Hair loss and Regrowth

Hair Loss treatment at the Proctor Clinic

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Dr Proctor: Laminins als likely play a role in other causes of hair loss.

J Dermatol Sci. 2010 Apr;58(1):43-54

Laminin-511, inducer of hair regrowth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced hair loss.
Imanishi H, et al

Abstract
BACKGROUND: Chemotherapy-induced alopecia (CIA) has a devastating cosmetic effect, especially in the young. Recent data indicate that two major basement membrane components (laminin-332 and -511) of the skin have opposing effects on hair growth.

OBJECTIVE: In this study, we examined the role and localization of laminin-332 and -511 in CIA.

METHODS: We examined the expression of laminin-332 and -511 during the dystrophic catagen form of CIA induced in C57BL/6 mice by cyclophosphamide (CYP) treatment.

RESULTS: Our data indicate that both laminin-332 and its receptor alpha 6 beta 4 integrin are up-regulated (both quantitatively and spatially) after mid to late dystrophic catagen around the outer root sheath (ORS) in the lower third of hair follicles in CIA. This up-regulation also occurs at the transcriptional level. In contrast, laminin-511 is down-regulated after mid dystrophic catagen at the protein level, with transcriptional inactivation of laminin-511 occurring transiently at the early dystrophic catagen stage in both epidermal and ORS keratinocytes. Laminin-511 expression correlates with expression of alpha 3 integrin in CIA and we also demonstrate that laminin-511 can up-regulate the activity of the alpha 3 integrin promoter in cultured keratinocytes. Injection of a laminin-511 rich protein extract, but not recombinant laminin-332, in the back skin of mice delays hair loss in CYP-induced CIA.

CONCLUSIONS: We propose that abrupt hair loss in CIA is, at least in part, caused by down-regulation of laminin-511 and up-regulation of laminin-332 at the transcriptional and translational levels.

edited for hair loss treatment blog

J Am Acad Dermatol. 2009 Oct;61(4):592.e1-9..

Phase I/II randomized bilateral half-head comparison of topical bexarotene 1% gel for alopecia areata.
Talpur R, Vu J, Bassett R, Stevens V, Duvic M.

Division of Internal Medicine, Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.

Abstract
BACKGROUND: Alopecia areata, hair loss caused by perifollicular T-cell infiltrates, is refractory to therapy. Bexarotene, a retinoid X receptor is a selective retinoid, induces T-cell apoptosis. OBJECTIVE: We sought to determine the safety, including the dose-limiting toxicities with adverse events, and efficacy, ie, response rate, of bexarotene in alopecia areata. METHODS: We conducted a phase I/II randomized, half-head trial of 1% bexarotene gel applied twice daily for 6 months. RESULTS: In all, 42 patients (11 male and 31 female) with alopecia totalis (n = 3), alopecia universalis (n = 5), or alopecia areata (n = 34) applied 1% bexarotene gel for 24 weeks. Five of 42 (12%) had 50% or more partial hair regrowth on the treated side, and 6 of 42 (14%) on both sides including 3 complete responders. In all, 31 patients had mild irritation; 4 had grade-3 irritation. LIMITATIONS: This design cannot differentiate between drug-induced and spontaneous regrowth. CONCLUSION: Topical bexarotene 1% application is well tolerated and possibly effective. A randomized placebo-controlled trial should be conducted.

modified for Hair loss and hair loss treatment blog

Singh G. Androgenic alopecia (pattern hair loss). Indian J Dermatol Venereol Leprol 2002;68:40

In pattern hair loss, the shortening of the anagen phase of the hair cycle leads to the consequent increase in the proportion of telogen hairs. Autosomal dominant inheritance with increased penetrance in males had been suggested, but there are reports of multifactorial inheritance as well. The role of androgen along with their interaction with genetic factors is demonstrated in men, but in women baldness is often associated with elevated levels of circulating androgens (e.g. in polycystic ovary disease). In both the sexes, the factor determining pattern hair loss is the manner in which the follicles of the frontal and vertex region of the scalp react to the circulating androgens. Till date the correlation between testosterone levels and the extent of pattern baldness has not been established.

A man coming for the treatment of hair loss is first prescribed minoxidil 2% solution, I ml to be applied topically twice daily for 6 to 12 months. The patient is advised to use ketoconazole shampoo. In about one third of men, there is significant conversion of miniaturized hairs to terminal hairs. The response is better in younger males having a smaller area of hair loss that too in the early stage of baldness. The only side effect is occasional local irritation but the benefits last only as long as the drug is applied. The hair loss recurs 3-6 months after discontinuing application, reaching the level it would have reached had minoxidil not been used. The males who do not respond appreciably to topical minoxidil are prescribed tablet finasteride 1 mg daily. This leads to significant hair regrowth in another one third of the patients. Safety and tolerability levels are excellent with no significant impairment of fertility. snip..

