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Australasian Journal of Dermatology (2015) ••, ••–••
doi: 10.1111/ajd.12285
ORIGINAL RESEARCH
The association of androgenetic alopecia and insulin resistance is independent of hyperandrogenemia: A case-control study Demet Kartal,1 Murat Borlu,1 Salih L Çınar,1 Ayten Ferahbas¸,1 Yılmaz Ulas¸,2 Kürs¸ad Ünlühızarcı,3 Ümit Uks¸al4 and Fahrettin Keles¸timur3 1
Department of Dermatology and Venereology, 3Department of Endocrinology, Faculty of Medicine, Erciyes University, 2Department of Dermatology and Venereology, Kayseri Education and Research Hospital, Kayseri, and 4Department of Dermatology and Venereology, Taksim Alman Hospital, I˙stanbul, Turkey
ABSTRACT Background/Objectives: Androgenetic alopecia (AGA) occurs due to the effect of androgens and genetic predisposition. The association between hyperandrogenism and insulin resistance (IR) has been clearly documented. In recent years there have been reports supporting the presence of IR in AGA. The study aimed to investigate the presence of IR in women with AGA and discern whether or not it is associated with hyperandrogenism. Methods: Overall, 77 women with AGA were included in the study. Patients with Ludwig grades I–III AGA were enrolled in the study. Blood samples were drawn for measurements of hormone profile, basal insulin and fasting blood glucose (FBG). An oral glucose tolerance test was performed on another day. IR was assessed by the homeostasis model assessment score. Results: All IR parameters were significantly higher in the 75 study subjects without DM than in the control group (P < 0.05). After excluding five patients with IGT, the level of all IR parameters were still higher than in the control group (P < 0.05). Hyperandrogenemia was found in 30 (40%) patients. When this second group (n = 45) (excluding patients with hyperandrogenemia) was compared with the control group on IR, all parameters except for basal
Correspondence: Dr Demet Kartal, Dermatology and Venereology Department, School of Medicine, Erciyes University, 38039-Kayseri, Turkey. Email: [email protected] Demet Kartal, MD. Murat Borlu, MD. Salih L Çınar, MD. Ayten Ferahbas, MD. Yılmaz Ulas, MD. Kürsad Ünlühızarcı, MD. Ümit Uksal, MD. Fahrettin Kelestimur, MD. Conflict of interest: none Submitted 1 July 2014; accepted 27 October 2014. © 2015 The Australasian College of Dermatologists
insulin were significantly higher in the second group than in the controls (P < 0.05). Conclusion: Our results suggest a relation between IR and AGA in female patients. We showed for the first time that the association of AGA and IR is independent of hyperandrogenemia. Key words: androgenetic alopecia, drogenemia, insulin resistance.
hyperan-
Androgenetic alopecia (AGA) is a kind of hair loss that occurs from the effect of androgens in both sexes with a genetic predisposition. Androgens lead to hair loss by follicular miniaturisation and by causing a transition from the anagen to the telogen phase.1 Insulin resistance (IR) is a subnormal biological response despite sufficient concentrations of circulatory insulin. In practice, fasting insulin level, fasting glucose: insulin ratio, oral glucose tolerance test and homeostasis model assessment (HOMA) are the most commonly used tests to demonstrate IR.2,3 The association between hyperandrogenism and IR has been shown in previously published studies.4–6 Several studies have demonstrated that hyperandrogenism is
Abbreviations: AGA BMI DM FBG FSH fT HOMA IGT IR OGTT PCOS
androgenetic alopecia body mass index diabetes mellitus fasting blood glucose follicular stimulating hormone free testosterone homeostasis model assessment impaired glucose tolerance insulin resistance oral glucose tolerance test polycystic ovary syndrome
2
D Kartal et al.
involved in AGA pathogenesis. In recent years, studies on AGA have been focused on IR. In the light of these findings, we aimed to investigate the presence of IR in women with AGA and whether or not it is associated with hyperandrogenism.
