.gif "IP Gear")
- Joined
- Apr 9, 2021
- Messages
- 1,716
Distinguishing Prolactin versus Progestins
Author: Type-IIx
Introduction
Prolactin: Protein (peptide hormone; 227 AA, ~26 kDa) encoded by the PRL gene that primarily acts on the mammary gland to promote lactation
Progesterone: Female sex steroid hormone (C21-steroid, 20-oxo steroid, 3-oxo-Delta(4)) that primarily acts to maintain pregnancy & decrease uterine contractility
Of chief concern to this audience are the progestins (progesterone analogues), and specifically the subset of progestins that may be classified as progestagenic androgens (e.g., Nandrolone, Trenbolone, MENT): these are androgens that have affinity for the progesterone receptor (PR). Of secondary concern are the aromatizing androgens (e.g., Testosterone, Nandrolone, MENT, Dianabol) that may increase serum prolactin.
"19-Nortestosterone derivatives ['19-Nors'] are synonymous with progestagenic androgens"
False:
You will often hear the term "19-nor" or "19-nortestosterone derivative" bandied about as synonymous with androgens with progestagenic action and encompassing both Trenbolone & MENT.
A 19-nortestosterone derivative is a synthetic progestin derived from Nandrolone that is used in female contraception and menopausal hormone therapy [10]. While this fact in isolation is mostly a semantic argument against the "Nandrolone-DHT-Test" bro-science model, consider the following:
Trenbolone is a Δ4,9,11 androgen (conferring substantial AR potency and resistance to 5α-reductase & Aromatase), whereas MENT is an androgen distinguished from 19-nortestosterone by the attachment of an α-oriented methyl group to the C-7 of 19-nortestosterone: this attachment serves to increase its anabolic potency by ↑AR affinity, ↓reduction of the delta-4 (Δ⁴) bond and thus delta-5(10) isomers are the major excreted metabolites (hindering metabolic inactivation) & ↓affinity for SHBG binding [14].
Rather than whether (even if true that) androgen synthesis of a product may use 19-nortestosterone as a precursor, what truly characterizes potent progestagenic androgens is the 3-dimensional shape & electrochemical properties of the C-18 steroid that confers inherent potency to activate the AR, together with the fact that these properties that confer great AR affinity (e.g., Δ4,9,11 configuration or 7α-methylation) are inherently rooted in broad homology between the human nuclear receptor families (e.g., AR, ERα/β, GR, PR). That is, due to structural features shared by these receptors being similar to the AR, the most potent androgens are also inherently, due to their shape and electrochemical properties, good ligands for other nuclear receptors, including the PR.
EXAMPLE: The Δ4,9,11 steroid configuration of the trienes serves to flatten the steroid molecule, thereby making it fit into the AR like a knife; but this flattening of the steroid also serves to increase its affinity for the homologous non-AR nuclear receptors. This is why Trenbolone can serve to bind quite potently to the AR & PR, weakly to the ERs, and likely antagonize the MR analogously to methyltrienolone. Relatedly, though methyltrienolone exerts no direct activity in activating the GR, it does slighlty transactivate the GR as an antagonist [15]. Still, much of Trenbolone's particular antiglucocorticoid activity is due to its decreasing GR number (mRNA expression).
"Progestins increase estrogen sensitivity"
True:
Estrogens ↑prolactin expression (thereby suppressing LH & FSH), contributing to ↑HPG axis suppression. Progestins further directly contibute to HPG axis suppression by dysregulating hypothalamic regulation of T and gonadotropins via KNDy dendron signalling, disrupting GnRH pulsatility, and inhibiting pituitary LH secretion [11] [12]. Synthetic progestins used in contraception derive efficacy from this feature. Bebb, et al. randomized healthy men to receive either testosterone enanthate (100 mg weekly), or the same dosage of testosterone in combination with the progestin levonorgestrel, the addition of which virtually abolished LH and FSH secretion [13]. Decreased LH & FSH can cause secondary hypogonadism, thereby ↓androgen/estrogen ratio, causing gynecomastia.
"The effects of progestins relate to their interactions with receptors: AR (e.g., acnea, lipid effects); glucocorticoid receptors (GR) (eg., salt and water retention, bloating); or mineralocorticoid receptors (e.g., decreased water retention and weight). Anti-androgenic progestins may act in several ways. They can exert competitive inhibition of the AR, or bind to the enzyme 5-alpha reductase and hence interact with the conversion of testosterone into dihydrotestosterone (its active metabolite). When combined with estrogen the non-androgenic progestins do not oppose the estrogen-dependent increase in SHBG. The latter effect results in more binding of the circulating androgens and less free T available for action at the receptor level. Thus, anti-androgenic progestins may have beneficial effects (e.g., controlling endogenous androgen and decreasing acnea or hirsutism)." [10].