Hair loss treatment in women is started only after ruling out other causes of hair loss….. Minoxidil 2% solution applied topically is the first treatment of choice. In case it fails, tablet spironolactone 1 00mg is given daily for 3 out of every 4 weeks along with oral contraceptives……

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Journal of Andrology, Vol. 29, No. 5, September/October 2008
The Effect of 5 -Reductase Inhibitors on Erectile Function
ONDER CANGUVEN AND ARTHUR L. BURNETT
Abstract
edited
The 5 -reductase inhibitors, which inhibit conversion of testosterone to dihydrotestosterone, are used for miscellaneous clinical applications, including the treatment of benign prostatic hyperplasia and male pattern hair loss, and for possible reduction of the risk of prostate cancer. Erectile dysfunction has been associated with 5 -reductase inhibitors. Overall, reports in the literature suggest rates of erectile dysfunction to be between 0.8%–33% in men using these medications. However, randomized controlled studies report the rates of erectile dysfunction to be between 0.8%–15.8%. The possible risk association is that these medications impact androgen function, which is understood to contribute to normal erectile physiology. The 5 -reductase inhibitors result in a drop in median serum dihydrotestosterone levels by 60%–93% within 2 years, but there is no major change in testosterone levels. In this review, we surveyed studies on erectile dysfunction in patients treated with 5 -reductase inhibitors and critically examined the evidence that associates 5 -reductase inhibitors and erectile dysfunction. We conclude that 5 -reductase inhibitors do not lead to erectile dysfunction to a significant degree, and we support the position that dihydrotestosterone is less relevant than testosterone in erectile function.

The 5 -reductase inhibitors (5ARIs) have been successfully used for more than 20 years for treatments of benign prostatic hyperplasia (BPH) and male pattern hair loss, and lately they have been evaluated for reduction in prostate cancer risk. Presently available orally administered 5ARIs, finasteride and dutasteride, inhibit 5 -reductase, an enzyme that catalyzes the irreversible reduction of testosterone (T) to dihydrotestosterone (DHT), with NADPH as the hydrogen donor (Russell and Wilson, 1994). There are 2 isoenzyme forms (types I and II). Type I is located predominantly in the skin, in both hair follicles and sebaceous glands, as well as in the liver, prostate, and kidney and is responsible for approximately one-third of circulating DHT. Type II is found in the prostate, seminal vesicles, epididymis, hair follicles, and liver, and is responsible for the remaining two-thirds of circulating DHT. Finasteride inhibits type II, while dutasteride is an inhibitor of both types and may decrease circulating DHT to a greater extent than finasteride.

The sex steroidal influence in the physiology of the erectile response has been an issue of controversy for many years. Points of view have ranged from thought that the androgens offer an unneeded role in physiological mechanisms of penile erection to the view that these hormones critically influence structural and functional circumstances required for the erectile response.

We are able to treat patients for prostatic or hair diseases by decreasing their DHT levels. Do we also lessen the quality of their sexual lives? In this review, we summarize information from animal models and clinical studies with regard to the effect of 5ARIs on erectile function. We begin with a description of 5 -reductase deficiency (male pseudohermaphroditism) and continue with an overview of the role of T and DHT on erectile capability by highlighting the physiological properties and molecular interactions of the intriguing hormone DHT in general. Then, within the context of several specific studies, we explore the impact of currently available 5ARIs on erectile function in men……

Deficiency in 5 -Reductase

The effect of androgens on the physiology of the penis has been a topic of discussion for many years. In 1974, Imperato-McGinley and colleagues (1974) discovered an autosomal recessive form of incomplete male pseudohermaphroditism, which was shown to result from 5 -reductase deficiency. This disorder, also known as pseudovaginal perineoscrotal hypospadias, or type 2 familial male pseudohermaphroditism, is characterized by a 46,XY karyotype, ambiguity of the external genitalia (female phenotype at birth), and virilization at puberty. During fetal development, the decrease in DHT results in incomplete masculinization of the external genitalia. Later in puberty, affected individuals develop a muscular male habitus with growth of the phallus and scrotum, and their voices change into adulthood. In adulthood, they have decreased body hair, a scant to absent beard, no temporal hair line recession, and a small prostate. However, subjects have normal erections and ejaculations and a libido directed towards females (Imperato-McGinley et al, 1974).

Anatomic investigations have shown that mesonephric duct structures (ie, testis, epididymis, seminal vesicles, ejaculatory duct, and prostate) are developed, but that the external genitalia are incompletely masculinized. The mean plasma T levels in affected adults are significantly higher and the mean plasma DHT levels significantly lower when compared with those of normal subjects (Imperato-McGinley et al, 1974; Peterson et al, 1977). The plasma T:DHT ratios range from 35 to 84 compared with 8 to 16 in normal subjects. In affected subjects, the metabolic clearance rates of T and DHT are normal, but the conversion ratio of T (using radioactive T) to DHT is less than 1% (Peterson et al, 1977).

