Androgenetic alopecia as an early marker of benign prostatic hyperplasia

n Buend a-Eisman, PhD,a Salvador Arias-Santiago, MD, PhD,a Miguel Angel Arrabal-Polo, MD,b Agust b a  n, PhD, Mar  n-Prieto, MD,a n, PhD, Mar a Teresa Guti a Sierra Giro Miguel Arrabal-Mart errez-Salmero b c n Naranjo-Sintes, PhD,a Antonio Jimenez-Pacheco, PhD, Jaime Eduardo Calonje, MD, Ramo b Armando Zuluaga-Gomez, PhD, and Salvio Serrano Ortega, PhDa Granada, Spain, and London, United Kingdom
Background: Androgenetic alopecia (AGA) and benign prostatic hyperplasia are both androgendependent entities that respond to the blocking of 5-alpha-reductase. Objectives: The objective of this study was to determine whether prostatic volumes and urinary ow changes were higher in patients with early-onset AGA than in healthy control subjects. Methods: This was an observational case-control study of 87 men: 45 with early-onset AGA diagnosed in the dermatology department and 42 control subjects. End-point variables were prostatic volume, measured by transrectal ultrasound, and urinary ow, measured by urinary owmetry. A hormone study was performed on all participants, and the International Prostate Symptom Score and International Index of Erectile Function score were determined. Results: The groups did not signicantly differ in mean age (cases, 52.7 years vs control subjects, 49.8 years; P = .12). Patients with AGA had significantly higher mean prostate volume (29.65 vs 20.24 mL, P \ .0001), International Prostate Symptom Score (4.93 vs 1.23, P \ .0001), and prostate-specific antigen value (1.53 vs 0.94 ng/mL, P \ .0001) and significantly lower maximum urinary flow (14.5 vs 22.45 mL/s, P \ .0001) versus control subjects. Binary logistic regression analysis showed a strong association between the presence of AGA and benign prostatic hyperplasia after adjusting for age, urinary volume, urination time, International Prostate Symptom Score, abdominal obesity, glucose levels, systolic blood pressure, insulin levels, fibrinogen, and C-reactive protein (odds ratio = 5.14, 95% confidence interval 1.23-47.36, P = .041). Limitations: The study of larger sample sizes would facilitate stratied analyses according to the Ebling type of androgenetic alopecia. Conclusion: There is a relationship between the presence of AGA and prostate growth-associated urinary symptoms, likely attributable to their pathophysiological similarity. This study suggests that early-onset AGA may be an early marker of urinary/prostatic symptomatology. Future studies may clarify whether treatment of patients with AGA may benet the concomitant benign prostatic hypertrophy, which would be present at an earlier stage in its natural evolution. ( J Am Acad Dermatol 2012;66:401-8.) Key words: androgenetic alopecia; androgens; benign prostatic hyperplasia; maximum urinary ow; prostate volume.

ale androgenetic alopecia (AGA) is the most prevalent form of alopecia and is largely determined by genetic factors and

the peripheral action of androgens. Various authors have reported a relationship between AGA and cardiovascular involvement.1-3 The aim of the
2010 and received the First Award: Urinary symptoms in patients with androgenetic alopecia. Reprint requests: Salvador Arias-Santiago, MD, PhD, San Cecilio University Hospital, Av Dr Oloriz 16, Granada, 18012, Spain. E-mail: salvadorarias@hotmail.es. Published online August 12, 2011. 0190-9622/$36.00 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.023

From the Dermatologya and Urologyb Units, San Cecilio University, Granada, Spain and the Dermatology Unit,c St Thomas Hospital, London. Funding sources: None. Conflicts of interest: None declared. Accepted for publication December 22, 2010. Presented as a pilot study at the 68th Annual Meeting of the American Academy of Dermatology in Miami, Florida, in March

