How to make minoxidil work(Arylsulfatase-inhibitors)

[ElToso]

Last night i was thinking of adding minoxidil sulfate to my regimen since classic minoxidil never worked for me.
It would be a pain in the ***, I would have to do daily batches (or make small batches on Eppendorf tubes to thaw every night).
I wrote about this to @MrOscar and he found this publication

Simultaneous determination of minoxidil and minoxidil sulfate by high-performance liquid chromatography with UV-detection and its applications

Minoxidil is a hair growth drug for treating androgenetic alopecia. Although minoxidil is generally administered as a topical formulation, this prodru…

www.sciencedirect.com

Aims​

Minoxidil is a hair growth drug for treating androgenetic alopecia. Although minoxidil is generally administered as a topical formulation, this prodrug must be converted to its active form (minoxidil sulfate) by sulfotransferase in hair follicle tissue. Therefore, its effect may be affected by the sulfureting of minoxidil and de-sulfureting of minoxidil sulfate in hair follicles. To investigate the biotransformation of minoxidil sulfate to minoxidil in hair follicle component cells, a method for simultaneous determination of minoxidil and minoxidil sulfate by high-performance liquid chromatography with UV-detection was established.

Main methods​

Minoxidil and minoxidil sulfate were separated by a reversed-phase chromatography. Minoxidil sulfate was incubated with human hair follicle keratinocyte- and dermal papilla cell-derived arylsulfatases as well as snail-derived sulfatase. The enzyme mixture was applied on HPLC system directly.

Key findings​

Minoxidil and minoxidil sulfate were separated simultaneously. The limit of detection of minoxidil and minoxidil sulfate was 25 and 100 pg inj−1, respectively. Snail-derived sulfatase as well as human hair follicle keratinocyte- and dermal papilla cell-derived arylsulfatases hydrolyzed minoxidil sulfate to minoxidil. Arylsulfatase in hair follicle metabolized the active form of minoxidil to the inactive form. Inactivation of active minoxidil (sulfate) was inhibited by the natural substrate of arylsulfatase A, ascorbate-2-sulfate.

Significance​

Arylsulfatase inhibitors may sustain the effect of minoxidil sulfate in Androgenetic Alopecia therapy. The developed technique was effective for studies of minoxidil metabolism and bioavailability.

Steroid sulfatase inhibitors for the tropical treatment of skin disorders

researchportal.bath.ac.uk

Inhibition of steroid sulfatase (STS) activity in skin is a potential new treatment strategy for a number of skin disorders, including hirsutism, androgen-dependent alopecia, acne and psoriasis. In skin and its appendages, STS regulates the hydrolysis of dehydroepiandrosterone sulfate to dehydroepiandrosterone, a weak androgen, which can be converted to the biologically active androgens testosterone and 5 alpha-dihydrotestosterone by other steroidogenic enzymes also present in skin. A number of potent, irreversible STS inhibitors have been developed based around a core arylsulfamate ester motif, the active pharmacophore required for potent STS inhibition. Such inhibitors include AHBS and STX-64. Topical application of AHBS to the skin of mice or pigs resulted in almost complete inhibition of skin STS activity. Furthermore, when applied to the skin of Gottingen minipigs daily for 2 weeks, by day 10 AHBS had inhibited sebum production, a desired requisite for an antiacne drug. When applied topically to the skin of nude mice at 1.0 and 10.0 mg/kg STX-64 inhibited skin STS activity by > 90%, but it also inhibited liver STS activity. While preclinical studies have confirmed the ability of topically applied STS inhibitors to inhibit skin STS activity, further studies using preclinical models of skin disorders and clinical trials are needed to test their efficacy in treating skin disorders.