Further, "progesterone and its derivatives...& progesterone mimics...were moderate binders to the AR. We earlier demonstrated that progesterone derivatives do not compete with 17β-estradiol (E₂) for ER binding (18, 30). It appears that progesterone derivatives could alter both AR- & PR- but not ER-mediated tissue responses." [3].
Estrogens up-regulate PR synthesis [2]. Further, activation of progesterone receptors has been linked to reduced expression of AR, thereby hampering the androgen-mediated inhibition on breast tissue growth observed in condition of normal hormonal homeostasis [16].
Progesterone and its derivatives may further cause gynecomastia by enhancing the effect of estradiol on breast tissues [6].
"Anabolic steroids increase serum prolactin"
Partly True, Mostly False:
Rather, aromatizing androgen (e.g., Testosterone [7], MENT [8]) show a tendency (a trend; rather than a significant effect) to increase serum prolactin as a consequence of their aromatic products (i.e., estrogens) acting as stimulatory factors to the secretion of prolactin from the anterior pituitary [7]. Noteworthy, Nandrolone at lower doses appears to have no significant effect on serum prolactin (likely due to sub-normal E₂ levels) [9].
Conversely, nonaromatizing androgen (e.g., Tren, Primo, Var, etc.) likely reduce serum prolactin. This is an empirical observation based on human bloodwork results, as well as the basis for a prevailing hypothesis, to this author's knowledge, being first advanced by De Las Heras and colleagues in 1979:
"Prolactin induces gynecomastia"
Unclear:
While data shows a trend for a decrease in serum testosterone in cases of hyperprolactinemia (usually caused by a prolactin-secreting tumor and certain drugs), there is not a clear causal relationship [4]. Prolactin can certainly disrupt hypothalamic GnRH release during breastfeeding, acting as a natural contraceptive likely via disrupting KNDy neurons in the hypothalamus (22,23) [4].
Practically, as the increase in prolactin from aromatizing androgen is ascribed to estrogens effectively acting as stimulatory agents to the secretion of prolactin from the anterior pituitary [7], the use of an aromatase inhibitor (AI) like exemestane/Aromasin may be used to reduce this increase in prolactin.
Speculatively, a potential mechanism in the induction of gynecomastia by elevated serum prolactin may be due to cross-talk between prolactin and GH (24) [16]. Progesterone receptors have been identified in some samples of male breast tissue (23), but the clinical significance is unknown [16].
Author: Type-IIx
Introduction
Prolactin: Protein (peptide hormone; 227 AA, ~26 kDa) encoded by the PRL gene that primarily acts on the mammary gland to promote lactation
Progesterone: Female sex steroid hormone (C21-steroid, 20-oxo steroid, 3-oxo-Delta(4)) that primarily acts to maintain pregnancy & decrease uterine contractility
Of chief concern to this audience are the progestins (progesterone analogues), and specifically the subset of progestins that may be classified as progestagenic androgens (e.g., Nandrolone, Trenbolone, MENT): these are androgens that have affinity for the progesterone receptor (PR). Of secondary concern are the aromatizing androgens (e.g., Testosterone, Nandrolone, MENT, Dianabol) that may increase serum prolactin.
"19-Nortestosterone derivatives ['19-Nors'] are synonymous with progestagenic androgens"
False:
You will often hear the term "19-nor" or "19-nortestosterone derivative" bandied about as synonymous with androgens with progestagenic action and encompassing both Trenbolone & MENT.
A 19-nortestosterone derivative is a synthetic progestin derived from Nandrolone that is used in female contraception and menopausal hormone therapy [10]. While this fact in isolation is mostly a semantic argument against the "Nandrolone-DHT-Test" bro-science model, consider the following:
Trenbolone is a Δ4,9,11 androgen (conferring substantial AR potency and resistance to 5α-reductase & Aromatase), whereas MENT is an androgen distinguished from 19-nortestosterone by the attachment of an α-oriented methyl group to the C-7 of 19-nortestosterone: this attachment serves to increase its anabolic potency by ↑AR affinity, ↓reduction of the delta-4 (Δ⁴) bond and thus delta-5(10) isomers are the major excreted metabolites (hindering metabolic inactivation) & ↓affinity for SHBG binding [14].
Rather than whether (even if true that) androgen synthesis of a product may use 19-nortestosterone as a precursor, what truly characterizes potent progestagenic androgens is the 3-dimensional shape & electrochemical properties of the C-18 steroid that confers inherent potency to activate the AR, together with the fact that these properties that confer great AR affinity (e.g., Δ4,9,11 configuration or 7α-methylation) are inherently rooted in broad homology between the human nuclear receptor families (e.g., AR, ERα/β, GR, PR). That is, due to structural features shared by these receptors being similar to the AR, the most potent androgens are also inherently, due to their shape and electrochemical properties, good ligands for other nuclear receptors, including the PR.
