A Comprehensive Clinical and Pharmacological Monograph on Dydrogesterone (DB00378)

I. Drug Identification and Physicochemical Profile

Dydrogesterone is a well-established synthetic progestogen that has been utilized in clinical practice for over six decades. Its enduring presence in gynecology and obstetrics is attributable to a unique molecular structure that confers a highly specific pharmacological profile, distinguishing it from both endogenous progesterone and other synthetic progestins. This section provides a definitive summary of its identity and core physicochemical characteristics, which are fundamental to understanding its biological activity and therapeutic utility.

A. Core Identification

Dydrogesterone is classified as a small molecule drug belonging to the therapeutic class of hormonal agents, specifically synthetic progestogens.[1] Its systematic classification and various identifiers are crucial for unambiguous reference in clinical, regulatory, and research contexts.

• Generic Name: Dydrogesterone [1]
• DrugBank ID: DB00378 [1]
• Type: Small Molecule [1]
• CAS Number: 152-62-5 [3]
• Drug Class: Dydrogesterone is categorized as a synthetic progestogen and a hormonal agent.[2] More specifically, it is a retroprogesterone, a stereoisomer of natural progesterone, characterized by a reversed configuration at carbons 9 and 10.[5] This unique stereochemistry is central to its pharmacological properties.
• Anatomical Therapeutic Chemical (ATC) Classification: The primary ATC code for Dydrogesterone as a single agent is G03DB01, which places it in the group G03D (Progestogens) and subgroup G03DB (Pregnadien derivatives).[4] It is also found in combination products, such as with estrogen, under codes like G03FB08.[6]
• Other Identifiers: A comprehensive list of identifiers ensures cross-database compatibility and accurate data retrieval. These include:
• UNII (Unique Ingredient Identifier): 90I02KLE8K [3]
• European Community (EC) Number: 205-806-8 [3]
• ChEBI ID: CHEBI:31527 [3]
• ChEMBL ID: CHEMBL1200853 [3]
• KEGG ID: D01217 [3]
• Human Metabolome Database (HMDB) ID: HMDB0014522 [3]
• NCI Thesaurus Code: C65501 [3]

B. Chemical and Physical Properties

The therapeutic efficacy and safety profile of Dydrogesterone are direct consequences of its distinct molecular architecture. It is a derivative of retroprogesterone, specifically (9β,10α)-pregna-4,6-diene-3,20-dione.[7] This "retro" configuration, involving a stereochemical inversion of the hydrogen atom at carbon 9 (from α to β) and the methyl group at carbon 10 (from β to α) relative to natural progesterone, combined with an additional double bond between carbons 6 and 7, results in a "bent" molecular conformation.[5]

This specific three-dimensional shape is not a minor chemical curiosity; it is the cornerstone of Dydrogesterone's pharmacological distinction. The bent structure enhances the molecule's rigidity and is thought to be directly responsible for its high binding affinity and remarkable selectivity for the progesterone receptor (PR).[8] This high selectivity ensures that Dydrogesterone exerts potent progestogenic effects while avoiding significant interactions with other steroid hormone receptors, such as androgen, estrogen, glucocorticoid, and mineralocorticoid receptors.[1] Consequently, the common off-target side effects associated with other synthetic progestins, particularly androgenic effects like acne, hirsutism, and adverse lipid profile changes, are largely absent with Dydrogesterone.[11] This direct causal link between its unique stereochemistry and its favorable clinical profile of potent, targeted action with minimal unwanted hormonal activity is a central theme in its therapeutic application.

The key physicochemical properties of Dydrogesterone are summarized in Table 1, consolidating data from various chemical and drug databases. This information is vital for pharmaceutical formulation, analytical chemistry, and understanding its behavior in biological systems.

Table 1: Chemical and Physical Properties of Dydrogesterone

Property	Value	Source(s)
Molecular Formula	C21​H28​O2​	3
Molecular Weight	312.4 g/mol (Average: 312.4458)	1
IUPAC Name	(9β,10α)-pregna-4,6-diene-3,20-dione	7
SMILES	[H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@]1([H])[C@@]2([H])C=CC2=CC(=O)CC[C@@]12C	13
InChI Key	JGMOKGBVKVMRFX-HQZYFCCVSA-N	13
Physical Description	White to off-white, odorless, crystalline powder. Crystals from acetone + hexane.	3
Melting Point	168-170 °C	1
Solubility	Water: 4.86 mg/L. Soluble in acetone, chloroform; sparingly soluble in methanol; slightly soluble in fixed oils.	3
LogP (Octanol-Water Partition Coefficient)	3.4	3
pKa (Strongest Acidic)	19.4	1
pKa (Strongest Basic)	-4.8	1
Optical Rotation	Specific optical rotation: -484.5 deg at 25 °C/D (chloroform)	3
Number of Rings	4	1

II. Pharmacological Profile: Mechanism and Disposition

The clinical utility of Dydrogesterone is defined by its pharmacodynamic actions at the receptor level and its pharmacokinetic behavior within the body. Its mechanism as a selective progesterone receptor agonist, combined with a favorable oral absorption and metabolic profile, underpins its efficacy and patient-friendly administration route across a spectrum of gynecological and obstetric conditions.

A. Pharmacodynamics and Mechanism of Action

Dydrogesterone's primary mechanism of action is its function as a potent and selective agonist of the progesterone receptor (PR), a nuclear receptor encoded by the gene NR3C3.[1] Upon binding to PRs located in target tissues such as the uterus, breasts, and brain, Dydrogesterone initiates a cascade of genomic and non-genomic events that mimic the physiological effects of endogenous progesterone.[2]

