Different biological effects may be produced by administered progestogens, due to the specific influence of each progestogen and its metabolites on the conformation of the progestogen receptor and its subsequent activation of transcription in target cells.
Pharmacokinetics absorption, distribution, and excretion determine how much of the progestogen administered is available to tissues, primarily by measuring its blood level, and the amount that enters the cells is determined by the extent to which it is bound to carrier proteins that cannot cross the cell membranes.
After a progestogen enters the systemic circulation, it is distributed between blood and tissues by passive diffusion. The pattern of distribution of the progestogen is mainly regulated by its binding to transport proteins and tissue receptors. In the blood compartment, all progestogens are bound with low affinity and high capacity to albumin.
In addition, some of the progestogens that are structurally related to testosterone also bind with high affinity but low capacity to SHBG; they include norethindrone, levonorgestrel, etonogestrel, and gestodene 13 , 14 Table 2. A relatively smaller amount of progesterone is also bound with high affinity and low capacity, but not to SHBG; instead, it is bound to corticosteroid-binding globulin 15 Table 2. The binding of progestogens to transport proteins is reversible, so that a change in the concentration of a binding protein in one compartment is followed by a reequilibration of these compounds in that compartment.
Alterations in binding protein concentrations may contribute to the kinetic variability of a progestogen. It is well recognized that the non-protein-bound unbound or free fraction of a steroid is available for metabolism in steroid-metabolizing cells or binding to a receptor in target cells. However, because the binding of steroids to albumin is relatively weak, albumin-bound steroids are also generally considered to be available for metabolism or binding to receptors. There is a paucity of data on free and bioavailable albumin-bound plus free fractions of progestogens.
The most common route of progestogen administration for postmenopausal HT and steroidal contraception is oral, yet there is a paucity of information on the pharmacokinetics of progestogens by this route. Progestogens given orally generally reach a maximum concentration within 1—3 h; the maximum concentration and area under the curve are dose dependent. Information on bioavailability and half-life has been derived from frequent blood sampling during 24 h after oral dosing.
Half-life is the time in hours over which a drug's blood level drops to one half of its highest value after dosing. Approximate values taken from the literature 16 — 31 for bioavailabilities and half-lives of progestogens are summarized in Table 3.
Chlormadinone acetate, cyproterone acetate, and nomegestrol acetate have the longest half-lives Progesterone and other progestogens related to progesterone including MPA, megestrol acetate, dydrogesterone, and trimegestone have even shorter half-lives, ranging from 15—24 h. The longest half-life occurs with drospirenone Circulating levels and pharmacokinetic parameters of a progestogen given orally can vary considerably, by up to 5-fold or more, among women. Bioavailability can be significantly affected by age because of decreased hepatic cytochrome P content with aging, which reduces the extent of hepatic first-pass metabolism resulting in increased oral bioavailability.
Elderly women may also have reduced renal clearance of circulating drug as well as a volume of distribution that is enhanced for lipid-soluble drugs and diminished for water-soluble drugs.
To a lesser extent, pharmacokinetics can also vary within the same individual under different conditions. In an attempt to avoid the hepatic first-pass metabolism of progestogens, a variety of parenteral routes of administration have been used, which include im, vaginal, percutaneous, intranasal, sublingual, and rectal.
The limited data that exist concerning the pharmacokinetics of those that are more commonly used are discussed below. In one study, four doses 10, 25, 50, or mg of progesterone in oil were injected im in six postmenopausal women A typical depot effect was seen, with elevated progesterone levels persisting for 24—48 h.
Circulating progesterone levels similar to those seen in a normal menstrual cycle luteal phase could be achieved with a single mg im injection of progesterone in oil. A comparative study of vaginal and im administration of micronized progesterone found the intravaginal dosing to be an effective, acceptable, and convenient alternative to im injections In this study, 15 women received mg micronized progesterone intravaginally every 6 h, whereas another group of 15 women were given two im injections of 50 mg progesterone in oil, during a h period.
Endometrial progesterone concentrations in biopsies taken after 7 d of treatment were considerably higher after intravaginal than im dosing, despite the higher serum progesterone levels after im injection. This study highlights the potential importance of the vaginal route in menopausal HT, because the endometrium is the most important target of progesterone action in this application.