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current study was to analyze the relationship METHODS between AGA and urinary symptoms associated Study subjects and design with prostate growth. This case-control study included 87 Caucasian Benign prostatic hyperplasia (BPH) is highly participants aged 35 to 65 years: 45 with AGA prevalent among elderly men but infrequent in those consecutively examined in the outpatient clinic of younger than 40 years. Its prevalence progressively San Cecilio University Hospital, Granada, Spain, and increases above the age of 60 years. The two most 42 without AGA. Control subjects were recruited important factors implicated among workers at the hospiin BPH have been patient age tal (guards, security guards, CAPSULE SUMMARY and androgenic function. health care workers). Study Both AGA and BPH inclusion criteria for the paAndrogenetic alopecia (AGA) and benign are androgen-dependent distient group were: early-onset prostatic hyperplasia are both androgeneases in which testosterone (age \35 years) type III, IV, dependent entities that share a common and dihydrotestosterone or V AGA on the Ebling scale; pathogenesis. AGA, which manifests (DHT) are involved and in age between 35 and 65 years; some decades before the onset of which the enzyme 5-alphaand written informed conbenign prostatic hyperplasia, may serve reductase, which transforms sent for study participation. as an early marker of prostate symptoms. testosterone into DHT, plays Exclusion criteria were: hisa key role. In the scalp, the Patients with AGA had significantly tory of prostate disease; prosDHT responsible for follicular higher mean prostate volume, tatitis; neurogenic bladder; miniaturization is largely International Prostate Symptom Score, previous consultation with produced by the action of and prostate-specific antigen values and urologist or family physician 5-alpha-reductase type 2 on significantly lower maximum urinary for prostate problems; and testosterone. In the prostate, flow versus control subjects. treatment with minoxidil DHT derived from the action (in previous 6 months), Early-onset AGA behaved as an early on testosterone of both isoa-blockers, testosterone, 5marker of urinary symptoms, in that enzymes (5-alpha-reductase alpha-reductase inhibitors, these patients had a larger prostate and types 1 and 2) is implicated or any other hormone therincipient urinary flow changes. in the growth and developapy. The study was approved ment of the prostate gland. by the Ethics Committee of Some authors reported increased DHT concenSan Cecilio University Hospital. trations in the prostate tissue of patients with BPH versus healthy tissue,4 whereas others found no differences.5 Nevertheless, the activity of 5Clinical parameters alpha-reductase and number of androgenic recepThe AGA diagnosis was based on clinical ndings: tors are still considered to be higher in patients pattern of increased hair thinning on frontal/parietal with BPH than in control subjects. Scalp biopsy scalp with greater hair density on occipital scalp; the specimens of patients with AGA have shown inpresence of miniaturized hairs and diversity of hair creased DHT concentrations and 5-alpha-reductase diameter (measured by dermatoscopy); and the activity.6,7 Ebling type. Patients were asked about any family Because both entities share a common pathohistory of AGA or BPH, personal history of cardiogenesis and AGA manifests some decades before vascular disease, alcoholism ([40 g/d), smoking BPH onset, AGA may serve as an early marker of ([5 cigarettes/d), or sedentary lifestyle (physical prostate symptoms. The main objective of this study exercise \30 min/d), diet (sodium intake), and drug was to determine whether early-onset AGA behaves intake (antihypertensives, diuretics, hypocholesteras an early subclinical marker of prostate signs and olemics, and oral antidiabetics). Data were collected symptoms in patients with no history of urinary/ by a single examiner. prostate symptoms. Study end-point variables were Total testosterone, follicle-stimulating hormone, the prostate volume, measured by studio transrectal luteinizing hormone, prolactin, estrogen, albumin, ultrasound, and the maximum urinary ow in prostate-specic antigen (PSA), sex hormoneebindpatients with AGA and healthy control subjects. ing globulin (SHBG), triglycerides, high-density Secondary variables were hormone study results, lipoprotein cholesterol, low-density lipoprotein International Prostate Symptom Score (IPSS), cholesterol, glycemia, insulin levels, brinogen, and International Index of Erectile Function (IIEF) and C-reactive protein (CRP) were studied in samscore. ples drawn between 8 AM and 9 AM after a 12-hour
d d d

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Abbreviations used: AGA: BP: BPH: CI: CRP: DHT: IIEF: IPSS: OR: PSA: SHBG: androgenetic alopecia blood pressure benign prostatic hyperplasia confidence interval C-reactive protein dihydrotestosterone International Index of Erectile Function International Prostate Symptom Score odds ratio prostate-specific antigen sex hormoneebinding globulin

the Pearson coefficient and binary logistic regression models (Wald method), obtaining adjusted odds ratios (OR) with 95% confidence intervals (CI) for the association between prostate volume greater than 30 mL and AGA. Differences were considered significant at P # .05 and marginally significant at .05 \ P # .1.