Imperato-McGinley and colleagues (1974) mentioned that T is required for differentiation of embryonic mesonephric duct structures, and that DHT is required for differentiation of the embryonic urogenital sinus and tubercle into male external genitalia. Male psychosexual development and virilization at puberty are mediated by T, while adult prostatic growth and male pattern baldness are mediated by DHT (Imperato-McGinley et al, 1974; Tarter and Vaughan, 2006).

Type 2 familial male pseudohermaphroditism, which features lack of prostate growth and male pattern baldness, provides a model for the development of 5ARIs. Some diseases (eg, BPH and androgenetic alopecia) are treated using these medications. However, these medications change serum levels of androgens, mainly DHT. If androgen levels affect erectile function, then it stands to wonder whether changes in DHT levels can affect erectile function as well.

Role of Androgens in Erectile Function

T is the major androgenic hormone produced by Leydig cells of the testes in response to stimulation by luteinizing hormone of the pituitary gland. T, regulated by the hypothalamic-pituitary-testis axis, is converted to DHT in the liver, skin, and organs that originate from the mesonephric duct, such as the prostate. The enzyme that is responsible for conversion of T to DHT is 5 -reductase. T either directly or subsequent to its conversion into DHT exerts important physiological actions on muscle, bone, prostate, bone marrow, the central nervous system, and erectile function (Saad et al, 2007). T exerts both humoral endocrine and local paracrine effects, whereas DHT is largely a paracrine hormone and exerts effects in the tissues of origin (Tarter and Vaughan, 2006).

Although the role of androgens in erectile function in men is controversial, primary or secondary hypogonadism is considered key in the pathophysiology of erectile dysfunction (ED) (Korenman et al, 1990; Aversa et al, 2004; Yassin and Saad, 2007). Androgens exert not only genomic effects, for example, by stimulating the expression of the neuronal isoform of nitric oxide (NO) synthase (Reilly et al, 1997; Park et al, 1999), but also nongenomic effects, for example, by relaxing the smooth musculature of coronary arteries and the aorta (Yue et al, 1995; Deenadayalu et al, 2001). Criteria representing nongenomic effects include a rapid onset of action within seconds or minutes, effects elicited by androgens that do not enter the cytosol. An interesting matter is that androgenic actions associated with nongenomic effects are not blocked by inhibitors of the androgen receptor or by inhibitors of transcription (Yue et al, 1995; Deenadayalu et al, 2001). Waldkirch and associates (2008) demonstrated that T and DHT dose-dependently reversed the noradrenalin-induced tension of human cavernosal arteries and corpus cavernosum strips, indicating the clinical significance and supporting the concept of threshold levels.

T is important for modulating the central and peripheral regulation of ED. Erectile function depends on a normal penile anatomy and a functioning venoocclusive mechanism, which implies integrity of the structural and cellular components. It was demonstrated that T deprivation causes apoptosis of cells from cavernosal and spongiosal tissues, which can be prevented by androgen administration (Podlasek et al, 2005).

Smooth muscle, a vital component of the penile anatomy, is a critical structure for tumescence. Using a rat model, investigators established that experimental castration caused significant reduction in trabecular smooth muscle and a significant increase in connective tissue deposition concomitant with loss of erectile function, indicating that T is vital for smooth muscle integrity (Traish et al, 2003). Further support for the androgenic requirement for penile erection derives from scientific knowledge of the molecular basis for NO function in the penis. It was shown that the NO pathway plays a critical role in initiation and maintenance of erectile function (Burnett, 2004). In animals, the expression of NO synthase (NOS) isoforms in the corpus cavernosum is regulated by androgens. Researchers found that NOS activity is decreased in erectile tissues of castrated animals, as is the erectile response to pelvic nerve stimulation (Lugg et al, 1995; Park et al, 1999; Baba et al, 2000). These investigators further established that T restores the erectile response and normalizes NOS protein expression and activity.

On the whole, the mechanism of penile erection is a function of corporal smooth muscle relaxation required for blood filling and engorgement of the penis in response to sexual excitement, exerted at the molecular level by cGMP by way of its effector cGKI (Andersson, 2001). Type 5 phosphodiesterase enzyme (PDE5), the predominant phosphodiesterase expressed in the corpus cavernosum, has regulatory control of penile vasorelaxant actions. In the animal model, castration resulted in reduced protein expression and activity of PDE5, although androgen treatment up-regulated the expression of PDE5 activity (Morelli et al, 2004). In addition, the efficacy of PDE5 inhibitors to elicit erections induced by electrostimulation of the cavernous nerves following castration was decreased. After castrated animals were treated with T, the tissue relaxation caused by PDE5 inhibitors was successfully restored (Traish et al, 1999; Morelli et al, 2004).