• Uterine Effects and Menstrual Cycle Regulation: The most critical action of Dydrogesterone occurs in the uterus. In an endometrium that has been proliferatively primed by estrogen, Dydrogesterone induces a profound secretory transformation.[1] This process involves the maturation of endometrial glands, an increase in vascularity, and the accumulation of glycogen and other nutrients, creating an environment receptive to embryo implantation.[9] By orchestrating the healthy growth and subsequent organized shedding of the uterine lining, Dydrogesterone helps to regulate the menstrual cycle, making it effective for treating disorders like irregular cycles, dysfunctional uterine bleeding, and secondary amenorrhea.[6]
• Lack of Ovulation Inhibition: A key feature that distinguishes Dydrogesterone from many other synthetic progestins is its lack of an inhibitory effect on ovulation at standard therapeutic doses.[1] It does not interfere with the hypothalamic-pituitary-ovarian axis in a way that suppresses the luteinizing hormone (LH) surge, nor does it disrupt the function of the corpus luteum.[1] This property is of paramount clinical importance, as it allows for the treatment of conditions like endometriosis or dysmenorrhea in women who are actively trying to conceive.[18] Furthermore, unlike natural progesterone, it does not induce a thermogenic effect (an increase in basal body temperature), which simplifies cycle tracking for fertility purposes.[1]
• High Hormonal Specificity: The unique retro-steroid structure of Dydrogesterone confers high selectivity for the progesterone receptor. It is characterized by a lack of significant androgenic, estrogenic, corticoid, or anabolic activity.[1] It possesses only weak antimineralocorticoid activity.[18] This high degree of specificity is clinically advantageous, as it minimizes the risk of undesirable side effects commonly associated with less selective progestins, such as weight gain, fluid retention, acne, hirsutism, and negative impacts on lipid profiles.[11]
• Anti-Estrogenic Action in Hormone Replacement Therapy (HRT): When used as a component of HRT in postmenopausal women with an intact uterus, Dydrogesterone exerts a crucial protective, anti-estrogenic effect on the endometrium. It effectively counteracts the proliferative stimulation of estrogen, preventing the development of endometrial hyperplasia and reducing the associated risk of endometrial cancer.[2] This makes it an essential component for ensuring the safety of long-term estrogen therapy.

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

The pharmacokinetic profile of Dydrogesterone is characterized by rapid oral absorption and extensive metabolism into a highly active metabolite, which together provide a significant clinical advantage over other progesterone formulations. This profile underpins what can be described as its "oral advantage."

Natural progesterone, when administered orally in micronized form, suffers from poor and variable absorption and extensive first-pass metabolism in the liver, resulting in low bioavailability.[8] This limitation often necessitates vaginal or intramuscular administration routes, which can be inconvenient and lead to lower patient compliance.[18] In stark contrast, Dydrogesterone was designed for oral efficacy.

Upon oral administration, Dydrogesterone is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations (Tmax​) reached between 0.5 and 2.5 hours.[5] Its absolute oral bioavailability is approximately 28%, a figure significantly higher than that of oral micronized progesterone, ensuring reliable systemic exposure.[1]

Following absorption, Dydrogesterone undergoes rapid and extensive metabolism, primarily in the liver via the cytochrome P450 3A4 (CYP3A4) enzyme system.[4] The principal metabolic pathway is the reduction of the C20-keto group, leading to the formation of its main active metabolite, 20α-dihydrodydrogesterone (DHD).[5] This metabolite is not merely a byproduct; it is a potent progestogen in its own right and is responsible for a substantial portion of the drug's clinical activity.[14] Plasma levels of DHD are significantly higher than those of the parent drug; the area under the curve (AUC) and peak concentration (

Cmax​) ratios of DHD to Dydrogesterone are approximately 40 and 25, respectively.[5] This indicates that DHD is the primary mediator of Dydrogesterone's therapeutic effects after oral administration.

The elimination half-lives of Dydrogesterone and DHD are relatively short. The mean terminal half-life for Dydrogesterone ranges from 5 to 7 hours, while for the more abundant DHD, it ranges from 14 to 17 hours.[5] This pharmacokinetic profile, characterized by rapid absorption and clearance, means that steady-state concentrations are reached after approximately 3 days of treatment and that multiple daily doses are typically required to maintain therapeutic levels.[5] Comparative pharmacokinetic studies have confirmed this rapid absorption and clearance profile, suggesting that administration frequency is as important as the dose itself for maintaining consistent effects.[21]

Excretion is primarily renal. After administration of a radiolabeled dose, an average of 63% is excreted in the urine, mainly as glucuronic acid conjugates of its metabolites, with excretion being largely complete within 72 hours.[5] Unlike natural progesterone, Dydrogesterone is not excreted as pregnanediol, which can be useful for diagnostic differentiation.[6]

This combination of good oral bioavailability, rapid conversion to a potent active metabolite, and predictable pharmacokinetics provides a significant advantage in patient convenience, compliance, and satisfaction when compared to vaginal or intramuscular progesterone formulations, particularly for long-term use in ART and HRT.[9]

Table 2: Summary of Key Pharmacokinetic Parameters for Dydrogesterone

Parameter	Value / Description	Source(s)
Administration Route	Oral	18
Bioavailability	28% (for a 20 mg oral dose vs. 7.8 mg IV infusion)	1
Time to Peak Concentration (Tmax​)	Dydrogesterone: 0.5 - 2.5 hours; DHD: ~1.5 hours	5
Peak Concentration (Cmax​)	Following a 10 mg dose, Cmax​ for Dydrogesterone is ~2.9-3.6 ng/mL; for DHD, it is ~77-88 ng/mL.	21
Metabolism	Extensive hepatic metabolism, primarily by CYP3A4, to its main active metabolite.	4
Primary Active Metabolite	20α-dihydrodydrogesterone (DHD)	5
Elimination Half-Life (t1/2​)	Dydrogesterone: 5 - 7 hours; DHD: 14 - 17 hours	5
Route of Excretion	Primarily renal; ~63% of the dose is excreted in urine within 72 hours as metabolites.	5

III. Clinical Applications and Therapeutic Efficacy

Dydrogesterone has demonstrated efficacy across a wide range of clinical indications where progesterone supplementation or modulation is required. Its unique pharmacological profile makes it a versatile tool in the management of gynecological disorders, reproductive medicine, obstetrics, and menopausal hormone therapy. Clinical evidence, including large-scale trials and meta-analyses, supports its use, although nuances and areas of debate exist for certain applications.

A. Management of Gynecological Disorders

Dydrogesterone is effective in treating several common gynecological conditions that are often associated with progesterone deficiency or an imbalance between estrogen and progesterone.

