Androgenetic Alopecia Comparative Study- Gene Expression Differences

[sktboiboi]

https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.14278 <=== ( use sci-hub for full study )

Genomewide differential expression profiling of long non‐coding RNAs in androgenetic alopecia in a Chinese male population

Abstract
Background
Androgenetic alopecia (Androgenetic Alopecia), or male pattern baldness (male pattern baldness), is the most common form of hair loss in males. A combination of genetic and androgen causes have been suggested as factors that contribute to the development of Androgenetic Alopecia. However, the specific molecular mechanisms that underly Androgenetic Alopecia remain largely unknown. Long non‐coding RNAs (lncRNAs), a new class of regulatory non‐coding RNAs that are longer than 200 nucleotides, have been shown to play important roles in a number of cellular processes, including transcription, chromosome remodelling and post‐transcriptional processing. The dysregulation of lncRNAs is associated with many forms of diseases, but it remains unknown whether lncRNAs are associated with Androgenetic Alopecia.

Objective
The aim of this study was to identify Androgenetic Alopecia‐associated lncRNAs and predict the potential roles of these lncRNAs in Androgenetic Alopecia.

Methods
A genomewide microarray was used to identify lncRNAs that are differentially expressed between Androgenetic Alopecia and adjacent normal tissues. Real‐time qRT‐PCR was used to validate the microarray data.

Results
A large number of lncRNAs were differentially expressed (fold change >2.4) between Androgenetic Alopecia and adjacent normal tissues. Of these, 770 were upregulated and 1373 were downregulated. Moreover, pathway analysis revealed that 53 functional pathways were associated with the upregulated transcripts, while 11 pathways were associated with the downregulated transcripts.

Conclusion
To our knowledge, this is the first study to investigate Androgenetic Alopecia‐associated lncRNAs. lncRNA profiles are altered in Androgenetic Alopecia, and these lncRNAs and their target genes may serve as novel candidates for preventing and treating Androgenetic Alopecia.

From the analysis, of the downregulated genes, the Hedgehog signalling pathway was the most enriched network and it consisted of five target genes that were signifi- cantly differentially expressed between the two samples, while the most enriched upregulated genes were associated with the Tcell receptor signalling pathway, which consisted of 26 target genes that were found to be significantly differentially expressed between Androgenetic Alopecia and adjacent normal tissues. Figure 7a shows the top 10 upregulated pathways, and Figure 7b shows the top 10 downregulated pathways.

"Of these, T-cell receptor signalling was the most upregulated pathway, and Hedgehog signalling pathway was the most downregulated pathway. The Hedgehog pathway has been a focus of research in recent years. The Hedgehog pathway has been shown to be closely related to hair cycle control, and the inhibition of this pathway can lead to hair loss, in alignment with our results.17,18 The T-cell receptor signalling pathway plays important roles in human immune functions.19 It has been reported that this pathway is associated with the generation of alopecia areata, which is an autoimmune disease.19 However, a relationship between Androgenetic Alopecia and this pathway had not previously been reported. Our results reveal that Androgenetic Alopecia might be significantly and importantly involved with the immune system, but this requires further investigation. Among the most differentially expressed lncRNAs, some are closely related to coding genes, such as CTD-2636A23.2, which is associated with the coding gene HMGCS1. This gene was shown to be associated with cellular responses to follicle stimulating hormone stimuli, cellular responses to cholesterol, cholesterol biosynthetic processes and male gonad development( aka testicles), all of which are tightly associated with Androgenetic Alopecia mechanisms.20–23 The lncRNAs RP4-742J24.2 and AC137932.5 are related to the coding genes BTBD3 and ANKRD11, respectively. ANKRD11 has been found to be associated with tissue homoeostasis,24 and BTBD3 is related to cerebral cortex development.25 Other lncRNAs, such as RP11-818024.3 and RP11-76908.2, are associated with the genes CRK and YES1, respectively, which are involved in ion channel binding, the vascular endothelial growth factor receptor signalling pathway, cellular responses to transforming growth factor-beta and platelet-derived factor.26–29 It is interesting to note that the functions of these genes are associated with the processes underlying and the development of Androgenetic Alopecia."

So 1 of these significantly, differentially expressed incRNAs is(2nd most downregulated gene in alopecic scalp- 33+ folds lower than adjacent normal scalp tissue);

ASHGV40041683 33.8073415 Down ENST0000 0565748 CTD2636A23.2 GENCODE 5 Natural antisense HMGCS1 Hydroxy methylglutarylCoA synthase

https://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_synthase

it's main function is in the cholesterol biosynthetic and cellular reponses to cholesterol pathway. In other words, it's associated with cholesterol. we are going to need to increase HMGCS1 in Androgenetic Alopecia scalp.

HMGCS1 is activated by https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factor_4_alpha

Interactions[edit]
Hepatocyte nuclear factor 4 alpha has been shown to interact with:

• Beta-catenin,[15]
• CREB binding protein,[16][17]
• MED1,[18][19]
• MED14,[18][19]
• Small heterodimer partner[20]
• Testicular receptor 4,[21]

and that's because HMGCS1 is a target gene of HNF4A:

https://www.ncbi.nlm.nih.gov/pubmed/19088433

Transcriptional regulation of HMG-CoA synthase and HMG-CoA reductase genes by human ACBP.
Vock C1, Döring F, Nitz I.
Author information

Abstract
The acyl-CoA binding protein (ACBP) is an ubiquitary expressed multi-functional protein which regulates basic cellular functions such as fatty acid and steroid metabolism. Since ACBP is described to interact with the transcription factor hepatocyte nuclear factor 4 alpha (HNF-4alpha), we investigated the role of human ACBP on transcriptional regulation of the putative HNF-4alpha target gene HMG-CoA synthase 1 (HMGCS1). As shown by promoter-reporter assays ACBP represses the HNF-4alpha-induced activity of a 617bp HMGCS1 promoter fragment by approximately 80% in HepG2 cells as well as in non-endodermal HeLa cells devoid of HNF-4alpha. Interestingly, reporter assays without co-transfection of HNF-4alpha revealed that ACBP reduces the activity of the HMGCS1 promoter by about 60 to 80% in both cell lines. Activities of 417bp and 317bp HMGCS1 promoter fragments were 2.5 to 4 fold decreased by ACBP. Concordantly, the levels of HMGCS1-mRNA and -protein were diminished to 60% and 70% in ACBP-expressing HeLa cells, respectively. Additionally, ACBP reduces the promoter activity and the mRNA levels of the cholesterogenic HMG-CoA reductase (HMGCR). In conclusion, we provide evidence that ACBP is a transcriptional regulator of the HMGCS1 and HMGCR genes encoding rate-limiting enzymes of cholesterol synthesis pathway.