Clinical studies also indicate the direct influence of androgens on erectile responses to PDE5 inhibitors. Investigators carrying out clinical trials in androgen-deficient men confirmed these observations and found that with androgen substitution these men displayed enhanced responses to the ED treatment (Aversa et al, 2004; Shabsigh et al, 2004; Morelli et al, 2007). These studies strongly suggest that T exerts vital physiological actions in erectile function.

Experimental Animal Models

Description of 5 -reductase deficiency in male pseudohermaphroditism caused investigators to study the influence of 5ARIs on erectile function in animal models. To begin to unravel this issue, Bradshaw and associates (1981) designed a study in which they administered the 5ARI, 17-beta-testosterone carboxylic acid and T propionate or 5 -DHT propionate, after castration of animals. The investigators observed significantly attenuated stimulatory effects of T propionate on penile erections. However, when they administered 5 -DHT propionate to castrated rats, penile erections were preserved, implying the importance of DHT in erectile function (Bradshaw et al, 1981).

The work of Baum and colleagues (1983) suggested an opposite conclusion. These investigators implanted subcutaneous silastic capsules containing either the aromatase inhibitor androst-1,4,6-triene-3, 17-dione (ATD), the 5ARI testosterone-17-beta-carboxylic acid (17 beta C), or no hormone into male ferrets for 15 days beginning on the day of birth. All ferrets were gonadectomized when they were 11 weeks of age and were subsequently tested for masculine sexual behavior after a latin-square sequence of treatments with subcutaneous silastic capsules containing T, estradiol, or DHT. After T administration, control males displayed significantly more neck gripping, mounting, and pelvic thrusting than males treated neonatally with ATD. After DHT administration, little masculine sexual behavior was shown by any group. These consequences suggest that behavioral masculinization in the male ferret results primarily from the neonatal action of T itself in the brain, and not from its estrogenic or 5 -reduced androgenic metabolites (Baum et al, 1983).

Lugg et al (1995) further investigated which androgen is vital for function of the penis with respect to erectile function. They performed a study to determine whether the T effects on erectile function are mediated via its conversion to DHT. In their study, castrated rats were implanted with silastic brand silicon tubing containing T or DHT with or without daily injections of the 5ARI finasteride. Orchiectomy reduced the electrical field stimulation-induced erectile response by 50% in comparison with intact rats, and T restored this decrease to normal. When finasteride was given to these T-treated castrated rats, erectile response was not restored. DHT was as effective as T in restoring response to stimulation in castrates, and this effect was not decreased by finasteride (Lugg et al, 1995). The results seem to corroborate the information of Bradshaw and associates (1981). The data suggested that DHT is the active androgen that prevents erectile failure in castrated rats.

With recent discoveries of PDE5 inhibitors as well NOS signaling in the penis, Park et al (1999) examined whether DHT influences the erectile response and the mRNA expressions of NOS isoforms in the penile corpus cavernosum of castrated rats. For this purpose, rats were separated into 5 groups: sham, castrated alone, and castrated receiving T, DHT, or T with the 5ARI finasteride. Both T and DHT effectively restored the erectile response to normal. NOS activity and the amount of neuronal NOS (nNOS) mRNA were also reduced in castrated rats but restored by both T and DHT replacement. Although there was no significant difference in NOS activity between the androgens, nNOS mRNA expression was higher in rats treated with DHT. Strikingly, there were no effects of T in rats treated with finasteride, since the ratio of maximum intracavernosal pressure to systolic blood pressure (ICPmax/SBP ratio), NOS activity, and amount of nNOS mRNA were decreased (Park et al, 1999).

Further evaluation of the role of DHT in the penis has been done at the penile morphologic level. Shen et al (2000) investigated the ultrastructural changes of the penile corpus cavernosum and tunica albuginea in rats representing 3 groups: sham control, castrated, and treated with finasteride. Four weeks later, blood samples were obtained for the determination of serum T and DHT levels, and penile tissues were taken for scanning electron microscopy. The T and DHT levels in castrated rats and the DHT level in finasteride-treated groups were significantly lower than those in the control group. In the castrated animals, there was a high degree of fibrosis in the corpus cavernosum with irregularly arranged collagenous fibers and a marked decrease in smooth muscle fibers, while in the DHT-inhibited group (finasteride-treated), the corpus cavernosum comprised a substantial amount of thick and irregularly arranged collagenous fibers, but the degree of fibrosis was less than that of the castration group (Shen et al, 2000). This work suggests that because finasteride inhibits the action of DHT but not T on the corporal cavernosal tissue, the degree of fibrosis was less in the DHT-inhibited group than in the castration group. In the castration group, the thickness of tunica albuginea decreased significantly and the elastic fibers were mostly supplanted by collagenous fibers, and in the DHT-inhibited group, the elastic fibers were replaced by disorganized and thick collagenous fibers. Since the tunica albuginea plays a major role in the erectile mechanism of the penis, the latter results offer an explanation for the presentation of ED in patients treated with 5ARIs.