PATIENTS AND METHODS This is a case-control study, which was approved by the Institutional Ethics Committee of Erciyes University. All patients and controls gave their written, informed consent before enrolment into the study. The patients were recruited from those admitted to the Dermatology and Venereology Outpatient Clinic of Erciyes University Medical School Hospital, and the controls were recruited from patients who were admitted to the Family Health Care Outpatient Clinic of Erciyes University Medical School Hospital for a check-up (the recruitment of the control group is summarised in the flow chart) (Fig. 1). Overall, 77 women aged 18–40 years with Ludwig7 grades I–III AGA were included in the study. Patients were questioned for their age at reaching puberty, any history of acne, hirsutism, diabetes mellitus, whether they were pregnant or lactating and
n= 77
2 paents with DM were excluded
30 paents with hyperandrogenemia were excluded
n= 75
whether they were taking medications. A modified Ferriman–Gallwey scoring system was used to evaluate hirsutism. Individuals with a score ≥ 8 were defined as hirsute. All participants were assessed by the same clinician using the Ludwig scale to grade AGA. Their body-mass index (BMI) was calculated according to the following equation: bodyweight/height2 (kg/m2). The waist circumference was measured at the midpoint between the lower rim of the twelfth rib and iliac crest in all participants. All tests were performed after an overnight fast during the follicular phase of the menstrual cycle in both the study and control groups. Blood samples were drawn for measurements of follicular stimulating hormone, luteinising hormone, oestradiol, dehydroepiandrostenedione sulphate (DHEAS), sex hormone binding globulin, total testosterone, free testosterone (fT), prolactin, 17 hydroxyprogesterone (17-OHP), androstenedione, serum fasting insulin and serum fasting glucose (FBG) in both the study and control groups. On another day, all patients underwent an oral glucose tolerance test at 08:00 am after an overnight fast with 75 g glucose. Glucose tolerance was evaluated using the American Diabetes Association criteria, and impaired glucose tolerance (IGT) was defined as a glucose level between 140 mg/dL and 200 mg/dL 2 h after glucose ingestion.8 The glucose and insulin responses to the oral glucose tolerance test (OGTT) were also expressed as area under the curve (AUC), according to the trapezoidal rule.9 The estimate of IR by the homeostasis model assessment (HOMA) score was calculated according to following formula:
HOMA score = fasting serum insulin (μU mL ) × fasting plasma glucose ( mmol L ) 22.5 .10
BMI:22.3 HOMA-IR=(median)2.63
5 paents with IGT were excluded
n= 45 BMI=22.2 HOMA-IR= (median) 2.9
n= 70 BMI:22.8 HOMA-IR= (median) 2.5
Figure 1 Study sample. BMI, body-mass index; DM, diabetes mellitus; HOMA-IR, homeostasis model assessment insulin resistance; IGT, impaired glucose tolerance.
Table 1
All patients and controls underwent abdominopelvic sonography to evaluate the morphology of their ovaries and adrenal glands. In the present study, glucose measurements were performed by the glucose oxidase method using a Konelab 60 (Kusti, ThermoClinical Labsystems; Vantaa, Finland) automated analyzer at the Central Laboratory of Erciyes University Medical School. The inter and intra variations of the hormone assay and names of manufacturers are given in Table 1.
Hormone assay intra variations and inter variations and manufacturers
Method DHEAS Androstenedione SHBG Insulin LH FSH Oestradiol Testosterone
RIA RIA IRMA IRMA Chemiluminescence Chemiluminescence Chemiluminescence RIA
Intra variation (%) 6 3 5 5 3 10 4
Inter variation (%)
Manufacturers
10 7 6 6 6 5 12 5
Immunotech, Marseilles, France Immunotech, Marseilles, France Orion Diagnostica, Espoo, Finland Biosource, Nivelles, Belgium ACS:180, Bayer, Leverkusen, Germany ACS:180, Bayer, Leverkusen, Germany ACS:180, Bayer, Leverkusen, Germany Biosource, Nivelles, Belgium
17-OHP, 17 hydroxyprogesterone; DHEAS, dehydroepiandrosterone; Lh, lutenising hormone; FSH, follicular stimulating hormone, IRMA, immunoradiometric assay: RIA, radioimmunoassay; SHBG, sex hormone binding globulin. © 2015 The Australasian College of Dermatologists
Androgenetic alopecia, insulin resistance Hyperandrogaenemia was defined as higher serum androgen levels than the reference values of the assays (DHEAS > 5070 ng/mL, androstenedione > 2.99 ng/mL and ft > 3.99 pg/mL). Patients with normal glucose tolerance were separately assessed by excluding patients with IGT (n = 70 patients). A total of 30 patients with increased levels of either DHEAS, androstenedione or fT levels were found to have hyperandrogenemia. In order to exclude the effect of hyperandrogenemia on IR, we intended to analyse patients with AGA but without hyperandrogenemia. A new group (n = 45 patients) was formed by excluding the patients with hyperandrogenemia. The study sample is shown in Fig. 2).