• Endometriosis: This chronic and often debilitating disease is characterized by the growth of endometrial-like tissue outside the uterus, leading to pelvic pain, dysmenorrhea (painful menstruation), and dyspareunia (painful intercourse). Dydrogesterone has been shown to provide significant relief from these symptoms. A key advantage in this context is its non-inhibitory effect on ovulation, which allows patients to pursue pregnancy while on treatment.[18] Clinical studies have reported statistically significant reductions in pelvic pain, dysmenorrhea, and dyspareunia after the first cycle of treatment following laparoscopic surgery for endometriosis. Furthermore, the amount and duration of menstrual bleeding are significantly reduced, and one study observed clinical improvement of endometriosis in 71% of patients.[18] It is considered particularly suitable for managing endometriosis in women who wish to conceive and to prevent associated bleeding problems.[18]
• Dysmenorrhea: For primary dysmenorrhea, which is a common complaint among women of reproductive age, clinical studies have confirmed that treatment with Dydrogesterone provides effective symptom relief and a reduction in menstrual pain.[18]
• Menstrual Irregularities: Dydrogesterone is widely used to manage various menstrual disorders, including dysfunctional or abnormal uterine bleeding (AUB), secondary amenorrhea (absence of periods), and irregular cycles.[16] By inducing a secretory endometrium and promoting organized shedding, it helps to regulate the menstrual cycle.[17] In cases of secondary amenorrhea where the endometrium is sufficiently primed by endogenous estrogen, Dydrogesterone can adequately induce withdrawal bleeding. In situations where endogenous estradiol levels are low, its efficacy is enhanced when co-administered with an estrogen supplement.[18]
• Premenstrual Syndrome (PMS): Dydrogesterone has demonstrated reasonable efficacy in alleviating both the mood-related symptoms (e.g., mood swings) and the physical symptoms associated with PMS.[18]
• Other Gynecological Uses: Cyclic treatment with low-dose Dydrogesterone (e.g., 10 mg/day) has also been found to be effective in treating fibrocystic breast changes and the associated breast pain (mastalgia).[18]

B. Role in Reproductive Medicine and Assisted Reproductive Technology (ART)

Dydrogesterone plays a critical role in modern reproductive medicine, particularly as luteal phase support (LPS) in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). The luteal phase is the post-ovulatory period where adequate progesterone is essential for preparing the uterine lining for embryo implantation and sustaining an early pregnancy.[10]

• Luteal Phase Support (LPS): In many ART protocols, the natural production of progesterone can be suppressed, necessitating exogenous support. Dydrogesterone effectively supplements the luteal phase, enhancing endometrial receptivity for the embryo.[10] Its primary advantage in this setting is its oral route of administration, which offers superior patient convenience, tolerability, and satisfaction compared to the more cumbersome vaginal or painful intramuscular progesterone formulations.[9]
• Clinical Trial Evidence and a Clinical Paradox: The efficacy of Dydrogesterone for LPS is supported by robust evidence. Two large, Phase III non-inferiority trials, LOTUS I and LOTUS II, demonstrated that oral Dydrogesterone was as effective as micronized vaginal progesterone (MVP) capsules or gel for LPS in fresh-cycle IVF.[8] However, a subsequent meta-analysis of individual patient data (IPD) from nine randomized controlled trials, including the LOTUS studies, revealed a more compelling finding. This comprehensive analysis indicated that oral Dydrogesterone was associated with a statistically significant higher chance of ongoing pregnancy and live birth compared to MVP.[8]

This finding presents a clinical paradox when viewed alongside detailed pharmacodynamic studies. A head-to-head, randomized crossover study meticulously compared the pharmacokinetic profiles and endometrial effects of oral Dydrogesterone and MVP.[22] This study confirmed the very different plasma concentration profiles: oral Dydrogesterone led to sharp peaks and rapid clearance, whereas MVP resulted in more sustained, lower-level plasma concentrations. Despite these marked differences in systemic exposure, the study found that the resulting molecular signatures at the endometrial level—assessed by histology and transcriptomics—were remarkably similar between the two treatments.[22]

This discrepancy between large-scale clinical outcomes (where Dydrogesterone appears superior) and focused molecular studies (where endometrial effects appear equivalent) suggests that the mechanism for Dydrogesterone's potential superiority may not be solely due to creating a "better" endometrium. Several hypotheses could explain this paradox. First, the superior convenience of the oral route may lead to better real-world patient compliance, resulting in more consistent dosing and improved outcomes in large trials, an effect that might be less apparent in the highly controlled setting of a short-term pharmacokinetic study. Second, the high systemic concentrations of Dydrogesterone and its active metabolite DHD may exert beneficial effects beyond the endometrium, such as systemic immunomodulatory actions that facilitate implantation and pregnancy maintenance. Finally, it is possible that the analyses used in the molecular study did not capture subtle but clinically relevant differences in endometrial function. This unresolved question represents a key area for future research and highlights the complexity of translating molecular pharmacology into clinical outcomes.

C. Application in Obstetrics (Threatened and Recurrent Miscarriage)

The use of Dydrogesterone to prevent pregnancy loss is one of its most established yet debated indications. It is prescribed for both threatened miscarriage (vaginal bleeding in early pregnancy with a closed cervix) and recurrent miscarriage (history of three or more consecutive pregnancy losses).