Clinical Investigations

Clinical Studies Testing the Effect of DHT on Erectile Function— In order to evaluate the direct effect of 5ARIs on sexual life, investigators studied erectile function in patients taking these drugs. Cunningham and Hirshkowitz (1995) designed a sleep-related erection study, with the aim of measuring erectile function objectively during double-blind administration of finasteride or placebo. Their purpose was to find the answer to the question, “Does finasteride impair erectile function?” Sleep-related erection studies provide objective measures of erection physiology and pathophysiology. Naturally occurring, spontaneous episodes of nocturnal penile tumescence (NPT) occur with consistent regularity during rapid eye movement (REM) sleep in all sexually potent men. Twenty healthy, sexually active men were randomized to receive either placebo or 5 mg/day finasteride for 12 weeks according to a double-blind study design. Erection physiology was assessed by a polysomnography device. The investigators found that finasteride did not consistently suppress sleep-related erections compared with placebo (Cunningham and Hirshkowitz, 1995). They explained the most likely reason that finasteride did not impair erectile function was that it did not sufficiently inhibit 5 -reductase activity in critical areas of the brain. They acknowledged that DHT involvement in the maintenance of libido and potency is not excluded.

Uygur and associates (1998) investigated the effects of finasteride on the serum levels of gonadal, hypophyseal, and adrenal hormones and the clinical significance of these effects. In this prospective clinical study, serum levels of T, DHT, dehydroepiandrosterone, and luteinizing hormone were determined, and erectile function was evaluated in 48 BPH patients using a brief sexual function questionnaire, which included a total of 11 self-administered questions (O’Leary et al, 1995). DHT levels decreased by 60%, and T levels increased by 15% after finasteride was given. Finasteride led to ED in 22% by month 3 and in 33% by month 6 (Uygur et al, 1998). Despite the suggestion of a high level of ED associated with finasteride use in this study, an accurate determination of this risk is precluded by the lack of a control group.

Anderson and colleagues (1999) compared the effects of 7 -methyl-19-nortestosterone (MENT), a potent synthetic androgen (selective androgen receptor modulator), which can be converted by aromatase to an active estrogen, 7 -methyl estradiol, but is resistant to 5 -reductase actions, with T enanthate on erectile function in 20 hypogonadal men. It is worth emphasizing that DHT is not formed from MENT. Both MENT and T treatment resulted in significant increases in spontaneous erection (both by self-report and NPT measurement) and positive moods (Anderson et al, 1999). The study demonstrated that MENT is sufficient to restore androgen-dependent physiology in hypogonadal men, lending indirect evidence that DHT is not required for mediation of these responses in men (Anderson et al, 1999).

Clinicians counsel more or less on a drug’s sexual side effects. Could this counseling trigger ED as a placebo effect? Mondaini et al (2007) investigated whether a discrepancy exists in finasteride-related sexual adverse effects between double-blind trials and clinical practice, and if the difference might be partially related to a placebo effect. The patients were asked to complete the International Index of Erectile Function (IIEF) and the Male Sexual Function-4 (MSF-4; contains questions about interest in sex, quality of erection, achievement of orgasm, and achievement of ejaculation) questionnaires (Mondaini et al, 2007). Finasteride was prescribed to 120 patients with or without counseling on the drug’s sexual side effects. The estimation of side effects was conducted at 6 and 12 months using the MSF-4 questionnaire and a self-administered questionnaire. In this study, finasteride was associated with a significantly higher proportion of ED in patients informed of possible erectile side effects as compared with that in patients for whom the same information was withheld. The incidence of ED was 9.6% for the group without counseling and 30.9% for the group with counseling (Mondaini et al, 2007). The placebo effect demonstrated here has to be taken into account when managing finasteride-related EDs.

When the results of clinical studies are examined, it is not clearly evident that 5ARIs have a negative effect in men as seen in animal studies. This may be explained by the fact that in animals DHT levels were either zero or normal. It was shown that treatment with 5ARIs results in a reduction in median serum DHT levels in men by 60%–93% after 2 years (Imperato-McGinley et al, 1974; Uygur et al, 1998; Andriole and Kirby, 2003; Clark et al, 2004; Marberger et al, 2006). The 5ARIs cause a reduction in DHT levels but do not eliminate it completely from the circulation. For example, since finasteride inhibits only type II 5 -reductase receptors, circulating DHT is only reduced by two-thirds (Thigpen et al, 1993a; Thigpen et al, 1993b; Gisleskog et al, 1998).