3
Systemic illness were excluded by Family Health Care laborotory tests results (n = 65)
Having a systemic disease is a criterion for exclusion (n = 22)
Controls matching our paents with respect to sex, age and BMI were directed to Dermatology Outpaent Clinic (n = 43)
Statistical analysis Data analysis was performed using the IBM SPSS Statistics 20.0 (Armonk, NY, USA) and SigmaStat 3.5 (Witzenhausen, Germany). The Shapiro–Wilk test was used to examine the normality of their distribution. Qualitative variables were analysed with the Mann–Whitney U test. Values were reported as medians with 25–75% or min–max; statistical significance was attributed to a two-tailed P < 0.05.
RESULTS Overall, 77 women with AGA and 20 healthy women were included in the study. The mean age was 28.0 ± 7.2 years in the patient group and 26.4 ± 4.8 years in the control group. The BMI was 23.2 ± 3.6 kg/m2 in the patient group and 22.7 ± 3.0 kg/m2 in the control group. No significant difference was found between the patient and control groups regarding their age and BMI values. There were seven patients (9%) with grade I AGA, 46 patients (60%) with grade II AGA and 24 patients (31%) with grade III AGA. In two patients the Ferriman–Galwey score was 10 and 9, the others were not hirsute. There was no significant difference in the waist: hip ratio between patient and control groups. According to the OGTT results, IGT was found in five (6%) and DM was found in two (3%) of the 77 patients. The patients with DM were excluded from the analysis. In the remaining 75 patients, serum basal insulin level, FBG, AUC glucose and AUC insulin levels as well as their HOMA score were significantly higher than in the control group (Table 2). The patients with normal glucose tolerance were separately assessed by excluding those with IGT. When compared to the control group on parameters of IR, FBG, basal insulin, AUC glucose and AUC insulin as well as HOMA score, the scores in this group were still significantly higher than in the control group (Table 3). This group was then compared to the control group on their hormone profile: their oestradiol, sex hormone binding globulin and androstenedione levels were significantly higher in the study group (Table 3). On the abdominopelvic sonography, no polycystic ovaries were detected. In all, 30 patients were hyperandrogenic. The patients without hyperandrogenemia (n = 45) and the control group were re-assessed on parameters of IR and
Controls were quesoned for age at puberty, history of acne, hirsusm, diabetes mellitus, pregnancy, lactaon and for taking medicaons (n = 43)
Posive answer is a criterion for exclusion (n = 15)
Controls were examined for dermatological diseases (n = 28)
Having any dermatological disease is a criterion for exclusion (n = 8)
Accepng to control group (n = 20) Figure 2
Flow chart showing the recruitment of the control group.
no significant difference was found in terms of their waist: hip ratio and BMI value. Serum fasting glucose, AUC insulin and AUC glucose as well as the HOMA score were significantly higher in the AGA patients without hyperandrogenemia (Table 4).
DISCUSSION In addition to hirsutism and acne, AGA is one of the symptoms of hyperandrogenism.11–13 The relationship between glucose intolerance and hyperandrogenism was first © 2015 The Australasian College of Dermatologists
4
D Kartal et al.
