Red clover is a dark pink herbaceous flowering plant that contains coumestrol, a potent phytoestrogen and antioxidant agent.  Due to the low molecular weight, coumestrol is able to pass through cell membranes and mimic the biological activities of estrogen whilst reducing cell damage by reactive oxidative species.

Coumesterol has a similar binding affinity to that of estradiol to estrogen receptors, though the effect of is coumesterol binding is lower than estradiol. As an anti-oxidising agent, coumestrol is able to reduce inflammation and encourage repair of the hair follicle niche.


Estrogens are a category of steroid hormones responsible for the development and regulation of the female sex characteristics and reproductive health.  There are two major estrogens with estrogenic hormonal activity: Estradiol and estrone. Estradiol and estrone are the two estrogens that are involved in hair follicle cycling.

Estradiol is synthesised from from testosterone and estrone is synthesised from androstenedione (a weak androgen) by the enzyme aromatase.  Estradiol and estrone increases vascularisation and collagen production of the area surrounding the hair follicle and also raises the activity of pigment cells within the hair follicle whilst suppressing hair follicle sebaceous gland activity.  This control of sebaceous gland activity regulates the sebum production where scalps are oily.

Estradiol is about 10X more potent than estrone about 100X more potent than estriol.  The potency of estradiol and estrone is measured by their ability to bind with estrogen receptors.

The molecular shape of coumestrol orients its functional oxygen and hydrogen group in the same position of the functional oxygen and hydrogen group as estradiol allowing for binding with estrogen receptors.  The binding of estrogen receptor α upregulates the expression of genes that code for insulin-like growth factor and epidermal growth factor, leading to a longer anagen phase in the hair cycle, and increasing the anagen to telogen ratio.
Hair cycle; growth and regression of the hair follicle


Hormonal alterations can effect hair growth because they can increase or decrease substances such as growth factors that influence hair follicle survival.  Growth factors directly control how long hair remains in anagen phase (growth phase) and when hair goes into telogen (resting phase) in preparation to be shed.

Induction of anagen phase is dependant on transforming growth factor beta and keratinocyte (keratin cell) growth factor (KGF) or fibroblast growth factor (FGF).  Maintenance of anagen phase is controlled by insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF).

Estrogens and estrogen receptors play an important role in the signalling pathways that regulate hair growth. The anagen-to-catagen transition involves cross-talk between keratinocyte growth factor and transforming growth factor-beta.  Functional cross-talk between estrogens and receptors regulate the action of growth factors that control the hair growth cycle.

Growth Factor Action Modulation
Insulin -like growth factor-1 (IGF-1) Stimulates hair growth Estrogen receptor cross-talk
Vascular endothelial growth factor (VEGF) Development of blood vessels that surround the hair follicle unit Estrogen increases production
Transforming growth factor beta (TGF-B) Stimulates resting and shedding phase of the hair cycle Estrogen receptor cross-talk
Keratinocyte growth factor (KGF) An important mediator of hair follicle growth and development Estrogen receptor crosstalk


Phytoestrogens are a general term for compounds of various structures, originating in plant sources and mimicking or modulating the action of estrogenic hormones.  The estrogenic potential of certain plants was first reported in the 1940s from an observation of sheep that suffered reproductive disorders as a consequence of a diet mostly based on clover.

Phytoestrogens in the body act like weak estrogens and when applied topically will not impact hormonal balance in the body.  Estrogens profoundly alter hair growth by binding to estrogen receptors in the hair follicle.  Besides altering estrogen dependant genes, estrogen modify hair follicle metabolism in the hair follicle and the sebaceous gland.


In a study investigating the effects of phytoestrogens on hair growth it was found that hair regrowth in alopecia areata patients was greatly accelerated when phytoestrogens were administered for 4 weeks. It was found that plasma levels of insulin-like growth factor were significantly increased from baseline. When compared to those given a placebo, the percentage of volunteers who showed hair regrowth was significantly higher, 64.5% experienced some level of hair regrowth within 5 months when compared to 11.8% given a placebo.

It is likely that hair regrowth  in alopecia areata patients occurred due to the antioxidant effect of phytoestrogens.

These antioxidants have a high scavenging activity for the increased level of reactive oxidative species often associated with alopecia areata relapse.


Two types of estrogen receptor are distinguishable in the human hair follicle.  Estrogen receptor α is involved in keeping the hair follicle in anagen (growth activation of the hair follicle), while estrogen receptor β is responsible for inducing telogen in preparation for the hair to be shed.  In humans estrogen receptor α is the predominant estrogen receptor in hair follicles.

Due to the mixed ability of coumesterol to interact with estrogen receptor α and estrogen receptor β, this compound is able to exert actions that increase hair follicle growth.  Human estrogen (17 β — estradiol) tends to interact with estrogen receptor β (the primary estrogen receptor in the hair follicle).

Phytoestrogens can act as an anti- estrogen by temporarily binding to estrogen receptor β, thus inhibiting the telogen inducing activity of human estrogen by blocking binding sites.  This means coumesterol can prevent activation of estrogen receptor β and reduce premature telogen and extend anagen phase.

Substrates binding to an estrogen receptor usually have a preferential affinity to one receptor type. In this regard, the majority of phytoestrogens show a preference for estrogen receptor β, while coumesterol predominantly binds to estrogen receptor α.


Whilst research supports supplementation of phytoestrogens, topically applied phytoestrogens, such as coumesterol in red clover, may be preferable to prevent systemic changes of hormone concentration.