and low levels of HNF4A = loss of lipid homeostasis

https://www.ncbi.nlm.nih.gov/pubmed/21071704

CONCLUSIONS:
Loss of hepatic HNF4α results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4α activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4α is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.[/quote]

Not to mention HNF4A is tied up with SHBG levels https://en.wikipedia.org/wiki/Sex_hormone-binding_globulin . SHBG renders circulating hormones to the inactive state- estrogens and androgens.

Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to serum albumin (~54%) and corticosteroid-binding globulin (CBG) (AKA transcortin), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1-2% is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG.

Promoter activation[edit]
The mechanism of activating the promoter for SHBG in the liver involves hepatocyte nuclear factor 4 alpha (HNF4A) binding to a DR1 like cis element which then stimulate production. Competing with HNF4A at a third site on the promoter is PPARG-2 which reduces copying the gene to RNA. If HNF4A level is low then COUP-TF binds to the first site and turns off production of SHBG.[5]

So low levels of HNF4A = low levels of SHBG.

So to increase HNF4A, https://examine.com/supplements/berberine/ is an option as seen in Wiki:

The alkaloid berberine upregulates the expression of HNF4A.[11]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760199/

"Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner"

Now the most upregulated gene in alopecic scalp,from the study- is:

http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRAC2 (69+folds higher than adjacent normal scalp tissue)

ASHGV40021887 69.7530454 Up NM_001282275 PRAC2 17 Hs.236557 Prostate cancer susceptibility candidate 2

Prostate Cancer Susceptibility Candidate 2
This gene is highly expressed in prostate, rectum, colon, and testis. This gene may produce a non-coding RNA or may encode a short protein that might localize to the nucleus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

https://www.ncbi.nlm.nih.gov/pubmed/12746837

PRAC2: a new gene expressed in human prostate and prostate cancer.
Olsson P1, Motegi A, Bera TK, Lee B, Pastan I.
Author information

Abstract
BACKGROUND:
The database of human Expressed Sequence Tags was previously used to identify PRAC (Prostate 47:125-131, 2001), a novel gene specifically expressed in human prostate, prostate cancer, rectum, and distal colon. In this report, we have identified PRAC2, another gene with a similar expression pattern that is located adjacent to the original PRAC gene on chromosome 17q21.3.

METHODS:
Using a computer-based analysis, a cluster of sequence homologous ESTs was identified that is mainly derived from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The PRAC2 transcript and protein were identified using Northern blot analysis, RACE-PCR, primer extension, and Western blots.

RESULTS:
PRAC2 encodes a 564 nucleotide RNA found in prostate, rectum, distal colon, and testis. Weak expression was also found in placenta, peripheral blood leukocytes, skin, and in two prostate cancer cell lines: LNCaP and PC-3. The transcript seems to encode a 10.5-kDa nuclear protein. The PRAC2 gene is located on chromosome 17 at position 17q21, between the Hoxb-13 gene and the recently discovered PRAC gene.

CONCLUSIONS:
Because of the higher expression of PRAC2 in prostate and its proximity to Hoxb-13, PRAC2 may have a function in prostate growth and development.

Cholesterol and Prostate cancer(in addition to the former being a precursor to sex hormones and vitamin D)- is correlated:

https://www.sciencedirect.com/science/article/pii/S0304419X13000036

Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective

Abstract
Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs.

Concurrent to this observation, intense efforts have been expended in cardiovascular research to better understand the regulators of cholesterol homeostasis. Here, we apply this knowledge to elucidate the molecular mechanisms driving the accumulation of cholesterol in PCa. For instance, recent evidence from our group and others shows that major signalling players in prostate growth and differentiation, such as androgens and Akt, modulate the key transcriptional regulators of cholesterol homeostasis to enhance cholesterol levels. This includes adjusting central carbon metabolism to sustain greater lipid synthesis. Perturbations in cholesterol homeostasis appear to be maintained even when PCa approaches the advanced, ‘castration-resistant’ state. Overall, this provides a link between cholesterol accumulation and PCa cell growth. Given there is currently no cure for castration-resistant PCa, could cholesterol metabolism be a novel target for PCa therapy?

Overall, this review presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy. Consequently, we recommend future investigations, both to better elucidate the mechanisms driving this accumulation and applying it in novel chemotherapeutic strategies.

and we know Androgenetic Alopecia is largely caused by an abhorrent level of lipid synthesis in the scalp:

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.14767 (<== use sci hub for full study)

We identified 1,339 differential transcripts between samples from Cluster III and II (Figure 2B and G), and found up-regulation of metabolism (electron carrier activity, respiratory chain and monosaccharide metabolic process), lipid biosynthesis, response to hormone stimulus and steroid hormone biosynthesis related genes (Figure 2F, Table S2, S5). The up-regulation of genes in the respiratory chain (CYB5R3, SDHA) may impact on the redox state in Androgenetic Alopecia-affected hairs 7, 8. Furthermore, the up-regulation of anti-oxidation genes (GPX4 and PRX3) suggests that patient vertex scalps may be exposed to greater oxidative stress than control scalps, possibly resultant from increased respiratory chain activity 9, 10. Increased levels of GPX4 would also protect the increased amount of lipid synthesized in the patient vertex scalp from phospholipid hydroperoxides-mediated oxidation


What we can gather here is the major mechanism of Androgenetic Alopecia is an involvement of Cholesterol and the resulting downstream mechanisms(sex hormones and even downstream lipids like prostaglandins and leukotrienes)

