I can see some confusion. So imo take what we know about NBE and throw out the play book. Meaning a confusion exists (well imo) of when and how long to take supplements that will be effective. It also explains that how receptor recycling (degradation) and not just steriod receptors gets excreted and recycled again and again. What this means is (and I'll try to explain so all can follow), that taking supplements in shorter (and less) bursts to follow the steroid half life's (this means receptor control too) cycle.
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08-12-2014, 07:33 PM
So the process once hormones are stimulated (30-60 minutes) takes seconds to minutes (also known as transcription) or in layman---- G-R-O-W-T-H.... 
______________________________
Small-Molecule Hormones: Molecular Mechanisms of Action
Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes.
Small-Molecule Hormones: Molecular Mechanisms of Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603355/#
![[Image: attachment.php?aid=8509]](http://www.breastnexus.com/attachment.php?aid=8509)
______________________________
Small-Molecule Hormones: Molecular Mechanisms of Action
Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes.
Small-Molecule Hormones: Molecular Mechanisms of Action
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603355/#
08-12-2014, 08:20 PM
Actions : Docking :: Receptor Binding
Nuclear Receptors Trigger Gene Expression
All nuclear receptors (receptors found in the cell’s nucleus and cytoplasm), whether they bind to hormones or to other kinds of ligands, are transcription factors. That is, they are proteins that regulate gene expression by attaching to the promoter region of a gene and inhibiting or stimulating gene transcription. Transcription is a process where a piece of DNA is used as a template to make a complimentary RNA strand - called a messenger RNA - that transmits genetic commands from the nucleus to other parts of the cell.
With hormone signaling, the entire gene expression effort, and subsequent protein synthesis, depends on the hormone receptor.
Before binding to hormones, nuclear hormone receptors are linked to chaperone proteins. The quiescent androgen, progestin, glucocorticoid, and mineralocorticoid receptors reside in the cytoplasm while estrogen receptors are found in the cytoplasm and the nucleus. When a hormone binds to a receptor, the activated receptor disconnects from the chaperone protein and partners with another hormone-bound receptor to form a dimer. Dimers in the cytoplasm then move into the nucleus where the DNA is located.
In the nucleus, the activated hormone receptor pairs attach to the hormone response element, which is a specific sequence of DNA located in the promoter region of the target gene. The attached receptor is the primary transcription factor, serving as the foundation where all the other transcription factors anchor. Once in place, the receptor initiates gene transcription by interacting with other transcription factors, such as TFIIA, TFIIB, and many others.
Generally, many different transcription factors pile onto the attached hormone receptor at the same time. One group of transcription factors helps unwind the DNA making it accessible to the enzyme RNA polymerase. A second group of transcription factors then recruits RNA polymerase to join the stack. This sparks gene transcription - RNA polymerase uses a DNA template to make messenger RNA (mRNA) - followed by translation - the ribosomes in the cytoplasm build a protein by reading mRNA's code and recruiting transfer RNA (tRNA) to supply the protein's amino acid building blocks.
Androgen Receptor BindingCAPTION: Testosterone activates genes to produce proteins. CREDIT: Tulane/Xavier Center for Bioenvironmental Research.
![[Image: attachment.php?aid=8511]](http://www.breastnexus.com/attachment.php?aid=8511)
An example is shown in the animation above. When the androgen hormone testosterone (blue) binds to an androgen receptor (purple) in the cytoplasm, the receptor leaves the chaperone protein (green) and pairs with another activated androgen receptor to form a dimer. The dimer moves to the nucleus where it binds to the DNA and interacts with other transcription factors (multiple colors). This molecular huddle promotes DNA unraveling, exposing the appropriate DNA template used to make new mRNA that will carry a genetic message to the cytoplasm where ribosomes assemble the proteins during translation.
http://e.hormone.tulane.edu/learning/doc...genes.html
Nuclear Receptors Trigger Gene Expression
All nuclear receptors (receptors found in the cell’s nucleus and cytoplasm), whether they bind to hormones or to other kinds of ligands, are transcription factors. That is, they are proteins that regulate gene expression by attaching to the promoter region of a gene and inhibiting or stimulating gene transcription. Transcription is a process where a piece of DNA is used as a template to make a complimentary RNA strand - called a messenger RNA - that transmits genetic commands from the nucleus to other parts of the cell.
With hormone signaling, the entire gene expression effort, and subsequent protein synthesis, depends on the hormone receptor.