Table 2 Hormonal and insulin resistance parameters in women with androgenetic alopecia (AGA) (excluding diabetic patients) and controls. Values were reported as median (min–max)
BMI Waist/hip FSH (mIU/mL) LH (mIU/mL) Oestradiol (pg/mL) Free testosterone (pg/mL) Total testosterone(pg/mL) DHEAS (ng/mL) Androstenedione (ng/mL) SHBG (nmol/L) FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR
Patients with AGA (n = 75)
Controls (n = 20)
P
22.37 (17.48–37.50) 0.72 (0.68–0.79) 6.17 (1.75–72.97) 4.44 (12.26–150.1) 63.1 (12.26–150.1) 1.68 (073–4.2) 29 (1.93–416) 1608 (1.74–8616) 2.66 (0.31–71) 47 (2–416) 92 (16–111) 11 (1–69) 13920 (8805–25305) 6975 (1299–91575) 2.63 (1.2–18.1)
22.72 (19.56–30.46) 0.74 (0.69–0.76) 5.15 (2.52–11.3) 4.13 (2.07–10.41) 82.5 (31–198) 1.5 (1.05–2.11) 24.5 (6–74) 1325 (254–4400) 1.91 (0.85–3.45) 61 (23–105) 75 (62–111) 9.5 (4.37–14) 10252.5 (72–13950) 3349 (1470–6570) 1.7 (0.9–8.3)
NS NS NS NS < 0.05 NS NS NS < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
AUC, area under the curve; BMI, body mass index; DHEAS, dehydroepiandrosterone; FPG, fasting plasma glucose; FSH, follicular stimulating hormone; HOMA-IR, homeostasis model assessment-insulin resistance; LH, lutenising hormone; NS, not significant; SHBG, sex hormone binding globulin. Table 3 Hormonal and insulin resistance parameters in women with androgenetic alopecia (AGA) (excluding impaired glucose tolerance and diabetes mellitus patients) and control subjects. Values were reported as median (min–-max))
FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR FSH (mIU/mL) LH (mIU/mL) Oestradiol (pg/mL) Free testosterone (pg/mL) DHEAS (ng/mL) Androstenedione (ng/mL) SHBG (nmol/L)
Patients with AGA (n = 70)
Controls (n = 20)
P
92 (16–111) 11 (1–69) 13500 (8805–22215) 6868 (1299–91575) 2.5 (0.1–18.1) 6.65 ± 2.32 4.4 (1.49-20.9) 63.3 (12.2–150) 1.69 (0.73–4.2) 1611 (1.74–8616) 2.71 (0.31–71) 47.5 (2–416)
75 (62–111) 9.5 (4.37-14) 10252.5 (72–13950) 3349 (1470–6570) 1.7 (0.9-8.3) 5.69 ± 2.02 4.13 (2.07–10.41) 82.5 (31–198) 1.5 (1.05–2.11) 1325 (254–4400) 1.91 (0.85–3.45) 61 (23–105)
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NS NS < 0.05 NS NS < 0.05 < 0.05
AUC, area under the curve; FPG, fasting plasma glucose; FSH, follicular stimulating hormone; HOMA-IR, homeostasis model assessmentinsulin resistance; LH, lutenising hormone; NS, not significant. Table 4 Insulin resistance parameters in women with androgenetic alopecia (excluding patients with hyperandrogenemia) and controls. Values were reported as median (25–75%)
FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR
Patients with androgenetic alopecia (n = 45)
Controls (n = 20)
P
92 (87.5–100) 10.75 (8.5–15.8) 14175 (12637.5–15900) 6941.2 (3295–9504.6) 2.9 (1.9–4)
75 (62–111) 9.5 (4.37–14) 10252.5 (72–13950) 3340 (1470–6570) 1.7 (0.9–8.3)
< 0.05 NS < 0.05 < 0.05 < 0.05
AUC, area under the curve; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment-insulin resistance; NS, not significant.
described by Achard and Thiers in 1921 when it was called diabetic-bearded women.14 The relationship between polycystic ovary syndrome (PCOS) and IR has previously been shown and PCOS and AGA involve the same alleles on the gene that regulates androgen secretion and activation.15–20 Matilainen and colleagues evaluated women aged 63 years with AGA.21 The authors used a basal insulin meas© 2015 The Australasian College of Dermatologists
urement and OGTT to detect IR. In our study, FBG, basal insulin, AUC glucose, AUC insulin and HOMA scores were used to detect IR. Our findings suggest that IR is present in AGA. We recruited young patients since use of prescription drugs at advanced age and comorbid systemic diseases might affect IR. In a study by Hirsso and colleagues 105 women aged 63 with Ludwig grades II–III AGA were
Androgenetic alopecia, insulin resistance compared with 225 patients with Ludwig grades 0–I AGA. The authors used The quantitative insulin-sensitivity check index (QUICKI), glucose level at 2 h after glucose load and basal insulin level to detect IR and found that their QUICKI index was significantly higher.22 Although our study and that of Hirsso used different tests for the evaluation of IR, both studies support the presence of IR in patients with AGA. In another study, Ekmekçi and colleagues evaluated IR in 41 non-obese women aged 22–44 years, with Ludwig grades I–II AGA and 25 healthy women.23 The authors investigated IR by assessing OGTT, basal insulin, HOMA score and the QUICKI index. They concluded that AGA is associated with IR. The larger sample size in our study makes our results more meaningful when compared to the other studies. The main limitations of studies in the literature were the absence of hormonal levels due to advanced age or the failure to detect hyperandrogenism by laboratory findings in younger age groups. In the present study, the patients were assessed by both hormone profile and abdominopelvic sonography. We found hyperandrogenemia in 30 patients with AGA, but without any other clinical findings of hyperandrogenism. This result suggests that AGA may be the sole manifestation of hyperandrogenemia and it might be due to the polymorphism of the androgen receptor. In the study by Ekmekçi and colleagues hyperandrogenism was excluded using only clinical findings. However, our results show that hyperandrogenism may not be completely reflected in a clinical presentation; thus, patients should be evaluated by their hormone profile. There are several studies confirming that hyperandrogenism causes IR. In our study, when we repeated our analyses by excluding patients with hyperandrogenemia in the patient group, it was found that IR still persisted. Thus, IR was notable in female patients with AGA regardless of hyperandrogenemia. The association of AGA and IR is independent of hyperandrogenemia. Further studies are needed to clarify the association between AGA and IR.