The use of progesterone in the form of transdermal delivery via topical creams or gels has been a subject of some concern because of speculation that the low serum progesterone levels achieved with these agents indicate an insufficient secretory effect on the endometrium The effects of topical progesterone creams on the endometrium should therefore be based on histological examination of the endometrium rather than on serum levels.
An important caveat with progesterone cream products that are readily available over the counter is that some of these products do not contain progesterone but instead contain wild yam extract in which the precursor for the synthesis of progesterone, diosgenin, is present. However, the chemical reactions required to convert the diosgenin in wild yam extract to progesterone can be carried out only in a laboratory and do not occur in the body.
Two different progestins, levonorgestrel and norethindrone acetate, are used in different transdermal systems, each in combination with estradiol. Both systems are adhesive-based matrix transdermal patches designed to release estradiol and levonogestrel or norethindrone acetate continuously for 7 or 3.
After its application, in one study, levonogestrel concentrations were maximal after approximately 2. The potential interaction of progestogens with other drugs has been the subject of numerous reports since the early s. Some interactions are well documented and therapeutically relevant; however, many remain unproven or are the subject of continuing controversy.
Strong evidence indicates that griseofulvin an antifungal drug , rifampin an antituberculosis drug , and certain anticonvulsants phenobarbital and phenytoin induce hepatic enzymes and decrease oral contraceptive OC effectiveness. An unproven, but widely accepted, drug interaction involves the effect of antibiotics on OC efficacy. Despite a number of reports implicating penicillins, tetracyclines, and other antibiotics in causing OC failure, no firm evidence links antibiotic administration with altered circulating levels of progestogens.
The intracellular actions of progestogens are mediated predominantly via the PR, a ligand-activated transcription factor and member of the steroid receptor and nuclear receptor families of receptors Progestins are designed to be potent, high-affinity PR agonists that mimic the actions of progesterone but with better bioavailability.
However, many progestins bind to other members of the steroid receptor family, which includes the androgen receptor AR , glucocorticoid receptor GR , and mineralocorticoid receptor MR , and exhibit off-target effects via these receptors 41 , Progestogens do not bind to the ER, the other member of the steroid receptor family.
It is not surprising that progestogens cross-react with several members of the steroid receptor family, because the PR, AR, GR, MR, and ER share significant amino acid homology in certain regions, while exhibiting a highly conserved overall domain structure.
These domains include an unconserved amino-terminal domain of variable length, a highly variable transcriptional activation function-1 TAF-1 domain situated near the N terminus, a highly conserved DNA-binding domain DBD , as well as a moderately conserved C-terminal ligand-binding domain LBD. The TAF-1 domain has been reported to be ligand independent and required for optimal transcriptional activity via protein-protein interactions with general transcription factors as well as cofactors The DBD, the most conserved domain of the steroid receptors, contains two zinc finger motifs and is responsible for sequence-specific and high-affinity DNA binding, as well as playing a role in receptor dimerization, interaction with cofactors 44 , and nuclear localization The LBD, toward the C terminus, determines ligand specificity and affinity, as well as playing a role in dimerization, nuclear localization, and interaction with chaperone proteins and cofactors 45 — A highly conserved TAF-2 domain is present within the LBD, which contains at least one cofactor interaction motif important for ligand-dependent transcriptional activity 46 , Progestogen action via steroid receptors is further complicated by the presence of several receptor isoforms for each receptor.
Similarly, other steroid receptors exist in several isoforms that exhibit differential expression profiles and functions 40 , 59 , The PR is expressed in the female reproductive tract, mammary gland, brain, and pituitary gland as well as some immune-function cells 61 , Ratios of the individual PR isoforms vary in the ovary, breast, and uterus 63 , where they have different physiological functions in various target cells 63 , 64 , most likely in part due to the distinct and promoter-specific transactivation effects of PR-A and PR-B The AR is expressed in the mammary gland, muscle, prostate, skin, vagina, bone marrow, and testes Thus, AR effects are likely to be responsible for differential progestogen actions in these tissues, particularly in the breast.
