Dydrogesterone
[CAS# 152-62-5]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones >> Estrogen/progestogen receptor agonist
• Name: Dydrogesterone
• Synonyms: (9beta,10alpha)-Pregna-4,6-diene-3,20-dione; 17-Acetyl-10,13-dimethyl-1,2,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one
• Molecular Formula: C₂₁H₂₈O₂
• Molecular Weight: 312.45
• CAS Registry Number: 152-62-5
• EC Number: 205-806-8
• SMILES: CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@@H]3[C@H]2C=CC4=CC(=O)CC[C@@]34C)C

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 462.8±45.0 ºC 760 mmHg (Calc.)^*
• Flash point: 172.2±25.7 ºC (Calc.)^*
• Solubility: 10 mM in DMSO (Expl.)
• Index of refraction: 1.557 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08;GHS09 Danger
• Hazard Statements: H372-H410
• Precautionary Statements: P260-P264-P270-P273-P319-P391-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Reproductive toxicity	Repr.	1B	H360

Discovory and Applicatios

Dydrogesterone, with the molecular formula C₂₁H₂₈O₂ and CAS number 152-62-5, is a synthetic progestogen used in hormone replacement therapy and for treating gynecological disorders. Structurally, it is a retroprogesterone, characterized by a 6,7-double bond and a 9,10-alpha configuration, distinguishing it from natural progesterone. Its discovery and applications are well-established in the literature, rooted in the development of synthetic steroids for medical use.

The discovery of dydrogesterone emerged from the mid-20th century efforts to develop synthetic progestogens with improved oral bioavailability and specificity compared to progesterone. In the 1950s, researchers at Philips-Duphar (later Solvay Pharmaceuticals) in the Netherlands synthesized dydrogesterone as part of a program to modify the progesterone scaffold. By introducing a double bond between carbons 6 and 7 and altering the stereochemistry at the 9,10-position, they created a molecule with enhanced stability and progestogenic activity. The retroprogesterone structure was found to mimic progesterone’s effects on the endometrium while avoiding significant androgenic or estrogenic side effects. Dydrogesterone was first introduced in the 1960s under the brand name Duphaston, addressing the need for effective treatments for menstrual disorders, infertility, and pregnancy complications. Its development built on advances in steroid chemistry, particularly in selective hydrogenation and isomerization techniques.

Synthetically, dydrogesterone is prepared from a steroidal precursor, typically derived from plant-based sapogenins like diosgenin. A common route starts with progesterone or a related pregnane derivative, which undergoes photochemical or chemical isomerization to invert the 9,10-configuration, forming the retroprogesterone backbone. The 6,7-double bond is introduced via selective dehydrogenation, often using reagents like chloranil or selenium dioxide. The 17-alpha-acetyl group is retained, while the 3-keto group is preserved to maintain progestogenic activity. Key steps include stereoselective reductions and oxidations to ensure the correct configuration at critical chiral centers. These processes rely on well-established protocols in steroid synthesis, optimized to achieve high purity and yield. The final product is a crystalline solid, formulated into tablets for oral administration.

The primary application of dydrogesterone is in gynecological and obstetric medicine. As a progestogen, it supports the maintenance of pregnancy by promoting endometrial development and preventing uterine contractions, making it effective for treating threatened or recurrent miscarriage and luteal phase defects. It is also used to manage menstrual disorders, such as dysmenorrhea, irregular cycles, and premenstrual syndrome, by stabilizing the endometrium. In hormone replacement therapy, dydrogesterone is combined with estrogens to protect the endometrium from hyperplasia in postmenopausal women, offering a favorable safety profile due to its lack of androgenic, estrogenic, or glucocorticoid activity. Additionally, it is prescribed for endometriosis and infertility caused by progesterone deficiency, supporting implantation and early pregnancy. Its oral bioavailability, attributed to the retroprogesterone structure, allows effective dosing without the need for injections, unlike natural progesterone.

In academic research, dydrogesterone is studied for its pharmacological properties, including its selective binding to progesterone receptors and minimal off-target effects. Its role in reproductive medicine has driven investigations into progestogen mechanisms, endometrial physiology, and pregnancy maintenance. The compound’s synthesis has contributed to advancements in retrosteroid chemistry, particularly in controlling stereochemistry and introducing double bonds in steroidal frameworks. Clinically, dydrogesterone is valued for its efficacy and tolerability, with studies confirming its safety in long-term use and pregnancy.

The significance of dydrogesterone lies in its role as a potent, selective progestogen that addresses critical needs in women’s health. Its development reflects progress in steroid synthesis and gynecological therapeutics. By providing effective, orally active treatment for a range of hormonal disorders, it has become a cornerstone in reproductive medicine and hormone therapy.

References

2019. Cross-linked hyaluronan gel to improve pregnancy rate of women patients with moderate to severe intrauterine adhesion treated with IVF: a randomized controlled trial. Archives of Gynecology and Obstetrics, 300(6).
DOI: 10.1007/s00404-019-05368-6

2018. Does anti-Mullerian hormone predict the outcome of further pregnancies in idiopathic recurrent miscarriage? A retrospective cohort study. Archives of Gynecology and Obstetrics, 298(5).
DOI: 10.1007/s00404-018-4946-7

2008. Advances in hormone replacement therapy: making the menopause manageable. BMC Women's Health, 8(1).
DOI: 10.1186/1472-6874-8-22