The May newsletter from Iron Dragon describes the differences between the three PGD2 inhibitors they offer:
Clearing up the confusion: Types of PGD2 Inhibitors
There are three basic routes to PGD2 inhibition, also called PGD2 blocking. In addition to this, there is another important prospective experimental pathway that should be further investigated by researchers into PGD2’s effects on baldness.
Mast Cell Stabilizers
PGD2 release may be prevented by mast cell stabilizers. Norris (2004) writes that
“Mast cells play a key role in the induction of allergic disorders, such as asthma and rhinitis, through the release of mediators including histamine, arachidonate products, proteases and several cytokines, which are found in relatively high quantities in these cells. A significant number of therapeutic approaches for allergies have been designed based on antagonising specific mediators released from mast cells and on selectively inhibiting the activation of these cells.”[1]
Chromoglycate is an example of a mast cell stabilizer.
PTGDS Inhibitors
An enzyme that selectively reduces existing molecules into other molecules through a chemical reaction is called a synthase. Prostaglandin D2 is created from other prostaglandins by a synthase called prostaglandin D synthase. There are actually two convergent (functionally identical, but developed independently of one another) forms of PTGDS: one that is found primarily in the central nervous system and one that is found nearly everywhere throughout the body. PTGDS can create PGD2 anywhere prostaglandin H2 is found.
PTGDS inhibitors work by reducing or eliminating the activity of PTGDS and can reduce or eliminate levels of PGD2. Indomethacin is a COX inhibitor and PTGDS inhibitor. Cyclooxygenase (COX) is also responsible for converting arachidonic acid into prostaglandin H2.
PGD2 Receptor Antagonists “True PGD2 Blockers”
When it comes to referring to PGD2 inhibitors substances that reduce effects of PGD2, or prevent it from being formed or release as “PGD2 blockers,” there is one substance for which this label is most apt. PGD2 receptor antagonists bind to the PGD2 receptor also known as the GPR-44 receptor or the CRTH2 receptor and rather than activate it, like PGD2, they inactivate it as well as prevent PGD2 from exerting any activity.
Indomethacin is a weak PGD2 agonist with a net antagonistic effect, meaning that it can bind to the PGD2 receptor. It displaces active PGD2 and prevents PGD2 from exerting any effect; because its effect is one-tenth that of PGD2, in effect it blocks PGD2. Ramatroban is a PGD2 blocker with zero effect at the PGD2 receptor that is highly effective at displacing active PGD2, making it an ideal candidate for PGD2 receptor antagonism.
Prostaglandin F2-alpha Analogs: The Next Frontier of Hair-loss Research
Even before PGD2 was spotlighted in 2012 as an endogenous compound with a major role in baldness, it was well-known that even very small amounts (such as one one-thousandth of a gram or even less) of substances known as PGF2a analogs could cause hair-regrowth under some conditions. Bimatoprost and latanoprost were originally used for their reduction effects on intraocular pressure, but after a few years of clinical usage, healthcare providers noticed hypertrichosis (excessive hair growth) on the foreheads, eyebrows, eyelids, and cheeks of patients.
Bimatoprost and latanoprost have both been turned into successful eyelash-enhancement topical cosmetics available by prescription in many countries (Latisse and Lumigan), and trials in the last two decades have also examined the effects of “prost” compounds (PGF2a analogs) on hair-regrowth in bald men with androgenic alopecia or suitable animal models such as the stump-tailed macaque[2,3,4,5].
Results were mixed, with a higher dose of latanoprost (500 mcg/ml applied daily to the scalp) found to be much more effective than 50 mcg/ml. The dose typically found in eyelash-enhancement products is 50-100 mcg/ml, which is effective to enhance growth of eyelashes[6]. Fluprostenol and lower doses of latanoprost have been found effective in mice but not in balding male humans or macaques. It is reasonable to conclude that the inhibitory effects of PGD2 are at least possibly responsible for the lack of effectiveness of PGF2a at lower doses.
D-cloprostenol, a PGF2a super-agonist analog, is 50-100 times more powerful than fluprostenol, latanoprost, bimatoprost, and PGF2a. [7] PGE2 and its analogs (such as viprostol) have thus far been found effective in solo trials, but caused hair-growth when combined with a PGF2a analog [7,8].
