Progesterone and Progestins (progestogens)
Besides progesterone, the endogenous physiological progestin, there are several synthetic progestins whose properties are not completely similar to those of progesterone and which are used, especially in combination with ethinylestradiol, as hormonal contraceptives.
The progestational activity of progesterone is mainly: preparing the endometrium for ovum implantation and maintaining gestation in a castrated pregnant female. Progesterone has physiologically these two effects, but not all the synthetic progestins. Moreover, some have another hormonal activity, androgenic for example, being likely to elicit masculinization of the female fetus if they were given to pregnant woman.
Progesterone is synthesized primarily by the ovary and, to a lesser degree, by the testis, adrenal glands and the placenta during the second part of pregnancy. Moreover, a non-endocrine synthesis of progesterone, at the level of neurons in particular, is possible.
It is synthesized from cholesterol: under the influence of a desmolase, the cholesterol is converted to pregnenolone which, under the influence of a deshydrogenase and an isomérase, gives progesterone.
Progesterone secretion is not constant during the menstrual cycle: elicited by LH, it appears just before ovulation and continues during the second part of the cycle. Its fall at the end of the cycle plays a part in menstruation.
If there is fecundation, the trophoblast secretes the chorionic hormone which maintains in function the corpus luteum which secretes progesterone. From the third month of pregnancy, the placenta secretes estrogens and progesterone.
In plasma, progesterone is in free form and in bound form with albumin, with a glycoprotein and with transcortin. Its half-life is of approximately 30 minutes. In women its concentration during the follicular phase is low, of the same order as that found in men, but it rises considerably during the luteal phase.
Progesterone, a lipophilic molecule, is stored in adipose tissues from where a progressive release is possible.
The catabolism of progesterone is carried out primarily in the liver where, catalyzed by several enzymes, it is converted successively into pregnanedione, pregnanolone and finally pregnanediol.
Progesterone is itself a metabolic intermediary leading to testosterone, aldosterone and cortisol.
Progesterone acts on nuclear receptors and modifies the transcription of target genes.
- Progestational action
The essential function of progesterone is to prepare the uterus for nidation then to maintain gestation.
- At the level of endometrium, it induces the cessation of mitoses elicited by estrogens and the development of a secretory aspect favourable to implantation of the ovum. The endometrium is by far the richest tissue in progesterone receptors.
- In the myometrium, it has an anti-estrogenic action resulting in decrease of uterine contractility.
- In the cervix, it changes the cervical mucus which becomes viscous.
- In uterine tubes, it could slow down the transit of the ovum.
- On breasts, it acts in synergy with estrogens and pituitary hormones to induce the development of acini and to inhibit, after a transitory stimulation, the epithelial mitoses elicited by estrogens.
- Gonadostimulin secretion
Progesterone inhibits the secretion of pituitary gonadostimulins, but synthetic progestins are much more effective than progesterone. They reduce the frequency of the peaks of secretion and increase their amplitude.
- Androgenic and anti-androgenic effects
Progesterone has a very low androgenic and anti-androgenic activity which can be highlighted at very high doses. Administered at high dose to male castrated rats, it increases the weight of the prostate, androgenic action, but, administered at the same time as testosterone, it reduces the effect of the latter.
- Antiestrogenic effect
Progesterone acts by induction of the 17-hydroxysteroid dehydrogenase which accelerates the conversion of estradiol into estrone and by induction of estrogen sulfotransferase.
- Blastocyte implantation
It seems that the expression of LIF (leukemia inhibitory Factor), a pleiotropic cytokine, by the endometrium is dependant on progesterone. However, LIF appears to play an essential part in the differentiation and the implantation of the blastocyte (the fertilized egg divides and forms a crown of cells surrounding a central cavity, it is the blastocyte). Its deficiency could induce certain sterilities.
- Other effects, it causes:
- a temperature rise of approximately 0.5°C during the second part of the menstrual cycle.
- An anti-mineralocorticoid action by inhibition of aldosterone receptors, which induces a decrease of plasma sodium by increase in its urinary elimination.
- A sedating action by potentiating GABA effect on GABAA receptors.
- Probably a stimulant action on myelin synthesis.
Synthetic progestins are different from progesterone by several chemical modifications. There are derivatives of 17-a-hydroxyprogesterone, 19-norprogesterone and 19-nortestosterone. The “NOR” term is used when there is no methyl substitute in position 19.
The principal products used in therapeutics are medrogestone, chlormadinone, medroxyprogesterone, cyproterone, nomegestrol, demegestone, promegestone, norethisterone, lynestrenol, ethynodiol, norgestrienone, levonorgestrel.
They have progestational effects on the endometrium and are generally able to maintain gestation but they should not be used for this because they have other properties, different from those of progesterone, for example androgenic or anti-androgenic effects.
They inhibit ovulation, primarily by an inhibitory feedback effect. They decrease the migration of the spermatozoa through the cervical mucus. They can be used as contraceptives.
Synthetic progestins with no androgenic properties are desogestrel, gestodene and norgestimate.