In contrast, the GR is ubiquitously expressed, although its levels are regulated in a tissue- and cell-cycle-specific manner Therefore, differential progestogen effects mediated by the GR are likely to occur in most tissues and in particular those where GR levels are high, such as in immune-function cells. Interestingly, GR levels have been shown to vary widely in different breast carcinoma subtypes 69 , suggesting a particularly important role of varying GR levels in the determination of effects of progestogens such as MPA in breast cancer.
The MR, although not as widely expressed as the GR, is also expressed in many tissues, including the kidney, colon, central nervous system, heart, adipocytes, and vascular cells 40 , 70 — Thus, physiological functions in these tissues are likely to be modulated selectively by progestogens via the MR.
To determine the affinity of a progestogen for a particular receptor, binding studies have been developed. These have been performed in a wide range of models including animal or human tissue, human cell lines expressing endogenous receptors, cell lines deficient in endogenous receptors but overexpressing exogenous human steroid receptors, or even in in vitro systems using recombinant purified human receptor.
Binding assays are usually performed using a constant concentration of radiolabeled reference agonist incubated with varying concentrations of unlabeled competitor test ligand to obtain an IC 50 for the competitor steroid. Affinities are usually expressed as relative binding affinity RBA , which is calculated by dividing the IC 50 of the test steroid by the IC 50 of the reference steroid, multiplying by , and expressing the RBA as a percentage.
RBAs are often only an approximate measure of relative affinity because IC 50 can vary with receptor concentration, concentration of radiolabeled steroid, and whether or not equilibrium has been reached for both steroids.
More accurate affinities can be obtained by determination of time to reach equilibrium for the steroids under investigation as well as by performing homologous and heterologous displacement assays with determination of equilibrium dissociation constants using the Cheng-Prusoff equation or by saturation binding analysis From Table 4 , which summarizes some of the available data on RBAs of progestogens to different steroid receptors, it is immediately apparent that the data show a wide variability.
One of the reasons for this is undoubtedly due to different methods used to determine affinity, as discussed above. Another source of variability is the use of different cell or tissue models, which vary in the relative concentrations of different steroid receptors. Off-target binding of the progestogen to receptors other than the one under investigation could effectively lower the apparent RBA, especially if the progestogen has a relatively high affinity for a competing receptor, because the concentration of unlabeled competitor progestogen available for binding to the target receptor will be effectively less than the added concentration.
Thus, experiments that determine equilibrium dissociation constants and those using cell lines deficient in endogenous receptors and overexpressing exogenous human steroid receptors or even in vitro systems using recombinant purified human receptor are likely to yield more accurate results. Another source of variability is the species from which tissue is obtained as well as the variation in age and pretreatment of the animal or human donor.
Note that direct comparisons between the values determined by competition binding using different reference radiolabeled agonists [ e. Nevertheless, despite these sources of error and variability in binding experiments, several valuable insights have been obtained.
RBAs were determined by competitive binding assays using a radiolabeled reference ligand and increasing concentrations of unlabeled competitor ligand and are based on IC 50 values in most cases a and b , whereas K i equilibrium dissociation constant for an unlabelled competitor or inhibitor ligand competing for binding of the radiolabeled reference ligand to the receptor values were determined by homologous and heterologous displacement and using the Cheng-Prusoff equation c Hormonal activities are based on animal experiments and taken from Refs.
All the steroids are progestogenic, and all exhibit antiestrogenic activity in animal models via a mechanism independent of the progestin binding to ER. None of them, except norethindrone, exhibits estrogenic activity 7. ND, Not determined. Values were compiled by cross-comparisons from several competitive binding studies that used different methods and were taken from Ref.
Most of the data are from animal tissues or cell lines expressing several receptors, and hence, some are likely to be inaccurate. Values were determined using recombinant human receptor binding in vitro RBAs were calculated from K i equilibrium dissociation constant for an unlabelled competitor or inhibitor ligand competing for binding of the radiolabeled reference ligand to the receptor values, determined by expressing the human recombinant GR in the A cell line 73 or the human recombinant AR or MR in the COS-1 cell line, both deficient in steroid receptors, using the methods outlined in Ref.