Before binding to hormones, nuclear hormone receptors are linked to chaperone proteins. The quiescent androgen, progestin, glucocorticoid, and mineralocorticoid receptors reside in the cytoplasm while estrogen receptors are found in the cytoplasm and the nucleus. When a hormone binds to a receptor, the activated receptor disconnects from the chaperone protein and partners with another hormone-bound receptor to form a dimer. Dimers in the cytoplasm then move into the nucleus where the DNA is located.
In the nucleus, the activated hormone receptor pairs attach to the hormone response element, which is a specific sequence of DNA located in the promoter region of the target gene. The attached receptor is the primary transcription factor, serving as the foundation where all the other transcription factors anchor. Once in place, the receptor initiates gene transcription by interacting with other transcription factors, such as TFIIA, TFIIB, and many others.
Generally, many different transcription factors pile onto the attached hormone receptor at the same time. One group of transcription factors helps unwind the DNA making it accessible to the enzyme RNA polymerase. A second group of transcription factors then recruits RNA polymerase to join the stack. This sparks gene transcription - RNA polymerase uses a DNA template to make messenger RNA (mRNA) - followed by translation - the ribosomes in the cytoplasm build a protein by reading mRNA's code and recruiting transfer RNA (tRNA) to supply the protein's amino acid building blocks.
Androgen Receptor BindingCAPTION: Testosterone activates genes to produce proteins. CREDIT: Tulane/Xavier Center for Bioenvironmental Research.
An example is shown in the animation above. When the androgen hormone testosterone (blue) binds to an androgen receptor (purple) in the cytoplasm, the receptor leaves the chaperone protein (green) and pairs with another activated androgen receptor to form a dimer. The dimer moves to the nucleus where it binds to the DNA and interacts with other transcription factors (multiple colors). This molecular huddle promotes DNA unraveling, exposing the appropriate DNA template used to make new mRNA that will carry a genetic message to the cytoplasm where ribosomes assemble the proteins during translation.
http://e.hormone.tulane.edu/learning/doc...genes.html
08-12-2014, 10:27 PM
If you've never seen this site it's worth the time to educate yourself on how hormones work, one of the best educational series out there.
Endocrine Disruption Tutorial
http://e.hormone.tulane.edu/learning/doc...nding.html
Actions : Docking :: Receptor Binding
Every second of your life, hormone messengers are working to keep your body on track. These powerful endocrine system signalers regulate a variety of cell processes. Among other things, they stimulate cells to release chemicals, send electrical or chemical signals, grow, or produce proteins. All of these actions begin with the same step: a hormone binding to a specific hormone receptor either embedded in the cell’s outer surface membrane or floating inside the cell’s cytoplasm or nucleus.
Regardless of location, the union of hormone and receptor spurs action by relaying instructions through a cell’s molecular signaling networks. Binding produces two distinct signaling routines: either slower via gene expression (hours to days) or very rapidly via molecular exchanges, or cascades (seconds to minutes). In both cases, the cell responds to the signals by manipulating proteins or building new ones. The affected workhorse proteins carry out specialized functions, such as controlling cell processes, building cells and tissues, or carting messages elsewhere within the cell or around the body.
Some natural and synthetic compounds called endocrine disrupters (EDs) can sometimes interfere with normal hormone binding to convey inaccurate signals or send mixed messages that may result in altered health outcomes.
Water Loving/Fat Loving?
Whether a hormone binds to a receptor inside or outside a cell depends on the chemical nature of the hormone and its compatibility with the cell’s fatty outer membrane. The membrane’s fat layers impede water-friendly hormones from passing through but allow fat-derived hormones to readily enter the cell.
Some hormones can easily go into cells to find matching receptors. The fat-based steroid hormones - estrogens, androgen, progestins, etc. - belong to this category. These messengers prefer fat (fat, or lipid, soluble) surroundings and shun water (water insoluble). They can easily pass through the cell membrane but need chaperone proteins to accompany them through the watery bloodstream. Steroid receptors, then, can be found in either the cell’s outer membrane, cytoplasm, or nucleus.
Other hormones stay outside the cell and attach to the receptors wedged in the outer membrane. Insulin, growth hormone, and other protein-based peptide hormones dissolve in water (water soluble) and shun fat (fat insoluble). The cell’s fatty membrane impedes these water-loving messengers from readily entering the cell. Therefore, peptide hormones stay outside the cell and bind only with receptors in the cell’s outer membrane.