RESULTS
All 87 participants completed the study: 45 in the early-onset AGA group and 42 in the control group. The groups did not signicantly differ in age (AGA, 52.7 years vs control, 49.8 years, P = .128) or body mass index (27.71 vs 27.08 kg/m2, P = .062). The mean age at AGA onset was 27.6 years; 36.5% of the AGA group was Ebling type III, 31.1% type IV, and 33.3% type V. The AGA group more frequently reported a family history of alopecia (88% vs 12%, P \ .0001; OR 59.2, 95% CI 15.85-221.11) and family history of BPH (37.5% vs 12.5%, P = .01; OR 3.64, 95% CI 1.27-10.44) versus the control group. Patients with AGA had a signicantly greater abdominal perimeter (101.8 vs 96.7 cm, P = .009), systolic BP (133.8 vs 123.7 mm Hg, P = .017), and glucose levels (103.6 vs 88.7 mg/dL, P = .028) than control subjects, respectively. No significant differences were observed in diastolic BP (85.2 vs 82.3 mm Hg, P = .29), triglyceridemia (164.3 vs 137.4 mg/dL, P = .22), high-density lipoprotein cholesterol (47.7 vs 49.1 mg/dL, P = .65), or low-density lipoprotein cholesterol (123.8 vs 115.2 mg/dL, P = .22) in patients with AGA and control subjects, respectively. Biochemical analyses revealed that patients with AGA presented higher significant insulin levels (11.1 vs 7.2 U/mL, P = .0007), fibrinogen (342.1 vs 288.2 mg/dL, P = .009), and nearly significant CRP (0.46 vs 0.31 mg/dL, P = .096) than the control group, respectively. No differences in alcohol consumption, diet (sodium intake), sedentarism, smoking, antihypertensives, anticholesterolemics, or oral antidiabetic intake were found between groups. No patient with AGA or control subject had history of myocardial infarction or cerebrovascular disease. No signicant difference was found in total testosterone, SHBG, albumin, or IIEF score between the AGA and control groups, respectively (Table I). Free testosterone values were higher in the AGA versus control groups (0.0978 vs 0.0865 ng/mL, P \ .0001). No significant differences were found between AGA and control groups, respectively, in estradiol (27.45 vs 26.01 pg/mL, P = .28), luteinizing hormone (4.7 vs 4.52 mIU/mL, P = .75), follicle-stimulating hormone (5.53 vs 4.44 mIU/mL, P = .27), or prolactin (7.8 vs 7.22 ng/mL, P = .45). A negative significant correlation was observed between free testosterone

fasting period; all blood analyses were carried out in the central hospital laboratory. Free testosterone was calculated using the formula of Vermeulen et al.8 Data were also gathered on age, weight, height, and body mass index (kg/m2). Systolic and diastolic blood pressure (BP) was measured after a 5-minute rest and again 10 minutes later, recording the mean value. All participants underwent transrectal ultrasound examination at the urology department (single examiner who did not know the purpose of the study) to determine the prostate volume and were studied with urinary owmetry to determine the maximum ow rate, the urination time, and volume. Tests were performed after a minimum of 4 hours without urinating. Patients and control subjects completed the IPSS and IIEF questionnaires. The IPSS (for prostate symptoms) comprises 7 items scored from 0 to 5, giving a maximum global score of 35 points. The IIEF test comprises 30 items on the frequency of erection during sexual activity, number of sexual partners, and ejaculation and satisfaction in sexual relationships, yielding a maximum score of 30 points. BPH was dened by9: prostate volume greater than 30 mL (by transrectal ultrasound), peak urinary flow rate less than 15 mL/s, mean urinary flow rate less than 10 mL/s, void volume of 200 to 400 mL, and PSA less than 10 ng/mL. Statistical analyses Software (SPSS, Version 16.0 for Windows, SPSS Inc, Chicago, IL) was used for the univariate, bivariate, and stratied analyses of the data. Qualitative variables were analyzed by constructing contingency tables with Pearson x2 test or Fisher exact test, when conditions for the former were not met. The Student t test was applied for the comparison of quantitative variables after establishing their normal distribution by means of the Shapiro-Wilk test and Levene test for equality of variance. Analysis of variance was used for multiple comparisons of quantitative variables. Correlations among variables were studied by using

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Table I. Mean (SD) levels of various parameters in patients and control subjects
AGA group Control group P value*

Table II. Differences in prostate volume and maximum urinary flow (study end-point variables) as a function of Ebling type of androgenetic alopecia
Ebling type Prostate volume, mL P value* Maximum urinary flow, mL/s P value*

Testosterone Albumin SHBG PSA Prostate volume Maximum flow IPSS IIEF score

4.93 (1.26) ng/mL 4.19 (0.22) mg/dL 37.16 (12.22) nmol/L 1.53 (0.76) ng/mL 29.65 (12.03) mL 14.5 (5.42) mL/s 4.93 (4.70) points 29 (0.73) points

4.72 (1.31) ng/mL 4.16 (0.29) mg/dL 41.68 (12.96) nmol/L 0.94 (0.41) ng/mL 20.24 (7.51) mL 22.45 (4.68) mL/s 1.23 (1.74) points 29.24 (0.75) points

.44 .60 .157 \.001 \.001 \.001 \.001 .142

III IV V

27.9 28.0 32.7

.45

15.9 14.4 13.3

.42

*Analysis of variance test for multiple comparisons of quantitative variables.

