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General Description:

Gestrinone, identified by CAS number 16320-04-0, is a notable compound with significant therapeutic applications. Gestrinone, also known as ethylnorgestrienone, is a synthetic steroid of the 19-nortestosterone group that is marketed in Europe, Australia, and Latin America, though not the United States or Canada, and is used primarily in the treatment of endometriosis. Gestrinone was developed in the early 1970s and was tested clinically as a weekly oral contraceptive in Europe and North America. Without significant advantages over other oral contraceptives and with its high cost, gestrinone was no longer used after the Stage II clinical trials. However, from 1982 this drug attracted increased interest due to significant therapeutic effects in the treatment endometriosis. Under different endocrine conditions, gestrinone possesses estrogenic, progestational, androgenic, antiestrogenic and antiprogesterone actions .

Indications:

This drug is primarily indicated for: Endometriosis with or without accompanying sterility. Treatment is limited to a single course of 6 months duration per lifetime . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Gestrinone undergoes metabolic processing primarily in: Gestrinone undergoes hydroxylation in the liver. Gestrinone is actively metabolized in the liver, mainly by hydroxylation, to conjugated metabolites 16b-hydroxy,13-ethyl (1-OH) and D-homo gestrinone. In vitro studies have shown that the metabolites are active but weaker than the unchanged drug . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Gestrinone are crucial for its therapeutic efficacy: The oral absorption of gestrinone is 30% ±30 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Gestrinone is an important consideration for its dosing schedule: Plasma half-life is 24 hr . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Gestrinone from the body primarily occurs through: About 40-45% of a dose is excreted in the urine and 30-35% in the feces . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Gestrinone is distributed throughout the body with a volume of distribution of: 67 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Gestrinone is a critical factor in determining its safe and effective dosage: Renal Excretion accounts for < 1 % . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Gestrinone exerts its therapeutic effects through: Gestrinone is a synthetic steroidal hormone which has androgenic, anti-estrogenic and anti-progestogenic properties . The findings of several studies suggest that gestrinone is as effective as danazol in the treatment of infertility associated with endometriosis and is better tolerated, in terms of adverse effects . Gestrinone has moderate anti-estrogen, and anti-gonadal properties, which can lead to increased concentrations of free testosterone, and decrease the level of sex hormone-binding globulin, suppress the FSH and LH hormone peak levels and decrease the LH mean to reduce estrogen levels. In addition, gestrinone has a direct effect on the endometrium and ectopic endometrial receptors, which have the roles of anti-progesterone and anti-estrogen effects lead to endometrial and ectopic endometrial atrophy to achieve therapeutic effects . Gestrinone inhibits the release of pituitary gonadotropins. The effect on ovarian hormone secretion results in the atrophy of endometrial tissue, resulting in the regression of endometriosis. Gestrinone is structurally related to norgestrel and possesses some androgenic and progestogenic activity. However, the gestrinone has an antiprogesterone effect on endometrial tissue . The effect of oral gestrinone, 2.5 mg biweekly for 6 months, was studied in a group of 11 women with mild or moderate endometriosis laparoscopically confirmed. Painful symptoms were alleviated in all patients within 8 weeks from the start of treatment. Gonadotropins, prolactin (PRL) 17 beta-estradiol (17 beta-E2), estrone (E1), progesterone (P), androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S) remained in the physiological follicular phase range . Total testosterone (TT) and sex hormone-binding globulin (SHBG) decreased, and free testosterone (FT) slightly increased. Metabolic studies showed a decrease in total triglyceride level, very low-density lipoprotein (VLDL) triglycerides, and high-density lipoprotein (HDL) and VLDL cholesterol . Low-density lipoprotein cholesterol and apoprotein B were found to be increased during gestrinone therapy. It can be extrapolated that gestrinone possesses antiestrogenic, androgenic, and progestogenic effects at therapeutic dosages both by acting on both central and peripheral steroid receptors . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Gestrinone functions by: Gestrinone has weak agonist activity on progesterone receptors in the rabbit endometrium and progesterone antagonist activity in various other pharmacological test systems. In addition, it has moderate agonist activity on prostatic androgen receptors in vitro. In several in vivo experiments, this activity was found to be low . The primary action of gestrinone is on the hypothalamic-pituitary axis where it inhibits gonadotrophin release with a weak inhibitory effect on its synthesis. It also possesses anti-estrogen activity. The suppression of the ovular gonadotrophin peak is observed after the first month of treatment; the resulting decline in ovarian hormone secretion rapidly leads to endometrial atrophy. Aside from its central action, gestrinone also has anti-progesterone activity on cell receptors in both endometrium and extra-uterine ectopic implants. Gestrinone has no direct estrogen and/or uterotrophic effects . A study was done to examine the efficacy of gestrinone in emergency contraception. The data from the study suggest that the mechanism of action of gestrinone used for the purposes of emergency contraception is likely the inhibition of implantation by acting on the endometrium as opposed to the inhibition of ovulation . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Gestrinone belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane, classified under the direct parent group Estrogens and derivatives. This compound is a part of the Organic compounds, falling under the Lipids and lipid-like molecules superclass, and categorized within the Steroids and steroid derivatives class, specifically within the Estrane steroids subclass.

Categories:

Gestrinone is categorized under the following therapeutic classes: Adrenal Cortex Hormones, Antigonadotropins and Similar Agents, Contraceptive Agents, Female, Contraceptive Agents, Hormonal, Contraceptives, Oral, Contraceptives, Oral, Hormonal, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Fused-Ring Compounds, Genito Urinary System and Sex Hormones, Hormonal Contraceptives for Systemic Use, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Norpregnanes, Norpregnatrienes, Norsteroids, Progestin Contraceptives, Progestins, Reproductive Control Agents, Sex Hormones and Modulators of the Genital System, Steroids. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Gestrinone include:

• Melting Point: 150-152
• Boiling Point: 507.638