Steroid sulfatase in the human hair follicle concentrates in the dermal papilla - PubMed

5 alpha-dihydrotestosterone is known to play a crucial part in the regulation of hair growth and in the development of androgenetic alopecia. 5 alpha-dihydrotestosterone is formed locally within the hair follicle from the systemic precursor testosterone by cutaneous steroid 5 alpha-reductase...

pubmed.ncbi.nlm.nih.gov

5 alpha-dihydrotestosterone is known to play a crucial part in the regulation of hair growth and in the development of androgenetic alopecia. 5 alpha-dihydrotestosterone is formed locally within the hair follicle from the systemic precursor testosterone by cutaneous steroid 5 alpha-reductase. Moreover, adrenal steroids such as dehydroepiandrosterone are converted to 5 alpha-dihydrotestosterone by isolated hair follicles, which may provide an additional source of intrafollicular 5 alpha-dihydrotestosterone levels. Elevated urinary dehydroepiandrosterone and serum dehydroepiandrosterone sulfate have been reported to be present in balding young men. These reports suggest that dehydroepiandrosterone sulfate may act as an important endocrine factor in the development of androgenetic alopecia. Hence the question arises whether the dehydroepiandrosterone sulfate can be metabolized within the hair follicles to yield dehydroepiandrosterone by the microsomal enzyme steroid sulfatase, and where steroid sulfatase might be localized. We therefore performed immunostaining for steroid sulfatase on human scalp biopsies as well as analysis of steroid sulfatase enzyme activity in defined compartments of human beard and occipital hair follicles ex vivo. Using both methods steroid sulfatase was primarily detected in the dermal papilla. Steroid sulfatase activity was inhibited by estrone-3-O-sulfamate, a specific inhibitor of steroid sulfatase, in a concentration-dependent way. Furthermore, we show that dermal papillae are able to utilize dehydroepiandrosterone sulfate to produce 5 alpha-dihydrotestosterone, which lends further support to the hypothesis that dehydroepiandrosterone sulfate contributes to androgenetic alopecia and that steroid sulfatase inhibitors could be novel drugs to treat androgen-dependent disorders of the hair follicle such as androgenetic alopecia or hirsutism.

https://patents.google.com/patent/EP1393518B1/en

Therefore inhibiting Arylsulfatase can be useful to people like me who do not respond to minoxidil.

 

[TheBlackSuit]

Did you try microneedling and tretinoin? It also helps with upregulating follicular sulfotransferase enzymes.

 

[DogoDiLaurentiis]

For all that I've said about minoxidil in the past I am going to give it a try again, however I am going to use a formulation that does not use propylene glycol as part of the carrier.

I would recommend for those who potentially have retinoid sensitivities, be careful when using tretinoin and first use the minoxidil, and then introduce tretinoin in small increments. It's not going to hurt your hair regrowth and could potentially spare you a lot of extreme frustration if you are retinoid sensitive and it induces more shedding than regrowth if you use more than your body is able to tolerate.

Retinoids could potentially be a huge improvement for hair regrowth, but each person is different and one of the main and critical drawbacks of long term retinoid use (accutane/differin/etc) is that they can accelerate hair loss instead of improving it.

As long as you get the growth induction properties of minoxidil along with the sulfotransferase upregulation benefits of tretinoin in perfect balance it could be a very effective combination, but retinoids are not a joke (just like finasteride) and can immediately start hurting you as soon as you exceed your body's threshold for tolerance.

To anyone trying this combination for the first time, or who has not had extensive experience with retinoids for the treatment of acne in the past, take it slow and easy, titrate and balance and pay exceptional care to how your hair is doing and don't be in too much of a hurry, retinoids build up in your body just like finasteride does.

 

[MrOscar]

I think the angle of this thread is different: microneedling and tretinoin are supposed to increase the level of sulfotransferase, but we are discussing what the authors say, so that a different way of increasing potentially the effect of minoxidil could by the inhibition of sulfatases, so the enzymes that convert again minoxidil sulfate formed on the skin, to minoxidil free base.
I see there are many inhibitors available.
The aliphatic esters (sulphates are esterase enzymes), are weak inhibitors. Aliphatic ester are used in cosmetics and topical formulation with relatively high concentration, so their weakness might be compensated by using them at high dosage, say 5%.
Thinking about isopropyl myristate or palmitate or the compounds reported in the patent like sodium lauroyl glutamate etc.
Quercetin and Naringenin are also inhibitors, but I can't remember what was the drawback identified here.
@pegasus2 what's the potential problem with these as topical?

