Pharmacological profile of progestins

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as “pure” progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone^® is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.     

Routes of delivery for progesterone and progestins

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies.     

Differential effects of progestins on hemostasis

Recently large, prospective, randomized studies on hormone replacement therapy (HRT) have indicated that the progestin use might interfere with hemostasis and thus increase venous thrombotic events. Therefore, available publications were evaluated to determine whether progestins interfere with hemostasis, either when given alone via oral or parenteral routes or in combination with ethinylestradiol as synthetic estrogen or natural estrogens. There are indications that such interference is dependent upon the type and dose of the progestin, the route of application, the length of treatment and the type and dose of the estrogen with which it is combined. For natural progesterone, no negative effects on the hemostatic system were seen with either oral or parenteral application, in cyclic or continuous regimens, for the doses investigated. Similarly, no unwanted effects were seen with progestin only pills (POP), independent of the type and dose of progestin, or parenteral progestins. With the high-dose progestins used in gynaecological oncology, the increased activation of the hemostatic system resulting from the disease itself has to be taken into account when looking at any increased incidence of thromboembolic events in these patients. For estrogen/progestin combinations, the risk of venous thromboembolism is attributed to the estrogen used. Recent studies showed an increased rate of thromboembolic events in association with desogestrel-and gestodene-containing oral contraceptives, compared with those containing levonorgestrel. With HRT, a decrease in antithrombin factors could explain the increased rate of venous thrombotic events. In conclusion, progestins seems to have different effects on the hemostatic system due to their different pattern of biological activities. This was also shown in the arterial vascular system, where some progestins may reduce the endothelium-dependent vasodilating action of estrogens and stimulate intima proliferation and upregulate thrombin receptor expression while other progestins did not.     

Differential effects of progestins on the brain

Interactions exist between progestins and the gamma-aminobutyric acid (GABA) receptor subtype A where C(21)-steroids function as activators. Other interactions between progesterone and neurotransmitter systems include stimulation of dopamine release in striatal tissue, stimulation of GnRH release from hypothalamic neurons and inhibition of opioid receptor binding and activation. Cyproterone acetate increases dopaminergic responses and binds to opiate receptors independently of its classical effect on the androgen receptor. Progesterone substitution in perimenopausal women promotes length and quality of sleep. This effect seems most prominent for progesterone administered vaginally. Progestins also play a role in the pathogenesis of migraine. Migraine symptoms occur predominantly during the perimenstrual stage. Women who suffer from menstrual migraine triggered by premenstrual progesterone loss often benefit from cyclic progesterone administration. This may be because progesterone and allopregnenolone reduce meningeal release of substance P and inhibit the development of neurogenic oedema. Women whose migraine symptoms subside during pregnancy, however, benefit from intramuscular medroxyprogesterone acetate. Progesterone, generated from pregnenolone by Schwann cells, also enhances myelin synthesis. Myelination of axons is promoted when progesterone is added to cultures of rat dorsal root ganglia. No reliable data exist with respect to the effects of other progestins on demyelinating disease. Progestins promote the growth of meningioma as progesterone receptors predominate in meningioma tissue. Progesterone and synthetic progestins should therefore not be prescribed in these patients.     

Differential effects of progestins on breast tissue enzymes

There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E2) from circulating precursors. Two principal pathways are implicated in the final steps of E2 formation in breast cancer tissue: the 'aromatase pathway' that transforms androgens into estrogens and the 'sulfatase pathway' that converts estrone sulfate (E1S) into estrone (E1) via estrone sulfatase. The final step is the conversion of weak E1 to potent biologically active E2 via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. One of the possible means of blocking E2 effects in breast cancer is to use anti-estrogens, which act by binding to the estrogen receptor (ER). Another option is to block E2 using anti-enzymes (anti-sulfatase, anti-aromatase, or anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD). Various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, 17-deacetyl norgestimate, dydrogesterone and its 20-dihydro derivative), as well as tibolone and its metabolites, have been shown to inhibit estrone sulfatase and 17beta-hydroxysteroid dehydrogenase. Some progestins and tibolone can also stimulate sulfotransferase activity. These various progestins may therefore provide a new option for the treatment of breast cancer.     

Overview on the effects of progestins on bone

In view of the fact that fractures are the clinically relevant events, risk factors for fractures are discussed first. Bone mineral density (BMD) appears to be a much less important risk factor for the most severe hip fractures than the risk of falling. No results of experimental studies on hormones and fractures at advanced age are available. An overview of the effects of progestins on bone is given. Effects of progestins on bone have been studied by in vitro experiments using cell lines and by more relevant clinical observations. Prospective studies have been conducted following the use of progestins contained in oral contraceptives, alone or in combination with oestrogens; long-term contraception by injection of depot preparations; so-called "add-back" hormonal therapy attempting to reverse the adverse effects of gonadotropin releasing hormone agonists on bone and after different regimens of hormone replacement therapy (HRT) in postmenopausal women. From the data there are no indications that the various progestins, used in clinical practice, have either a bone-protective or an oestrogen antagonistic activity. Progestins do not add or subtract much of the protective action of oestrogens on the bones.     

The differential effects of oestrogens and progestins on vascular tone.