EXAMPLE: The Δ4,9,11 steroid configuration of the trienes serves to flatten the steroid molecule, thereby making it fit into the AR like a knife; but this flattening of the steroid also serves to increase its affinity for the homologous non-AR nuclear receptors. This is why Trenbolone can serve to bind quite potently to the AR & PR, weakly to the ERs, and likely antagonize the MR analogously to methyltrienolone. Relatedly, though methyltrienolone exerts no direct activity in activating the GR, it does slighlty transactivate the GR as an antagonist [15]. Still, much of Trenbolone's particular antiglucocorticoid activity is due to its decreasing GR number (mRNA expression).
"Progestins increase estrogen sensitivity"
True:
Estrogens ↑prolactin expression (thereby suppressing LH & FSH), contributing to ↑HPG axis suppression. Progestins further directly contibute to HPG axis suppression by dysregulating hypothalamic regulation of T and gonadotropins via KNDy dendron signalling, disrupting GnRH pulsatility, and inhibiting pituitary LH secretion [11] [12]. Synthetic progestins used in contraception derive efficacy from this feature. Bebb, et al. randomized healthy men to receive either testosterone enanthate (100 mg weekly), or the same dosage of testosterone in combination with the progestin levonorgestrel, the addition of which virtually abolished LH and FSH secretion [13]. Decreased LH & FSH can cause secondary hypogonadism, thereby ↓androgen/estrogen ratio, causing gynecomastia.
"The effects of progestins relate to their interactions with receptors: AR (e.g., acnea, lipid effects); glucocorticoid receptors (GR) (eg., salt and water retention, bloating); or mineralocorticoid receptors (e.g., decreased water retention and weight). Anti-androgenic progestins may act in several ways. They can exert competitive inhibition of the AR, or bind to the enzyme 5-alpha reductase and hence interact with the conversion of testosterone into dihydrotestosterone (its active metabolite). When combined with estrogen the non-androgenic progestins do not oppose the estrogen-dependent increase in SHBG. The latter effect results in more binding of the circulating androgens and less free T available for action at the receptor level. Thus, anti-androgenic progestins may have beneficial effects (e.g., controlling endogenous androgen and decreasing acnea or hirsutism)." [10].
Further, "progesterone and its derivatives...& progesterone mimics...were moderate binders to the AR. We earlier demonstrated that progesterone derivatives do not compete with 17β-estradiol (E₂) for ER binding (18, 30). It appears that progesterone derivatives could alter both AR- & PR- but not ER-mediated tissue responses." [3].
Estrogens up-regulate PR synthesis [2]. Further, activation of progesterone receptors has been linked to reduced expression of AR, thereby hampering the androgen-mediated inhibition on breast tissue growth observed in condition of normal hormonal homeostasis [16].
Progesterone and its derivatives may further cause gynecomastia by enhancing the effect of estradiol on breast tissues [6].
"Anabolic steroids increase serum prolactin"
Partly True, Mostly False:
Rather, aromatizing androgen (e.g., Testosterone [7], MENT [8]) show a tendency (a trend; rather than a significant effect) to increase serum prolactin as a consequence of their aromatic products (i.e., estrogens) acting as stimulatory factors to the secretion of prolactin from the anterior pituitary [7]. Noteworthy, Nandrolone at lower doses appears to have no significant effect on serum prolactin (likely due to sub-normal E₂ levels) [9].
Conversely, nonaromatizing androgen (e.g., Tren, Primo, Var, etc.) likely reduce serum prolactin. This is an empirical observation based on human bloodwork results, as well as the basis for a prevailing hypothesis, to this author's knowledge, being first advanced by De Las Heras and colleagues in 1979:
[5]
"Prolactin induces gynecomastia"
Unclear:
While data shows a trend for a decrease in serum testosterone in cases of hyperprolactinemia (usually caused by a prolactin-secreting tumor and certain drugs), there is not a clear causal relationship [4]. Prolactin can certainly disrupt hypothalamic GnRH release during breastfeeding, acting as a natural contraceptive likely via disrupting KNDy neurons in the hypothalamus (22,23) [4].
Practically, as the increase in prolactin from aromatizing androgen is ascribed to estrogens effectively acting as stimulatory agents to the secretion of prolactin from the anterior pituitary [7], the use of an aromatase inhibitor (AI) like exemestane/Aromasin may be used to reduce this increase in prolactin.
Speculatively, a potential mechanism in the induction of gynecomastia by elevated serum prolactin may be due to cross-talk between prolactin and GH (24) [16]. Progesterone receptors have been identified in some samples of male breast tissue (23), but the clinical significance is unknown [16].