The further interesting point is sulfatases take part of formation of DHT by alternative routes.

 

[DogoDiLaurentiis]

Quercetin is a phytoestrogen and it also potentially increases testosterone because it actively prevents testosterone excretion, if you are strongly looking to increase hair growth and reverse miniaturization you may need to avoid it.

Phytoestrogens are not good for regrowing hair, maybe maintenance, but certainly not if you have problems with testosterone.

 

[LouisSarkozy]

For all that I've said about minoxidil in the past I am going to give it a try again, however I am going to use a formulation that does not use propylene glycol as part of the carrier.

I would recommend for those who potentially have retinoid sensitivities, be careful when using tretinoin and first use the minoxidil, and then introduce tretinoin in small increments. It's not going to hurt your hair regrowth and could potentially spare you a lot of extreme frustration if you are retinoid sensitive and it induces more shedding than regrowth if you use more than your body is able to tolerate.

Retinoids could potentially be a huge improvement for hair regrowth, but each person is different and one of the main and critical drawbacks of long term retinoid use (accutane/differin/etc) is that they can accelerate hair loss instead of improving it.

As long as you get the growth induction properties of minoxidil along with the sulfotransferase upregulation benefits of tretinoin in perfect balance it could be a very effective combination, but retinoids are not a joke (just like finasteride) and can immediately start hurting you as soon as you exceed your body's threshold for tolerance.

To anyone trying this combination for the first time, or who has not had extensive experience with retinoids for the treatment of acne in the past, take it slow and easy, titrate and balance and pay exceptional care to how your hair is doing and don't be in too much of a hurry, retinoids build up in your body just like finasteride does.

how are you planning on counteracting minoxidil skin aging sides ? thanks

i'm planning to get back on the drug aswell

 

[DogoDiLaurentiis]

I'm not sure if that's even going to be an issue, somebody whom I was talking to about it thinks that that was exclusively due to propylene glycol acting as a synergistic compound. There are plenty of people who don't experience that, and one of the things that pg does is enhance penetration into the skin.

Which means all of the adjoining capillaries and veins on your scalp would feed topical minoxidil into those and potentially cause problems. Also I had a particularly bad nightmare reaction to pg, meaning that some of the actual skin problems I experienced might have been caused by the pg and only slightly exacerbated by the minoxidil.

I'm using a non-PG formulation of minoxidil, also I'm using 17b estradiol to bolster skin hydration and collagen synthesis systemically.

And all I can say is I'm already loving the estrogel, I really don't think any of the nightmare side effects others claim might be a problem will be, what I have noticed is that my vision is clear, much more clear than it ever was when my test was high, and I attest this to estrogen lowering blood pressure, specifically intraocular pressure as well as improving insulin response which has been a problem for me.

FYI there are so many supplements that can unknowingly keep your estrogen down or increase excretion of estrogen, so unless your liver is one of those kinds that is a slow metabolizer of hormones, you should easily be able to keep your estrogen from building up past critical levels.

My scalp doesn't feel dry or rough, my hair and scalp feel softer already, which are prime conditions for hair growth.

The next step is to get both forms of minoxidil and then to report back in a few months to see what's what.

 

[real kombo]

For all that I've said about minoxidil in the past I am going to give it a try again, however I am going to use a formulation that does not use propylene glycol as part of the carrier.

I would recommend for those who potentially have retinoid sensitivities, be careful when using tretinoin and first use the minoxidil, and then introduce tretinoin in small increments. It's not going to hurt your hair regrowth and could potentially spare you a lot of extreme frustration if you are retinoid sensitive and it induces more shedding than regrowth if you use more than your body is able to tolerate.