5. 6.
7. 8. 9.
10.
11. 12. 13. 14.
15.
16.
17. 18.
19.
20.
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Trüeb RM. Molecular mechanism of androgetic alopecia. Exp. Gerontol. 2002; 37: 981–90. Altuntas Y, Bilir M, Öztürk B et al. Comparison of various simple insulin sensitivity and cell function indices in lean hyperadrogenemic and normoandrogenemic young hirsute women. Fertil. Steril. 2003; 80: 133–42. Legro RS, Castracone VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet. Gynecol. Surv. 2004; 59: 141–54. Ünlühizarcı K, Keles¸timur F, Bayram F et al. The effects of metformin on insulin resistance and ovarian steroidogenesis
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in women with polycystic ovary syndrome. Clin Endocrinol 1999; 51: 231–6. Sheehan MT. Polycystic ovarian syndrome: diagnosis and management. Clin. Med. Res. 2004; 2: 13–27. Apridonidze T, Essah A, Iuorno MJ. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2005; 90: 1929–35. Olsen EA. Female pattern hair loss. J. Am. Acad. Dermatol. 2001; 45: 70–80. American Diabetes Association: clinical practice recommendations 1997. Diabetes Care 1997; 20 (Suppl. 1): S1–70. Bonora E, Moghetti P, Zancarano C et al. Estimates of in vivo insulin action in man: comparison of insulin tolerance test with euglycemic and hyperglycemic glucose clamp studies. J. Clin. Endocrinol. Metab. 1989; 68: 374–78. Bonora E, Targher G, Alberiche M et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care 2000; 23: 57–63. Davis S. Syndromes of hyperandrogenism in women. Aust. Fam. Physician 1999; 28: 447–51. Redmond GP. Androgens and women’s health. Int. J. Fertil. Womens Med. 1998; 43: 91–7. Derman RJ. Androgen excess in women. Int. J. Fertil. Menopausal Stud. 1996; 41: 172–76. Piatti PM, Monti LD, Caumo A et al. The continuous low dose insulin and glucose infusion test: a simplifıed and accurate method for the evaluation of insulin sensitivity and insulin secretion in population studies. J. Clin. Endocrinol. Metab. 1995; 80: 34–40. Ünlühızarcı K, Çolak R, S¸ahin Y et al. Prevalence of glucose intolerance in women with polycystic ovary syndrome. Turk. J. Endocrinol. Metab. 2000; 4: 135–37. Teede HJ, Hutchison S, Zoungas S et al. Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS. Endocrine 2006; 30: 45–53. Diamanti-Kandarakis E. Insulin resistance in PCOS. Endocrine 2006; 30: 13–7. Otto-Buczkowska E, Jarosz-Chobot P, Deja G. Early metabolic abnormalities – insulin resistance, hyperinsulinemia, impaired glucose tolerance and diabetes, in adolescent girls with polycystic ovarian syndrome. Przegl. Lek. 2006; 63: 234–38. Carey AH, Chan KL, Short F et al. Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin. Endocrinol. 1993; 38: 653–58. Carey AH, Waterworth D, Patel K et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum. Mol. Genet. 1994; 3: 1873–76. Matilainen V, Laakso M, Hirsso P et al. Hair loss, insulin resistance, and heredity in middle-aged women. A population-based study. J. Cardiovasc. Risk 2003; 10: 227–31. Hirsso P, Rajala U, Laakso M et al. Health-related quality of life and physical well-being among a 63-year-old cohort of women with androgenetic alopecia; a Finnish population-based study. Health Qual. Life Outcomes 2005; 24: 49. Ekmekçi TR, Ucak S, Basat O et al. The presence of insulin resistance and comparison of various insulin sensivity indices in women with androgenetic alopecia. Eur. J. Dermatol. 2007; 17: 21–5.