Clinical Studies for Benign Prostatic Hyperplasia— Mechanisms of BPH, the most prevalent disease of the prostate, are multifactorial and are not yet completely understood. Nevertheless, BPH is known to depend on androgens, especially on DHT, which also plays a crucial role in the early development and normal growth of the prostate. The 5ARIs finasteride and dutasteride are used to treat BPH and to prevent urinary complications according to randomized, controlled trials. Finasteride, an inhibitor of type II 5 -reductase isozyme, was the first 5ARI used in men with BPH (Sudduth and Koronkowski, 1993). It has no binding affinity for androgen receptor sites, and it possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. It is well-absorbed after oral administration, with absolute bioavailability in humans of 63% (range 34%–108%). snip..

Concerns regarding the adverse metabolic side effects of finasteride emerged from the analysis of the Finasteride Study Group. snip… The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary symptom scores but had an increase of 1.4 mL per second in the maximal urinary flow rate and an 18% decrease in prostatic volume. There was also a higher incidence of ED in the finasteride-treated groups compared with placebo. snip…

The Finasteride Study Group further assessed the long-term safety and efficacy of finasteride in the treatment of symptomatic BPH in patients treated with 5 mg finasteride for 36 months (Stoner, 1994). ED at the end of 1 year was reported by 3.7% of the men in the 5 mg finasteride-treated group compared with 1.1% of the men in the placebo-treated group. Interestingly, by the end of 3 years, 45% of adverse erectile effects had resolved in the group taking 5 mg finasteride. Finasteride was well-tolerated, and there was no evidence of increased adverse experiences with increased duration of treatment (Stoner, 1994). These data indicated that although there was a 3.7% incidence of ED at the beginning of treatment, ED declined to 2.1% at the end of 3 years (Table).

Additional evidence regarding the effects of finasteride on erectile function comes from the ALFIN Study, a randomized, double-blind, multicenter trial involving 1051 patients, which assessed the additive benefit of combining an 1-blocker and a 5ARI (Debruyne et al, 1998). From the point of view of erectile function, Debruyne et al reported that the ratio of ED was 6.7%, which was higher in patients treated with finasteride, alone or in combination, than with alfuzosin alone (Debruyne et al, 1998). A limitation of this study is that it was not placebo-controlled. The investigators also did not use any questionnaire for examining erectile function. The adverse events communicated spontaneously by patients or from notes taken by the investigator during examination were reported during the whole study.

A placebo-controlled study involving a large population evaluated over a long period may offer the best determination of outcomes associated with 5ARI treatment. The Proscar Long-Term Efficacy and Safety Study (PLESS), a 4-year, double-blind, placebo-controlled finasteride study of more than 3000 men with BPH, was designed to prospectively determine the efficacy of finasteride, as well as the incidence of erectile adverse effects over time (Wessells et al, 2003). The drug-related ED profile for finasteride was similar for men with and without a history of ED at baseline. Wessells et al reported that ED was a consistent side effect of finasteride in a maximum percentage of 12.6% (mild, moderate, or severe ED) after 1 year of therapy. However, the incidence of severe ED was 5% in the finasteride group and 5% in the placebo group during years 2–4 of treatment (Table). Wessels et al concluded that ED was mild to moderate in intensity and resolved in about half of men after discontinuation of either finasteride or placebo, consistent with the natural history of ED in this patient population and likely concurrent with a substantial placebo effect (Wessells et al, 2003).

McConnell and colleagues (2003) conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy (doxazosin and finasteride; Table). The reduction in risk of overall clinical progression of BPH was associated with combination therapy to a significantly greater extent than that associated with doxazosin or finasteride treatment alone. McConnell and colleagues also demonstrated that long-term combination therapy was safe. On the other hand, ED occurred to a significantly greater degree in the finasteride-treated group than in the placebo-treated group (4.53 vs 3.32 incidents per 100 person-years; McConnell et al, 2003).

Dutasteride, a newer 5ARI available for the treatment of symptomatic BPH, is a dual inhibitor of type I and II human 5 -reductase. It is possible that it may decrease circulating DHT to a greater extent than finasteride (Clark et al, 2004). Since it blocks both of the 2 known 5 -reductase isozymes, does it cause a higher incidence of ED? Marberger and associates (2006) evaluated the results of 4254 men with BPH participating in 2-year, randomized, double-blind and placebo-controlled dutasteride (0.5 mg) trials. The Sexual Function Inventory (SFI) was administered at baseline and 1 year to assess perceptions of problems associated with sexual drive, erection, or ejaculation (3 items). In men with normal baseline serum T (300 ng/dL), drug-related ED occurred in 6.7% of the dutasteride-treated group, compared with 4.0% of the placebo-treated group (Marberger et al, 2006). In this study with a large population, an increased incidence of ED was generally not observed unless T levels were less than 225 ng/dL (Table).