Although all progestogens bind with high relative affinity to the PR, most bind with a greater affinity than progesterone Table 4. As the natural progestational agent of all mammals, progesterone was an obvious choice as the reference steroid for many binding assays and was used in conjunction with [ 3 H]progesterone in competitive binding studies with PRs. More recently, the highly potent synthetic progestin, promegestone R , has replaced progesterone as the reference compound because most progestins have greater progestational activity than progesterone itself.
In the other study 76 , which used human uterine tissue instead of rabbit, norgestimate showed very little binding to the PR RBA, 0. This illustrates the difficulties of extrapolating animal RBA data to human tissues. Progestogens vary greatly in their reported affinities for the AR, with some of the older-generation progestins such as MPA, norethindrone, and levonorgestrel binding with high affinity relative to testosterone 77 — 86 , although some researchers report similar affinities for progesterone, MPA, norethindrone acetate, and DHT for the AR Table 4.
In contrast, drospirenone, dienogest, and trimegestone exhibit low RBA 74 , 87 , 88 , although reported relative values differ for several progestogens, whereas nesterone does not bind at all to the AR Progesterone, trimegestone, and drospirenone have a relatively high affinity for the MR Table 4 90 — The latter two progestogens were developed for their antimineralocorticoid properties for contraceptive usage 94 and for their predicted beneficial effects on blood pressure and cardiovascular function 31 , 90 , 95 , However, other progestins such as MPA and norethindrone acetate bind weakly to the MR 41 , whereas several progestins such as dienogest, nomegestrol acetate, and promegestone do not bind at all 87 , In contrast to PR and AR binding, relatively few progestogens bind to the GR with affinities in the significant pharmacological range, with the notable exceptions of MPA, gestodene, and nestorone Table 4.
Gestodene binds with a relatively high affinity to the GR However, progestins such as norethindrone, levonorgestrel, dienogest, and trimegestone, like progesterone, bind the GR with low relative affinity 31 , 73 , 74 , 82 , 87 , 88 , 99 , In summary, a major determinant of differential intracellular progestogen actions is the variable affinity of progestogens for binding to the PR and to other members of the steroid receptor family.
Affinities, together with concentrations of progestogens and competing endogenous ligands, determine receptor occupancy for a particular steroid receptor. Fractional occupancy is in turn a major determinant of the biological response. Although the equilibrium dissociation constants for a particular progestogen or endogenous ligand for a particular steroid receptor do not change 41 , the fractional occupancy of a receptor changes depending on ligand concentration, which in turn varies according to its relative affinity for, and concentrations of, the different steroid receptors present.
Although useful binding data are available, much of it may be inaccurate; additional experiments are required to more accurately determine equilibrium binding constants for most of the progestogens for different steroid receptors and their isoforms, in the absence of confounding factors such as the sources of the receptors, the methods of binding analysis, and the presence of off-target receptors.
Given that the relative levels of different receptors and their isoforms vary greatly in different tissues, this is also likely to be a major determinant of differential actions via progestogens. Progestogens exhibit considerable variation in their potencies and efficacies as well as the resulting extent of agonist, partial agonist, or antagonist responses, i.
Potency is defined in this context as the concentration of ligand required for half of the maximal biological response, whereas efficacy is the maximal induced response for that particular ligand Agonists, partial agonists, and antagonists all bind to a particular receptor, with an agonist resulting in an efficacy similar to that of the natural ligand, whereas a partial agonist gives a similar response to that of the natural ligand but with a lower efficacy, and an antagonist inhibits the response of an agonist.
Partial agonists and antagonists can exhibit varying degrees of antagonism depending on the relative concentrations of competing ligands and their affinities for a particular receptor as well as on receptor concentration. Much of the data on potency, efficacy, and biocharacter via different steroid receptors has been obtained from animal experiments 41 Table 4.
These data do reflect to some extent the actions of a progestogen via a particular steroid receptor but also suffer from the same source of variability as the binding studies when it comes to off-target effects via other receptors, which would lead to inaccurate potency estimates. In addition, the animal data are also confounded by pharmacokinetic factors, metabolism, binding to serum proteins, and indirect actions of the progestogens via target proteins other than steroid receptors.