© 2015 The Australasian College of Dermatologists
Australasian Journal of Dermatology (2015) ••, ••–••
doi: 10.1111/ajd.12285
ORIGINAL RESEARCH
The association of androgenetic alopecia and insulin resistance is independent of hyperandrogenemia: A case-control study Demet Kartal,1 Murat Borlu,1 Salih L Çınar,1 Ayten Ferahbas¸,1 Yılmaz Ulas¸,2 Kürs¸ad Ünlühızarcı,3 Ümit Uks¸al4 and Fahrettin Keles¸timur3 1
Department of Dermatology and Venereology, 3Department of Endocrinology, Faculty of Medicine, Erciyes University, 2Department of Dermatology and Venereology, Kayseri Education and Research Hospital, Kayseri, and 4Department of Dermatology and Venereology, Taksim Alman Hospital, I˙stanbul, Turkey
ABSTRACT Background/Objectives: Androgenetic alopecia (AGA) occurs due to the effect of androgens and genetic predisposition. The association between hyperandrogenism and insulin resistance (IR) has been clearly documented. In recent years there have been reports supporting the presence of IR in AGA. The study aimed to investigate the presence of IR in women with AGA and discern whether or not it is associated with hyperandrogenism. Methods: Overall, 77 women with AGA were included in the study. Patients with Ludwig grades I–III AGA were enrolled in the study. Blood samples were drawn for measurements of hormone profile, basal insulin and fasting blood glucose (FBG). An oral glucose tolerance test was performed on another day. IR was assessed by the homeostasis model assessment score. Results: All IR parameters were significantly higher in the 75 study subjects without DM than in the control group (P < 0.05). After excluding five patients with IGT, the level of all IR parameters were still higher than in the control group (P < 0.05). Hyperandrogenemia was found in 30 (40%) patients. When this second group (n = 45) (excluding patients with hyperandrogenemia) was compared with the control group on IR, all parameters except for basal
Correspondence: Dr Demet Kartal, Dermatology and Venereology Department, School of Medicine, Erciyes University, 38039-Kayseri, Turkey. Email: [email protected] Demet Kartal, MD. Murat Borlu, MD. Salih L Çınar, MD. Ayten Ferahbas, MD. Yılmaz Ulas, MD. Kürsad Ünlühızarcı, MD. Ümit Uksal, MD. Fahrettin Kelestimur, MD. Conflict of interest: none Submitted 1 July 2014; accepted 27 October 2014. © 2015 The Australasian College of Dermatologists
insulin were significantly higher in the second group than in the controls (P < 0.05). Conclusion: Our results suggest a relation between IR and AGA in female patients. We showed for the first time that the association of AGA and IR is independent of hyperandrogenemia. Key words: androgenetic alopecia, drogenemia, insulin resistance.
hyperan-
Androgenetic alopecia (AGA) is a kind of hair loss that occurs from the effect of androgens in both sexes with a genetic predisposition. Androgens lead to hair loss by follicular miniaturisation and by causing a transition from the anagen to the telogen phase.1 Insulin resistance (IR) is a subnormal biological response despite sufficient concentrations of circulatory insulin. In practice, fasting insulin level, fasting glucose: insulin ratio, oral glucose tolerance test and homeostasis model assessment (HOMA) are the most commonly used tests to demonstrate IR.2,3 The association between hyperandrogenism and IR has been shown in previously published studies.4–6 Several studies have demonstrated that hyperandrogenism is
Abbreviations: AGA BMI DM FBG FSH fT HOMA IGT IR OGTT PCOS
androgenetic alopecia body mass index diabetes mellitus fasting blood glucose follicular stimulating hormone free testosterone homeostasis model assessment impaired glucose tolerance insulin resistance oral glucose tolerance test polycystic ovary syndrome
2
D Kartal et al.
involved in AGA pathogenesis. In recent years, studies on AGA have been focused on IR. In the light of these findings, we aimed to investigate the presence of IR in women with AGA and whether or not it is associated with hyperandrogenism.
