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.     

Exogenous progestagens and the human breast

The role of progestins (or progestagens) on the breast tissue remains controversial. However, according to the molecule and the duration of application, cell differentiation and apoptosis may predominate over proliferation. Progestins are also used as second-line agents for the treatment of metastatic breast cancer. In young women with benign breast disease, long-term treatment with 19-nortestosterone progestins had a trend to decrease breast cancer risk contrarily to what was observed in postmenopausal women receiving estrogens. Several compounds with progestational activity have been used for HRT. Small differences in the structure of the molecules may lead to pronounced differences in activities, some progestins exerting androgenic effects and some exerting estrogenic or glucocorticoid like activities. While most progestins do not bind to the estrogen receptors, it has been shown that some androgenic progestins stimulate MCF7 cells proliferation while progestins derived from progesterone did not induce cell multiplication in the same cell lines. Therefore, different progestins may induce different effects on the breast cells. Whether the progestins available to date are able to bind specifically to the progesterone receptors PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is still unclear. Although the relationship between progestin use and breast cancer risk is still the subject of debate and controversy, the data reported to date suggest that 5 years of treatment carry a low risk but further duration of use increases the risk. Further studies are still needed, randomised long-term prospective studies as well as from the laboratory, especially to determine whether a sequential or continuous regimen would be preferable as far as breast-cell response and apoptosis are concerned, and what are the effects of the various molecules used for HRT.     

Progestogens in hormonal replacement therapy: new molecules, risks, and benefits.

While the benefits of progestogen use in hormone replacement therapy (HRT) are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. Several risks are attributed to progestogens as a class-effect; however, the progestogens used in HRT have varying pharmacological properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones (Nestorone, nomegestrol acetate, trimegestone), do not bind to the androgen receptor and, hence, do not exert androgenic side effects. Newly synthesized molecules such as drospirenone or dienogest have no androgenic effect but do have a partial antiandrogenic effect. Drospirenone derives from spironolactone and binds to the mineralocorticoid receptor. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on the lipid profile as well as the vasomotion. On the other hand, other progestogens devoid of androgenic properties do not exert these deleterious effects. The epidemiological data do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease, HRT may not protect against further heart attacks when the progestogen selected possesses androgenic properties. The data related to the progestogen effect on breast tissue has been interpreted differently from country to country. However, it has been admitted that, according to the type of progestogen used and the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any significant difference between the estrogens given alone or combined with progestogens in HRT. Complying with the classic contraindications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.     

The pharmacology of dienogest

Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position, which may make the compound elicit fewer hepatic effects than other C-19 nortestosterone derivatives. Its similarity to norethisterone is reflected in its high endometrial efficacy, which could explain the high stability of the menstrual cycle women achieve when they use DNG in combination with ethinyl estradiol (EE) or with estradiol valerate (E2V). Its strong endometrial efficacy underlies the use of DNG (on its own) to treat endometriosis, and gives it antiproliferative and anti-inflammatory effects in the treatment of endometriotic lesions. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. However, DNG also has some of the properties of typical of progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity, the latter increased by its lack of affinity to the sex-hormone binding globulin (SHBG), in contrast to other C-19 progestogens. DNG has no glucocorticoid and no antimineralocorticoid activity. It also has no antiestrogenic activity, which suggests that it should not antagonize estradiol's beneficial effects. This is important for its use in the treatment of endometriosis, because, due to DNG's low gonadotropic activity, E2 levels are not decreased to zero, in contrast to treatments with gonadotropin-releasing hormone (GnRH) analogues. This maintenance beneficial E2 effects is of particular importance for the general tolerability of the first contraceptive pill to use E2V instead of EE, although clinical endpoint studies are still ongoing. These studies are expected, on the basis of its pharmacology, to demonstrate the cardiovascular safety of the new pill.     

