Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy.

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Bone Marrow Transplant 2002 Nov;30(9):593-7

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy.

Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated the relationships between total exposure to these three compounds and their different metabolites in the high-dose CTC regimen, and the subsequent development of irreversible alopecia. Twenty-four patients received two or three courses of high-dose CTC, each followed by peripheral blood progenitor cell transplantation. Plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its active metabolite tepa, and carboplatin were determined, and the area-under-the-plasma concentration-versus-time curves (AUC) of the compounds were calculated. Eight of the 24 patients included in the study developed permanent alopecia, while seven had normal hair regrowth and nine patients developed incomplete and/or thin hair regrowth. The carboplatin AUC and the summed AUC of thiotepa and tepa were both significantly associated with increasing irreversibility of hair loss. These results suggest that high exposure to carboplatin and the sum of the thiotepa and tepa exposure may lead to the development of permanent alopecia. This knowledge could guide therapeutic drug monitoring in order to prevent the occurrence of permanent alopecia and thereby improve the patients' quality of life.

J Am Acad Dermatol 2002 Nov;47(5):795

Female pattern hair loss.

In this issue of the Journal (pages 733-9), Shum et al1 describe 4 female patients with increased androgens whose central scalp hair loss responded to finasteride. This is an important observation and one that highlights why the term androgenetic or androgenic alopecia, as used to describe the hereditary pattern balding of men, should be replaced with the term female pattern hair loss when applied to women.2 It is clear that only a small but distinct subset of women with central scalp pattern hair loss, such as the patients presented in the report by Shum et al, has signs of hyperandrogenism such as acne, hirsutism, and irregular periods with or without elevation of serum androgens. Therefore these women may have hair loss resulting from a different mechanism and may respond differently to treatments targeted at androgen blockade than women with a similar type of hair loss but without evidence of hyperandrogenism. Certainly these women with hyperandrogenemia may develop, in contradistinction to those without hyperandrogenemia, a Hamilton pattern of hair loss (male pattern baldness). Many of these women may, on more careful evaluation, have polycystic ovarian syndrome.

It is not surprising that a 5-reductase inhibitor such as finasteride, which has documented efficacy in men with androgenetic alopecia3,4 and has been shown to advantageously affect hirsutism,5,6 may cause hair growth in women with female pattern hair loss and hyperandrogenism. The fact that finasteride has not previously been shown to induce hair growth in postmenopausal women with “androgenetic alopecia”7 speaks for (1) adoption of different terminology for this type of hair loss in women and (2) separate evaluation of the different subgroups of women with female pattern hair loss as recently described,2 that is, early onset with and without hyperandrogenemia and late onset/postmenopausal with and without hyperandrogenemia. We should not be too quick to rule out efficacy of a potential therapeutic agent in all women with female pattern hair loss without first testing it in all the various subsets of women.

Clearly, finasteride may be an effective treatment for women with early-onset female pattern hair loss and hyperandrogenemia, but definitive results would require a large, well-controlled trial. Such a trial would likely necessitate inclusion of a “placebo” run-in phase with an oral contraceptive, both to protect these women of child-bearing potential from getting pregnant while taking a drug known to cause genital abnormalities in male fetuses and to rule out any effect from the oral contraceptive alone on female pattern hair loss (a study that needs to be conducted in any case). Anecdotal reports, such as that presented by Shum et al,1 should ignite interest in evaluating finasteride and other 5-reductase inhibitors, either type II or combination type I/II, in women with female pattern hair loss, a group of patients whose current treatment options are extremely limited.

Exp Gerontol 2002 Aug-Sep;37(8-9):981-90

Molecular mechanisms of androgenetic alopecia.

Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern. While the genetic involvement is pronounced but poorly understood, major advances have been achieved in understanding principal elements of the androgen metabolism involved: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR). DHT-dependent cell functions depend on the availability of weak androgens, their conversion to more potent androgens via the action of 5 alpha-reductase, low enzymatic activity of androgen inactivating enzymes, and functionally active AR present in high numbers. The predisposed scalp exhibits high levels of DHT, and increased expression of the AR. Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle. Current available treatment modalities with proven efficacy are oral finasteride, a competitive inhibitor of type 2 5 alpha-reductase, and topical minoxidil, an adenosine-triphosphate-sensitive potassium channel opener which has been reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla cells. Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.

J Invest Dermatol. 2003 May;120(5):771-5.

Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice.

Alopecia areata is an autoimmune disease that targets actively growing (anagen) hair follicles in humans, mice, rats, dogs, horses, and cattle. C3H/HeJ mice spontaneously develop alopecia areata from 5 mo of age and older in females and later in males. Frequency of disease approached 20% in a colony by 18 mo of age. C57BL/6J mice do not develop alopecia areata. A segregating F2 population of female mice (n=1096) was generated from crossing these two strains. Alopecia areata (n=138) and clinically normal (n=214) mice were genotyped at 12 mo of age using 211 microsatellite probes. The peak logarithm of odds ratio score on mouse chromosome 17 (10.9) was around marker D17Mit134 at 16.9 cM from the centromere. The mouse histocompatibility locus, H2, the mouse equivalent of human leukocyte antigen in humans, was a likely candidate. Twelve-month-old C3H.SW-H2b/SnJ mice (C3H/HeJ congenic mice in which the H2k purported susceptibility locus was replaced with the H2b purported resistance locus) did not develop alopecia areata, supporting this locus as being important in alopecia areata. A suggestive linkage was also found on mouse Chromosome 9 (logarithm of odds ratio score 2.0) around D9Mit206, 20 cM from the centromere. The interval on mouse Chromosome 17 contains several orthologous genes potentially associated with human alopecia areata.

Being such a complex biological process, hair growth biology is still a work in progress. Noetheless, several therapeutic methods, including drugs, surgery, and suppelements have been in use to help those who attempt to restore their hair. None of these approaches are perfect due to the diversity in the causes underlying hair loss. Also, most of chemical drugs and hair transplantation surgeries are accompanied by undesirable side effects.

DreamPharm offers Hair Million to address hair loss problems. Numerous anecdotal cases have demonstrated that this herbal formula based on authentic Chinese herbs actually improves the age-related hair thinning and hair loss among a significant fraction of people who take it regularly. We still do not understand the mechanisms of action as to how Hair Million works to stop hair loss and promote hair growth, despite all the positive anecdotal observations. Neither scientific research nor placebo controlled clinical analysis has been conducted because it will cost dearly. Lack of scientific/clinical research is quite common in herbal arena. Just because science hasn't scrutinized we should not stop taking daily food and herbal supplements altogether: our life must go on until we have better understandings of food and herb. There are two merits in this hair restoration herbal formula: Firstly, Hair Million is relatively inexpensive, and secondly, it is made of edible herbs that are known to be safe when consumed in regular quantities. For scientifically proven prescription medication, check Propecia.

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