PATIENTS AND METHODS This is a case-control study, which was approved by the Institutional Ethics Committee of Erciyes University. All patients and controls gave their written, informed consent before enrolment into the study. The patients were recruited from those admitted to the Dermatology and Venereology Outpatient Clinic of Erciyes University Medical School Hospital, and the controls were recruited from patients who were admitted to the Family Health Care Outpatient Clinic of Erciyes University Medical School Hospital for a check-up (the recruitment of the control group is summarised in the flow chart) (Fig. 1). Overall, 77 women aged 18–40 years with Ludwig7 grades I–III AGA were included in the study. Patients were questioned for their age at reaching puberty, any history of acne, hirsutism, diabetes mellitus, whether they were pregnant or lactating and
n= 77
2 paents with DM were excluded
30 paents with hyperandrogenemia were excluded
n= 75
whether they were taking medications. A modified Ferriman–Gallwey scoring system was used to evaluate hirsutism. Individuals with a score ≥ 8 were defined as hirsute. All participants were assessed by the same clinician using the Ludwig scale to grade AGA. Their body-mass index (BMI) was calculated according to the following equation: bodyweight/height2 (kg/m2). The waist circumference was measured at the midpoint between the lower rim of the twelfth rib and iliac crest in all participants. All tests were performed after an overnight fast during the follicular phase of the menstrual cycle in both the study and control groups. Blood samples were drawn for measurements of follicular stimulating hormone, luteinising hormone, oestradiol, dehydroepiandrostenedione sulphate (DHEAS), sex hormone binding globulin, total testosterone, free testosterone (fT), prolactin, 17 hydroxyprogesterone (17-OHP), androstenedione, serum fasting insulin and serum fasting glucose (FBG) in both the study and control groups. On another day, all patients underwent an oral glucose tolerance test at 08:00 am after an overnight fast with 75 g glucose. Glucose tolerance was evaluated using the American Diabetes Association criteria, and impaired glucose tolerance (IGT) was defined as a glucose level between 140 mg/dL and 200 mg/dL 2 h after glucose ingestion.8 The glucose and insulin responses to the oral glucose tolerance test (OGTT) were also expressed as area under the curve (AUC), according to the trapezoidal rule.9 The estimate of IR by the homeostasis model assessment (HOMA) score was calculated according to following formula:
HOMA score = fasting serum insulin (μU mL ) × fasting plasma glucose ( mmol L ) 22.5 .10
BMI:22.3 HOMA-IR=(median)2.63
5 paents with IGT were excluded
n= 45 BMI=22.2 HOMA-IR= (median) 2.9
n= 70 BMI:22.8 HOMA-IR= (median) 2.5
Figure 1 Study sample. BMI, body-mass index; DM, diabetes mellitus; HOMA-IR, homeostasis model assessment insulin resistance; IGT, impaired glucose tolerance.
Table 1
All patients and controls underwent abdominopelvic sonography to evaluate the morphology of their ovaries and adrenal glands. In the present study, glucose measurements were performed by the glucose oxidase method using a Konelab 60 (Kusti, ThermoClinical Labsystems; Vantaa, Finland) automated analyzer at the Central Laboratory of Erciyes University Medical School. The inter and intra variations of the hormone assay and names of manufacturers are given in Table 1.
Hormone assay intra variations and inter variations and manufacturers
Method DHEAS Androstenedione SHBG Insulin LH FSH Oestradiol Testosterone
RIA RIA IRMA IRMA Chemiluminescence Chemiluminescence Chemiluminescence RIA
Intra variation (%) 6 3 5 5 3 10 4
Inter variation (%)
Manufacturers
10 7 6 6 6 5 12 5
Immunotech, Marseilles, France Immunotech, Marseilles, France Orion Diagnostica, Espoo, Finland Biosource, Nivelles, Belgium ACS:180, Bayer, Leverkusen, Germany ACS:180, Bayer, Leverkusen, Germany ACS:180, Bayer, Leverkusen, Germany Biosource, Nivelles, Belgium
17-OHP, 17 hydroxyprogesterone; DHEAS, dehydroepiandrosterone; Lh, lutenising hormone; FSH, follicular stimulating hormone, IRMA, immunoradiometric assay: RIA, radioimmunoassay; SHBG, sex hormone binding globulin. © 2015 The Australasian College of Dermatologists
Androgenetic alopecia, insulin resistance Hyperandrogaenemia was defined as higher serum androgen levels than the reference values of the assays (DHEAS > 5070 ng/mL, androstenedione > 2.99 ng/mL and ft > 3.99 pg/mL). Patients with normal glucose tolerance were separately assessed by excluding patients with IGT (n = 70 patients). A total of 30 patients with increased levels of either DHEAS, androstenedione or fT levels were found to have hyperandrogenemia. In order to exclude the effect of hyperandrogenemia on IR, we intended to analyse patients with AGA but without hyperandrogenemia. A new group (n = 45 patients) was formed by excluding the patients with hyperandrogenemia. The study sample is shown in Fig. 2).