Bioassays have been developed that test the effects of progestogens on uterine glandular proliferation, pregnancy maintenance, delay of parturition, or inhibition of ovulation in rabbits or rats.
The Clauberg test is based on initial observations made by Clauberg in the s and is the most widely used bioassay for progestational agents. It was later developed into specific protocols by McPhail in The principle of the test is to measure glandular proliferation in rabbit endometrium that has been primed with estrogen, in response to progestogens given orally or parenterally.
McPhail used a standardized scale for grading the complex glandular proliferation of the rabbit endometrium in response to the different progestogens. The Clauberg test is, however, subject to considerable variation in estimates of potency Problems arise in interpretation of the test because dose-response curves for commonly employed test substances are not parallel.
Other commonly used bioassays also have various limitations For example, bioassays that measure pregnancy maintenance as a progestational effect cannot use estrogens, which will inhibit the active progestogens when given at sufficient doses; the bioassay for delay of parturition cannot distinguish between the various progestogens; and the ovulation inhibition bioassay in the laboratory gives different progestogen potencies when compared with those obtained in women.
Despite these limitations, bioassays have led to significant insights into progestogen actions, although they frequently do not correlate with the steroid receptor-binding affinity data, in particular for the AR, GR, and MR. Several general tends have emerged from both the animal bioassays and in vitro binding affinity studies.
Although all progestogens bind to the PR Table 4 and act as progesterone agonists, they exhibit differences in the potency of the progestogenic responses Table 4 — On the other hand, progestogens exhibit a wide spectrum of activities via the AR, ranging from no effect to agonist, partial agonist, and antiandrogenic activity Table 4.
For example, some of the older-generation progestins such as MPA, norethindrone acetate, norethindrone, and levonorgestrel, which bind with relatively high affinity to the AR, have been reported to act as agonists or partial agonists in some contexts, unlike progesterone Table 4 77 — 86 , although the androgenic biological activities reported for MPA and progesterone vary greatly in the literature.
In contrast, drospirenone, dienogest, and trimegestone, which exhibit low RBA for the AR, exhibit no AR-mediated agonist activity but exhibit variable to potent antiandrogenic properties Table 4 74 , 87 , Nestorone has no activity via the AR Table 4 89 , whereas nomegestrol acetate, which binds the AR, has no agonist activity and displays partial antiandrogenic activity Table 4 22 , , Consistent with their binding activities, MPA has partial to full agonist activity via the GR in some contexts 41 , whereas gestodene exhibits partial agonist activity in some contexts However, progestogens such as norethindrone, levonorgestrel, dienogest, and trimegestone show no or very little glucocorticoid-like activity in most contexts, whereas the reported effects of progesterone via the GR vary Table 4 Certain progestogens like trimegestone and drospirenone with a relatively high affinity for the MR exhibit weak partial MR agonist activity.
However, both progesterone and drospirenone exhibit potent antagonist activity toward aldosterone via the MR, whereas the reported antagonistic effects of trimegesterone are variable Table 4 90 — Other progestins such as MPA and norethindrone acetate, which bind weakly to the MR, exhibit no antimineralocorticoid activity in rat models Table 4 41 , whereas dienogest neither binds to nor displays agonist or antagonist activity for the MR Table 4 87 , In addition to in vitro binding affinity tests and bioassays, clinical tests have been used to assess the relative biological effects of progestogens in women; they include those based on delay of menses, induction of secretory changes in the endometrium, inhibition of ovulation, and changes in vaginal cytology and cervical mucus.
Traditionally, in these clinical tests, the term potency is often used to refer to a relative response obtained at a chosen progestogen dose, using equivalent mass doses, without dose-response analysis. Alternatively, some assays refer to potency as the comparative dose in mass required to give a particular level of response, usually not a maximal response.
Hence, these are not true measures of potency or efficacy in terms of the definitions discussed above. Thus, the term potency reported from such clinical studies needs to be interpreted with these limitations in mind.
Greenblatt and co-workers were the first to describe the delay-of-menses test for progestogenic potency. In this test, the progestogen is administered beginning on the sixth or seventh day after ovulation and continuing for 3 wk or more. If the progestogen is effective, it will delay menstrual bleeding until 2—3 d after treatment is discontinued.