Hormone messengers can also mix it up. The amino-acid derived thyroid hormones, which behave more like steroids than like their peptide cousins, can bind to receptors located both on the cell surface and inside the cell.
Hormone Receptors
Hormone receptors are large, flexible protein molecules that interlock with hormones and read and respond to their signals. Compatible structures facilitate binding between the two - like a baseball in a glove - but the fit is not restrictive, perfect, stiff, or permanent. Hormone and receptor both bend and flex, slightly changing shape to accommodate the other - similar to two hands coming together in a handshake.
Hormones, though, only bind to certain, compatible receptor types. Thyroid hormones and each steroid hormone group - the estrogens, androgens, progestins, glucocorticoids (stress hormones), and mineralocorticoids (water and ion-regulating hormones) - have a matching hormone receptor type. For instance, estrogen hormones, like estrone, bind to estrogen receptors (ER); androgen hormones, such as testosterone, bind to androgen receptors; and so on.
But, steroid hormone receptors for each hormone group can occur in several versions that differ in form, function, and location. So, steroid and thyroid hormones are not restricted to interact with only one receptor, in one tissue, to produce one kind of action. The hormones can easily bind and activate several versions of their matching receptor type. An example is the estrogen 17-beta-estradiol. It binds to both the ER alpha and ER beta receptors but not to androgen, progestin, or thyroid receptors.
Each receptor version may turn on and off different responses in different cells in different parts of the body. For instance, ER alpha, promotes tissue growth and is found in greater amounts in the uterus, pituitary gland, and epididymis (the male sperm storing structure). ER alpha stimulates certain breast cancer cells to grow in response to estrogen hormones. The other version, ER beta, inhibits growth (possibly suppressing cancer) and prevails in the ovary and prostate. It can act like a dimmer switch for ER alpha, turning down its growth-stimulating effect.
Endocrine Disruption Tutorial
http://e.hormone.tulane.edu/learning/doc...nding.html
Actions : Docking :: Receptor Binding
Every second of your life, hormone messengers are working to keep your body on track. These powerful endocrine system signalers regulate a variety of cell processes. Among other things, they stimulate cells to release chemicals, send electrical or chemical signals, grow, or produce proteins. All of these actions begin with the same step: a hormone binding to a specific hormone receptor either embedded in the cell’s outer surface membrane or floating inside the cell’s cytoplasm or nucleus.
Regardless of location, the union of hormone and receptor spurs action by relaying instructions through a cell’s molecular signaling networks. Binding produces two distinct signaling routines: either slower via gene expression (hours to days) or very rapidly via molecular exchanges, or cascades (seconds to minutes). In both cases, the cell responds to the signals by manipulating proteins or building new ones. The affected workhorse proteins carry out specialized functions, such as controlling cell processes, building cells and tissues, or carting messages elsewhere within the cell or around the body.
Some natural and synthetic compounds called endocrine disrupters (EDs) can sometimes interfere with normal hormone binding to convey inaccurate signals or send mixed messages that may result in altered health outcomes.
Water Loving/Fat Loving?
Whether a hormone binds to a receptor inside or outside a cell depends on the chemical nature of the hormone and its compatibility with the cell’s fatty outer membrane. The membrane’s fat layers impede water-friendly hormones from passing through but allow fat-derived hormones to readily enter the cell.
Some hormones can easily go into cells to find matching receptors. The fat-based steroid hormones - estrogens, androgen, progestins, etc. - belong to this category. These messengers prefer fat (fat, or lipid, soluble) surroundings and shun water (water insoluble). They can easily pass through the cell membrane but need chaperone proteins to accompany them through the watery bloodstream. Steroid receptors, then, can be found in either the cell’s outer membrane, cytoplasm, or nucleus.
Other hormones stay outside the cell and attach to the receptors wedged in the outer membrane. Insulin, growth hormone, and other protein-based peptide hormones dissolve in water (water soluble) and shun fat (fat insoluble). The cell’s fatty membrane impedes these water-loving messengers from readily entering the cell. Therefore, peptide hormones stay outside the cell and bind only with receptors in the cell’s outer membrane.
Hormone messengers can also mix it up. The amino-acid derived thyroid hormones, which behave more like steroids than like their peptide cousins, can bind to receptors located both on the cell surface and inside the cell.
Hormone Receptors
Hormone receptors are large, flexible protein molecules that interlock with hormones and read and respond to their signals. Compatible structures facilitate binding between the two - like a baseball in a glove - but the fit is not restrictive, perfect, stiff, or permanent. Hormone and receptor both bend and flex, slightly changing shape to accommodate the other - similar to two hands coming together in a handshake.
