Experimental regimen: Limiting bottom growth

Apologies to whoever is going to make the footnotes for this! I will start to collect information for the references section.

Let’s buckle up, enbies. This is going to be long.

(This is not a guide, by the way)

Other factors at play/misc. notes
Hey everyone! This is simply a note that this is much more complicated then I originally thought.

There are multiple factors at play. Simply downregulating AR receptors or their action is not enough.

Furthermore, TGF beta-1 may play a role in the function of the corpora cavernosum. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011715/ hCG has a role in penile growth as well. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214853/

The krt33b gene may have influence on penile growth as well. It's found in rats and humans, and T activates this gene activity, so the amount of hair one has might be a somewhat reliable indicator of bottom growth during puberty.

Targeting clitoromegaly by messing with the NO pathway unfortunately is not the answer to this. However, I do intend to truly get to the bottom of the cause of clitoral growth (no pun intended) but this will take a lot more research. If you have anything to add (genetic-wise is preferred, though hormones would be helpful too) things that can be targeted in penile growth), please leave a message on my Talk page!

Basic information on Nitric Oxide Synthase:
(The page on Nitric Oxide Synthase and Sex Hormones has the same information as this section.)

NOS (nitric oxide synthase) synthesizes nitric oxide (NO) and L-citrulline from L-arginine (and oxygen).

There are three different NOS isoforms, which are found throughout the body and have different uses in it. Some functions of note are for cardiovascular health, immune system response, and neurotransmission— in short, NOS and NO are important compounds!

The three different isoforms are:

— eNOS/NOS 3 (in endothelial/blood vessel tissue)

— iNOS/NOS 2 (in immune cells, largely undetectable unless you are sick)

— nNOS/NOS 1 (mostly in the brain and neurons)

eNOS and nNOS activate at a certain calcium threshold (100nM), while iNOS is calcium independent and essentially always active. iNOS is also independent of cellular location. (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=253)

Malfunctions in NOS have been linked to cancer, diabetes (when NO spreads across all of an organ), and heart disease (due to lack of NO and NO synthase). (https://sites.google.com/a/udel.edu/nitricoxidesynthase/project-definition)

Inhibiting all forms of NOS systemically can increase risk of death (mostly in those with cardiovascular conditions) because NOS handles so many bodily functions. Therefore, researchers ideally look for ways for decrease certain NOS forms in certain areas of the body, as previous drugs have had increased mortality rates in human cardiac studies. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664049/ and https://www.hindawi.com/journals/mi/2012/318087/)

If you ever see the acronym cNOS, it is simply referring to calcium dependent NOS (eNOS and nNOS) http://www.atsjournals.org/doi/pdf/10.1164/rccm.2011144

The rest of this page will be about eNOS and nNOS.

Background on sexual function
(and possible application to stopping erections and bottom growth)

NOS has to do with erections because nNOS is found in nitrergic nerves in the penis (and clitoris) and helps with vasodilation of these nerves. NO is produced by these nerves. Some nNOS has to be found in order for medications like sildenafil and tadafil to act, as they inhibit phosphodiesterase 5 in nitrergic nerves that are moderated by the cyclical GMP which nNOS controls. nNOS raises levels of cyclical GMP, which acts as a vasodilator. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345541/#!po=8.18182).

In other words, nNOS controls erections through nerve action, and therefore it is needed for erections (and possibly indirectly for growth– you can’t have penile erections without the penis appearing bigger).

However— NO is not the only factor mediating and controlling erection, as cGMP also partially acts independently of NO levels. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2269210/#!po=61.1111

Estrogen may also have to do with cGMP, as ER receptors produce cGMP. (www.sciencedirect.com/science/article/pii/S1226845316300240)

Both nNOS and eNOS are found in penile and clitoral tissue. By inhibiting both of these synathases (primarily nNOS, ideally locally) erections and possibly bottom growth could be stopped or at least slowed.

