1. ^*Department of Dermatology, University Hospital Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
2. ^†Department of Internal Medicine, Charité, Berlin, Germany

Correspondence: MD Ralf Paus, Department of Dermatology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Email: paus@uke.uni-hamburg.de

Received 31 May 2003; Revised 25 November 2003; Accepted 4 February 2004; Published online 6 August 2004.

Abstract

Hair loss, as it occurs with telogen effluvium and androgenetic alopecia, provokes anxieties and distress more profound than its objective severity would appear to justify. This reflects the profound symbolic and psychosocial importance of hair. Stress has long been implicated as one of the causal factors involved in hair loss. Recently, in vivo studies in mice have substantiated the long-held popular belief that stress can exert profound hair growth-inhibitory catagen-inducing and hair-damaging pro-inflammatory effects. Insights into the negative impact of stress on hair growth and the integration of stress-coping strategies into the management of hair loss disorders as well as the development of new pharmacotherapeutic strategies might lead to enhanced therapeutic modalities with the alleviation of clinical symptoms as well as the concomitant psychological implications.

Although a benign medical condition, affected individuals experience great psycho-emotional stress, often leading to a reduction of quality of life and secondary morbidity. Some patients' suffering can reach a level where the burden of hair loss is comparable with that caused by many more severe chronic or life-threatening diseases (^{de Koning et al, 1990; Cash, 2001}).

In recent years, correlations between specific coping strategies and quality of life have emerged. Particularly, the development of better instruments for assessing quality of life has allowed identification and intervention of coping patterns (Table II) (^{Schmidt et al, 2001}).

Stress has long been implicated as one of the causal factors involved in hair loss (^{Bosse and Gieler, 1987; Paus, 2000; Botchkarev, 2003}). With respect to the connections between psycho-emotional stress and hair loss, several levels of interactions can be distinguished: (a) acute or chronic stress as a primary inducer of telogen effluvium, (b) acute or chronic stress as an aggravating factor in a hair loss disorder whose primary pathogenesis is of endocrine, toxic, metabolic or immunological nature (e.g. AGA, alopecia areata), and (c) stress as a secondary problem in response to prior hair loss. The latter might also contribute to the perpetuation or aggravation of hair loss and induce a self-perpetuating vicious circle (Figure 1).Table I

Figure 1.

Vicious circles of hair loss induced psychoemotional and psychosocial responses. problem; problem-solving approach; effects/counter-effects; inhibits/aggravates.

Full figure and legend (25K)

Table I - Patient-perceived negative effects of hair loss.

Full table

Recent studies in mice have substantiated the long-held popular belief that stress can exert profound hair growth-inhibitory catagen-inducing and hair-damaging pro-inflammatory effects, with a likely key role for substance P (SP) (^{Arck et al, 2001, Arck et al, 2003}) (Fig S1, see full-text version online) and corticotrophin releasing hormone (^{Aoki et al, 2003}). If transferable to the human system, the stress effects elucidated for murine hair follicles would result in a marked telogen effluvium under clinical conditions. Administration of a specific SP receptor (NK 1) antagonist can abrogate the stress-induced hair-growth-inhibiting or hair follicle-damaging effects in mice (^{Arck et al, 2001, 2003}).Table II

Table II - Coping strategies for diffuse and androgenetic alopecia.

Full table

Stress-induced hair growth inhibition is promoted by nervegrowth factor (NGF) which appears to be up-stream of SP (^{Peters et al, 2004}). These findings are noteworthy in two respects: They have identified missing molecular links between psycho-emotional stressors and well-defined parameters that reflect hair follicle growth and function—the neuropeptide SP and the neurotrophin NGF. In addition, the finding that an NK1 antagonist could counteract most of the stress-induced negative effects on the hair follicle is particularly intriguing since NK1 antagonists are under clinical investigation as a potential new class of anti-depressive drugs (^{Rupniak and Kramer, 1999}). Therefore, it is tempting to speculate that NK1 antagonists might be especially well-suited to inhibit the adverse hair growth effects of psycho-emotional stress at the basis of the underlying molecular pathogenesis chain, while at the same time offering helpful pharmacotherapeutic support to allow affected patients with hair loss to break away from the depressing pyscho- and socio-dynamic vicious circles of hair loss (Figure 1).

Besides SP, a plethora of other stimuli and mediators (neurotransmitters, neuropeptides, neurohormones, neurotrophins, etc.) must now be considered as potential local or systemic mediators of stress-induced hair growth inhibition—not the least since the hair follicle has been identified as both a prominent peripheral target organ and a source for many bioregulatory molecules recognized as mediators of stress responses (^{Paus and Cotsarelis, 1999; Paus, 2001; Arck et al, 2001, Arck PC et al, 2003; Botchkarev 2003; Peters et al, 2004}). For example, in mice and/or man, hair follicle cycling, whose alteration lies at the basis of telogen effluvium (^{Paus and Cotsarelis, 1999}), is modulated by catecholamins, prolactin, and nerve growth factor, three classical bioregulators of systemic stress responses. Stress responses, mediated by typical stress hormones, like catecholamines, prolactin, ACTH, CRH, -endorphins, glucocorticoids, and SP, directly and indirectly may alter hair growth by interacting and disturbing the release of the various neuropeptides (^{Paus, 1999; Slominski et al, 1999, 2000; Botchkarev, 2003}). Also, the hair follicle itself can generate an abundance of stress mediators and expresses cognate receptors and thus may directly be involved in the modulation of stress responses at the local level, possibly as part of a "skin stress system" (^{Slominski et al, 2000}). Recently, it has also become apparent that inflammatory stimuli, especially agents involved in neurogenic inflammation, may play an important role in hair growth modulation (^{Paus, 1999; Rückert et al, 2000; Arck et al, 2001, 2003; Botchkarev, 2003}). Although further investigation is required to fully elucidate the interactions of these factors in human hair follicle biology, as well as the impact of psycho-emotional stress (acute and chronic) on the release of neuropeptides and their effects on human hair growth, these stimuli should now be considered when discussing strategies for the management of hair loss.

No specific pharmacological intervention is currently available to manage stress-induced hair loss in man. An effective therapeutic intervention in this respect would have to prolong the anagen phase of the hair cycle, thus preventing the premature onset of catagen, which forms the basis of stress-induced telogen effluvium (^{Paus and Cotsarelis, 1999}). Topical minoxidil (MXL) may be considered a reasonable candidate drug for the management of stress-related hair loss since it is known to prolong anagen (^{Buhl, 1989}). Also, recent results from a well-established mouse model on stress-induced hair loss demonstrate that most of the stress-induced hair growth-inhibitory changes along the "brain–hair axis" (^{Arck et al, 2001}), including premature hair cycle progression towards catagen, could be downregulated by topical MXL application (^{Arck et al, 2003a}). Whether MXL is also capable of counteracting negative effects of "stress" on human hair growth remains to be investigated.

Insights into the negative impact of stress on hair growth particularly encourage one to integrate stress-coping strategies into the management of hair loss disorders and to therapeutically interfere with the stress-aggravating factors indicated in Figure 1. Hair loss patients, therefore, require complex, comprehensive and careful management beyond drug prescription in order to alleviate their clinical symptoms and the concomitant psychological implications.