination products containing estrogen, the efficacy may be reduced by broad-spectrum antibiotics that alter the gut flora, potentially interfering with the enterohepatic recirculation of the estrogen component.[28]
• Food Interactions: Grapefruit and grapefruit juice are potent inhibitors of intestinal CYP3A4. Their consumption can increase the bioavailability and plasma concentrations of dienogest and should be avoided during treatment to prevent an increased risk of adverse effects.[59]

Table 5: Clinically Significant Drug-Drug and Drug-Food Interactions

Interacting Agent/Class	Examples	Mechanism of Interaction	Clinical Consequence & Management
CYP3A4 Inducers	Rifampicin, Carbamazepine, Phenytoin, Phenobarbital, St. John's wort 14	Induction of hepatic and/or intestinal CYP3A4, leading to increased metabolic clearance of dienogest.	Decreased plasma levels and reduced efficacy of dienogest. Risk of treatment failure (pain recurrence, breakthrough bleeding, unintended pregnancy). Avoid concomitant use or use additional non-hormonal contraception. 14
CYP3A4 Inhibitors (Strong)	Ketoconazole, Itraconazole, Ritonavir 31	Inhibition of CYP3A4-mediated metabolism of dienogest.	Increased plasma concentrations of dienogest and potential for increased incidence or severity of adverse effects. Use with caution and monitor for side effects. 31
Broad-Spectrum Antibiotics	Amoxicillin, Ampicillin, Tetracyclines 28	(Theoretical) Alteration of intestinal flora, potentially disrupting the enterohepatic recirculation of the estrogen component in COCs.	Potential for reduced contraceptive efficacy. While the clinical significance is debated, advising a back-up contraceptive method during and shortly after antibiotic use is a prudent measure. 28
Food	Grapefruit, Grapefruit Juice 59	Inhibition of intestinal CYP3A4 by furanocoumarins present in grapefruit.	Increased oral bioavailability and plasma concentrations of dienogest, leading to a higher risk of adverse effects. Patients should be advised to avoid consumption. 64

VI. Dosage and Administration

The recommended dosage and administration of dienogest vary depending on the indication and whether it is used as a monotherapy or in a combination product.

A. Endometriosis

For the management of pelvic pain associated with endometriosis, the standard and approved dosage is one 2 mg tablet taken orally once daily.[23] Adherence to a continuous regimen is critical for efficacy.

• Administration Schedule: Tablets must be taken continuously, without any pill-free interval, even during menstrual bleeding.[23] When one blister pack is finished, the next pack should be started on the following day without interruption.[59]
• Timing: The tablet should be taken at approximately the same time each day to maintain stable plasma concentrations.[23] It can be taken with or without food.[59]
• Initiation of Therapy: Treatment can be initiated on any day of the menstrual cycle.[59]
• Missed Doses: If a dose is missed, or if vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet (compromising absorption), the missed tablet should be taken as soon as remembered, and the next tablet should be taken at the usual time. The efficacy of dienogest may be reduced in these instances.[23]

B. Contraception and Heavy Menstrual Bleeding (Natazia/Qlaira)

When used for contraception and/or the treatment of heavy menstrual bleeding, dienogest is part of a combination product with estradiol valerate (Natazia/Qlaira) that follows a complex, multi-phasic 28-day schedule. Strict adherence to the prescribed order of tablets is essential for efficacy.[28]

• Administration Schedule: One tablet is taken orally at the same time each day in the precise order indicated on the blister pack.[28] The 28-day cycle includes tablets with different hormone combinations and placebo tablets:
• Days 1-2: Estradiol valerate 3 mg
• Days 3-7: Estradiol valerate 2 mg and dienogest 2 mg
• Days 8-24: Estradiol valerate 2 mg and dienogest 3 mg
• Days 25-26: Estradiol valerate 1 mg
• Days 27-28: Inert (placebo) tablets [4]
• Initiation and Back-up Contraception: When starting this regimen for the first time or switching from certain other methods, a non-hormonal back-up method of contraception (e.g., condoms) is required for the first 9 consecutive days to ensure contraceptive protection.[28]
• Missed Doses: The instructions for managing missed doses are complex and depend on which day of the cycle the tablet was missed. Patients should be advised to consult the product labeling or their healthcare provider for specific guidance, as missing tablets, particularly in the middle of the cycle, significantly increases the risk of pregnancy.[66]

VII. Regulatory Status and History

The global regulatory journey of dienogest has been multifaceted, leading to a notable divergence in its approved indications and availability between major markets like the United States and the European Union. This reflects distinct clinical development programs and market-specific regulatory strategies pursued by the manufacturer.

A. United States Food and Drug Administration (FDA)

In the United States, dienogest is not approved or available as a standalone medication for any indication.[4] Its entry into the U.S. market was exclusively as a component of a combination oral contraceptive.