• Evidence Supporting Efficacy: A significant body of evidence and numerous clinical guidelines support the use of Dydrogesterone in these conditions. Multiple sources, including meta-analyses, report that treatment with Dydrogesterone is associated with a substantial and statistically significant reduction in the rate of miscarriage, often cited as an approximately two-fold reduction compared to placebo or standard care (which typically involves bed rest).[9] A completed Phase 3 clinical trial specifically investigated its use for habitual abortion (recurrent miscarriage).[23] Guidelines from bodies like the Federation of Obstetric and Gynaecological Societies of India (FOGSI) recommend oral Dydrogesterone as a first-choice treatment for threatened miscarriage, citing evidence of its superiority over vaginal progesterone in reducing miscarriage risk.[24] The rationale is that by supplementing progesterone levels, Dydrogesterone can support the endometrium, maintain uterine quiescence (by inhibiting prostaglandin synthesis), and facilitate a favorable immune environment for the ongoing pregnancy.[9]
• Contradictory Evidence and Nuanced Interpretation: Despite this widespread use and supportive evidence, the efficacy of Dydrogesterone in preventing miscarriage is not universally confirmed and represents an area of active clinical debate. It is crucial for an expert-level assessment to acknowledge the conflicting data. A recent high-quality, randomized, double-blind, placebo-controlled trial found that oral Dydrogesterone (20 mg/day) did not significantly reduce the rate of miscarriage in women with threatened miscarriage compared to placebo.[26] Similarly, the large PRISM trial, which investigated vaginal micronized progesterone, also found no overall benefit in preventing miscarriage in a broad population of women with threatened miscarriage.[26]

The existence of such contradictory findings necessitates a more nuanced interpretation of Dydrogesterone's role. Miscarriage is a multifactorial event, with a large proportion of early pregnancy losses being caused by fetal chromosomal abnormalities, which are not amenable to hormonal support.[26] Progestogen supplementation is biologically plausible and likely to be effective only in cases where the underlying cause of the miscarriage is a true progesterone deficiency, such as in luteal phase defect.[9] Therefore, the conflicting trial results may be explained by differences in the underlying causes of miscarriage within the studied populations. Trials that happen to enroll more women with progesterone deficiency would likely show a benefit, while those enrolling a more heterogeneous population would not.

The expert conclusion is that while Dydrogesterone is widely used and supported by some strong evidence and clinical guidelines for preventing miscarriage, its efficacy is not universal. Its use should be considered on a case-by-case basis, with the greatest potential for benefit in women with a documented history or strong clinical suspicion of progesterone deficiency (e.g., in recurrent miscarriage). It is unlikely to prevent miscarriages stemming from genetic or other non-hormonal causes.

D. Use in Menopausal Hormone Replacement Therapy (HRT)

Dydrogesterone is a key component of modern menopausal hormone replacement therapy (HRT) for women who have not had a hysterectomy.

• Endometrial Protection: The primary role of a progestogen in HRT is to protect the endometrium from the proliferative effects of estrogen. Unopposed estrogen therapy significantly increases the risk of endometrial hyperplasia and adenocarcinoma.[2] Dydrogesterone, when added to estrogen therapy either cyclically (to induce a regular withdrawal bleed) or continuously (to maintain an atrophic, non-bleeding endometrium), effectively provides this crucial protection.[14]
• Favorable Safety Profile in HRT: Compared to other synthetic progestins used in HRT, Dydrogesterone offers a potentially more favorable safety profile. Its lack of androgenic activity means it is less likely to cause side effects like acne, greasy skin, or adverse changes in lipid profiles.[28] Furthermore, some evidence from observational studies suggests that HRT regimens containing Dydrogesterone may be associated with a lower risk of venous thromboembolism (VTE) and potentially a lower risk of breast cancer compared to regimens containing other progestogens, such as medroxyprogesterone acetate (MPA).[28] While this evidence is compelling, it is important to note that all hormonal therapies carry risks that must be weighed against the benefits for each individual patient. HRT guidelines from various bodies include Dydrogesterone as a suitable progestogen option for both sequential and continuous-combined regimens.[27]

IV. Dosage, Administration, and Formulations

The dosing of Dydrogesterone is highly specific to the clinical indication, reflecting the different physiological goals of treatment, from cycle regulation to pregnancy support and endometrial protection. It is available primarily as oral tablets, typically in a 10 mg strength, and sometimes in sustained-release (SR) formulations of 20 mg and 30 mg.[31] The oral route of administration is a key feature, enhancing patient convenience and compliance.[18] For higher daily doses, the total amount should be divided and taken at intervals throughout the day to maintain more stable plasma levels.[32] Table 3 provides a consolidated summary of recommended dosing regimens for the principal indications, compiled from various product information labels and clinical guidelines. It is intended as a reference for healthcare professionals; treatment must always be individualized based on clinical response and patient characteristics.

Table 3: Recommended Dosage and Administration of Dydrogesterone by Indication

Indication	Dosing Regimen (Dose, Frequency, Cycle Day)	Duration / Notes	Source(s)
Endometriosis	10 mg two to three times daily (20-30 mg/day). Administered either cyclically from day 5 to day 25 of the menstrual cycle or continuously.	Treatment aims to relieve pain and can be continued long-term. Starting at the highest dose is recommended.	32
Dysmenorrhea (Painful Periods)	10 mg twice daily (20 mg/day) from day 5 to day 25 of the menstrual cycle.	Treatment is aimed at pain relief during the menstrual cycle. Starting at the highest dose is recommended.	33
Irregular Cycles / Dysfunctional Uterine Bleeding (DUB)	To arrest bleeding: 10 mg twice daily (20 mg/day) for 5 to 7 days. To prevent further heavy bleeding: 10 mg twice daily (20 mg/day) from day 11 to day 25 of the cycle.	For prevention, treatment is typically continued for 2-3 cycles. May be combined with estrogen.	32
Secondary Amenorrhea	10 mg twice daily (20 mg/day) from day 11 to day 25 of the cycle.	This regimen requires an adequately estrogen-primed endometrium. Often co-administered with an estrogen from day 1 to day 25.	32
Infertility due to Luteal Insufficiency	10 mg daily from day 14 to day 25 of the cycle.	Treatment should be continued for at least 6 consecutive cycles. If pregnancy occurs, it is often continued.	33
Luteal Phase Support in ART (IVF/ICSI)	10 mg three times daily (30 mg/day).	Treatment starts on the day of oocyte retrieval and continues for up to 10-12 weeks if pregnancy is confirmed.	33
Threatened Miscarriage	Loading dose: 40 mg (four 10 mg tablets) at once. Maintenance dose: 10 mg every 8 hours (30 mg/day).	The maintenance dose is continued until symptoms remit, then maintained for one week before gradual reduction. If symptoms recur, treatment is resumed. Some guidelines suggest continuing until 16-20 weeks.	24
Recurrent (Habitual) Miscarriage	10 mg twice daily (20 mg/day).	Treatment should preferably start before conception and is continued until at least the 12th, and often up to the 20th, week of pregnancy.	17
Hormone Replacement Therapy (HRT) - Sequential	10 mg daily for the last 12-14 days of each 28-day estrogen cycle.	This regimen induces a regular withdrawal bleed. The dose may be increased to 20 mg/day if bleeding is unacceptable or endometrial response is inadequate.	27
Hormone Replacement Therapy (HRT) - Continuous Combined	10 mg daily, taken continuously with daily estrogen.	This regimen is for postmenopausal women and aims to be "period-free." Lower dose combinations (e.g., 2.5 mg or 5 mg dydrogesterone) are also available (Femoston-conti).	27