Retinoids could potentially be a huge improvement for hair regrowth, but each person is different and one of the main and critical drawbacks of long term retinoid use (accutane/differin/etc) is that they can accelerate hair loss instead of improving it.

As long as you get the growth induction properties of minoxidil along with the sulfotransferase upregulation benefits of tretinoin in perfect balance it could be a very effective combination, but retinoids are not a joke (just like finasteride) and can immediately start hurting you as soon as you exceed your body's threshold for tolerance.

To anyone trying this combination for the first time, or who has not had extensive experience with retinoids for the treatment of acne in the past, take it slow and easy, titrate and balance and pay exceptional care to how your hair is doing and don't be in too much of a hurry, retinoids build up in your body just like finasteride does.

I am using minoxidil for hairloss and was prescribed tretinoin 0.1% for my acne on my forehead, close to my receding temples. For a first time user, what do you reccomend to be a good dosage? I'm about to incorporate dermarolling as well.

 

[FollicleGuardian]

@ElToso Is minoxidil sulfate really so unstable that you need daily made batches?

 

[DogoDiLaurentiis]

I am using minoxidil for hairloss and was prescribed tretinoin 0.1% for my acne on my forehead, close to my receding temples. For a first time user, what do you reccomend to be a good dosage? I'm about to incorporate dermarolling as well.

I have only used differin, which as with all retinoids can cause problems, however I have read promising results albeit also counterbalanced with conflicting reports on its interactions with inflammatory prostaglandins.

I feel like with my new upcoming regime, I am very strongly going to have to resist the obsessive compulsive approach that many people have when they want results that equates to more = better.

I just found out that minoxidil applied topically can have a half life of 22 hours, considering that I was reading some old posts about a young 23 year old minoxidil user who had terrible aging issues with it, and the fact that he found that he had to seriously limit his dosing schedule and amount, this makes perfect sense.

Differin and Retin-A aren't exactly the same and you cannot expect a 1:1 translation of results, all I can say is that back in 2008 I was on differin for a sudden and uncomfortable bout of acne and skin inflammation and my hair did not all fall out, so that's good news I suppose. In fact, it kind of coincided with my hair recovering, so that's weird now that you mention it, because I was on it after I had started recovering from my catastrophic shedding event.

I'm going to use tretinoin specifically to offset the potential collagen interfering properties of minoxidil on parts of my face I do not want that to happen, but I'm also not using a PPG formulation of minoxidil, which apparently PPG greatly increases systemic absorption and causes inflammation, so I probably won't have the same problems. The tret will absorb systemically on its own, I don't know how I feel about applying it directly to the scalp, I really really do not want to overload my scalp or follicles, more is really not better in this case IMO. Your systemic absorption of tret should do the job.

Nevertheless, I am even considering halving my first bottle of 5% minoxidil without PG and using a dilute version and applying every other day, same with tret, I'm going to apply it very conservatively to my forehead, and undereye/cheeks, a very thin layer every other day.

Both retinoids and minoxidil and finasteride all have the probability to saturate in tissues and continually absorb systemically into the body.

There's absolutely no way I can tell you what "dosage" of tret to use because it's in a gel, there's a standard ratio of product to suspension so it's all about the timing because it's all about how much your body absorbs and processes it. All I can say is I will go with 0.1% tret and I think it's a good idea to apply it conservatively and not every single day.

All I can say is don't be in a hurry if you are worried about adverse sides as I am.

 

[nagual]

how are you planning on counteracting minoxidil skin aging sides ? thanks

i'm planning to get back on the drug aswell

would some one please elaborate regarding Minoxidil skin aging side effects? This is the first time am hearing this.

 

[ElToso]

@ElToso Is minoxidil sulfate really so unstable that you need daily made batches?