Table III. Binary logistic regression analysis showing that androgenetic alopecia is an independent risk factor for prostate volume greater than 30 mL after adjusting for age, urination volume, urination time, and International Prostate Symptom Score
OR 95% CI P value

AGA, Androgenetic alopecia; IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; PSA, prostate-specific antigen; SHBG, sex hormoneebinding globulin. *Bilateral Student t test for comparison of quantitative variables after establishing their normal distribution by means of ShapiroWilk test and Levene test for equality of variance.

Presence of AGA Age (per year) Urination volume (per mL) Urination time (per second) IPSS (per point)

14.25 1.08 0.99 1.07 1.47

1.19-98.24 0.98-1.19 0.98-1.01 0.99-1.15 1.01-2.16

.036 .098 .534 .067 .05

AGA, Androgenetic alopecia; CI, confidence interval; IPSS, International Prostate Symptom Score; OR, odds ratio.

Fig 1. A, Normal urinary flowmetry in control subject. B, Obstructive urinary flowmetry in patient with androgenetic alopecia.

and SHBG values (r = e0.43, P = .04) and a positive significant correlation between total testosterone and IIEF score (r = 0.286, P = .007). The AGA group had a signicantly higher mean prostate volume, PSA value, and IPSS and a signicantly lower maximum urinary ow versus control group (Fig 1 and Table I). Prostate volume was negatively correlated with maximum urinary flow (r = e0.46, P \ .0001) and positively correlated with IPSS (r = 0.48, P = .0001). No significant differences in prostate volume or urinary flow were observed as a function of Ebling alopecia type, although there was

a tendency toward higher prostate volume and lower urinary flow in patients with type V (Table II). The AGA group had a signicantly lower urination volume (261.25 vs 329.69 mL, P = .012) but similar urination time (38.78 vs 35.76 seconds, P = .40) in comparison with control group, explaining the lower urinary flow. Mean prostate volume was greater than 30 mL in 48.9% of patients with AGA versus 4.8% of control subjects (P \ .0001, Fisher exact test; OR 19.1, 95% CI 4.11-88.85). Maximum urinary flow was greater than 15 mL/s in 95.2% of control subjects versus 28.9% of patients with AGA (P \ .0001, OR 49.23, 95% CI 10.34-234.18). BPH diagnostic criteria8 were met by 48.9% of patients with AGA versus 4.8% of control subjects (P \ .0001, Fisher exact test; OR 19.1, 95% CI 4.11-88.85). Positive signicant correlations between prostate volume and abdominal obesity (r = 0.35, P = .034), glucose levels (r = 0.27, P = .042), insulin levels (r = 0.39, P = .001), and CRP (r = 0.29, P = .025) were found in patients with AGA. Binary logistic regression analysis (Table III) showed a strong association between the presence of AGA and a prostate volume greater than 30 mL after adjusting for age, urination volume, urination time, and IPSS (OR 14.25, 95% CI 1.19-98.24). AGA was found to be an independent risk factor (Table IV)

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Table IV. Binary logistic regression analysis showing that androgenetic alopecia is an independent risk factor for maximum urinary flow less than 15 mL, adjusted for age, prostate volume, urination time and volume, and International Prostate Symptom Score
OR 95% CI P value

Presence of AGA Age (per year) Prostate volume (per mL) Urination time (per second) Urination volume (per mL) IPSS (per point)

8.24 0.981 1.123 1.088 0.975 1.649

1.094-62.172 0.90-1.07 0.991-1.273 1.005-1.178 0.958-0.992 1.085-2.506

.041 .663 .070 .037 .004 .019

AGA, Androgenetic alopecia; CI, confidence interval; IPSS, International Prostate Symptom Score; OR, odds ratio.

for a urinary flow less than 15 mL/s after adjusting for age, prostate volume, urination time, urinary volume, and IPSS (OR 8.24, 95% CI 1.09-62.17; P = .041). The presence of AGA was also an independent risk factor for the presence of BPH9 after adjusting for age, IPSS, urination time, urinary volume, abdominal obesity, glucose levels, systolic BP, insulin levels, fibrinogen, and CRP (OR 5.14, 95% CI 1.23-47.36, P = .041).

