Differential Effects Of Progestins Research Articles

Human and Zebrafish Nuclear Progesterone Receptors Are Differently Activated by Manifold Progestins.

The environmental risk of natural and synthetic ligands of the nuclear progesterone receptor (nPR) has been pointed out, however there is still a lack of mechanistic information regarding their ability to interact with nuclear PR in aquatic species. To identify possible interspecies differences, we assessed in vitro the ability of manifold progestins to transactivate zebrafish (zf) and human (h) PRs, using two established reporter cell lines, U2OS-zfPR and HELN-hPR, respectively. Reference ligands highlighted some differences between the two receptors. The reference human agonist ligands promegestone and progesterone induced luciferase activity in both cell lines in a concentration-dependent manner, whereas the natural zebrafish progestin 17α,20β-dihydroxy-4-pregnen-3-one activated zfPR but not hPR. The potent human PR antagonist mifepristone (RU486) blocked PR-induced luciferase in both cell models but with different potencies. In addition, a set of 22 synthetic progestins were screened on the two cell lines. Interestingly, all of the tested compounds activated hPR in the HELN-hPR cell line, whereas the majority of them acted as zfPR antagonists in U2OS-zfPR. Such zfPR-specific response was further confirmed in zebrafish liver cells. This study provides novel information regarding the activity of a large set of progestins on human and zebrafish PR and highlights major interspecies differences in their activity, which may result in differential effects of progestins between fish and humans.

Differential effects of progestins on the circulating IGF-I system

Objective: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. Method: All available reports on the effects of different forms of HRT have been taken into account. Results: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects—the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)—tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. Conclusion: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

Differential effects of progestins on the brain

Interactions exist between progestins and the γ-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 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 breast tissue enzymes

There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E 2) from circulating precursors. Two principal pathways are implicated in the final steps of E 2 formation in breast cancer tissue: the ‘aromatase pathway’ that transforms androgens into estrogens and the ‘sulfatase pathway’ that converts estrone sulfate (E 1S) into estrone (E 1) via estrone sulfatase. The final step is the conversion of weak E 1 to potent biologically active E 2 via reductive 17β-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 E 2 effects in breast cancer is to use anti-estrogens, which act by binding to the estrogen receptor (ER). Another option is to block E 2 using anti-enzymes (anti-sulfatase, anti-aromatase, or anti-17β-hydroxysteroid dehydrogenase (17β-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 17β-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.

Effects of progestins on cardiovascular diseases: the haemostatic system.

The effect of progestin-only therapy on the haemostatic system has mainly been studied in premenopausal women. Although these studies are difficult to compare, most authors agree that there is no consistent pattern of effects on haemostasis. Oestrogen-progestin combinations have been extensively studied in pre- (combined oral contraceptives) and postmenopausal women (sequential and continuous combined hormone replacement therapy), but mostly with emphasis on the effects of oestrogens. Comparative studies into the differential effects of progestins in combined preparations are scarce. Based on these studies, there is evidence for modifying effects of progestins on oestrogen-induced changes, particularly on fibrinogen, factor VII and the fibrinolytic system. The modifying effects appear to vary among certain progestins, the variation being most likely due to differential effects on lipid metabolism. The clinical interpretation of steroid-induced effects on the haemostatic system is difficult. Retrospective analyses linking certain patterns of haemostatic regulation to the risk of venous or arterial vascular diseases are subject to bias, and no interventional studies are yet available. In the absence of such prospective studies and well-designed comparative studies, the available data do not support the notion of a superiority of certain progestins with regard to cardiovascular risks of combined preparations.

Differential Effects of Progestins and Estrogens on Long Control Regions of Human Papillomavirus Types 16 and 18

We have studied effects of a series of progestins and estrogens on regulation of human papillomavirus (HPV) types 16 and 18 gene expression via long control region (LCR), using a transient expression assay which represented the episomal state of HPVs in precancerous lesions. Results showed that HPV gene expression induced by these steroid analogs were diverse. Gene expression via HPV16-LCR was up-regulated 2-3 fold under treatment with 10−7M estriol, 17β-estradiol, and several progestins including pregnenolone, 17α-hydroxy-progesterone, norethynodrel and cyproterone acetate. However, transcription via HPV18-LCR was not or weakly stimulated by these analogs. Our results can divide these analogs into HPV-enhancing and HPV-nonenhancing groups and accordingly impact the relative risk of individual oral contraceptive ingredient in cervical carcinogenesis.