 

[sktboiboi]

a very old study for 1 of the Androgenetic Alopecia locus on chromosome 20p11 that is universally present in both Asian and Caucasian men- is Pax1:

https://en.wikipedia.org/wiki/PAX1

Function[edit]
This gene is a member of the paired box (PAX) family of transcription factors which are essential during fetal development. It is required for the development of the ventral vertebral column. Its expression is limited to the pharyngeal pouches and the cells that surround the developing vertebrae near the top where the head will be established to help give rise to the neck and the start of the formation of the shoulders and arm buds. Cancers, such as ovarian and cervical cancers, add a methyl (CH3) group which silences, or disables, the gene which may be able to suppress the tumor by regulating when other cells divide and increase. A substitution or deletion of this gene in mice can produce variants of the mutant undulated which is characterized by segmentation abnormalities along the inner spine. Mutations in the human gene may contribute to the condition of Klippel–Feil syndrome, which is the failure of the vertebrae to segment near the top of the spine and possibly further down with symptoms including a short, immovable neck and a low hairline on the back of the head.[7][8][9][10]



Reading this leads us to the skull expansion theory and other alternative Androgenetic Alopecia theories about cranial shape and stuff.

Now Pax-1 is involved with spine development:



https://www.nature.com/articles/ncomms7452

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10−9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10−10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition.

and coincidentally in the diagram of the study, 1 of the genes mentioned in https://media.nature.com/original/n...15/150318/ncomms7452/extref/ncomms7452-s1.pdf on page 11- is HNF4 (HNF4 has 2 isoforms- https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factor_4_alpha and https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factor_4_gamma )

 

[sktboiboi]

As mentioned above in the study, the Hedgehog pathway is downregulated in Androgenetic Alopecia. https://en.wikipedia.org/wiki/Sonic_hedgehog is required for hair growth. There was even a synthetic agonist developed for it, but was cancelled due to 'safety concerns':

https://www.ncbi.nlm.nih.gov/pubmed/16185261

Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway.
Paladini RD1, Saleh J, Qian C, Xu GX, Rubin LL.
Author information

Abstract
The hedgehog (Hh) family of intercellular signaling proteins is intricately linked to the development and patterning of almost every major vertebrate organ system. In the skin, sonic hedgehog (Shh) is required for hair follicle morphogenesis during embryogenesis and for regulating follicular growth and cycling in the adult. We recently described the identification and characterization of synthetic, non-peptidyl small molecule agonists of the Hh pathway. In this study, we examined the ability of a topically applied Hh-agonist to modulate follicular cycling in adult mouse skin. We report that the Hh-agonist can stimulate the transition from the resting (telogen) to the growth (anagen) stage of the hair cycle in adult mouse skin. Hh-agonist-induced hair growth caused no detectable differences in epidermal proliferation, differentiation, or in the endogenous Hh-signaling pathway as measured by Gli1, Shh, Ptc1, and Gli2 gene expression when compared with a normal hair cycle. In addition, we demonstrate that Hh-agonist is active in human scalp in vitro as measured by Gli1 gene expression. These results suggest that the topical application of Hh-agonist could be effective in treating conditions of decreased proliferation and aberrant follicular cycling in the scalp including androgenetic alopecia (pattern hair loss).

And guess what, the body's only endogenous ligand for Sonic hedgehog(via https://en.wikipedia.org/wiki/Smoothened )-, is none other than Cholesterol.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035717/

Cellular cholesterol directly activates Smoothened in Hedgehog signaling

Summary
In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols(aka cholesterol and its many derivatives) activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and unique among CRD-containing receptors. We demonstrate Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol.

 

[sktboiboi]

Main study above indicated HMGCS1 is downregulated in Androgenetic Alopecia tissue.

high HNF4A1 => high HMGCS1 + high SHBG

low SHBG = higher free androgens and estrogens + higher metabolic syndrome in men:

https://www.ncbi.nlm.nih.gov/pubmed/24714992

Association between sex hormone-binding globulin (SHBG) and metabolic syndrome among men.

Abstract
CONTEXT AND OBJECTIVE:
Metabolic syndrome consists of a set of factors that imply increased risk of cardiovascular diseases. The objective here was to evaluate the association between sex hormone-binding globulin (SHBG), sex hormones and metabolic syndrome among men.

DESIGN AND SETTING:
Retrospective analysis on data from the study "Endogenous oestradiol but not testosterone is related to coronary artery disease in men", conducted in a hospital in São Paulo.

METHODS:
Men (aged 40-70) who underwent coronary angiography were selected. The age, weight, height, waist circumference, body mass index and prevalence of dyslipidemia, hypertension and diabetes of each patient were registered. Metabolic syndrome was defined in accordance with the criteria of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP-ATPIII). Serum samples were collected to assess the levels of glucose, total cholesterol, HDL-cholesterol (high density lipoprotein), triglycerides, albumin, SHBG, estradiol and total testosterone (TT). The levels of LDL-cholesterol (low density lipoprotein) were calculated using Friedewald's formula and free testosterone (FT) and bioavailable testosterone (BT) using Vermeulen's formula.

RESULTS:
141 patients were enrolled in the study. The prevalence of metabolic syndrome was significantly higher in the first SHBG tercile than in the second and third terciles. A statistically significant positive association between the SHBG and TT values was observed, but no such association was seen between SHBG, BT and FT.

CONCLUSION:
Low serum levels of SHBG are associated with higher prevalence of metabolic syndrome among male patients, but further studies are required to confirm this association.

and higher metabolic syndrome = Androgenetic Alopecia(and cardiovascular diseases):

https://www.ncbi.nlm.nih.gov/pubmed/27279298

Metabolic syndrome in androgenic alopecia.
Gopinath H1, Upadya GM1.
Author information

Abstract
BACKGROUND:
Androgenic alopecia has been associated with an increased risk of coronary heart disease in various studies. The relationship between androgenic alopecia and metabolic syndrome, a known risk factor for atherosclerotic cardiovascular disease, is still poorly understood.

AIM:
To study the association between metabolic syndrome and early-onset androgenic alopecia.