V. Comprehensive Safety and Tolerability Assessment

Dydrogesterone is generally considered a well-tolerated progestogen, a characteristic largely attributed to its high selectivity for the progesterone receptor and lack of significant off-target hormonal activities. However, like all medications, it is associated with a profile of potential adverse effects, contraindications, and drug interactions that require careful consideration by prescribing clinicians.

A. Adverse Effect Profile

The side effects of Dydrogesterone are typically mild to moderate in intensity and often transient, diminishing as the body adjusts to the medication. Acute toxicity is very low, with no serious toxicity observed even at high doses in preclinical studies.[1]

• Common Adverse Effects: The most frequently reported adverse reactions in clinical trials and post-marketing surveillance include [16]:
• Neurological: Headache and migraine.
• Gastrointestinal: Nausea, vomiting, abdominal pain, and bloating. Taking the medication with food can help mitigate GI discomfort.[38]
• Reproductive: Breast pain and tenderness. Menstrual irregularities are also common, particularly during the first few months of treatment, and may manifest as breakthrough bleeding or spotting.[16]
• Other Reported Effects: A range of other side effects have been noted, though generally less frequently [39]:
• Psychiatric: Mood swings, irritability, and in some cases, feelings of depression.
• General: Dizziness, drowsiness, or light-headedness, which may affect the ability to perform tasks requiring mental alertness.
• Metabolic/Dermatologic: Weight changes (either gain or loss), skin reactions such as rash or itching, and less commonly, acne or skin pigmentation.[39]
• Serious Adverse Events (Rare):
• Hypersensitivity Reactions: Severe allergic reactions are rare but require immediate medical attention. Symptoms include angioedema (swelling of the face, lips, tongue), difficulty breathing (dyspnea), and widespread itchy skin rashes (urticaria).[39]
• Hepatic Effects: Infrequently, treatment has been associated with alterations in liver function, sometimes accompanied by clinical symptoms like jaundice, malaise, or abdominal pain. Treatment should be discontinued in cases of severe hepatic impairment.[36]
• Thromboembolic Risk: While some evidence suggests Dydrogesterone may have a more favorable profile than other progestins, its use, particularly as part of HRT, is associated with a potential increased risk of venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism.[29] This risk is influenced by the estrogen component, dose, and individual patient risk factors.

B. Contraindications and Clinical Precautions

Certain conditions preclude the use of Dydrogesterone, while others necessitate close supervision and a careful risk-benefit assessment.

• Absolute Contraindications: Dydrogesterone should not be used in patients with [36]:
• Known hypersensitivity to Dydrogesterone or any of the excipients in the formulation.
• Undiagnosed vaginal bleeding. The etiology of any abnormal bleeding must be investigated before initiating treatment to rule out underlying malignancy.[34]
• Known or suspected progestogen-dependent neoplasms.
• Severe hepatic disease or dysfunction, or a history of liver disease where liver function tests have not returned to normal.
• When used in combination with an estrogen for HRT, the contraindications for estrogen (e.g., active or past VTE, arterial thromboembolic disease, estrogen-dependent tumors) also apply.
• Evolving Safety Information - Meningioma Risk: A significant and recent development in the safety profile of Dydrogesterone is the identification of a potential risk of meningioma, a type of tumor that arises from the membranes surrounding the brain and spinal cord. This risk has led to updated regulatory guidance. In July 2024, the European Medicines Agency's (EMA) Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) issued a position based on a review by the Pharmacovigilance Risk Assessment Committee (PRAC).[43] This review considered data from the literature and spontaneous post-marketing reports which suggested a causal relationship between dydrogesterone/estradiol use and meningioma. The evidence included cases with a suggestive temporal relationship and instances where the tumor stabilized or decreased in volume after the drug was discontinued.[44] Consequently, the EMA has recommended that "meningioma or a history of meningioma" be added as a contraindication to the product information for medicinal products containing Dydrogesterone and estradiol.[44] This is a critical update for clinicians, underscoring the importance of ongoing pharmacovigilance and the need to specifically question patients about any history of such tumors before prescribing these products.
• Precautions and Conditions Requiring Supervision: Caution is advised, and patients should be closely monitored if they have a history of the following conditions, as they may be aggravated during treatment [36]:
• Depression.
• Conditions sensitive to fluid retention, such as cardiac or renal dysfunction.
• Thromboembolic disorders (e.g., thrombophlebitis, cerebrovascular disorders, coronary artery disease).
• Porphyria.
• Diabetes mellitus, as progestogens can influence glucose tolerance.
• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take formulations containing lactose.[36]

C. Analysis of Drug-Drug Interactions

Dydrogesterone is a substrate of the CYP3A4 enzyme, making it susceptible to interactions with drugs that induce or inhibit this pathway. Additionally, its hormonal nature can lead to pharmacodynamic interactions. Clinicians must conduct a thorough medication review to avoid clinically significant interactions.