In a 2-year, prospective, double-blind randomized, placebo-controlled trial with an additional 2-year open-label phase for BPH with dutasteride (0.5 mg/day), 6.1% of dutasteride-treated subjects developed ED (control, 3.0%) in the first year (Roehrborn et al, 2004). The most commonly reported drug-related adverse events, including ED with new onset of these events, occurred primarily within the first year of treatment. Roehrborn and colleagues (2004) also showed that ED results diminished to 1.3% (control, 1.3%) at the end of 2 years.

Andriole and Kirby (2003) summarized the results of 4 large, randomized, double-blind clinical trials of dutasteride (n = 5655) and a comparator study of dutasteride and finasteride (n = 1630). The incidence of drug-related adverse events was not significantly different between dutasteride and finasteride. The investigators observed that the onset of the majority of possibly drug-related adverse events occurred within the first year of treatment, with a statistically significantly lower incidence of ED occurring in the placebo-treated group versus the dutasteride-treated group (1.7% vs 4.7%) from 0–6 months (Andriole and Kirby, 2003). Subsequently (7–12 months, 13–18 months, and 19–24 months), there were no significant differences with respect to ED between the dutasteride-treated (1.4%, 1.1%, and 0.8%, respectively) and placebo-treated (1.5%, 0.5%, and 0.9%, respectively) groups (Andriole and Kirby, 2003). Although suppression of both 5 -reductase isoenzymes with dutasteride resulted in greater and more consistent suppression of serum DHT than that observed with the selective inhibitor of the type II 5 -reductase finasteride, no significant difference in long term (19–24 months) erectile function was seen between dutasteride-treated and placebo-treated men (Andriole and Kirby, 2003; Clark et al, 2004).

Clinical Studies for Androgenic Alopecia— Androgens also have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Male pattern hair loss, known to depend on the presence of the DHT and on a genetic predisposition for this condition, affects approximately 50% of the male population (Otberg et al, 2007). Reduction in DHT results in a significant improvement in subjective and objective assessments of hair growth and density.

In clinical trials involving finasteride (1 mg for androgenic alopecia), ED has been reported from patients’ assessments in 1.4% of patients treated with the active drug and in 0.6% of patients taking a placebo in the first year of treatment (Finasteride Male Pattern Hair Loss Study Group, 2002). There are some studies that showed adverse erectile effects using validated questionnaires while treating male pattern hair loss. In one of the earliest studies using validated questionnaires, Tosti et al (2001) evaluated the erectile function in subjects taking 1 mg finasteride compared with placebo using the International Index of Erectile Function (IIEF-5). Statistical analysis showed no differences between scores obtained with the IIEF in subjects taking finasteride and controls. In a multicenter study, 186 patients with androgenic alopecia were asked to complete the erectile function domain of the IIEF before (at baseline) and 4 to 6 months after beginning finasteride treatment (Tosti et al, 2004). In this study, erectile function of all patients remained stable after 4 to 6 months of treatment with 1 mg finasteride, and no statistically significant changes were noted between active drug and placebo (Table; Tosti et al, 2004).

Clinical Studies for Prostate Cancer Prevention— In order to prevent prostate cancer, one of the most common cancers in the world, 5ARIs have been investigated in clinical trials. In a large study population, Moinpour and colleagues (2007) assessed ED in 17 313 Prostate Cancer Prevention Trial (PCPT) participants during a 7-year period. In this randomized, double-blind, placebo-controlled study, the efficacy of finasteride in preventing prostate cancer was examined. Sexual Activity Scale (SAS) scores were developed and used to assess sexual dysfunction. SAS has 4 items, including erection when desired, satisfaction, sexual performance, and frequency of sexual activities. Response levels ranged from 4–7 and were transformed to a 0–100 scale. Self-reported patient measures were obtained at study baseline and annually for 7 years. Results were that finasteride increased the SAS scores relative to placebo by 3.21 points at the first assessment, although its impact diminished over time, and at the end of the study it had decreased by 2.11 points (Moinpour et al, 2007). These data demonstrate that the effect of finasteride on erectile functioning is minimal for most men and that finasteride can be prescribed or taken comfortably (for hair loss treatment).

Redox signaling is an important component of hair loss and hair loss treatment.

Hair loss treatment blog

Hair loss blog

Hair loss treatment blog

Hair loss blog

Hair loss blog

J Dermatol Surg Oncol. 1989 Jan;15(1):50-3.

Topical minoxidil and hair transplantation.
Bouhanna P.

..Topical minoxidil was applied to the scalp of 16 patients aged 25 to 52 years with male pattern hair loss. Treatment began before surgery, was interrupted for 3 weeks, and was started again and continued for 3 months. Four-millimeter donor grafts were inserted into recipient sites. Follow-up utilizing macrophotography was done for 3 months on 4 grafts near a tattooed area. In 71% of the 64 grafts, partial or total hair regrows without the shedding that usually occurs 2-4 weeks after transplantation. Topical minoxidil seems to be an adjunct for a better evolution of grafts after hair transplantation surgery.