METHODS:
A hospital-based analytical cross-sectional study was done on men in the age group of 18-55 years. Eighty five clinically diagnosed cases with early-onset (<35 years) androgenic alopecia of Norwood grade III or above, and 85 controls without androgenic alopecia were included. Data collected included anthropometric measurements, arterial blood pressure and history of chronic diseases. Fasting blood and lipid profile were determined. Metabolic syndrome was diagnosed as per the new International Diabetes Federation criteria. Chi-square and Student's t-test were used for statistical analysis using Statistical Package for the Social Sciences (SPSS) version 17.00.

RESULTS:
Metabolic syndrome was seen in 19 (22.4%) patients with androgenic alopecia and 8 (9.4%) controls (P = 0.021). Abdominal obesity, hypertension and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia versus their respective controls.

LIMITATIONS:
The limitations of our study include small sample size in subgroups and the lack of evidence of a temporal relationship between metabolic syndrome and androgenic alopecia.

CONCLUSION:
A higher prevalence of metabolic syndrome is seen in men with early-onset androgenic alopecia. Early screening for metabolic syndrome and its components is beneficial in patients with early-onset androgenic alopecia.

and also prostate cancer:

https://www.ncbi.nlm.nih.gov/pubmed/28220805

Meta-analysis of metabolic syndrome and prostate cancer.
Gacci M1, Russo GI2, De Nunzio C3, Sebastianelli A1, Salvi M1, Vignozzi L4, Tubaro A3, Morgia G2, Serni S1.
Author information

Abstract
BACKGROUND:
Metabolic syndrome (MetS) and prostate cancer (PCa) are highly prevalent conditions worldwide. Current evidence suggests the emerging hypothesis that MetS could play a role in the development and progression of several neoplasms. The aims of this study are to evaluate the impact of MetS and MetS factors on PCa incidence, on the risk of high-grade PCa and to analyze the role of MetS and single MetS components on the development of aggressive PCa features.

METHODS:
A systematic literature search and analysis on PubMed, EMBASE, Cochrane and Academic One File databases until September 2015 was performed by 2 independent reviewers to evaluate the associations between MetS and PCa incidence, and between MetS and high-grade PCa incidence (bioptical Gleason Score⩾8, Prognostic Group 4-5 according to the novel prostate cancer grading system). Also the association between MetS and individual MetS components with pathological Gleason Score⩾8, extra-capsular extension, seminal vesicle invasion, positive surgical margins and biochemical recurrence (defined as two consecutive PSA values ⩾0.2 ng ml-1 after radical prostatectomy) was evaluated.

RESULTS:
24 studies were selected including a total of 132 589 participants of whom 17.35% had MetS. There was a slight association between MetS and PCa incidence (odds ratio (OR)=1.17 (1.00-1.36), P=0.04) and between high-grade PCa and MetS (OR= 1.89 (1.50-2.38), P<0.0001) but the studies were statistically heterogeneous. No association was found between MetS components and PCa risk except for hypertension. MetS was significantly associated with pathologic Gleason Score⩾8 (OR= 1.77 (1.34-2.34); P<0.01), extra-capsular extension (OR=1.13 (1.09-1.18); P<0.01), seminal vesicle invasion (OR=1.09 (1.07-1.12); P<0.01), positive surgical margins (OR=1.67 (1.47-1.91); P<0.01) and biochemical recurrence (OR=1.67 (1.04-2.69); P<0.01).

CONCLUSIONS:
The presence of MetS is associated with worse oncologic outcomes in men with PCa, in particular with more aggressive tumor features, and biochemical recurrence.

 

[sktboiboi]

IMO, so the period in a balding man's life when he had the best hair- would be right before he hit puberty. That's when levels of SHBG are sky high and circulating androgens and estrogens are very low.

Personally, i started balding at 16(coincidentally, that's when i suddenly started sprouting taller and family commented my voice started to sound different) and my hair was the thickest at 12.

 

[kiwipilu]

I have always had crazy high SHBG ,testosterone...

 

[whatevr]

IMO, so the period in a balding man's life when he had the best hair- would be right before he hit puberty. That's when levels of SHBG are sky high and circulating androgens and estrogens are very low.

Personally, i started balding at 16(coincidentally, that's when i suddenly started sprouting taller and family commented my voice started to sound different) and my hair was the thickest at 12.

My hair was the thickest at 18, and my libido was higher then than it is now.

 

[BalderBaldyBald]

Agree with whatevr, your hypothesis has a flaw here.

It's not about the hormone levels, but the androgen receptors sensitivity, always have been.

The "Oh My Gosh bald men are so virile cause they have much more T and DHT" argument is a fairy tale.
I agree that Androgenetic Alopecia people starting Test injections for gymceiling will see their hair falls like rain, but this does not apply to non balding people.

Same goes for puberty, if your sensitivity is triggered during that hormone rush, you're in deep sh*t (i started at 15)

Seems like scalp androgen receptors sensitivity has a scale amoung us too, we are not all fucked the same way, some of us this is just the tip, and others balls deep

 

[Armando Jose]

Before reading this interesting post, I would like to think that the genes that make a person have more dense hair, thicker hair, and even that the hair is something curved, these people are less likely to suffer from common alopecia.
We will see the result.

......

Read it and no mentions,...., but if cholesterol issues are greatly implicated, how explain the pattern and the timing of common hair loss?

 

[sktboiboi]

Agree with whatevr, your hypothesis has a flaw here.

It's not about the hormone levels, but the androgen receptors sensitivity, always have been.

The "Oh My Gosh bald men are so virile cause they have much more T and DHT" argument is a fairy tale

nope, i gave my personal experience only as a trivial(but true)anecdote. U may have started balding later and have experienced very different circumstances of Androgenetic Alopecia from me.

The main discussion here is about the first comparative study in this thread and that is that is the HMG-COA synthase gene that is downregulated in Androgenetic Alopecia tissue.

u r closed minded n only focusing on the downstream age-old hormonal aspect of Androgenetic Alopecia when the crucial point here is the cholesterol factor that Androgenetic Alopecia is involved with

 

[BalderBaldyBald]

nope, i gave my personal experience only as a trivial anecdote.