Table 4: Clinically Significant Drug-Drug Interactions with Dydrogesterone

Interacting Drug / Class	Mechanism of Interaction	Clinical Effect on Dydrogesterone	Management Recommendation	Source(s)
Strong CYP3A4 Inducers (e.g., Carbamazepine, Phenytoin, Phenobarbital, Rifampicin, St. John's Wort)	Induction of hepatic CYP3A4 enzymes.	Increased metabolism and clearance of Dydrogesterone.	Decreased plasma concentrations and potential loss of therapeutic efficacy.	Avoid concomitant use or consider dose adjustment of Dydrogesterone. Monitor for reduced clinical effect.
Strong CYP3A4 Inhibitors (e.g., Ritonavir, Ketoconazole, Itraconazole, Clarithromycin, Erythromycin, Grapefruit Juice)	Inhibition of hepatic CYP3A4 enzymes.	Decreased metabolism and clearance of Dydrogesterone.	Increased plasma concentrations and potential for increased incidence or severity of adverse effects.	Use with caution. Monitor patient for adverse effects. Dose reduction of Dydrogesterone may be necessary.
Anticoagulants (e.g., Warfarin, Apixaban, Rivaroxaban, Dabigatran)	Pharmacodynamic antagonism. Progestogens can have pro-thrombotic effects that may counteract the action of anticoagulants.	Potential decrease in the anticoagulant activity of the interacting drug.	Close monitoring of coagulation parameters (e.g., INR for warfarin) is warranted. Dose adjustment of the anticoagulant may be required.	1
Other Progestogens / Hormonal Agents (e.g., other progestins, estrogens)	Additive or synergistic pharmacodynamic effects.	Potential for enhanced hormonal effects, both therapeutic and adverse.	Concurrent use should be under expert guidance. Dydrogesterone is often intentionally combined with estrogen in HRT. Avoid unplanned combinations.	20
Ulipristal Acetate	Ulipristal is a selective progesterone receptor modulator (SPRM) with antagonistic properties at the PR.	Antagonism of Dydrogesterone's effect at the progesterone receptor.	Potential for decreased therapeutic efficacy of Dydrogesterone. Concomitant use is generally not recommended.	1
Retinoic Acid Derivatives (e.g., Adapalene, Alitretinoin, Tazarotene)	Unknown, but observed to decrease the efficacy of progestins.	Potential for decreased therapeutic efficacy of Dydrogesterone.	Monitor for clinical response when used concomitantly.	47

VI. Comparative Analysis with Other Progestogenic Agents

To fully appreciate the clinical role of Dydrogesterone, it is essential to compare it with other commonly used progestogenic agents. Its primary comparators are natural micronized progesterone (MVP), particularly in the context of pregnancy support and ART, and other synthetic progestins like norethisterone and medroxyprogesterone acetate (MPA) for cycle control and HRT.

A. Dydrogesterone versus Micronized Progesterone (MVP)

Dydrogesterone and MVP are the two most frequently utilized progestogens for luteal phase support in ART and for the management of threatened miscarriage. While both aim to supplement progesterone activity, they differ significantly in their structure, pharmacokinetics, and, according to some evidence, clinical outcomes.

• Pharmacokinetic and Structural Differences: Dydrogesterone is a synthetic retroprogesterone with a unique structure that confers high oral bioavailability (~28%) and metabolic stability.[5] In contrast, MVP is structurally identical to endogenous progesterone. When taken orally, MVP undergoes extensive first-pass metabolism, leading to very low and erratic bioavailability, which limits its oral use for indications requiring consistent high-level support.[8] Consequently, MVP is most often administered via the vaginal route (as capsules, gels, or suppositories) or intramuscularly to bypass the liver.[8] This fundamental difference in administration route is a major point of differentiation; the oral route of Dydrogesterone is significantly more convenient and is preferred by many patients over vaginal or intramuscular applications.[18]
• Efficacy in Assisted Reproductive Technology (ART): As discussed in Section III.B, the comparative efficacy in ART is a subject of intense study. While head-to-head non-inferiority has been established, large meta-analyses of IPD suggest that oral Dydrogesterone may be associated with a statistically significant higher live birth rate compared to MVP.[8] However, this finding is not universal across all studies. One randomized trial found that the live birth rate was significantly higher in a group receiving vaginal progesterone compared to oral Dydrogesterone for LPS.[49] Another study found comparable clinical success, miscarriage, and ongoing pregnancy rates between oral Dydrogesterone and vaginal MVP.[50] This highlights the ongoing debate and the potential influence of study design, patient population, and specific protocols on outcomes.
• Efficacy and Outcomes in Threatened Miscarriage: In the context of threatened miscarriage, both agents are used. Some studies suggest Dydrogesterone may be more effective. One study reported that the resolution of pain and bleeding was better in patients treated with oral Dydrogesterone compared to oral MVP.[51] However, a critical counterpoint comes from a study comparing oral Dydrogesterone with vaginal MVP in women with threatened abortion.[52] While the rates of miscarriage and other complications like preeclampsia were not significantly different, this study found that treatment with MVP was associated with a significantly lower incidence of subsequent preterm labor and low birth weight babies. The mean gestational age at delivery and baby weight were also significantly higher in the MVP group.[52] This important finding suggests that while both may be comparable in preventing the immediate miscarriage, MVP might confer additional benefits for the remainder of the pregnancy, a crucial consideration for clinicians.
• Side Effect Profile and Patient Preference: The oral route of Dydrogesterone is often cited for better patient satisfaction and compliance.[18] Vaginal administration of MVP can be associated with local side effects like vaginal discharge, irritation, and bleeding, while intramuscular injections are painful and can cause local abscesses.[19] Oral MVP can cause side effects like drowsiness and headaches due to its metabolites.[19] Dydrogesterone's side effect profile is generally well-tolerated, consisting mainly of headache, nausea, and breast tenderness.[16]

Table 5: Comparative Efficacy and Characteristics of Dydrogesterone vs. Micronized Vaginal Progesterone (MVP)

Feature	Dydrogesterone	Micronized Vaginal Progesterone (MVP)	Source(s)
Structure	Synthetic retro-progesterone (stereoisomer)	Bio-identical to natural progesterone	5
Primary Route	Oral	Vaginal (suppository, gel, capsule)	8
Oral Bioavailability	Good (~28%)	Poor and erratic	5
Efficacy in ART (LPS)	Non-inferior to MVP; some meta-analyses suggest superiority (higher live birth rates). Other studies show inferiority or equivalence.	Established efficacy; considered a standard of care.	8
Pregnancy Outcomes	Similar abortion rates to MVP. One study linked it to higher rates of preterm labor and low birth weight compared to MVP.	Similar abortion rates to Dydrogesterone. One study linked it to lower rates of preterm labor and low birth weight.	52
Side Effect Profile	Systemic effects: Headache, nausea, breast tenderness. Well-tolerated.	Local effects: Vaginal discharge, irritation. Less systemic drowsiness than oral MVP.	16
Patient Convenience	High (simple oral tablet)	Lower (requires vaginal insertion, can be messy)	18

