Gestrinone

2021-01-29

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 7


Pharmacodynamics


Gestrinone is a synthetic steroidal hormone which has androgenic, anti-estrogenic and anti-progestogenic properties 10. 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 1,2.

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 8.

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 8.

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 4.

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 4.

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 4.



Mechanism of action



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 11.

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 11.

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 5.


Metabolism


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 6,9,11.


Toxicity


Many of gestrinone's adverse effects occur due to its androgenic activity. These effects include acne, seborrhea, hirsutism, weight gain and deepening of the voice. Most patients develop at least one adverse event while taking this drug. This is because the drug is embryotoxic in some animals and may also cause masculinization of a female fetus. Gestrinone significantly reduces HDL concentrations 8.

It is advisable to monitor liver transaminases and cholesterol levels in hyperlipidemic patients, as well as glucose in diabetic patients. Gestrinone has shown to decrease in the concentration of thyroid-binding globulin. Therefore, a decrease in serum total thyroxine levels is commonly observed. This is without clinical significance as free thyroxine levels and thyroid-stimulating hormone levels remain within the normal reference range