Hormones, though, only bind to certain, compatible receptor types. Thyroid hormones and each steroid hormone group - the estrogens, androgens, progestins, glucocorticoids (stress hormones), and mineralocorticoids (water and ion-regulating hormones) - have a matching hormone receptor type. For instance, estrogen hormones, like estrone, bind to estrogen receptors (ER); androgen hormones, such as testosterone, bind to androgen receptors; and so on.
But, steroid hormone receptors for each hormone group can occur in several versions that differ in form, function, and location. So, steroid and thyroid hormones are not restricted to interact with only one receptor, in one tissue, to produce one kind of action. The hormones can easily bind and activate several versions of their matching receptor type. An example is the estrogen 17-beta-estradiol. It binds to both the ER alpha and ER beta receptors but not to androgen, progestin, or thyroid receptors.
Each receptor version may turn on and off different responses in different cells in different parts of the body. For instance, ER alpha, promotes tissue growth and is found in greater amounts in the uterus, pituitary gland, and epididymis (the male sperm storing structure). ER alpha stimulates certain breast cancer cells to grow in response to estrogen hormones. The other version, ER beta, inhibits growth (possibly suppressing cancer) and prevails in the ovary and prostate. It can act like a dimmer switch for ER alpha, turning down its growth-stimulating effect.
Red clover induces progesterone, (activates ER-a receptors too)
Biological characterization of non-steroidal progestins from botanicals used for women’s health
Progesterone plays a central role in women’s reproductive health. Synthetic progestins, such as medroxyprogesterone acetate (MPA) are often used in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Although MPA is clinically effective, it also promiscuously binds to androgen and glucocorticoid receptors (AR/GR) leading to many undesirable side effects including cardiovascular diseases and breast cancers. Therefore, identifying alternative progestins is clinically significant. The purpose of this study was to biologically characterize non-steroidal progestins from botanicals by investigating their interaction and activation of progesterone receptor (PR). Eight botanicals commonly used to alleviate menopausal symptoms were investigated to determine if they contain progestins using a progesterone responsive element (PRE) luciferase reporter assay and a PR polarization competitive binding assay. Red clover extract stimulated PRE-luciferase and bound to PR. A library of purified compounds previously isolated from red clover was screened using the luciferase reporter assay. Kaempferol identified in red clover and a structurally similar flavonoid, apigenin, bound to PR and induced progestegenic activity and P4 regulated genes in breast epithelial cells and human endometrial stromal cells (HESC). Kaempferol and apigenin demonstrated higher progestegenic potency in the HESC compared to breast epithelial cells. Furthermore, phytoprogestins were able to activate P4 signaling in breast epithelial cells without downregulating PR expression. These data suggest that botanical extracts used for women’s health may contain compounds capable of activating progesterone receptor signaling.
Biological characterization of non-steroidal progestins from botanicals used for women’s health
Progesterone plays a central role in women’s reproductive health. Synthetic progestins, such as medroxyprogesterone acetate (MPA) are often used in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Although MPA is clinically effective, it also promiscuously binds to androgen and glucocorticoid receptors (AR/GR) leading to many undesirable side effects including cardiovascular diseases and breast cancers. Therefore, identifying alternative progestins is clinically significant. The purpose of this study was to biologically characterize non-steroidal progestins from botanicals by investigating their interaction and activation of progesterone receptor (PR). Eight botanicals commonly used to alleviate menopausal symptoms were investigated to determine if they contain progestins using a progesterone responsive element (PRE) luciferase reporter assay and a PR polarization competitive binding assay. Red clover extract stimulated PRE-luciferase and bound to PR. A library of purified compounds previously isolated from red clover was screened using the luciferase reporter assay. Kaempferol identified in red clover and a structurally similar flavonoid, apigenin, bound to PR and induced progestegenic activity and P4 regulated genes in breast epithelial cells and human endometrial stromal cells (HESC). Kaempferol and apigenin demonstrated higher progestegenic potency in the HESC compared to breast epithelial cells. Furthermore, phytoprogestins were able to activate P4 signaling in breast epithelial cells without downregulating PR expression. These data suggest that botanical extracts used for women’s health may contain compounds capable of activating progesterone receptor signaling.
Quote:Only red clover (20 μg/ml) significantly activated PRE-luciferase induction
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