Then would this not mean that Progesterone can block the conversion of Testosterone to DHT? DHT being among the causes of hair thinning/destruction/male pattern baldness?
" The major metabolic pathway of progesterone is reduction by 5α-reductase[60] and 5β-reductase into the dihydrogenated 5α-dihydroprogesterone and 5β-dihydroprogesterone, respectively.[87][88][91][92] This is followed by the further reduction of these metabolites via 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase into the tetrahydrogenated allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone.[93][87][88][91] "
I don't know how long this metabolic action takes place, but if the enzyme is busy working with progesterone then it would not be able to take in any Testosterone passing by at that point in time to metabolize into DHT? If so then the more progesterone there is around then the busier that enzyme could possibly be. Wouldn't this reduce the amount of floating DHT in the blood?
Also:
" 5α-Reductase inhibitors such as finasteride and dutasteride inhibit the conversion of progesterone into the inhibitory neurosteroid allopregnanolone, and for this reason, may have the potential to reduce the sedative and related effects of progesterone.[92][93][94] "
Because Dutasteride and Finasteride bind to 5α-Reductase and keep it 'busy' it is able to reduce blood level DHT. Since this action also blocks the enzyme from reaching out to Progesterone would this not also mean Progesterone levels would remain longer?
And finally wouldn't use of both progesterone and dutasteride limit the conversion of T to DHT further because they are both competing for the same enzyme?
Quote from: Asakawa on August 25, 2018, 04:30:24 PM
Then would this not mean that Progesterone can block the conversion of Testosterone to DHT? DHT being among the causes of hair thinning/destruction/male pattern baldness?
" The major metabolic pathway of progesterone is reduction by 5α-reductase[60] and 5β-reductase into the dihydrogenated 5α-dihydroprogesterone and 5β-dihydroprogesterone, respectively.[87][88][91][92] This is followed by the further reduction of these metabolites via 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase into the tetrahydrogenated allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone.[93][87][88][91] "
I don't know how long this metabolic action takes place, but if the enzyme is busy working with progesterone then it would not be able to take in any Testosterone passing by at that point in time to metabolize into DHT? If so then the more progesterone there is around then the busier that enzyme could possibly be. Wouldn't this reduce the amount of floating DHT in the blood?
Also:
" 5α-Reductase inhibitors such as finasteride and dutasteride inhibit the conversion of progesterone into the inhibitory neurosteroid allopregnanolone, and for this reason, may have the potential to reduce the sedative and related effects of progesterone.[92][93][94] "
Because Dutasteride and Finasteride bind to 5α-Reductase and keep it 'busy' it is able to reduce blood level DHT. Since this action also blocks the enzyme from reaching out to Progesterone would this not also mean Progesterone levels would remain longer?
And finally wouldn't use of both progesterone and dutasteride limit the conversion of T to DHT further because they are both competing for the same enzyme?
So here is the irony ... 5a-Reductase deficiency was one of my chief diagnosis by the reproductive endocrinologist. I never had any real measurable T, but I STILL HAD HAIR LOSS at one point. It wasn't severe.. and I suspect it was due to hormone fluctuations, but it was still male patterned. WTH. Theoretically I can see that, but... ask your doctor, or even better a reproductive endocrinologist. Hopefully they'll explain why. Not that it really helped me lmao. I'm a mutant though so don't take me as a living example... for anything.
FYI I'm on an increased progesterone dosage now too related to other factors.. a very high dose actually. My hair is only getting thicker by the day :) Keeps me happy, and other ... things inside me happy. Happy is good.
Finasteride affects production of two types of alpha5-reductase. Specific to certain tissue types like prostate and skin. Finasteride can lower DHT by up to 60% in the body. Duteraside interferes with all three types of alpha5-reductase and can lower DHT by 90% or more.
Progesterone when taken orally is mostly metabolized in the liver. So while 10-20% of the P dose enters the blood as P, the rest enters as various metabolites. A5-reductase is needed for some conversions but not that many. One being the final conversion to the neuroregulator allopregnanolone.
