Types of Hair Loss
Androgenic Alopecia
Androgenic alopecia is a term used to refer to patterned hair loss starting from the front of the scalp, and working backwards while not significantly affecting the sides of the head; the common term for androgenic alopecia is either 'male pattern hair loss' or a receding hair line.[1] The early stages are associated with thinning of the follicular hair,[2][3] which is thought to be due to less anagen phase relative to telogen phase causing less overall time to grow.
At least in men, androgens are multidirectional regulators of hair growth. While the sides of the head (occipital scalp) and eyebrows/lashes are referred to as androgen insensitive, the frontal and vertex scalp (front and middle) and body hair appeared to be positively regulated;[1] this is evident in androgen insufficiency syndromes, which are not associated with scalp hair loss but a suppression of body hair.[4]
Hair Growth Cycles
Anagen
Telogen
Positive Regulators of Hair Growth
Positive regulators of hair growth are those that either directly or indirectly (via suppressing negative regulators) promote hair growth and should be sought out during hair growth protocols
Prostaglandins
Prostaglandins are a subset of eicosanoids, signalling molecules derived from fatty acids of either the omega-3 (fish oil) or omega-6 (arachidonic acid) class. Of these, differing prostaglandins have differing effects on hair growth depending on the receptors they activate.
They are released by the enzyme phospholipase A2 which is expressed on hair follicles.[5] Phospholipase A2per se is neither a positive regulator or negative regulator of hair growth as both eliminating the activity and increasing the activity cause hair loss.[5] This is due to prostaglandins derived from the enzyme being both positive and negative regulators.
Eicosanoids, particularly the prostaglandin classes, appear to be general regulators of hair growth
Prostaglandin E2 (PGE2, of omega-6 origin) is produced locally in a hair follicle[6] and appears to be 2.06-fold higher in the hairy areas of the head of men with androgenic alopecia relative to the balding area.[7] PGE2 does not appear to suppress testosterone production,[8] but there are a class of receptors that respond to both androgens and PGE2 (AKR1C1 to a lesser degree, and both CBR1 and AKR1C3[9] which are expressed in hair follicles[6]) and these receptors, via their posttranslational effects, may mediate hair loss/growth as well.
Interestingly, minoxidil is able to increase PGE2 and this is one of the possible mechanisms underlying its efficacy.[10]
The receptors for PGE2 are numerous, but the two receptors known as EP3 and EP4 have been detected in dermal papillae[11][12] and drugs that act upon these receptors (The PGE2 mimetic Viprostol) can induce hair growth when topically applied[13][14] via increasing anagen phase.[15]
PGE2 signalling through EP3 and EP4 appears to be a positive regulator of hair growth from the omega-3 class
Prostaglandin F2α signalling (of omega-6 origin), via binding to the PGF2α receptor at a concentration of 50-100nM,[16] appears to stimulate hair growth by prolonging anagen phase.[14]
Drugs that mimic PGF2α signalling (Latanoprost) can induce hair growth when topically applied[13][14] via increasing anagen phase.[15] Latanoprost in particular has shown efficacy in primeapes with moderate to advanced levels of androgenic baldness prior to testing, where 500mcg/mL or 0.05% (50mcg/mL barely effective) given at 0.5mL once daily on the frontal scalp (5 days a week) caused 5-10% conversion of vellus hairs to intermediate/terminal hairs,[17] a potency comparable to 5% minoxidil (10% conversion).[18] A subsequent trial in humans using double this dose (0.1% of solution in 50% ethanol; 50µg/L or one drop daily) presenting Hamiltion II-III stages of androgenic hair loss noted that half the group outperformed placebo in hair growth with an average increase (after 22 weeks) of 22% more hair density.[19] The authors made not that this dose is thought to be safe as it is 3.6-fold lower than the dose tolerated well intravenously.
One case study has made note that Latanoprost has repigmented white hair in an older woman using eye drops (the normal pharmaceutical usage of Latanoprost is for glaucoma).[20]
PGF2α signalling via its receptor is a positive regulator of hair growth, and applying agonists of this receptor to the scalp (Latanoprost) can induce hair growth in balded states
5-alpha reductase inhibitors
5α-reductase inhibitors (5-AR inhibitors) are molecules that inhibit the conversion of testosterone into its more androgenic metabolite known as dihydrotestosteorne (DHT), with the reference drug being finasteride (Propecia). There are two subsets of 5-AR receptors (type 1 and type 2) with the latter being more prevalent in hair follicles.[21][22] Finasteride is a selective inhibitor of 5-AR type 2 while the pharmaceutical known as Dutasteride is a dual inhibitor.[23][24]
Although both testosterone and DHT can bind to the androgen receptor to induce hair loss, DHT is approximately 5-fold more effective at the level of the hair follicle.[1] As signalling through the androgen receptor either causes hair loss or promotes changes that then induce hair loss, reducing signalling through the androgen receptor is thought to confer a preventative effect (reducing the rate of negative regulators, not inherently a hair growth effect).
DHT is furthermore thought to be a therapeutic target as men with a deficiency of the 5α-reductase enzyme have been reported[25][26] and these men appear to be protected from prostate enlargement and androgenic alopecia later in life.
Inhibiting the 5α-reductase enzyme suppresses DHT (and may elevated testosterone), but overall there is less androgenicity and signalling through the androgen receptor which then reduces the negative effects of androgens on hair growth
Binding of androgens to the receptor promote production of TGFβ1 and 2, which promote telogen and dermal papilla cell senescence.[27][28]
Negative Regulators of Hair Growth
Negative regulator of hair growth are mechanisms or phenomena that are able to suppress the rate of hair growth, and in a hair growth protocol should be avoided
Prostaglandins
Prostaglandins are a subset of eicosanoids, signalling molecules derived from fatty acids of either the omega-3 (fish oil) or omega-6 (arachidonic acid) class. Of these, differing prostaglandins have differing effects on hair growth depending on the receptors they activate.
Prostaglandin D2 (PGD2) of omega-6 origin and the enzyme that create it (prostaglandin D2 synthase, which is induced by androgens[29][30]) are 10.8-fold higher in the balding area of men (with androgenic alopecia) relative to the non-balding area of the same scalp.[7] PGD2 is thought to be a prime negative regulator of androgenic hair loss as signalling through its receptor (DP2; also known as GPR44 or CRTh2[31][32]) is able to suppress hair growth by shortening anagen phase and overexpressing the synthetic enzyme induces androgenic hair loss in rodents.[7] The other receptor of PGD2 (PGD2 receptor 1) does not appear to be implicated.[7]
Prostaglandin 15-delta J2 (15-ΔPGJ2) also appears to have suppressive effects.[7]
Selective shifting of prostaglandins of omega-6 origin towards PGD2 is able to promote androgenic alopecia
COX2
Cyclooxygenase-2 (COX2) is an enzyme that is induced in response to inflammatory stressors.
Genetically overexpressing COX2 is able to induce hair loss, which is restored with COX2 inhibitors.[33][34]