Lack of stimulatory effect of dienogest on the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by endothelial cell as compared with other synthetic progestins

Objectives: Monocyte adhesion to endothelial cells is an important initial event at the onset of atherosclerosis. It is partially mediated by the expression of adhesion molecules on the endothelial cell surface. While estrogens inhibit the development of atherosclerosis, the effect of co-administered progestin remains controversial. We examined the effect of progestins on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules. Methods: In HUVECs, mRNA expression of progesterone receptors (PRs) and androgen receptors (AR) was determined by RT-PCR. HUVECs were stimulated by interleukin-1β (IL-1β) for 24 h with or without various steroids, and then the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was semiquantified by ELISA. Results: In all preparations of HUVECs used in this study, RT-PCR confirmed mRNA expression of both isoforms of PR, PR-A and PR-B, as well as AR. Addition of progesterone (10⁻¹⁰–10⁻⁷ M) or dienogest (DNG) (10⁻¹⁰–10⁻⁸ M) did not affect IL-1β-stimulated ICAM-1 or VCAM-1 expression. In contrast, medroxyprogesterone acetate, norethindrone acetate and levonorgestrel (10⁻¹⁰–10⁻⁸ M) dose-dependently increased cell adhesion molecules. The progestin-induced increase was blocked by the concomitant addition of mifepristone, a PR antagonist, but not by hydroxyflutamide, an AR antagonist, indicating that the progestin stimulation was mediated predominantly via PR. Conclusions: These results suggest that DNG, unlike other synthetic progestins, lacks stimulation of cell adhesion molecules. For the prevention of atherosclerosis, estrogen in combination with DNG may be a suitable regimen in hormone replacement therapy in postmenopausal women.     

Androgenic progestins amplify the breast cancer risk associated with hormone replacement therapy by boosting IGF-I activity.

Recent epidemiology indicates that unopposed oral estrogen replacement therapy has a surprisingly small impact on breast cancer risk--little if any in overweight women--whereas combined regimens featuring synthetic progestins are attended by a much larger increase in this risk. These findings may reflect the fact that oral estrogen acts on the liver to down-regulate systemic IGF-I activity, whereas concurrent administration of androgens--including the androgenic progestins often used in replacement therapy--abrogates this effect. Increased systemic IGF-I activity has been linked to increased breast cancer risk, and may be largely responsible for the greater incidence of breast cancer in overweight postmenopausal women--who thus should have the most to gain from suppression of IGF-I activity by oral estrogen. Down-regulation of IGF-I may likewise account for the marked reduction in colon cancer risk associated with current estrogen replacement therapy. Fortunately, natural progesterone--now available in micronized oral preparations--does not oppose the hepatic effects of oral estrogen, and moreover may be preferable to androgenic progestins with respect to vascular function. Oral replacement therapy featuring micronized progesterone, if administered throughout postmenopausal life, can be expected to have a highly positive impact on vascular health, bone density, and risks for Alzheimer's disease and colon cancer--benefits which, in most women, may vastly outweigh the associated increase in risk for breast and endometrial cancers.     

Effect of megestrol caproate on the reproductive function of laboratory animals

In vivo experiments on rats and rabbits showed that megestrol caproate, a 17-alpha-hydroxyprogesterone derivative exhibits 10-fold higher gestagenic activity compared to progesterone and possesses no androgenic, anabolic, and estrogenic activities.     

Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors

BACKGROUND: Progestins have actions on the cardiovascular system, which depend on the structure as well as on receptor binding characteristics. Drospirenone (DRSP) is a progestin that uniquely interferes with the signaling of the mineralocorticoid receptor (MR). Hormone therapy containing DRSP results in blood pressure reduction in hypertensive post-menopausal women. METHODS: We describe the effects of DRSP on endothelial nitric oxide (NO) synthesis and compare them with those of progesterone (P) and of medroxyprogesterone acetate (MPA). In addition, we herein tested the relevance of the anti-mineralocorticoid activity of DRSP for NO synthesis. RESULTS: DRSP results in rapid activation of the endothelial NO synthase (eNOS) through mitogen-activated protein kinases and phosphatidylinositol 3-kinase as well as in enhanced eNOS expression. These actions depend on P receptor. When the cells are exposed to aldosterone, a reduction of eNOS expression is found that is antagonized by DRSP. This action is not shared by P or MPA. In addition, DRSP does not interfere with the induction or activation of eNOS induced by estradiol, as opposed to MPA. CONCLUSIONS: DRSP acts on endothelial cells via a combined action through the P and MRs. These results help to interpret the anti-hypertensive effects of hormonal therapies containing DRSP.     