I don't know that P can block DHT production.
Hi Doreen,
That is really cool that you are 5a deficient :) its also interesting to note that you still had mpb. I think a lot of that has also to do with genes, right? Do you get a lot of side effects from a high progesterone dosage? Sleepy, hungry, etc. Loved to know your hair is getting thicker :). With high p dosage have you experienced any pregnancy-like side effects?
Josie i read in wiki that there is a lot of 5a reductase in the liver too:
From wikipedia
" After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp. "
I think there is also some enzymes in the gut that break down the progesterone before it does the first liver pass. I think suppository, gel, or injection would be a better option to reduce passes through the liver.
Progesterone's action on DHT is only verifiable in vitro, there is no/little evidence it happens in vivo.
Quote from: Asakawa on August 26, 2018, 12:34:58 AM
Hi Doreen,
That is really cool that you are 5a deficient :) its also interesting to note that you still had mpb. I think a lot of that has also to do with genes, right? Do you get a lot of side effects from a high progesterone dosage? Sleepy, hungry, etc. Loved to know your hair is getting thicker :). With high p dosage have you experienced any pregnancy-like side effects?
Josie i read in wiki that there is a lot of 5a reductase in the liver too:
From wikipedia
" After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin. Hepatic expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp. "
I think there is also some enzymes in the gut that break down the progesterone before it does the first liver pass. I think suppository, gel, or injection would be a better option to reduce passes through the liver.
Ya genes...considering my sister had similar hair issues I wouldn't doubt it. And my mother. And well everyone else in the family lol. I do sometimes get slightly sleepy from the progesterone but usually I just get socially 'looser' almost like being drunk, but not quite. My social inhibitions diminish as a whole, and I'm smiling, outgoing sociable. Really the barriers are down that are normally always there.
Part of me insists that it has to be partly psychological in nature, but it really isn't. I can FEEL when the progesterone activates. I can also feel when that organ inside me that likes it deactivates. Without it life truly is hell... huddled in pain constantly.
At least I found out whats helping.. and every single doctor WILL know that I have to deal with.
Quote from: PurplePelican on August 26, 2018, 04:20:41 AM
Progesterone's action on DHT is only verifiable in vitro, there is no/little evidence it happens in vivo.
I'm talking about the enzyme though 5 alpha reductase which has an affinity for progesterone derived metabolites that are made from progesterone. I don't mean like Progesterone acts upon DHT. I meant 5 alpha reductase works on Progesterone metabolites. Also 5 alpha reductase works on Testosterone to make it into DHT. What I mean is the enzyme can't work on both substances at the same time so while busy any testosterone passing won't be bound to the enzyme at that time because it is already bound to a Progesterone metabollite and being turned into some of the substrates below.
List of conversions
The following reactions are known to be catalyzed by 5α-reductase:[9]
Cholestenone → 5α-Cholestanone
Progesterone → 5α-Dihydroprogesterone
3α-Dihydroprogesterone → Allopregnanolone
3β-Dihydroprogesterone → Isopregnanolone
Deoxycorticosterone → 5α-Dihydrodeoxycorticosterone
Corticosterone → 5α-Dihydrocorticosterone
Cortisol → 5α-Dihydrocortisol
Aldosterone → 5α-Dihydroaldosterone
Androstenedione → 5α-Androstanedione
Testosterone → 5α-Dihydrotestosterone
https://www.ncbi.nlm.nih.gov/pubmed/12742591
"In the human central nervous system, progesterone is rapidly metabolised to 5 alpha-dihydroprogesterone which subsequently is further reduced to allopregnanolone (AP). These conversions are catalysed by 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). "
and from wikipedia earlier:
" The major metabolic pathway of progesterone is reduction by 5α-reductase[60] and 5β-reductase into the dihydrogenated 5α-dihydroprogesterone and 5β-dihydroprogesterone, respectively.[87][88][91][92] This is followed by the further reduction of these metabolites via 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase into the tetrahydrogenated allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone.[93][87][88][91] "
https://www.ncbi.nlm.nih.gov/pubmed/9918575
"Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures. This action is hypothesized to require the metabolic conversion of progesterone to the gamma-aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5alpha-reductase isoenzymes followed by 3alpha-hydroxy oxidoreduction."