DISCUSSION
In this study, patients with early-onset AGA were found to have a larger prostate as measured by transrectal ultrasound, lower urinary ow value, and higher IPSS in comparison with individuals without AGA. AGA proved to be an independent risk factor for a prostate volume greater than 30 mL, urinary ow less than 15 mL/s, and BPH. None of the patients or control subjects reported a history of obstructive urinary symptoms or any consultations for this problem. No differences were detected between these groups in total testosterone, SHBG, albumin or IIEF score. These ndings suggest that in middle-aged patients with early-onset AGA the medical history should include questions to evaluate obstructive or irritative urinary symptoms, followed by appropriate physical examination and determination of PSA levels and IPSS score. Flowmetry and ultrasound studies should be performed in selected patients. Previous studies of the relationship between AGA and BPH were all in elderly patients and analyzed the prevalence of alopecia (53.8%-83.3%)9,10 in comparison with a control group; however, many of them did not use rectal ultrasound to reliably rule out the presence of BPH in the control subjects. In our study 51.1% of the patients with AGA do not meet the ultrasound 30-mL prostate volume criteria for benign prostate hypertrophy; this may be because patients

with AGA were younger than in other studies (median age was 52.7 years). Oh et al10 studied 225 patients with BPH and a mean age of around 70 years and found more severe alopecia on the Norwood scale and a greater frequency of family history of alopecia in comparison with control subjects, but no correlation was found between alopecia severity and IPSS results. All patients with BPH had undergone transurethral prostate resection. The presence of BPH could not be ruled out in the control subjects, because only digital rectal examination was used. Moreover, they used the IPSS as sole criterion for BPH diagnosis, and a correlation is not always found between obstructive/irritative symptoms and prostate size.11 In our study, family history of AGA, BPH, or both was more frequent in the patients with AGA, indicating a greater genetic propensity to both diseases. We also observed that a greater prostate volume in patients with AGA was associated with early urinary ow changes and a higher IPSS. In another similar study of elderly patients (mean age approximately 70 years), Chen et al9 observed a significantly higher prevalence of alopecia in those with prostate volume greater than 30 cm3 than in those with a smaller prostate (83.3% vs 61.3%, P \ .05); prostate size was slightly but nonsignificantly higher in the patients with AGA versus control subjects (42.7 vs 35.4 cm3) and did not vary as a function of alopecia type (Norwood-Hamilton scale). The presence of BPH in their control group cannot be ruled out because no transrectal ultrasound or urinary flowmetry studies were undertaken. Faydaci et al12 found no difference in the frequency of alopecia (Norwood scale) between 108 patients with BPH and 44 patients with prostate cancer; they observed no correlation between the presence of AGA and levels of free testosterone, total testosterone, SHBG, luteinizing hormone, or folliclestimulating hormone. In a later article on risk factors for AGA, they found no association between the presence of alopecia and urinary symptoms.13 No clinical or ultrasound ndings of prostate cancer were detected in any of our patients or control subjects, likely attributable to their young age and the sample size. The association between AGA and prostate cancer is controversial,14-18 with some authors reporting an adjusted OR of 1.5.16,18 Although there is a known relationship between testosterone levels and prostate cancer, advanced age and genetic factors appear to play a more important role.19 Finasteride (5 mg) and dutasteride have been reported to exert protective effects against prostate cancer.20,21 Finasteride, 5-alpha-reductase type 2