The main discussion here is about the first comparative study in this thread and that is that is the HMC-COA synthase gene. u r closed minded n only focusing on the age old hormonal aspect of Androgenetic Alopecia when the crucial point here is the cholesterol factor that gene is invovled in

this gene was shown to be associated with cellular responses to follicle stimulating hormone stimuli, cellular responses to cholesterol, cholesterol biosynthetic processes and male gonad development.

Crucial point of Androgenetic Alopecia ? Really ? We didn't read the same post then.A gene can have many purpose.Here it's associated to follicle stimulating hormone (which one ? This is not mentionned) and cellular responses to cholesterol (all body cells)

This study is not very clear though, abnormal scalp cells response to cholesterol ?

 

[sktboiboi]

this gene was shown to be associated with cellular responses to follicle stimulating hormone stimuli, cellular responses to cholesterol, cholesterol biosynthetic processes and male gonad development.

Crucial point of Androgenetic Alopecia ? Really ? We didn't read the same post then.A gene can have many purpose.Here it's associated to follicle stimulating hormone (which one ? This is not mentionned) and cellular responses to cholesterol (all body cells)

This study is not very clear though, abnormal scalp cells response to cholesterol ?

sorry i dont get it- u reaffirmed my point yourself - and that is Androgenetic Alopecia is tied with cholesterol. So whats the disagreement here

 

[BalderBaldyBald]

It's true that Androgenetic Alopecia patients have lower cholesterol than non balding people
We globally have an abnormal lipid profile, but to state that it's the main culprit of Androgenetic Alopecia, just Nope.

HRT won't have any result then, same goes for Big 3.

Interesting theory nonetheless

 

[sktboiboi]

It's true that Androgenetic Alopecia patients have lower cholesterol than non balding people
We globally have an abnormal lipid profile, but to state that it's the main culprit of Androgenetic Alopecia, just Nope.

HRT won't have any result then, same goes for Big 3.

Interesting theory nonetheless

u r getting even further this time. the study mentioned that cholesterol is involved- but it doesnt say whether we have to much or too little in Androgenetic Alopecia tissue.like u've mention- it is 'not clear'- even i myself do not know about that.

Also, the study does not propose any 'theories'- it's their findings. The study indicated that Androgenetic Alopecia is tied with the cholesterol pathway- and that HMGCS1 http://www.genecards.org/cgi-bin/carddisp.pl?gene=HMGCS1 is downregulated in balding tissue. So since it's downregulated in Androgenetic Alopecia tissue when comapred to normal tissue, we need to increase it.

Also the study here https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.14767 already stated we have an increased amount of lipids synthesiszed in balding scalp,.

If u have nothing informative to add on in this thread, please dont comment anymore. If u do, please post sources backing up what u've said and let us examine and discuss about it.

Thanks

 

[sktboiboi]

Before reading this interesting post, I would like to think that the genes that make a person have more dense hair, thicker hair, and even that the hair is something curved, these people are less likely to suffer from common alopecia.
We will see the result.

......

Read it and no mentions,...., but if cholesterol issues are greatly implicated, how explain the pattern and the timing of common hair loss?

Your question is a good question. However, I do not have a definite answer to it, because the primary study in this thread is a comparative study- that is it is looking at the molecular angle of Androgenetic Alopecia- as in which are are the gene expression differences between normal scalp and Androgenetic Alopecia scalps. e.g gene X is expressed Y folds lower in Androgenetic Alopecia scalp when compared to normal scalp.

Thus your question would be best discussed with a study along the lines of 'Evolutionary/anatomical causes for Androgenetic Alopecia' in hand.

 

[sktboiboi]

ok so an update:

so i've talked about this a few months ago on hedgehog signalling as indicated by the study that found it was the most downregulated pathway in Androgenetic Alopecia tissues. I will cut things short by pasting only selected paragraphs of the entire study(s), cos i know people are just lazy reading walls of text.

here goes:

the previous study compared Androgenetic Alopecia tissues and normal tissues:

Materials and methods
Subjects studied
This study included a total of 10 consecutive male subjects (30–
60 years old) with Androgenetic Alopecia who were treated between May 2015
and February 2016 in the Dermatology Department of the First
Affiliated Hospital, China Medical University, Shenyang, China.
All patients were of the Han Chinese ethnic group and from
Liaoning Province, China. Type V or VI Androgenetic Alopecia (<== almost slick bald)was diagnosed
according to the Norwood–Hamilton Scale, and the patients
were not biologically related. All enrolled patients had suffered
from Androgenetic Alopecia for more than 10 years without previous treatment.
Scalp tissues were obtained from the most severely affected Androgenetic Alopecia areas, where the follicle density was lower than 150/cm2
, and
adjacent normal areas 5 cm from the margin of the Androgenetic Alopecia areas
in which the follicle density was >325/cm2
. Samples were stored
in a 80°C freezer for subsequent experiments. All tissues were
confirmed by histopathology.