If testosterone isn't being turned as quickly as it was prior to progesterone adminitration due to progesterone and it's metabollites using the 5 alpha reductase enzyme then DHT levels should decline. It should be a little similar to how finasterinde and dutasteride work by binding to the enzyme and blocking Testosterone from taking the empty space. How long does the metabolism take? Not sure, but if more progesterone is present then there is more metabollites and progesterone for the 5 alpha reductase enzyme to work on.
Interesting compilation. I have some doubts as to the effectiveness to use up the enzyme within the body enough to drop DHT conversion. Mainly just because associative evidence. During pregnancy, the mothers very high progesterone levels do not inhibit the normal male fetus DHT enough to prevent masculinization of the genital folds.
The genital fold form the penis and scrotum with DHT or extremely high levels of other androgens. Normally anyone with the genetic complete loss of alpha5-reductase will be born with female external genitals much like complete androgen insensitivity causes. The difference is those with complete a5-reductase deficiency often develop male phenotype and many times identify as male gender because their bodily still responds to testosterone.
Quote from: josie76 on August 28, 2018, 05:24:43 AM
Interesting compilation. I have some doubts as to the effectiveness to use up the enzyme within the body enough to drop DHT conversion. Mainly just because associative evidence. During pregnancy, the mothers very high progesterone levels do not inhibit the normal male fetus DHT enough to prevent masculinization of the genital folds.
The genital fold form the penis and scrotum with DHT or extremely high levels of other androgens. Normally anyone with the genetic complete loss of alpha5-reductase will be born with female external genitals much like complete androgen insensitivity causes. The difference is those with complete a5-reductase deficiency often develop male phenotype and many times identify as male gender because their bodily still responds to testosterone.
I just know this: In a strange way progesterone serves to increase my overall stamina levels. It also completed my tanners stage development from a 1.5 to a 4. (Primarily breast & hip growth). Its not perfect, I still get winded easily. High levels of progesterone also decrease the constant horrific cramping & abdominal pain I get from my ... unidentified organ inside. Its located between the bladder & the rectum, below the pelvic floor, so not in the normal location for mullerian structures (typically above and laying on top the bladder). My hair is thicker too. What I don't get? My progesterone was always in normal limits. Why does my body appear to demand more, is something alien to me.
Doreen, I too feel much better with progesterone as part of my HRT. You girl, are definitely not an average case of any particular symptom. I am glad you have found some relief.
Quote from: josie76 on August 28, 2018, 05:24:43 AM
Interesting compilation. I have some doubts as to the effectiveness to use up the enzyme within the body enough to drop DHT conversion. Mainly just because associative evidence. During pregnancy, the mothers very high progesterone levels do not inhibit the normal male fetus DHT enough to prevent masculinization of the genital folds.
The genital fold form the penis and scrotum with DHT or extremely high levels of other androgens. Normally anyone with the genetic complete loss of alpha5-reductase will be born with female external genitals much like complete androgen insensitivity causes. The difference is those with complete a5-reductase deficiency often develop male phenotype and many times identify as male gender because their bodily still responds to testosterone.
Even if the mother's high levels of hormones were to cross into the baby (which I don't think that is how it works? Maybe the placenta keeps them separate / regulates / filters them prior to re-entrance into fetus blood stream?) The male fetus testis secretes these hormones independently to regulate the male organs development:
anti-müllerian hormone (AMH), testosterone, and dihydrotestosterone (DHT). Anti-müllerian hormone causes the paramesonephric ducts to regress.
https://en.wikipedia.org/wiki/Sexual_differentiation_in_humans#Internal_genital_differentiation
"Subsequent development of one set and degeneration of the other depends on the presence or absence of two testicular hormones: testosterone and anti-müllerian hormone (AMH). Disruption of typical development may result in the development of both, or neither, duct system, which may produce morphologically intersex individuals.