The delay-of-menses test was further developed and standardized by Swyer and Little for assessing comparative potency of progestogens and is consequently referred to as the Swyer-Greenblatt test. A literature review published in assessed the relative potency of progestogens used in oral contraception in the United States on the basis of available human data showing the effect of progestogens on the delay of menses by the Swyer-Greenblatt test as well as effects on subnuclear vacuolization as an indirect determination of glycogen deposition and lipid and lipoprotein levels The review concluded that norethindrone, norethindrone acetate, and ethynodiol diacetate are approximately equivalent in potency, whereas norgestrel and its biologically active enantiomer, levonorgestrel, are about 5—10 and 10—20 times as potent as a similar weight of norethindrone, respectively.
However, there are limitations in the studies that were reviewed. In another approach to determine progestogen potency from clinical data, a series of studies by King and co-workers — assessed progestogenic effects by analyzing biochemical and morphological features of endometria from estrogen-primed postmenopausal women.
First, the postmenopausal women were treated daily with either 0. At least three different doses of each of 5 orally administered progestogens, specifically, norethindrone, levonorgestrel, MPA, dydrogesterone, and progesterone, were studied. The endometria were analyzed for biochemical parameters including nuclear estradiol receptor levels, DNA synthesis, and isocitric and estradiol dehydrogenase activities. King and Whitehead reexamined the results of these studies to allow comparisons with corresponding premenopausal secretory-phase values and reported the potency of progestogens relative to a value of 1 for norethindrone.
The analysis showed that the potency of levonorgestrel was 8-fold greater, whereas the potencies of MPA, dydrogesterone, and progesterone were 10, 50, and times lower, respectively.
The recommended oral progestogen doses for endometrial protection Table 5 are based on the potencies established by the analysis of King and Whitehead ; they are 1, 0. Comparison of different progestogen potencies determined experimentally with corresponding therapeutic oral doses.
In contrast to animal experiments and clinical data, several researchers have done experiments in cell culture to investigate more directly the relative potency, efficacy, and biocharacter of progestogens via specific steroid receptors and on specific target genes.
These strategies include the use of cell lines as models for cells in a particular target tissue relevant to HT side effects, cell lines deficient in other receptors with transient overexpression of the receptor under investigation, or the genetic engineering of cell lines to overexpress a particular receptor. However, very few studies have verified the specificity of the response by, for example, small interfering RNA knockdown of a particular receptor or using receptor-specific antagonists.
Nevertheless, much valuable information has been obtained from these in vitro activity studies, including evidence for a lack of a class effect of progestogens. Ligand-activated steroid receptors directly regulate transcription of specific target genes by several genomic mechanisms that are conserved within the family of steroid receptors, although some mechanistic differences do occur.
Regulation of transcription of mammalian genes generally involves dynamic, regulated steroid receptor-mediated recruitment of multiprotein complexes. These complexes include chromatin-remodeling proteins that shift nucleosomes, coactivators that acetylate histone proteins to open up chromatin, or corepressors that deacetylate histone proteins resulting in more compact chromatin. Also involved are several other proteins such as mediator complexes, the basal transcription machinery including RNA polymerase and associated factors, and enzymes that modify components of the complexes, including methylases and kinases , Steroid receptors are key proteins in this process There is also evidence that receptor isoforms display differential subcellular localization in the absence of ligand.
For example, in endometrial cancer cells, the unliganded PR-A is predominantly located in the nucleus, whereas the unliganded PR-B is predominantly cytoplasmic , but both PRs are distributed in the nucleus and in the cytoplasm of several cell lines when overexpressed The receptors are held in an inactive conformation by the presence of a protein complex of the heat-shock proteins hsp hsp90 and hsp70, immunophilins, and other proteins The lipid-soluble steroid ligands diffuse passively across the plasma membrane and bind to the LBD of steroid receptors, inducing hyperphosphorylation, a conformational change in the receptor, changes in the composition of the protein complex, and nuclear translocation of the cytoplasmic receptors 44 , 60 , The genomic mechanisms whereby ligand-bound steroid receptors directly increase transcription of many target genes via direct DNA binding, or transactivation, involve binding of a receptor dimer to specific palindromic DNA sequences in promoters of target genes known as steroid-responsive elements SREs.