Since low concentrations of PGF2a analogs have been found ineffective for hair-regrowth but higher concentrations appear to exhibit a significant effect, and PGD2 is the likely limiting factor in PGF2a hypertrichotic efficacy, further trials of PGF2a’s effects in baldness models where PGD2 is inhibited through multiple pathways may prove to be an effective, comprehensive “baldness cure” in the future.
Isn’t PGD2 causing baldness just a “theory?”
Some potential customers have been emailing this type of question. While we cannot spend time answering all customer questions via email of this nature it is important to clarify some apparent confusion around this issue.
In scientific terminology a “hypothesis” and “theory” have very different meanings than they do in normal conversation. Most people in every-day conversation think of a “theory” as a statement that is unproven; that is exactly the opposite of how the term is used in science.
A hypothesis is a testable statement that is based on observation, and may be revised, falsified (disproven), or confirmed by further study. The key concept behind a hypothesis is the idea that it is specific enough to be testable. A theory is an explanation for a phenomenon that is backed by scientific evidence. When a hypothesis is published in a peer-reviewed scientific journal with evidence to back it, it can be said to “gain traction” as the claims are reviewed and the hypothesis is confirmed. In cases where the hypothesis is found to be partially incorrect it is revised. In cases where the hypothesis is found to be totally incorrect it is discarded.
As a hypothesis gains traction, if it fits reasonably with the scientific understanding of how the body works (for example), it becomes an accepted explanation for the phenomenon in question. At that point, once multiple peer-reviewed studies are published and the hypothesis is well-vetted, it may be referred to as a “theory.” In mainstream science there are not multiple conflicting “theories” to explain single phenomenon. Although scientific knowledge is always evolving, properly constructed hypotheses result in theories that are testable, and competing explanations of phenomena can be resolved through proper testing.
The 2012 Garza and Cotsarelis study is entitled “Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia,” and does an excellent job at defending those claims through multiple avenues of evidence: direct application of PGD2 to mice, observation of reasonable sample sizes of bald human males, and a transgenic animal model [1].
The authors state that “These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment” [1]. The first part of the statement is a testable claim and is transparent and well backed in the paper, and the second part of the statement is speculative in nature rather than being a claim.
Rather than being thought of as a new theory for androgenic alopecia, it is best to think of the PGD2 data as adding to an existing body of knowledge about baldness. Far from contradicting this existing body of knowledge, the authors state that “Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA)” [1] before going on to state their observations that Prostaglandin Synthase and PGD2 are elevated in the scalps of bald men.
Citations:
[1] Norris A.Targeting mast cells. Expert Opin Investig Drugs. 2004 Jul;13(7):739-41.
[2] Wolf R, Matz H, Zalish M, Pollack A, Orion E. Prostaglandin analogs for hair growth: Great expectations. Dermatology Online Journal 9(3): 7
[3] Kevin J. McElwee, PhD and Jerry Shapiro, MD, FRCPC. Promising Therapies for Treating and/or Preventing Androgenic Alopecia. Skin ther. Let.
[4] Uno H, Zimbric ML, Albert DM, Stjernschantz J. Effect of latanoprost on hair growth in the bald scalp of the stump-tailed macacque: a pilot study. Acta Derm Venereol. 2002;82(1):7-12.
[5] Blume-Peytavi U, Lnnfors S, Hillmann K, Garcia Bartels N. A randomized double-blind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia. J Am Acad Dermatol. 2012 May;66(5):794-800. doi: 10.1016/j.jaad.2011.05.026. Epub 2011 Aug 27.
[6] Sasaki S, Hozumi Y, Kondo S. Influence of prostaglandin F2alpha and its analogues on hair regrowth and follicular melanogenesis in a murine model. Exp Dermatol. 2005 May;14(5):323-8.
[7] Colombe L et al. Prostaglandin metabolism in human hair follicle. Exp Derm. Vol 16, 9, p7629, Sept 2007.
This article is intended solely as an educational write-up only.