B. Dydrogesterone versus Other Synthetic Progestins (e.g., Norethisterone, Medroxyprogesterone Acetate)

Dydrogesterone also competes with other synthetic progestins, such as norethisterone (a 19-nortestosterone derivative) and medroxyprogesterone acetate (MPA, a 17α-hydroxyprogesterone derivative), primarily for indications like abnormal uterine bleeding (AUB), endometriosis, and as the progestin component in HRT.

• Pharmacological Profile and Safety: The most significant difference lies in their hormonal activity profiles. Dydrogesterone is highly selective for the progesterone receptor and is devoid of androgenic activity.[11] In contrast, progestins derived from testosterone, like norethisterone, possess residual androgenic properties. This can lead to undesirable side effects such as acne, hirsutism, weight gain, and negative effects on lipid metabolism (e.g., lowering HDL cholesterol).[12] MPA also has a different side effect profile. This makes Dydrogesterone a "safer" and better-tolerated alternative, particularly for long-term use in HRT or in women who are sensitive to androgenic effects.[11] A study on human adipocytes showed that while both Dydrogesterone and the androgenic norethisterone increased expression of lipoprotein lipase (LPL) and decreased hormone-sensitive lipase (HSL), their differing effects on lipid profiles in vivo highlight the complexity of their metabolic actions.[12]
• Efficacy in Abnormal Uterine Bleeding (AUB): Clinical studies comparing Dydrogesterone and norethisterone for the management of AUB have yielded mixed results regarding cycle control, but consistently highlight Dydrogesterone's superior safety profile. Several studies have found that Dydrogesterone is as effective as norethisterone in controlling heavy menstrual bleeding, with both showing significant decreases in blood loss and improvements in hemoglobin levels.[11] However, some comparative studies have suggested that norethisterone may provide better menstrual cycle regulation.[53] Despite this, the consensus often favors Dydrogesterone as an equally efficacious but safer alternative due to its lack of androgenic side effects.[11]
• Efficacy in Progestin-Primed Ovarian Stimulation (PPOS) for ART: In the PPOS protocol, which uses a progestin to prevent a premature LH surge during ovarian stimulation, Dydrogesterone has been compared with MPA. Studies in various patient populations, including those with normal ovarian reserve, polycystic ovary syndrome (PCOS), and poor ovarian reserve (POR), have shown that Dydrogesterone is an effective alternative to MPA.[54] Both agents effectively suppress the LH surge and yield comparable numbers of retrieved oocytes and similar clinical pregnancy rates. A key potential advantage of Dydrogesterone is its milder pituitary suppression effect compared to MPA. This may translate into a requirement for a lower total dose of gonadotropins to achieve adequate follicular stimulation, which could reduce treatment costs and patient burden.[54]

VII. Regulatory Landscape and Market Presence

Dydrogesterone has a long and complex history of clinical use and regulatory oversight that varies significantly across major global jurisdictions. Its journey from development in the mid-20th century to its current status reflects evolving standards for clinical evidence, commercial market dynamics, and ongoing pharmacovigilance.

A. Historical Context and Global Availability

Dydrogesterone was developed in the 1950s and was first introduced for medical use in 1961, making it one of the more established progestogens in the pharmacopeia.[18] It was initially marketed by Duphar under the brand name Duphaston in the United Kingdom.[18] Its use quickly expanded, and it is now widely available throughout Europe, Asia, Central and South America, and parts of Africa and Australia.[18] Over its 65-year history, it is estimated that more than 147 million women have been treated with Dydrogesterone, resulting in over 20 million successful pregnancies, attesting to its extensive clinical experience.[56]

B. Regulatory Status in Major Jurisdictions

The regulatory pathways of Dydrogesterone in the United States and the European Union present a stark contrast, offering a compelling case study in how commercial factors and evolving safety signals can shape a drug's market presence.

• United States (FDA): Dydrogesterone was approved by the U.S. Food and Drug Administration (FDA) and marketed in the United States under the brand names Duphaston (approved 1962) and Gynorest (approved 1978).[18] However, Duphaston was removed from the U.S. market in 1979, and Gynorest is also no longer available.[18] This withdrawal has led to the common misconception that the drug was removed for safety or efficacy reasons. This is incorrect. A definitive clarification came in a 2017 notice in the U.S. Federal Register. The FDA, after reviewing a citizen petition and its own records, formally determined that Gynorest (dydrogesterone) oral tablets were not withdrawn from sale for reasons of safety or effectiveness.[57] The withdrawal was attributed to commercial reasons.[59] This regulatory determination is legally significant because it clears the path for the FDA to approve Abbreviated New Drug Applications (ANDAs) for generic versions of Dydrogesterone, should a manufacturer choose to pursue it.[57] As such, while Dydrogesterone is not currently available in the U.S., its re-introduction to the market remains a regulatory possibility.
• European Union (EMA): In contrast to the U.S., Dydrogesterone has maintained a continuous and active presence in the European market. It is widely authorized and used in many EU member states, both as a single agent and in combination with estradiol for HRT.[18] Its regulatory profile continues to evolve. For instance, it was first approved for use in ART in Europe in 2017.[56] Recent regulatory activity highlights the EMA's ongoing safety monitoring. As detailed previously, a July 2024 position from the CMDh, based on a PRAC recommendation, led to the addition of meningioma (or a history thereof) as a contraindication for dydrogesterone/estradiol combination products.[43] This demonstrates an active and responsive regulatory environment. Concurrently, the European market may be poised for change, with a 2024 announcement from the pharmaceutical company Adalvo indicating that it is in the pre-assessment phase for what could be the first EU generic approval of Dydrogesterone 10mg tablets, signaling potential for increased market competition and accessibility.[60]
• Other Regions: Dydrogesterone is approved and marketed in numerous other countries, including the United Kingdom, India, Australia, and Russia.[18] It is notably not available in Canada or New Zealand.[18]

C. Brand Names and Formulations

Dydrogesterone is marketed globally under a variety of brand names, both as a single-ingredient product and, very commonly, in fixed-dose combinations with estradiol for HRT.