The microarray data and qRT-PCR results matched well. The
differentially expressed genes were then organized into hierarchical
categories using heat maps and hierarchical clustering. Moreover,
the pathway analysis identified 64 pathways (53
upregulated and 11 downregulated) that may play key roles in
the mechanisms underlying Androgenetic Alopecia. Of these, T-cell receptor signalling
was the most upregulated pathway(Immune system pathway is the most upregulated in Androgenetic Alopecia tissue), and Hedgehog
signalling pathway was the most downregulated pathway(Hedgehog signalling pathway is the most downregulated in Androgenetic Alopecia). The
Hedgehog pathway has been a focus of research in recent years.
The Hedgehog pathway has been shown to be closely related to
hair cycle control, and the inhibition of this pathway can lead to
hair loss, in alignment with our results.17,18 The T-cell receptor
signalling pathway plays important roles in human immune
functions.19 It has been reported that this pathway is associated
with the generation of alopecia areata, which is an autoimmune
disease.19 However, a relationship between Androgenetic Alopecia and this pathway
had not previously been reported. Our results reveal that
Androgenetic Alopecia might be significantly and importantly involved with the
immune system, but this requires further investigation.
Among the most differentially expressed lncRNAs, some are
closely related to coding genes, such as CTD-2636A23.2, which
is associated with the coding gene HMGCS1. This gene was
shown to be associated with cellular responses to follicle-stimulating hormone stimuli, cellular responses to cholesterol,
cholesterol biosynthetic processes and male gonad development(Androgenetic Alopecia has got something to do with Cholesterol- it is not clearly stated whether there's too much or too little of it or any other related cholesterogenic metabolites- but is associated with/has something to do with it),
all of which are tightly associated with Androgenetic Alopecia mechanisms.20–23
The lncRNAs RP4-742J24.2 and AC137932.5 are related to the
coding genes BTBD3 and ANKRD11, respectively. ANKRD11
has been found to be associated with tissue homoeostasis,24 and
BTBD3 is related to cerebral cortex development.25 Other
lncRNAs, such as RP11-818024.3 and RP11-76908.2, are associated
with the genes CRK and YES1, respectively, which are
involved in ion channel binding, the vascular endothelial growth
factor receptor signalling pathway, cellular responses to transforming
growth factor-beta and platelet-derived factor.26–29 It is
interesting to note that the functions of these genes are associated
with the processes underlying and the development of
Androgenetic Alopecia.

Table 1 The 10 lncRNAs that were the most upregulated and downregulated in Androgenetic Alopecia tissues compared to adjacent normal tissues

HMGCS1 Hydroxy
methylglutarylCoA
synthase(<==== enzyme needed to produce cholesterol. It is 33+folds downregulated in Androgenetic Alopecia tissue- which is the 2nd most downregulated gene in them)

So Cholesterol is the endogenous ligand for Hedgehog signalling. i talked about how Cholesterol- used on Androgenetic Alopecia scalp should theoretically address Androgenetic Alopecia(pertaining to the findings of the study).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035717/

Summary
In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and unique among CRD-containing receptors. We demonstrate Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol.

However, 1 thing comes to mind when we look at this:

Cholesterol is mostly produced in the liver(about 80%) as well as in situ in individual cells- including the hair follicles. it will also get metabolised to steroids, as most of them dont stay as solely cholesterol in individual cells, while those that does and are in circulation(produced from the liver)- enters the colon as bile acids- before being reabsorbed( gets excreted in the feces) . It is the precursor to almost all of the hormones in our body.

DHT comes from Cholesterol up the chain- so does that means if we rub some cholesterol onto our balding scalp, are we are potentially exacerbating Androgenetic Alopecia since it will have to metabolise into something to exert its effects(e.g dht)? Rememeber, Androgenetic Alopecia scalp is already prone to high DHT levels- that means whatever miniscule levels of cholesterol there is- is constantly being preferentially converted to DHT. Also DHT is produced in situ in the hair follicles as well as in the prostate, this means balding and non-balding men might have the same serum DHT levels, but hair follicle DHT levels in Androgenetic Alopecia region-scalp tissue(as well as prostate tissue) would be very different.

Pertaining to all these information, we now come to the main point of the topic:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333021/

Hedgehog signaling stimulates the conversion of cholesterol to steroids

Abstract
Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc)(look at the steroidogenesis diagram- this gene is immediately downstream of cholesterol), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2(Progesterone and Estradiol). Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase(This 'Gli2' gene- is responsible for the metabolism aka conversion of cholesterol to Progesterone and Estradiol). Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels(downrgulation of hedgehog signalling = downregulation of Progesterone and Estradiol) derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.

Keywords: Cholesterol, Hedgehog signaling, Steroids

Now we are going to go deeper about this 'Gli2' gene .So what is this 'Gli2' gene?

:

https://www.wikipathways.org/index.php/Pathway:WP2840

it leads further down the pathway to hair follicle shape formation and:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450292/

The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity
Anna L. Furmanski,1,*‡ Alessandro Barbarulo,1 Anisha Solanki,1 Ching-In Lau,1 Hemant Sahni,1 Jose Ignacio Saldana,1 Fulvio D'Acquisto,2 and Tessa Crompton1
Author information ► Article notes ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.
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ABSTRACT
Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca2+ flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments.

KEY WORDS: Hedgehog, Gli2, T-cell, TCR, AP-1, NFκB, IL-2

It also decreases inflammation by downregulating T cell receptor signalling, which is the most upregulated pathway in Androgenetic Alopecia tissue as indicated by the earlier comparative study

"we took advantages of xenografts in ovariectomized nude mice, and demonstrated that systemic inhibition of Hh signaling reduced P4 and E2 production and resulted in the attenuation of uterine response to P4 and E2, providing further in vivo evidence of Hh signaling in the conversion of cholesterol into P4 and E2."

5. Conclusions
Cholesterol modification is essential for Hh ligands activities and intracellular transduction of Hh signaling. In this manuscript, we have uncovered that activation of Hh signaling triggers sequential conversion of cholesterol to its metabolites, progesterone and estradiol, by induction the expression of downstream target genes including Gli3-controlled P450scc and Gli2-controlled 3β-HSD1 and aromatase(Progesterone and Estradiol) n human trophoblasts. Our results are not only consistent with the importance of Hh signaling in the embryonic development of placenta, but we also identify the important roles of Hh signaling in maintenance of mature placental functions, and possibly of human pregnancy.


So it can now be inferred here that Progesterone and Estradiol are the downstream Cholesterol-derived steroidogenic products of activated Hedgehog signalling. There are already numerous studies stating that aromatase(e.g Estradiol) is responsible for the protective effect of retaining the frontal hair region in female patterned-hair loss- but what does Progesterone does?