The clitoris has nerve endings and bundles very similar to that of the penis, and in addition, NO can stimulate sexual engorgment of the penis, and has been shown to do the same in the clitoris. (https://www.ncbi.nlm.nih.gov/pubmed/18454796)

In addition, estrogen and androgens like testosterone and DHT could, or already have, strong roles to play in NOS activity.

ER activity affects overall eNOS activity positively, that is to say, more or stable levels of estrogen effect eNOS, as estrogen aids in transcription and activation of eNOS. More estrogen = more eNOS, especially at moderate levels. (https://www.ncbi.nlm.nih.gov/pubmed/12372846 and https://www.ncbi.nlm.nih.gov/pubmed/12053012 and https://academic.oup.com/endo/article/145/10/4550/2499775#52256271)

Less estrogen activity after an oophorectomy (with no estrogen replacement therapy afterwards) is compensated with by production of more eNOS and nNOS (in nonhuman studies). (https://www.nature.com/articles/3900687)

NO spurs LHRH production and therefore raises lutenizing hormone (LH) levels. Ventromedial nitregic nerves stimulated by estrogen play an important role in sexual function. (https://journals.viamedica.pl/folia_histochemica_cytobiologica/article/view/4581)

Both estrogen and NOS are found in the clitoris, which mostly contains ER alpha and nNOS, with smaller amounts of ER beta and eNOS. (https://www.ncbi.nlm.nih.gov/pubmed/11494077 and https://www.ncbi.nlm.nih.gov/pubmed/18793302)

Testosterone and DHT also have effects on genital tissue. In people with uteri they may (according to nonhuman studies) increase eNOS and nNOS content proximally and distally (more internal, more external), while estrogen reduces NOS activity proximally and increases arginase activity distally.

Furthermore, DHT appears to increase nNOS levels more than testosterone, and finasteride causes nNOS activity to drop. eNOS activity was seen to be independent of androgens. (https://www.ncbi.nlm.nih.gov/pubmed/10233504)

Inhibitors of NOS and possible effects
We’re almost there! This is the last important section. If you’ve made it this far, I’m throughly impressed.

(yes, this goes over what little natural inhibitors I can find too)

If you’re looking to simply decrease eNOS or nNOS (without using an inhibitor), increasing iNOS levels could help with this, though it also may increase or worsen already present inflammation, since iNOS controls inflammation. It would possibly decrease eNOS and nNOS because NOS itself is regulated by how much NO is present in different parts of the body. (http://circres.ahajournals.org/content/85/11/979)

Nitric Oxide (NO) itself reduces levels of NOS, as it interacts with the heme of nNOS and eNOS, inhibiting them both. This effect is significantly less in iNOS. (http://www.atsjournals.org/doi/pdf/10.1164/rccm.2011144)

Several NOS inhibitors (specifically to inhibit NOS) have been developed, however, none of them are readily marketed (except to research facilities). (https://www.hindawi.com/journals/mi/2012/318087/)

Despite this, medications that are already on the market can inhibit certain forms of NOS, for example, aminopyridine (a multiple sclerosis medication) inhibits nNOS without crossing the blood brain barrier. (https://cdn.intechopen.com/pdfs-wm/53809.pdf)

Possible inhibitors of NOS include antidepressant medications that are already on the market, perhaps because they inhibit nNOS or glutamate. . (https://www.ncbi.nlm.nih.gov/pubmed/21093491 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458139/) Inhibitors of nNOS (if they are systematic and also cross the blood brain barrier) could have effects that are antidepressant in nature and that could also have effects such as stopping or reducing erections or bottom growth.

L-arginine inhibitors would also inhibit NO, as NOS uses L-arginine to make NO.

Also, BH4 is a catalyst of NO production and helps with the function of eNOS. (https://academic.oup.com/cardiovascres/article/65/4/823/444415) Despite this, I would not recommend messing with eNOS systemically as it is an important factor in cardiovascular function.