Am J Dermatopathol. 1991 Jun;13(3):248-56.

Cell degeneration in alopecia areata. An ultrastructural study.
Tobin DJ, et al.

The morphology and prevalence of different forms of cell degeneration in hair follicles in acute alopecia areata were investigated. In addition to apoptosis and necrosis, a third morphological pattern of cell degeneration, dark-cell transformation, was evident. Patients with untreatedalopecia areata and three normal adults without hair loss were studied. Although apoptosis of outer root sheath keratinocytes produces normal hair follicle involution (catagen), increased levels of apoptosis, necrosis, and dark-cell formation appear to be related to the pathology of alopecia areata.

Hair.

Ebling FJ.

….most of man’s hair follicles are vestigial. Three problems of hair regrowth remain to be solved: (1) how the growth of hair follicles in both animals and man is controlled; (2) how the male hormone alters the hair cycle in human skin; and (3) why larger hairs are produced by testosterone in some areas of the body when in some individuals the hair follicles in the scalp regress.snip.. Both sexual hair and male-pattern baldness depend on androgenic hormones. Target organs of testosterone convert the hormone to active metabolites,.. snip…. The androgenic steroids, the enzymes that convert them to their active metabolites, and the proteins that bind them are undoubtedly very important to the problems of the growth of sexual hair and male-pattern baldness.

Free radicals and similar chemicals have a cellular messenger role now dubbed Redox signaling. This may play a key role in regulating the hair cycle, as well as in mediating pattern balding itself.

How minoxidil stimulates hair regrowth remains undetermined. Biopsies in androgenetic alopecia (male pattern hair loss ) demostrate the primary morphologic event in male pattern hair loss is miniaturization of terminal hair follicles, shortening of the hair regrowth cycle.

J Allergy Clin Immunol. 2009;123(:1355.

Risk analysis of early childhood eczema.
Bisgaard H, et al

BACKGROUND: The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition. OBJECTIVE: To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years. METHODS: The Copenhagen Study on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 children born of mothers with asthma. Eczema was diagnosed, treated, and monitored at the clinical research unit, and complete follow-up for the first 3 years of life was available for 356 children. Risk assessments included filaggrin loss-of-function mutation; parent’s atopic disease; sex; social status; previous deliveries; third trimester complications and exposures; anthropometrics at birth; month of birth; duration solely breast-fed; introduction of egg, cow’s milk, and fish; time spent in day care; cat and dog at home; feather pillow; nicotine in infant’s hair; and temperature and humidity in bedroom. RESULTS: Eczema developed in 43.5% of the infants. CONCLUSIONS: Dog exposure reduced the risk of eczema, whereas short length at birth, filaggrin mutation, and parental atopy increased the risk of eczema by age 3 years.

edited for hairnloss blog

Not technically related to hair loss treatment. But here is Dr Proctor’s organic semiconductor device in the Smithsonian institution’s “Smithsonian chips” collection.

Z Hautkr. 1977 Nov 15;52(22):1129-34.

Alopecia areata: successful half-side treatment with DNCB

Happle R, Echternacht K.

edited for hair loss blog

In 46 patients with hair loss due to alopecia areata, one side of the head was treated with weekly applications of DNCB, dissolved in acetone. The therapeutic aim was mild contact dermatitis. The other side of the head served as control region. A therapeutic effect was noted in 36 patients: 22 patients showed regrowth of hair exclusively on the treated side, and in 14 patients hair regrowth was considerably faster and more dense on the treated side. In 8 patients no regrowth was observed, and in 2 patients regrowth occurred on both sides without any difference of intensity. The difference between both sides with regard to hair growth was seen in all of the 7 patients with moderate involvement and in 12 out of 13 patients with extensive involvement; but also in 17 out of 26 patients with alopecia areata totalis or fere totalis. The difference was noted, in the majority of cases, within 3 months. These results prove the efficacy of DNCB treatment of alopecia areata.

Hair Loss Treatment at the Proctor Clinic

J Am Acad Dermatol. 1980 Dec;3(6):623-6.

Analysis of hair from alopecia congenita.
Baden HP, Kubilus J.

Edited for hair loss blog use

Two patients with alopecia congenita had short vellus hairs of the scalp but some apparently normal-sized hairs in other areas. Both fibrous and matrix proteins were detected in the scalp hairs by polyacrylamide gel electrophoresis (PAGE), and x-ray diffraction analysis revealed a normal alpha pattern. Amino acid analysis showed a decreased cystine content suggesting a quantitative or qualitative change in the matrix component. Scanning electron microscopic examination revealed pits and bulges in the cuticle cells which may be related to wearing a wig. The data suggest a defect in the development of the follicle rather than an abnormality in a component of the hair.