• Initial Approval: Dienogest was considered a New Molecular Entity (NME) in the U.S. at the time of its first approval. On May 6, 2010, the FDA approved Natazia, an oral contraceptive containing a quadriphasic combination of estradiol valerate and dienogest, under New Drug Application (NDA) 022252, submitted by Bayer HealthCare Pharmaceuticals.[15]
• Additional Indication: On March 15, 2012, the FDA expanded the approved indications for Natazia to include the treatment of heavy menstrual bleeding (menorrhagia) in women without organic pathology who choose to use an oral contraceptive as their method of contraception.[15]

The strategic decision to introduce dienogest to the U.S. market within a novel combination product for contraception, rather than as a monotherapy for endometriosis, has had a lasting impact on its clinical use. American physicians wishing to use dienogest for endometriosis must do so in an off-label manner, prescribing a combination contraceptive, which may not be ideal for all patients and can create challenges with insurance coverage and clinical guidelines.

B. European Medicines Agency (EMA) and National Authorisations

In contrast to the U.S., the regulatory pathway in Europe and other regions has focused heavily on dienogest as a primary treatment for endometriosis.

• Endometriosis Approval: Dienogest 2 mg, under the brand name Visanne, first received marketing authorisation for the treatment of endometriosis in Europe around 2010.[12] The approval was granted based on a robust clinical development program specifically designed to demonstrate its efficacy and safety in this indication.[10] This has established Visanne as a first-line medical therapy for endometriosis in the European Union, Japan, Australia, Canada, and numerous other countries.[10] European Public Assessment Reports (PARs) for Visanne and its subsequent generic versions confirm this regulatory history and provide detailed scientific discussion of the data supporting its approval.[69]
• Contraception Approval: Combination products containing dienogest have a long history in Europe. Formulations combining 2 mg of dienogest with 30 µg of ethinylestradiol (e.g., Valette) have been authorised for contraception via national procedures in many EU member states for over two decades.[71] The quadriphasic combination with estradiol valerate (Qlaira) is also widely approved for contraception.[4]
• Acne Indication: In 2016, a referral was initiated to review the use of dienogest/ethinylestradiol combinations for the treatment of acne.[72] In 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that these medicines are effective for moderate acne. However, balancing this benefit against the known, albeit low, risk of VTE associated with all COCs, the EMA recommended restricting its use for acne to a second-line therapy. Specifically, it should only be used after topical treatments or oral antibiotics have failed, and only in women who have already chosen to use an oral contraceptive for birth control.[71]

The separate and distinct regulatory approvals in Europe have solidified dienogest's position as a targeted, evidence-based treatment for endometriosis, a status it does not officially hold in the United States. This divergence illustrates how regulatory and marketing strategies can shape the clinical landscape and create different standards of care in different parts of the world for the same active substance.

VIII. Conclusion and Future Perspectives

Dienogest has emerged as a pivotal therapeutic agent in gynecology, distinguished by a meticulously tailored pharmacological profile that addresses key unmet needs in the management of endometriosis and other hormone-dependent conditions. As a fourth-generation, selective progestin, its unique chemical structure confers a combination of potent endometrial efficacy, moderate antigonadotropic action, and beneficial antiandrogenic properties, all while maintaining a high degree of receptor selectivity that minimizes off-target effects.

Its most significant contribution is in the long-term management of endometriosis. The body of clinical evidence robustly supports its efficacy in alleviating pelvic pain, with a performance comparable to the historical gold standard of GnRH agonists. Its defining advantage, however, is its superior long-term tolerability. By inducing only a moderate reduction in estrogen levels—maintaining them within a "therapeutic window"—dienogest effectively controls the disease without subjecting patients to the severe hypoestrogenic side effects that limit the chronic use of GnRH agonists. This has positioned dienogest as a first-line, sustainable medical therapy for a chronic, debilitating disease. In its combination formulations, it serves as a highly effective oral contraceptive with the validated, value-added benefit of treating heavy menstrual bleeding, thereby addressing two common and significant health issues for women.

Despite its established role, several areas warrant further investigation to refine its clinical use and expand its therapeutic potential.

• Long-Term Bone Health in Adolescents: The warning regarding the potential for reduced bone mineral density accrual in adolescents remains a critical area of concern. Long-term follow-up studies are needed to determine the full extent of this effect, its reversibility after treatment cessation, and its ultimate impact on peak bone mass and future fracture risk.
• Uterine Fibroids: The conflicting data on the effect of dienogest on uterine fibroids represent a significant knowledge gap. The recent evidence suggesting that dienogest may promote fibroid growth needs to be confirmed with prospective, well-controlled clinical trials. Clarifying this interaction is essential for the safe management of the large population of women who have co-existing endometriosis and uterine fibroids.
• Comparative Efficacy with Newer Agents: The treatment landscape for endometriosis is evolving with the introduction of new drug classes, such as oral GnRH antagonists (e.g., elagolix, relugolix). Head-to-head comparative efficacy and tolerability trials between dienogest and these newer agents would be invaluable for defining optimal, individualized treatment algorithms and clarifying the relative place of each therapy.[37]
• Expanded Indications: Promising preliminary data on the use of dienogest for adenomyosis suggest a potential for expanded indications. Further rigorous clinical trials are necessary to formally establish its efficacy and safety in this and other related gynecological conditions.

In conclusion, dienogest represents a significant advancement in hormonal therapy, offering an effective and well-tolerated option for the chronic management of endometriosis and as a component of modern oral contraceptives. Its development exemplifies a successful translation of targeted chemical design into a clinically meaningful therapeutic advantage. Future research focused on the unresolved questions outlined above will be crucial for further optimizing its use and solidifying its role in women's healthcare.

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