Biological activity[edit]
Progesterone is the most important progestogen in the body, the result of its action as a potent agonist of the nuclear progesterone receptor (nPR) (with an affinity of KD = 1 nM).[15][13] In addition, progesterone is an agonist of the more recently discovered membrane progesterone receptors (mPRs),[16] as well as a ligand of the PGRMC1 (progesterone receptor membrane component 1).[17] Moreover, progesterone is also known to be an antagonist of the sigma σ1 receptor,[18][19] a negative allosteric modulator of nicotinic acetylcholine receptors,[14] and a potent antagonist of the mineralocorticoid receptor (MR).(<== this is crucially involved with soft tissue inflammation and fibrosis https://www.ncbi.nlm.nih.gov/pubmed/25377230 )[20] Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids such as cortisol and corticosterone,[20] and produces antimineralocorticoid effects, such as natriuresis(excretion of sodium = lowering of artery constriction http://hyper.ahajournals.org/content/hypertensionaha/15/6_Pt_1/547.full.pdf ), at physiological concentrations.[21] In addition, progesterone binds to and behaves as a partial agonist of the glucocorticoid receptor (GR), albeit with very low potency (EC50 >100-fold less relative to cortisol).[22][23](This is the body's main anti-inflammatory hormone receptor(e.g drug target of Betamethasone, Dexametasone). However, too much activation of it causes Cushing syndrome aka 'Moon face' and torso obesity)

Progesterone, through its neurosteroid active metabolites such as 5α-dihydroprogesterone and allopregnanolone, acts indirectly as a positive allosteric modulator of the GABAA receptor.[24]

Progesterone and some of its metabolites, such as 5β-dihydroprogesterone, are agonists of the pregnane X receptor (PXR),[25] albeit weakly so (EC50 >10 µM).[26] In accordance, progesterone induces several hepaticcytochrome P450 enzymes,[27] such as CYP3A4,[28][29] especially during pregnancy when concentrations are much higher than usual.[30] Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.[28]

 

[sktboiboi]

Biological function[edit]
Hormonal interactions[edit]

Elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.[37]

Progesterone is sometimes called the "hormone of pregnancy",[44] and it has many roles relating to the development of the fetus:

• Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable to sperm. Progesterone is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen.[45] If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.
• During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
• Progesterone decreases contractility of the uterine smooth muscle.[44]
• In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.
• A drop in progesterone levels is possibly one step that facilitates the onset of labor.

and pregnant women have a thick mane of hair

https://www.livestrong.com/article/165275-why-does-hair-grow-so-fast-during-pregnancy/
https://www.dermveda.com/learn/hair...and-how-it-changes-during-and-after-pregnancy

Skin health[edit]
The estrogen receptor, as well as the progesterone receptor, have been detected in the skin, including in keratinocytes and fibroblasts.[54][55] At menopause and thereafter, decreased levels of female sex hormones result in atrophy, thinning, and increased wrinkling of the skin and a reduction in skin elasticity, firmness, and strength.[54][55] These skin changes constitute an acceleration in skin aging and are the result of decreased collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow.[54][55] The skin also becomes more dry during menopause, which is due to reduced skin hydration and surface lipids (sebum production).[54] Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.[54]

HRT, consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal women.[54][55] These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids.[54][55] Topical estrogen has been found to have similar beneficial effects on the skin.[54] In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal women.[55] Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.[55] These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.[55](though it exerts the same effects as estrogens, progesterone acts on its own)

Other effects[edit]

• Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually dimorphic proportions of those.[73][infringing link?](<==scalp tissue differences between men and women)
• During pregnancy, progesterone is said to decrease irritability.[74]
• During pregnancy, progesterone helps to suppress immune responses of the mother to fetal antigens, which prevents rejection of the fetus.[74]<==immunomodulatory
• Progesterone raises epidermal growth factor-1 (EGF-1) levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.[75]
• Progesterone increases core temperature (thermogenic function) during ovulation.[76]
• Progesterone reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated.(<== PGD Synthase and PGD2 in Immune Resposne - Hindawi
  https://www.hindawi.com/journals/mi/2012/503128 by M Joo - ‎2012 - ‎Cited by 50 - ‎Related articles
  May 3, 2012 - In mouse models of asthma and allergic disease, PGD 2 has a substantial proinflammatory effect, regulating many hallmark characteristics including eosinophilia, airway hyperreactivity, mucus production, and Th2 cytokine levels [40, 47])
• Progesterone acts as an antiinflammatory agent and regulates the immune response.
• Progesterone reduces gall-bladder activity.[77]
• Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.(<== normalizes trace elemental metals in tissue)
• Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation).[78]
• Progesterone appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
• Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes.[79][80]

Addiction[edit]
See also: Progesterone (medication) § Addiction
Progesterone enhances the function of serotonin receptors in the brain, so an excess or deficit of progesterone has the potential to result in significant neurochemical issues. This provides an explanation for why some people resort to substances that enhance serotoninactivity such as nicotine, alcohol, and cannabis when their progesterone levels fall below optimal levels.[70]

• Sex differences in hormone levels may induce women to respond differently than men to nicotine. When women undergo cyclic changes or different hormonal transition phases (menopause, pregnancy, adolescence), there are changes in their progesterone levels.[71]Therefore, females have an increased biological vulnerability to nicotine’s reinforcing effects compared to males and progesterone may be used to counter this enhanced vulnerability. This information supports the idea that progesterone can affect behavior.[70]
• Similar to nicotine, cocaine also increases the release of dopamine in the brain. The neurotransmitter is involved in the reward center and is one of the main neurotransmitters involved with substance abuse and reliance. In a study of cocaine users, it was reported that progesterone reduced craving and the feeling of being stimulated by cocaine. Thus, progesterone was suggested as an agent that decreases cocaine craving by reducing the dopaminergic properties of the drug.[72]

interestingly, in the earlier Androgenetic Alopecia comparative study, it states that:

Up-regulated Signaling pathway of DE genes(pathways upregulated in Androgenetic Alopecia tissues)

T cell receptor signaling pathway
Cell cycle
Basal transcription factors
TNF signaling pathway
RNA transport
Selenocompound metabolism
B cell receptor signaling pathway
Peroxisome
Natural killer cell mediated cytotoxicity
Dopaminergic synapse <== https://www.ncbi.nlm.nih.gov/pubmed/23176199

Dopamine is a novel, direct inducer of catagen in human scalp hair follicles in vitro.

Abstract
BACKGROUND:
Although there are clinical reports of hair loss associated with levodopa and dopamine agonists, it is unclear whether dopamine exerts any direct effects on the human hair follicle (HF).