This results in formation of a multiprotein complex on the promoter via protein-protein interactions, including chromatin-remodeling proteins, coactivators, and components of the transcriptional machinery, in a dynamic, complex interplay of factors leading to an increase in transcription initiation 41 , 44 , 47 , Fig. Although each steroid receptor exhibits selectivity and a higher affinity for specific SRE sequences, the high degree of structural and functional conservation within the DBDs of steroid receptors allows most steroid receptors to bind, at least in vitro , to the same DNA response element reviewed in Ref.
Schematic diagram to illustrate differential genomic nuclear and nongenomic extranuclear, cytoplasmic actions of progestogens and endogenous steroid hormones.
The two progestins, MPA and norethindrone, were chosen to illustrate the concept of differential actions compared with each other and progesterone. In genomic actions, all progestogens bind to the PR and act as agonists. The two best-characterized genomic mechanisms for steroid receptors are illustrated. The first is transactivation by steroid receptor dimers binding directly to SREs in the promoters of target genes, followed by recruitment of coactivators and increased transcription.
The second is transrepression via tethering of a steroid receptor monomer to other positively acting transcription factors, followed by recruitment of a corepressor and inhibition of transcription. Other complexes and higher-order effects on chromatin structure as discussed in the text are not depicted for simplicity. The depicted nongenomic or cytoplasmic actions include activation of various cytoplasmic targets by the classical nuclear steroid receptors or by membrane steroid receptors.
Note that cytoplasmic actions can also lead to genomic actions by targeting of nuclear proteins such as transcription factors, cofactors, and chromatin proteins or even steroid receptors.
Also depicted is the cross talk between the classical PR and other plasma membrane receptors R such as the epidermal growth factor receptor, as discussed in the text. Note that actions of progesterone as a weak GR or AR agonist are not depicted. The latter mechanism is often referred to as a tethering mechanism, which can also result in an increase in transcription, depending on the transcription factors involved and promoter architecture The details of these mechanisms are not well established for most members of the steroid receptor family but have been the focus of studies on GR actions due to their involvement in the antiinflammatory response , Each birth control pill brand may contain different doses of estrogen and different types of progestin.
A doctor can help a person decide which one is best. According to a article, most combination birth control pills contain ethinyl estradiol, which is an estrogen component, although the doses among brands will vary.
Ethinyl estradiol doses may vary between 20—35 micrograms mcg. According to ACOG , high levels of androgens can also play a role in acne and excess hair growth. Some people may want to use the birth control pill to help treat these conditions.
Different types of progestin vary in how androgenic they are. Other progestins do not act in this way and may help those who experience acne or excess hair growth. However, at present, there is no data to support one particular birth control pill being more effective than others at treating acne or excess hair growth. People might consider talking to a doctor or healthcare professional about which type of progestin will suit them best.
Some people may prefer to use a birth control pill that contains the progestin desogestrel. According to a article, it may help those with hair growth and acne. However, the article also indicates that there is limited evidence to confirm that it is better than other options is limited. Some of these birth control pills contain the same drugs in identical dosages but have different names.
For example, a doctor may prescribe Azurette and Kariva, or Reclipsen and Apri interchangeably because they have the same contents. Which drug a person gets may depend on a variety of factors, such as their insurance policy or availability of a specific brand.
Some people prefer birth control pills that contain the progestin drospirenone because it has diuretic properties , which helps prevent bloating. It is important to note, that according to the Food and Drug Administration FDA , drospirenone may increase the chance of blood clots.
However, ACOG state that the risk is low. According to a study , drospirenone can also help treat premenstrual dysphoric disorder PMDD , which is a severe type of premenstrual syndrome PMS. As before, it is important to note that a doctor may prescribe some brands interchangeably when they contain the same dosages, such as with Loryna and Yaz.