• Single-Agent Formulations: The most globally recognized brand name for Dydrogesterone is Duphaston.[18] Other brand names for single-agent Dydrogesterone include Gynorest (historical U.S. brand), Nalvee (UK), Dabroston (Macedonia), and numerous brands in India such as Dydrofrau, Zydrosterone, and Dydrocon.[61]
• Combination Formulations: Dydrogesterone is a frequent partner for estradiol in HRT products. The most common brand name for these combinations is Femoston, which is available in various strengths and regimens (e.g., Femoston 1/10, Femoston-conti) to allow for sequential or continuous-combined therapy.[1] Other combination brand names include Climaston.[61] These products are formulated to provide both the benefits of estrogen replacement and the necessary endometrial protection from Dydrogesterone.

VIII. Synthesis and Expert Recommendations

Dydrogesterone is a synthetic progestogen with a rich history and a well-defined, albeit evolving, place in contemporary medicine. Its clinical value is rooted in a unique pharmacological profile that distinguishes it from both natural progesterone and other synthetic analogues. A comprehensive analysis of the available evidence allows for a nuanced synthesis of its strengths, weaknesses, and optimal clinical positioning.

A. Summary of Dydrogesterone's Unique Profile

The central value proposition of Dydrogesterone can be summarized by three key attributes: high receptor selectivity, excellent oral bioavailability, and a non-inhibitory effect on ovulation.

1. High Selectivity and Favorable Safety: Its retro-progesterone structure confers a high affinity and selectivity for the progesterone receptor, resulting in potent progestogenic effects without significant androgenic, estrogenic, or corticoid activity. This translates directly into a superior safety and tolerability profile compared to many other synthetic progestins, particularly regarding the absence of androgenic side effects.
2. Oral Efficacy: Dydrogesterone was designed for oral administration and possesses good bioavailability, a stark contrast to the poor oral absorption of natural progesterone. This "oral advantage" enhances patient convenience, satisfaction, and likely compliance, which is a significant factor in long-term therapies like HRT and in the demanding context of ART.
3. Fertility-Sparing Action: At therapeutic doses, it does not inhibit ovulation. This unique property makes it an invaluable tool for treating gynecological conditions like endometriosis or dysmenorrhea in women who are concurrently seeking to conceive.

B. Optimal Clinical Positioning

Based on the balance of evidence regarding efficacy, safety, and patient convenience, the following recommendations can be made for the clinical positioning of Dydrogesterone:

• Strong Recommendation / Primary Consideration:
• Luteal Phase Support in ART: Given the strong evidence of non-inferiority, potential for superiority in live birth rates shown in large meta-analyses, and the significant patient preference for the oral route, Dydrogesterone should be considered a first-line or primary alternative to vaginal progesterone for LPS in IVF/ICSI cycles.
• Endometriosis in Women Desiring Fertility: Its ability to effectively manage pain symptoms without suppressing ovulation makes it an ideal choice for this specific patient population.
• Progestin Component in HRT: For women requiring HRT who have an intact uterus, Dydrogesterone is an excellent choice, particularly for those who are sensitive to or wish to avoid the androgenic side effects of other progestins. The evidence suggesting a potentially lower VTE and breast cancer risk compared to other synthetic progestins further strengthens its position.
• Contested Indication / Case-by-Case Consideration:
• Threatened and Recurrent Miscarriage: The evidence for Dydrogesterone in preventing miscarriage is conflicting. While supported by some meta-analyses and clinical guidelines, high-quality, placebo-controlled trials have failed to show a benefit. Therefore, its routine use for all women with threatened miscarriage cannot be universally recommended. A more prudent approach is to reserve its use for patients with a confirmed or strongly suspected underlying progesterone deficiency (e.g., women with a history of recurrent miscarriage and documented luteal phase defect). The decision should be a shared one between the clinician and patient, acknowledging the uncertainty in the evidence.

C. Future Research Directions

Despite its long history of use, several key questions about Dydrogesterone remain, highlighting areas for future research:

1. Resolving the Miscarriage Debate: There is a clear need for large, well-designed, prospective, randomized controlled trials in women with threatened and recurrent miscarriage. These trials should incorporate biomarkers to stratify patients based on their endogenous progesterone status to definitively identify the sub-population, if any, that truly benefits from supplementation.
2. Investigating the ART Superiority Paradox: The finding that oral Dydrogesterone may lead to higher live birth rates than MVP in ART warrants further investigation. Research should focus on elucidating the mechanism, exploring potential systemic immunomodulatory effects of Dydrogesterone and its metabolite DHD, and conducting real-world effectiveness and compliance studies to see if the oral advantage translates consistently from trials to practice.
3. Long-Term Safety and Meningioma Risk: The recent regulatory action by the EMA regarding meningioma risk highlights the need for continued, robust pharmacovigilance. Large-scale, long-term observational studies are needed to better quantify this risk, identify any predisposing factors, and determine if the risk applies to Dydrogesterone as a single agent or is specific to its combination with estrogen.

D. Final Conclusion

Dydrogesterone is a valuable and often advantageous therapeutic agent in the armamentarium of gynecology, obstetrics, and reproductive endocrinology. Its unique pharmacological properties—stemming directly from its retro-steroid structure—translate into distinct clinical benefits for specific patient populations, most notably its excellent oral efficacy and favorable safety profile. It stands as a primary option for luteal phase support in ART and as a progestin in HRT. Its role in preventing miscarriage remains an area of clinical debate, necessitating careful patient selection and evidence-based practice. The complex regulatory history in the U.S. and the evolving safety profile in the E.U. underscore that even for a well-established drug, the process of understanding its full clinical impact is continuous, demanding ongoing research and vigilant clinical oversight.

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