Inhibiting glutamate could work, as glutamate stimulates cells to produce NO. (https://journals.viamedica.pl/folia_histochemica_cytobiologica/article/view/4581) An easier route would be to inhibit NMDA receptors, as glutamate activates those receptors. http://www.sciencedirect.com/science/article/pii/0028390894900345

Arginase is another possible option, as it works through several mechanism actions to inhibit overall NOS production. It also contributes to erectile dysfunction.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664049/)

Ibuprofen downregulates NO in human studies (https://www.ncbi.nlm.nih.gov/pubmed/10336532)

IGF 1 and NO regulate each other. Raised IGF-1 lowers NO, and raised NO inhibits IGF. Both are reversible. http://www.oarsijournal.com/article/S1063-4584(04)00139-6/pdf

Whether you’re AFAB or AMAB, I recommend staying away from agmatine, as it increases levels of LH (through increasing levels of lutenizing hormone releasing hormone, LHRH) in studies on ovariectomized rats, and could theoretically increase T and E levels. (https://www.ncbi.nlm.nih.gov/pubmed/7478229)

Curcumin has been proven to lower levels of nNOS in nonhuman studies. (https://books.google.com/books?id=d42RCwAAQBAJ&pg=PA302&lpg=PA302&dq=curcumin+nNOS&source=bl&ots=iF_4p7pdnP&sig=gyIegiPTj3aSq1KCXwy5T-2AxCI&hl=en&sa=X&ved=0ahUKEwiyhveu_c3XAhUJ4oMKHaUKBFA4ChDoAQhHMAM#v=onepage&q=curcumin%20nNOS&f=false)

Green tea (specifically the epigallocatechin gallate/EGCG in it) lowers nNOS levels. (http://www.fasebj.org/content/27/1_Supplement/790.14) It also downregulates androgen receptors in prostate cancer studies, and shows positive effects in reducing breast cancer cells (though in the study on AR, EGCG was injected). (https://www.nature.com/articles/1203511)

l-Theanine (again in green tea) inhibits nNOS and iNOS. https://www.researchgate.net/publication/43340817_L-Theanine_protects_the_APP_Swedish_mutation_transgenic_SH-SY5Y_cell_against_glutamate-induced_excitotoxicity_via_inhibition_of_the_NMDA_receptor_pathway

Catechin hydrate, EGCG, curcumin, apigenin, naringenin, and gallotennin lower nNOS action (presumably through inhibition), with the first three lowering it the most. (http://onlinelibrary.wiley.com/store/10.1111/j.1742-4658.2009.07487.x/asset/j.1742-4658.2009.07487.x.pdf;jsessionid=C83321EFD552F72A85ACCD5C972A513F.f01t03?v=1&t=ja8nl6ix&s=f648eb3106514ebeb49d2bdef7a3677381af63a1)

EGCG shouldn’t cross the BBB at low-to-moderate doses. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585739/)

Hops inhibits nNOS. https://www.ncbi.nlm.nih.gov/pubmed/12033808

The flavonoids of several natural foods (garlic, mandarin orange peel, oryza savita l. rice) and herbs have anti-inflammatory properties that are now beginning to be attributed to iNOS inhibition. (https://www.omicsonline.org/open-access/natural-products-especially-fruits-and-vegetables-are-an-excellent-source-of-chemical-structures-with-a-wide-variety-of-biological-activity-2167-0501.1000e113.php?aid=5604)

Finally, L-Thiocitrulline inhibits both iNOS and nNOS, though this is reversible. I’m not sure whether L-Thiocitrulline crosses the blood brain barrier or not, though it raised blood pressure in studies on rats. Currently L-Thiocitrulline is not available for the general public. (http://www.jbc.org/content/269/42/26083.full.pdf)

Other thoughts
Though this is separate from NO, one gene that seems to have a lot to do with penis growth during puberty is the Krt33b mRNA gene (proven in rat studies. This compound is found in both rat and human hair, corpus cavernosum, and urethral blood vessel cells.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236322)