OBJECTIVES:
Given the widespread use of dopamine agonists and antagonists in clinical medicine, we sought to determine whether dopamine exerts direct effects on human HF growth and/or pigmentation in vitro, and whether human HFs express dopamine receptors (DRs).

METHODS:
Microdissected human scalp HFs from women were treated in serum-free organ culture for 7 days with dopamine (10-1000 nmol L ), and the effects on hair shaft production, HF cycling (i.e. anagen-catagen transition), hair matrix keratinocyte proliferation and apoptosis, and HF pigmentation were measured by quantitative (immuno-) histomorphometry.

RESULTS:
Dopamine had no consistent effect on hair shaft production, but did promote HF regression (catagen). It was also associated with significantly reduced proliferation of HF matrix keratinocytes (P < 0·01) and reduced intrafollicular melanin production. Dopamine receptor transcripts were identified in HFs and skin.

CONCLUSIONS:
These data provide evidence that dopamine is an inhibitor of human hair growth, via the promotion of catagen induction, at least in vitro. This may offer a rational explanation for the induction of telogen effluvium in some women treated with dopamine agonists such as bromocriptine. Moreover, dopaminergic agonists deserve further exploration as novel inhibitors of unwanted human hair growth (hirsutism, hypertrichosis).

© 2012 The Authors. BJD © 2012 British Association of Dermatologists.

 

[sktboiboi]

Down-regulated Signaling pathway of DE genes(pathways that are downregulated in Androgenetic Alopecia tissues)

Hedgehog signaling pathway
Progesterone-mediated oocyte maturation <== further implication of Progesterone in Androgenetic Alopecia pathology
Oocyte meiosis SNARE interactions in vesicular transport
Phospholipase D signaling pathway
Maturity onset diabetes of the young<==
Progesterone in gestational diabetes mellitus: guilty or not guilty?
Brănişteanu DD1, Mathieu C.
Author information

Abstract
Insulin resistance is one of the metabolic changes in pregnancy, but only a fraction of women develop overt impaired glucose tolerance or frank diabetes. Most women are able to compensate this altered metabolic state by increasing the amount of insulin produced by the pancreatic beta cells. Progesterone might well be the key to the development of gestational diabetes. Previously high progesterone levels have already been shown to be correlated with the development of glucose abnormalities in pregnancy and now, in a new paper, progesterone receptor-knockout mice are found to have improved glucose tolerance. These mice showed increased insulin secretion, which is probably linked to the presence of increased numbers of beta cells in their pancreas. Is progesterone therefore the 'ultimate bad guy', prohibiting normal adaptation of the pancreatic beta-cell reserve during pregnancy?

https://www.ncbi.nlm.nih.gov/pubmed/17989724

IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway.
Smith TM1, Gilliland K, Clawson GA, Thiboutot D.
Author information

Abstract
Understanding the factors that regulate sebum production is important in identifying therapeutic targets for acne therapy. Insulin and IGF-1 stimulate sebaceous gland lipogenesis. IGF-1 increases expression of sterol response element-binding protein-1 (SREBP-1), a transcription factor that regulates numerous genes involved in lipid biosynthesis.(hence, just like what https://onlinelibrary.wiley.com/doi/full/10.1111/bjd.14767 said, an increased in the amount of lipids synthesized in the balding scalp is part of the etiology of Androgenetic Alopecia) SREBP-1 expression, in turn, stimulates lipogenesis in sebocytes. The goal of this study was to identify the intracellular signaling pathway(s) that transduces the lipogenic signal initiated by IGF-1. Sebocytes were treated with IGF-1 and assayed for activation of the phosphoinositide 3-kinase (PI3-K) pathway and of the three major arms of the mitogen-activated protein kinase (MAPK) pathway (MAPK/extracellular signal-regulated kinase (ERK), p38 MAPK, and stress-activated protein kinase/c-Jun-N terminal kinase). IGF-1 activated the MAPK/ERK and PI-3K pathways. Using specific inhibitors of each pathway, we found that the increase in expression of SREBP-1 induced by IGF-1 was blocked in the presence of the PI3-K inhibitor but not in the presence of the MAPK/ERK inhibitor. Furthermore, inhibition of the PI3-K pathway also blocked the IGF-1-induced transcription of SREBP target genes and sebocyte lipogenesis. These data indicate that IGF-1 transmits its lipogenic signal in sebocytes through activation of Akt. Specific targeted interruption of this pathway in the sebaceous gland could be a desirable approach to reducing sebum production and improving acne.

Prostaglandin D2 Inhibits Hair Growth and Is Elevated in ... - NCBI - NIH
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/
by LA Garza - ‎2012 - ‎Cited by 154 - ‎Related articles
Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human Androgenetic Alopecia.


: no progesterone => more insulin secretion => more insulin receptor expression => more sebum secretion => PTGDS expression => PGD2 expression => CRTh2 expression




Synthesis and degradation of ketone bodies
Transcriptional misregulation in cancer
Pathways in cancer
Basal cell carcinoma <== https://en.wikipedia.org/wiki/Hedgehog_signaling_pathway

*The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include basal cell carcinoma.[1]*

Figure 7 Functional pathway analysis. (a) The top 10 pathways that were expressed at higher levels in the androgenetic alopecia (Androgenetic Alopecia) samples than in adjacent normal tissues. (b) The top 10 pathways that were expressed at lower levels in the Androgenetic Alopecia samples than in adjacent normal tissues.

Take note that the cancer and diabetic pathways are what is DOWNregulated in Androgenetic Alopecia tissues

 

[sktboiboi]

so here comes the soloution:

https://en.wikipedia.org/wiki/Topical_progesterone
https://en.wikipedia.org/wiki/Estradiol_(medication)#Pharmacokinetics <== topically only at a minimal amount ever possible

 

[Tano1]

Is it just me or have we been discovering more and more factors associated with hair loss?

Although that’s progress, it doesn’t look too well if you end up having to deal with alterating several gene expressions. At this point perhaps just creating brand new follicles through some form of hair neo genesis would be the optimal solution.