Inactivation of contraceptive steroid hormones by human intestinal clostridia.

Steroid hormones reduced in ring-A are devoid of hormonal activity. In metabolic experiments we found that human fecal flora reduced the delta 4-3-keto structure of natural progestins to 3 alpha-hydroxy, 5 beta-steroid metabolites (3 alpha,5 beta) and of synthetic progestins to a mixture of 3 alpha,5 beta and 3 beta,5 beta compounds. 3 alpha,5 beta-Reductase was synthesized by Clostridium paraputrificum and had a strong affinity for natural progestins such as progesterone. 3 beta,5 beta-Reductase was synthesized by Clostridium innoculin and had a stronger affinity for synthetic progestins. A third enzyme, 3 beta,5 alpha-reductase, was synthesized by St. Luke's strain 209 (Clostridium species "J-1") but was only observed when pure cultures were used. Ring-A reduction of synthetic progestins was 3 to 10 times slower than that of natural progestins, thus explaining the pharmacological superiority of synthetic progestins over naturally occurring analogs.     

Effects of various combined oral contraceptives on sex steroids, gonadotropins and SHBG

In women with preexisting virilization, it is advisable to prescribe contraceptive agents that do not provoke a further increase in free circulating androgens. This study evaluated the influence of 3 gestagens without androgenic effects on the endogenous sex hormone equilibrium and sex hormone-binding globulin (SHBG) concentrations. 122 women were administered 4 different combined contraceptives for up to 6 cycles. The estrogen component of each of the 4 preparations was estradiol estrogen (EE), while the gestagens were desogestrel (in 2 formulations in 2 different dosages), cyproterone acetate, and chlormadinone acetate. Most subjects had irregular cycles before treatment, and exhibited seborrhea, acne, and hirsutism. Luteinizing hormone, follicle-stimulating hormone, estrone, estradiol, progesterone, free testosterone, and dehydropeiandrosterone-sulfate levels were significantly reduced in all 4 treatment groups during tablet intake. However, SHBG concentrations increased in a highly significant manner during treatment. The elevation of SHBG is an expression of increased hepatic synthesis induced by EE. Concentrations of circulating SHBG determine the balance between estrogens and androgens. Since SHBG binds androgens better than estrogens, it effectively monitors androgenic activity. Because of their role in significantly lowering the active fraction of androgens, the preparations studied are considered appropriate contraceptives for androgenized women.     

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites.     

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.     

Progestogens and brain: An update

Each synthetic progestins has its own specific activities on different tissues, which can vary significantly between progestins of different classes and even within the same class. Indeed, different progestins may support or oppose the effects of estrogen depending on the tissue, thereby supporting the concept that the clinical selection of progestins for HRT is critical in determining potential positive or detrimental effects. These actions might be particularly relevant in the central nervous system (CNS) where progesterone (P) has pivotal roles besides reproduction and sexual behavior, going from neuropsychological effects to neuroprotective functions. Growing evidence supports the idea that synthetic progestins differ significantly in their brain effects, and clinical studies indicate that these differences also occur in women. Molecular and cellular characterization of the signaling properties of synthetic progestins in brain cells is therefore required and is hoped will lead to a better clinical utilization of the available compounds, as well as to new concepts in the engineering of new molecules. The aim of the present paper is to briefly review and compare neuroendocrine effects of progestogens with special reference to P metabolism into neuroactive steroids and the opioids system.     

Effects of androgens on haemostasis

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such as danazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone, an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostasis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations with pronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.     

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.     

Effects of androgens on haemostasis

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such as danazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone, an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostatis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations with pronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.     

Antiestrogen action of progesterone in the breast

This review analyzes recent data from international literature concerning the antiestrogen action of progesterone, progestins and the antiprogesterone RU 486 at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone, progestins and even RU 486 have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.     

Classification and pharmacology of progestins

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.     

Uses of DHEA in aging and other disease states

Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of pre-menopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically DHEA might be useful for improving psychological well-being in the elderly, reducing disease activity in people with mild to moderate systemic lupus erythematosus and myotonic dystrophy, improving mood in those clinically depressed, and improving various parameters in women with adrenal insufficiency. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials have clearly substantiated the utility and safety of long-term DHEA supplementation.