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inhibitor, does not reduce plasma testosterone and the dose of 1 mg/d is used in patients with AGA; higher doses (5 mg) are used to treat BPH.22 At the usual clinical dose (1 mg), finasteride reduces DHT concentrations by 70% in serum, by 64% to 69% in the scalp, and by 85% to 90% in the prostate. Use of 1 mg/d of finasteride for 48 weeks was reported to increase urinary flow and reduce prostate size.23 Dutasteride, a 5-alpha-reductase type 1 and 2 inhibitor that is also used to treat BPH, has recently been administered to patients with AGA with a good response.24 Our ndings may be explained by the common physiopathology of AGA and BPH, in which androgens play a pivotal role. The pathogenesis of AGA is characterized by an increase in peripheral sensitivity to the androgens responsible for follicular miniaturization, with no changes in serum levels of total testosterone, and this androgenic sensitivity may occur in the prostate, favoring its hyperplasia. The presence of higher free testosterone levels along with lower SHBG levels in patients with AGA favors a greater peripheral action of these androgens. 25 For this reason, AGA does not occur patients with hypogonadism, despite the fact that it can be induced by testosterone administration,26 and males with genetic 5-alpha-reductase defects do not develop AGA or clinically palpable prostate enlargement.27,28 The absence of hypogonadism among our study subjects explains why there were not any differences in the IIEF scale. Other pathogenic mechanisms that could explain the association between AGA and BPH are vitamin D levels and cardiovascular risk factors. Lower levels of vitamin D in subjects with BPH have recently been reported.29 In the development of BPH, 3 main components have been suggested, 30 a static component related to the overgrowth of prostate gland influenced by androgens (obstructive symptoms), a dynamic component associated with detrusor muscle hypercontractility31 (irritative symptoms), and a third component related to chronic inflammation leading to prostate overgrowth.32,33 Management of BPH with 1a,25-dihydroxyvitamin D3 and its analogues has recently been suggested, as these drugs might have a positively impact all 3 components of BPH pathogenesis. The role of vitamin D3 and the vitamin D receptor in the hair cycle is controversial. Defects in the vitamin D receptor are associated with alopecia34 and vitamin D3 and its analogues may play a protective role in radiation and chemotherapy-induced alopecia, possibly by upregulating the vitamin D receptor.35,36 Despite a cross-sectional study showing that the extent or severity of AGA does not appear to be related to

serum vitamin D levels,37 other authors suggest38 that additional studies to evaluate the role of vitamin D in AGA and the efficacy of vitamin D analogues in hair disorders and BPH should be done. Patients with AGA have a higher prevalence of cardiovascular risk factors. Several pathogenic mechanisms have been suggested to explain the increase in cardiovascular risk.39-42 Interestingly, some studies suggest that BPH is associated with abdominal obesity,43 insulin levels, diabetes, hypertension,44 and systemic inflammation.45 We have found a positive significant correlation between all of these parameters and prostate volume. The physiological mechanisms by which obesity promotes BPH remain to be described. A potential explanation is inflammation; obesity may influence prostate growth through mechanisms other than sex steroid growth pathways. Obesity is one of the main components of the metabolic syndrome and is associated with systemic inflammation and oxidative stress.46 There are multiple lines of evidence connecting BPH with inflammation: BPH in surgical specimens is associated with inflammation and the extent and severity of inflammation correspond to the degree of prostate enlargement45; in addition, the level of CRP is associated with higher risk of lower urinary track symptoms.47 Insulin secretion secondary to diabetes may induce an enlarged prostate because of its structural similarity with insulin-like growth factor48 and higher insulin is associated with lower SHBG, which may raise the androgen/estrogen ratio, increasing the risk of BPH.25 Despite cardiovascular risk factors being associated with prostate enlargement and AGA, we have shown that AGA is independently associated with BPH after controlling for all these parameters in a multivariate analysis. The study of larger sample sizes would facilitate stratied analyses according to the Ebling type and the exploration of possible associations with prostate cancer. Further research is also warranted into the long-term role of 5-alpha-reductase inhibitors. It would be of interest to determine whether the early application of nasteride treatment for AGA at 1 mg/d prevents the development of prostate symptoms or whether a higher dose is required. The precise role of dutasteride, widely used for BPH in patients with AGA, also deserves investigation. Some authors have suggested that the protective effects of nasteride and dutasteride against prostate cancer have yet to be conrmed. Early-onset AGA behaved as an early marker of urinary symptomatology, because these patients showed a larger prostate and incipient urinary ow changes but had not previously reported any urinary