The purpose of this paper is to present reported findings of the effects of ovarian steroids on vascular tone. The medical literature was reviewed for relevant contributions. Oestrogen replacement therapy in postmenopausal women is associated with a reduction in mortality from coronary artery disease. Many different cellular actions have been described which help explain the cardioprotective effects of oestrogens, and among these are effects on vascular tone. Oestrogens induce vasodilation through mechanisms involving the arterial endothelium and through endothelial-independent actions. Progestins have varying effects on arterial tone, including induction of vascular smooth muscle relaxation as well as induction of smooth muscle constriction. The effects of oestrogens and progestins on vascular tone are clinically meaningful. Pathophysiological arterial conditions, including angina pectoris and migraine headaches, have been associated with oestradiol deficiency and improvement has been associated with oestradiol replacement. Women with coronary artery disease show improved arterial vasodilator responses after oestradiol treatment which can be reduced by the addition of progestin treatment. Androgens are also vasoactive. Study of the effects of ovarian hormones on vascular tone has become an important area for basic and clinical research.     

The relative effects of progesterone and progestins in hormone replacement therapy

Hormone replacement therapy (HRT) was initially given to protect women against osteoporosis and alleviate menopausal symptoms, such as hot flashes, depression, sleep disturbances, and vaginal dryness. In view of the understanding of oestrogen deficiency as a major trigger for the acceleration of cardiovascular risk after menopause, HRT may also be proposed as a substantial beneficial cardioprotective agent. Progestins, which may be added to oestrogen in combined HRT to reduce the risk of uterine malignancy, have a number of potential adverse effects on the cardiovascular system which could even attenuate the benefit of unopposed oestrogen replacement therapy in post-menopausal women.     

Actions of progestins on estrous behaviour in female rats

The present study evaluated the facilitative actions of progesterone and the synthetic progestin R 5020 on estrous responsiveness in ovariectomized, estrogen-primed female rats. The dose-response and time-response characteristics of the behavior facilitating actions of both progesterone and R 5020 were measured. The threshold doses for the facilitation of estrous behavior in estrogen-primed female rats were 1 microgram of R 5020 and 100 micrograms of progesterone. These doses of progestins facilitated estrous responsiveness with a similar time course that approached maximum at one hour. To examine the possible mechanism(s) of action of each progestin the synthetic progestin antagonist RU 38486 was used. The inhibitory effects of RU 38486 on estrous behavior facilitated by a threshold dose of progesterone or R 5020 were found to be almost identical. RU 38486 (5 mg) administered 1 hr prior to progesterone or R 5020 suppressed lordosis behavior by 44% and 47% respectively. These results suggest that progesterone and R 5020 facilitate estrous responsiveness through the same mechanism.     

Synthetic progestins and sweetness preference in intact female Sprague-Dawley rats

Intact Sprague-Dawley female rats were treated with 0.25 μg or 1.25 μg ethinyl-estradiol (EE) in combination with one of 3 synthetic progestins: (5 μg) norethindrone, norethynodrel, or norgestrel. In Experiment 1 both dosages of EE in combination with the synthetic progestins suppressed sweetness preference, with a somewhat greater effect for the 1.25 μg EE dosage. Norgestrel in combination with EE produced the longest suppression of sweetness preference. In Experiment 2 progestins administered in the absence of EE showed no significant effect on sweetness preference. When 1.25 μg EE was administered singularly, a significant decline in sweetness preference occurred, but not as great a decline as in combination with a progestin.     

Mechanisms of relaxation of rat aorta in response to progesterone and synthetic progestins

Objective: To compare the acute effects of progesterone, chlormadinone acetate (CMA), norethisterone acetate (NETA) and dienogest (DNG) with those of 17β-estradiol (17β-E₂) on the vascular reactivity of male rat thoracic aorta. Methods: Aortic rings with or without endothelium were placed in an organ bath for isometric tension recording. The integrity of the endothelium was assessed by the relaxant response of precontracted rings to acetylcholine (1 and 10 μM), which was diminished after mechanical removal of the endothelium. The concentrations of the steroid hormones were 0.01–10 μM. Results: In vessels precontracted with phenylephrine (1 μM), CaCl₂ (3 mM) or KCl (30 mM), progesterone, CMA and NETA (10 μM each) an endothelium-independent relaxation of 20–35% resulted, with a maximum response after 20–30 min, while DNG had a negligible effect in all experiments. The same concentration of 17β-E₂ was twice as potent as the progestins. Indomethacin, the cyclooxygenase inhibitor and glibenclamide, an inhibitor of the ATP-sensitive potassium channels, did not affect the relaxant responses. The antagonists of progesterone receptors J 867 (1 μM) as well as of estrogen receptors ICI 182780 (1μM) did not counteract the relaxation induced by progesterone and 17β-E₂, respectively. Progesterone (10 μM) did not interfere with endothelium-dependent acetylcholine-induced relaxation of precontracted aortic rings. Pretreatment of the vessels with the hormones attenuated the maximal contractile response to phenylephrine. In the presence of verapamil (1 μM) or progesterone (10 μM) or 17β-E₂ (1 and 10 μM) the concentration-response curves for calcium-induced contractions in K⁺-depolarized vessels were shifted to the right, with suppression of the maximum response. Conclusions: These studies suggest that in addition to 17β-E₂ the progestins, progesterone, CMA and NETA caused a reduction of vascular tone, probably due to blockade of voltage-dependent and/or receptor-operated calcium channels.