Males: The SRY gene when transcribed and processed produces SRY protein that binds to DNA and directs the development of the gonad into testes. Male development can only occur when the fetal testis secretes key hormones at a critical period in early gestation. The testes begin to secrete three hormones that influence the male internal and external genitalia: they secrete anti-müllerian hormone (AMH), testosterone, and dihydrotestosterone (DHT). Anti-müllerian hormone causes the paramesonephric ducts to regress. Testosterone converts the mesonephric ducts into male accessory structures, including the epididymis, vas deferens, and seminal vesicle. Testosterone will also control the descending of the testes from the abdomen into the scrotum.[1] Many other genes found on other autosomes, includingWT-1, SOX9, SF-1 also play a role in gonadal development.[5] "
So even if Progesterone were to cross over (I keep thinking mother hormones and fetus hormones are kept separate though, but can't find any resource on it) The fetus testis secretes it's own hormones to regulate the growth. So 5 alpha reductase enzyme would not be able to stop T to DHT because the testis are already creating the product.
Another thing to note is that SHBG and Transcortin ( Bind to Progesterone) elevate during pregnancy to keep the steroids bound and unusable.
"Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to the two sex hormones: androgen and estrogen. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds."
https://en.wikipedia.org/wiki/Transcortin
"Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6 is a protein that in humans is encoded by the SERPINA6 gene. It is an alpha-globulin.[5][6][7]
Transcortin binds several steroid hormones at high rates:
Cortisol - Approximately 75% of the cortisol in circulation is bound to transcortin. (The rest is bound to serum albumin.) Cortisol is thought to be biologically active only when it is not bound to transcortin.[citation needed]
Cortisone[8]
Deoxycorticosterone (DOC)[8]
Corticosterone - About 78% of serum corticosterone is bound to transcortin.
Aldosterone - Approximately 17% of serum aldosterone is bound to transcortin, while another 47% is bound to serum albumin. The remaining 36% is free.[9]
Progesterone - Approximately 18% of serum progesterone is bound to transcortin, while another 80% of it is bound to serum albumin. The remaining 2% is free.[10]
17α-Hydroxyprogesterone[8]
In addition, approximately 4% of serum testosterone is bound to transcortin.[11] A similarly small fraction of serum estradiol is bound to transcortin as well.[citation needed]
Hepatic synthesis of corticosteroid-binding globulin more than doubles in pregnancy; that is, unbound plasma cortisol in term pregnancy is approximately 2.5 times that of nonpregnant women.[14]"
The unbound levels are still higher but mostly is bound. I still don't think these levels go into the baby and I think are kept separate from mother/fetus. Even then the male fetus testis is still creating it's own dht and other androgens for it's development per the quote mentioned earlier.
I can only say that non bioidenticle progestins are known to cross the placenta and known to affect the prenatal endocrine system. I don't have it handy but certain non human progestins are known to activate the androgen receptors and can partially masculinized a genetic female fetus. Also there is the well known history of DES crossing the placenta and blocking androgen receptors and others.
So if mothers progesterone does cross the placenta at any particular amount, it does not have any known effect on the fetus.
A male fetus androgens would be inconsequential to the mother if they cross over to her at any appreciable level.
That is good to know. I do still wonder if what I mentioned about Progesterone and its metabolites binding to 5a reductase can possibly reduce T to DHT conversation by crowding the enzyme. I guess there is no real way to know with out blood work, but you would need a guinea pig for that. Preferably male with regular T which I think would not happen. TG would already have lowered T unless they were starting? Or perhaps someone coming off Finasteride or Dutasteride and taking high levels of progesterone and knowing her DHT level prior to stopping the Finasteride or Dutasteride? I think it would sort of make sense at least from that view point. I don't know how long the 5 alpha reductase metabolism takes, but the drugs mentioned do bind to the enzyme and keep it blocked/busy thus T isn't turned into DHT and DHT drops. If the progeterone metabolites bind the same then the same should hold true more so in large quantities.