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symptoms. The association is explained by their common physiopathology, in which androgens play a key role.49 Other suggested pathogenic mechanisms include cardiovascular risk factors and vitamin D levels. If this observation is extended and confirmed in additional studies, dermatologists and primary care physicians should monitor patients with early-onset AGA for the development of urinary symptoms to permit an earlier diagnosis. Future studies may clarify if treatment of patients with AGA may benefit the concomitant benign prostatic hypertrophy, which would be present at an earlier stage in its natural evolution.
REFERENCES  n MT, Buend a-Eisman A, 1. Arias-Santiago S, Guti errez-Salmero  n-Prieto MS, Naranjo-Sintes R. Hypertension and aldosterGiro one levels in women with early-onset androgenetic alopecia. Br J Dermatol 2010;162:786-9.  n MT, Castellote-Caballero 2. Arias-Santiago S, Guti errez-Salmero L, Naranjo-Sintes R. Elevated aldosterone levels in patients with androgenetic alopecia. Br J Dermatol 2009;161:1196-8.  n MT, Castellote-Caballero 3. Arias-Santiago S, Guti errez-Salmero a-Eisman A, Naranjo-Sintes R. Male androgenetic L, Buend alopecia and cardiovascular risk factors: a case-control study. Actas Dermosifiliogr 2010;101:248-56. 4. Siiteri PK, Wilson JD. Dihydrotestosterone metabolism in prostate hypertrophy: the formation of content of dihydrotestosterone in the hypertrophic prostate of man. J Clin Invest 1970;49:1735-45. 5. Walsh PC, Hutchins GM, Ewing LL. Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supranormal. J Clin Invest 1983;72:1772-7. 6. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, et al. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab 1994;79:703-6. 7. Bingham KD, Shaw DA. The metabolism of testosterone by human scalp skin. J Endocrinol 1973;87:111-21. 8. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666-72. 9. Chen W, Yang CC, Chen GY, Wu MC, Sheu HM, Tzai TS. Patients with a large prostate show a higher prevalence of androgenetic alopecia. Arch Dermatol Res 2004;296:245-9. 10. Oh BR, Kim SJ, Moon JD, Kim HN, Kwon DD, Won YH, et al. Association of benign prostatic hyperplasia with male pattern baldness. Urology 1998;51:744-8. 11. Agrawal CS, Chalise PR, Bhandari BB. Correlation of prostate volume with international prostate symptom score and quality of life in men with benign prostatic hyperplasia. Nepal Med Coll J 2008;10:104-7.  ur K. 12. Faydaci G, Bilal E, Necmettin P, Fatih T, Asuman O, Ug Baldness, benign prostate hyperplasia, prostate cancer and androgen levels. Aging Male 2008;11:189-92. 13. Severi G, Sinclair R, Hopper JL, English DR, McCredie MR, Boyle P, et al. Androgenetic alopecia in men aged 40-69 years: prevalence and risk factors. Br J Dermatol 2003;149:1207-13. 14. Greenwald P, Damon A, Kirmss V, Polan AK. Physical and demographic features of men before developing cancer of the prostate. J Natl Cancer Inst 1974;53:341-6.

15. Demark-Wahnefried W, Schildkraut JM, Thompson D, Lesko SM, McIntyre L, Schwingl P, et al. Early onset baldness and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9: 325-8. 16. Hawk E, Breslow RA, Graubard BI. Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 2000;9:523-7. 17. Hsieh CC, Thanos A, Mitropoulos D, Deliveliotis C, Mantzoros CS, Trichopoulos D. Risk factors for prostate cancer: a casecontrol study in Greece. Int J Cancer 1999;80:699-703. 18. Giles GG, Severi G, Sinclair R, English DR, McCredie MR, Johnson W, et al. Androgenetic alopecia and prostate cancer: findings from an Australian case-control study. Cancer Epidemiol Biomarkers Prev 2002;11:549-53.  A, Vilella R, Ortiz AR, et al. 19. Bermudo R, Abia D, Benitez D, Carrio Discovery of genomic alterations through coregulation analysis of closely linked genes: a frequent gain in 17q25.3 in prostate cancer. Ann N Y Acad Sci 2010;1210:17-24. 20. Anderson WR, Harris NM, Holmes SA. Hormonal treatment for male-pattern hair loss: implications for cancer of the prostate? BJU Int 2002;90:682-5. 21. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al, REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362:1192-202. 22. Gormeley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnel JD, et al. The effect of finasteride in me with prostatic benign prostatic hyperplasia. N Engl J Med 1992;327:1185-91. 23. Yoshida O, Oishi K, Okada Y, Mizutani Y, Itokawa Y, Tomoyoshi T. Effect of long-term administration of finasteride (MK-906), an inhibitor of 5 alpha-reductase, in patients with benign prostatic hyperplasia. Hinyokika Kiyo 1996;42:323-31. 24. Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, et al, Dutasteride Alopecia Research Team. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006;55:1014-23.  n MT, Buend a-Eisman A, 25. Arias-Santiago S, Guti errez-Salmero n-Prieto MS, Naranjo-Sintes R. Sex hormone-binding globGiro ulin and risk of hyperglycemia in patients with androgenetic alopecia. J Am Acad Dermatol 2011;65:48-53. 26. Hamilton JB. Male hormone stimulation is a prerequisite and an incitant common baldness. Am J Anat 1942;71:451-80. 27. Anderson S, Berman DM, Jenkins EP, Ruxxel DW. Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature 1991;354:159-61. 28. Walsh PC, Madden JD, Harrod MJ, Godstein JL, MacDonald PC, Wilson JD. Familial incomplete male pseudohermaphroditism type II: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291:944-9. 29. Gali c J, Simunovi c D. Prostate disease prevalence with epidemiological and hormonal analysis in randomly selected male population in Croatia. Coll Antropol 2008;32:1195-202. 30. Adorini L, Penna G, Fibbi B, Maggi M. Vitamin D receptor agonists target static, dynamic, and inflammatory components of benign prostatic hyperplasia. Ann N Y Acad Sci 2010; 1193:146-52. 31. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 2004;84:935-86. 32. Nickel JC. Inflammation and benign prostatic hyperplasia. Urol Clin North Am 2008;35:109-15.