The birth control pills that contain levonorgestrel appear to have lower risks of side effects, such as venous thrombosis, than some of the other progestin options. Doctors consider pills containing levonorgestrel and ethinyl estradiol as first-line, and they are effective as long as a person takes them correctly. A doctor may prescribe these brands interchangeably, providing they contain the same ingredients and dosages, as in the case of Aviane, Lessina, and Sronyx. Norethindrone is a progestin that derives from testosterone.
Those who take birth control pills containing norethindrone may experience androgenic side effects. People who use birth control pills containing norgestimate or norgestrel may also experience androgenic side effects, such as hair growth and acne. There are also extended-cycle birth control pills, such as Seasonique , which contain 12 weeks of combined hormones ethinyl estradiol and levonorgestrel and one week of placebo or low dose ethinyl estradiol.
Some people prefer extended cycles because they only bleed once every 3 months. Studies show that continuous use is safe for up to 12 months. According to DailyMed , triphasic birth control pills contain 21 days of active hormonal pills with different doses of estrogen and progestin each week.
An example of a triphasic birth control pill is Ortho Tri Cyclen. Each pill contains 35 mcg of ethinyl estradiol, but the dose of norgestimate increases each week. Measure ad performance. Select basic ads. Create a personalised ads profile. Select personalised ads. Apply market research to generate audience insights.
Measure content performance. Develop and improve products. List of Partners vendors. There are eight different types of progestin that may be found in combination birth control pills along with estrogen typically ethinyl estradiol.
The term progestin is used for any natural or man-made substance that has properties similar to natural progesterone. Progestins are categorized by generation, which indicates primarily when they were introduced to the market.
To best understand how a progestin may be classified, it is helpful to clarify the types of effects a progestin may have on the female body :. In looking at the specific progestins, it's also helpful to define them by groups. Progestins are classified as first to fourth generation progestins based on when they were first available, but different generations also have some different characteristics.
Keep in mind that newer isn't necessarily better. When looking at progestins, it's noteworthy that some combination pills that sound very similar have different progestins. Norethindrone is a first-generation progestin available in monophasic, biphasic and triphasic formulations. It has low progestational and slight estrogenic activity. It tends to be less androgenic than the second-generation progestins levonorgestrel and norgestrel , but more androgenic than newer progestins, like desogestrel.
In low doses any pill containing less than 50 micrograms of ethinyl estradiol , this progestin improves lipid profiles by raising HDL and lowering LDL cholesterol.
Advantages : Improves lipid profile; first progestin in use so many years of data on safety; may be helpful in women who experience depression on other oral contraceptive combinations.
Disadvantages : In between as to effects on acne. Norethindrone acetate is another first-generation progestin with low progestational activity and slight estrogenic effects. It tends to be less androgenic than the second-generation progestins, but more androgenic than newer progestins, like desogestrel.
The brand Estrostep was designed to more closely mimic a woman's natural menstrual cycle by providing increasing levels of estrogen with a constant progestin dose. It is the only triphasic brand with this progestin. This brand may be helpful for women who experience minor estrogen-related side effects such as nausea, migraines, or fluid retention with other pill combinations. Advantages : May help women who experience migraines or nausea on birth control pills.
Disadvantages : In between effects on acne. Examples : Loestrin , Junel, Estrostep. Ethynodiol diacetate is a first-generation progestin of medium progestational activity.
It has minor estrogenic effects and little androgenic activity. Ethynodiol diacetate is a derivative of norethindrone, so it is easily converted to norethindrone within the body. Birth control pills containing ethynodiol diacetate tend to be associated with increased early or mid-cycle spotting as compared to other combination pills.
However, higher estrogen dosages can counteract the likelihood of breakthrough bleeding , so pill brands that contain higher levels of estrogen can alleviate this side effect. Advantages : May be helpful for women with endometriosis. Disadvantages : Breakthrough bleeding spotting. Examples : Demulen, Kelnor, Zovia. Levonorgestrel is a second-generation progestin and is the most widely prescribed contraceptive progestin worldwide.
It has high progestational and androgenic effects. Levonorgestrel negatively affects serum lipoproteins. Several low-dose estrogen brands containing this progestin are available. The FDA has stated that all combination pills with this progestin are safe and effective for emergency contraception under the Yuzpe method.
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