408 Arias-Santiago et al

J AM ACAD DERMATOL

MARCH 2012

33. Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 2004;172:1784-91. 34. Bergman R, Schein-Goldshmid R, Hochberg Z, Ben-Izhak O, Sprecher E. The alopecias associated with vitamin D-dependent rickets type IIA and with hairless gene mutations: a comparative clinical, histologic, and immunohistochemical study. Arch Dermatol 2005;141:343-51. 35. Baltalarli B, Bir F, Demirkan N, Abban G. The preventive effect of vitamin D3 on radiation-induced hair toxicity in a rat model. Life Sci 2006;78:1646-51. 36. Wang J, Lu Z, Au JL. Protection against chemotherapy-induced alopecia. Pharm Res 2006;23:2505-14. 37. Bolland MJ, Ames RW, Grey AB, Horne AM, Mason BH, Gamble GD, et al. Does degree of baldness influence vitamin D status? Med J Aust 2008;189:674-5. 38. Amor KT, Rashid RM, Mirmirani P. Does D matter? The role of vitamin D in hair disorders and hair follicle cycling. Dermatol Online J 2010;16:3.  n MT, Castellote-Caballero 39. Arias-Santiago S, Guti errez-Salmero a-Eisman A, Naranjo-Sintes R. Androgenetic alopecia L, Buend and cardiovascular risk factors in men and women: a comparative study. J Am Acad Dermatol 2010;63:420-9.  n MT, Buend a-Eisman A, 40. Arias-Santiago S, Guti errez-Salmero n-Prieto MS, Naranjo-Sintes R. A comparative study of Giro dyslipidemia in men and woman with androgenic alopecia. Acta Derm Venereol 2010;90:485-7.  n MT, Buend a-Eisman 41. Arias-Santiago S, Guti errez-Salmero  n-Prieto MS, Naranjo-Sintes R. Lipid levels in A, Giro women with androgenetic alopecia. Int J Dermatol 2010; 49:1340-2.

 n MT, Castellote-Caballero 42. Arias-Santiago S, Guti errez-Salmero L, Naranjo-Sintes R. Factores de riesgo cardiovascular en lico ndrome metabo pacientes con alopecia androgen etica: s y ateromatosis carotidea. Actual Med 2009;94:14-23. 43. Lee SH, Kim JC, Lee JY, Kim JH, Oh CY, Lee SW, et al. Effects of obesity on lower urinary tract symptoms in Korean BPH patients. Asian J Androl 2009;11:663-8. 44. Parsons JK, Carter HB, Partin AW, Windham BG, Metter EJ, Ferrucci L, et al. Metabolic factors associated with benign prostatic hyperplasia. J Clin Endocrinol Metab 2006;91:2562. 45. Di Silverio F, Gentile V, De Matteis A, Mariotti G, Guiseppe V, Luigi PA, et al. Distribution of inflammation, pre-malignant lesions, incidental carcinoma in histologically confirmed benign prostatic hyperplasia: a retrospective analysis. Eur Urol 2003;43:164-75. 46. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakijima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004;114:1752-61. 47. Rohrmann S, De Marzo AM, Smit E, Giovannucci E, Platz EA. Serum C-reactive protein concentration and lower urinary tract symptoms in older men in the Third National Health and Nutrition Examination Survey (NHANES III). Prostate 2005;62: 27-33. 48. Sarma AV, Jaffe CA, Schottenfeld D, Dunn R, Montie JE, Cooney KA, et al. Insulin-like growth factor-1, insulin-like growth factor binding protein-3, and body mass index: clinical correlates of prostate volume among black men. Urology 2002;59:362-7. 49. Kaplan SA. Patients with a large prostate show a higher prevalence of androgenetic alopecia. J Urol 2005;174:1905.