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Systemic illness were excluded by Family Health Care laborotory tests results (n = 65)
Having a systemic disease is a criterion for exclusion (n = 22)
Controls matching our paents with respect to sex, age and BMI were directed to Dermatology Outpaent Clinic (n = 43)
Statistical analysis Data analysis was performed using the IBM SPSS Statistics 20.0 (Armonk, NY, USA) and SigmaStat 3.5 (Witzenhausen, Germany). The Shapiro–Wilk test was used to examine the normality of their distribution. Qualitative variables were analysed with the Mann–Whitney U test. Values were reported as medians with 25–75% or min–max; statistical significance was attributed to a two-tailed P < 0.05.
RESULTS Overall, 77 women with AGA and 20 healthy women were included in the study. The mean age was 28.0 ± 7.2 years in the patient group and 26.4 ± 4.8 years in the control group. The BMI was 23.2 ± 3.6 kg/m2 in the patient group and 22.7 ± 3.0 kg/m2 in the control group. No significant difference was found between the patient and control groups regarding their age and BMI values. There were seven patients (9%) with grade I AGA, 46 patients (60%) with grade II AGA and 24 patients (31%) with grade III AGA. In two patients the Ferriman–Galwey score was 10 and 9, the others were not hirsute. There was no significant difference in the waist: hip ratio between patient and control groups. According to the OGTT results, IGT was found in five (6%) and DM was found in two (3%) of the 77 patients. The patients with DM were excluded from the analysis. In the remaining 75 patients, serum basal insulin level, FBG, AUC glucose and AUC insulin levels as well as their HOMA score were significantly higher than in the control group (Table 2). The patients with normal glucose tolerance were separately assessed by excluding those with IGT. When compared to the control group on parameters of IR, FBG, basal insulin, AUC glucose and AUC insulin as well as HOMA score, the scores in this group were still significantly higher than in the control group (Table 3). This group was then compared to the control group on their hormone profile: their oestradiol, sex hormone binding globulin and androstenedione levels were significantly higher in the study group (Table 3). On the abdominopelvic sonography, no polycystic ovaries were detected. In all, 30 patients were hyperandrogenic. The patients without hyperandrogenemia (n = 45) and the control group were re-assessed on parameters of IR and
Controls were quesoned for age at puberty, history of acne, hirsusm, diabetes mellitus, pregnancy, lactaon and for taking medicaons (n = 43)
Posive answer is a criterion for exclusion (n = 15)
Controls were examined for dermatological diseases (n = 28)
Having any dermatological disease is a criterion for exclusion (n = 8)
Accepng to control group (n = 20) Figure 2
Flow chart showing the recruitment of the control group.
no significant difference was found in terms of their waist: hip ratio and BMI value. Serum fasting glucose, AUC insulin and AUC glucose as well as the HOMA score were significantly higher in the AGA patients without hyperandrogenemia (Table 4).
DISCUSSION In addition to hirsutism and acne, AGA is one of the symptoms of hyperandrogenism.11–13 The relationship between glucose intolerance and hyperandrogenism was first © 2015 The Australasian College of Dermatologists
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D Kartal et al.
Table 2 Hormonal and insulin resistance parameters in women with androgenetic alopecia (AGA) (excluding diabetic patients) and controls. Values were reported as median (min–max)
BMI Waist/hip FSH (mIU/mL) LH (mIU/mL) Oestradiol (pg/mL) Free testosterone (pg/mL) Total testosterone(pg/mL) DHEAS (ng/mL) Androstenedione (ng/mL) SHBG (nmol/L) FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR
Patients with AGA (n = 75)
Controls (n = 20)
P
22.37 (17.48–37.50) 0.72 (0.68–0.79) 6.17 (1.75–72.97) 4.44 (12.26–150.1) 63.1 (12.26–150.1) 1.68 (073–4.2) 29 (1.93–416) 1608 (1.74–8616) 2.66 (0.31–71) 47 (2–416) 92 (16–111) 11 (1–69) 13920 (8805–25305) 6975 (1299–91575) 2.63 (1.2–18.1)
22.72 (19.56–30.46) 0.74 (0.69–0.76) 5.15 (2.52–11.3) 4.13 (2.07–10.41) 82.5 (31–198) 1.5 (1.05–2.11) 24.5 (6–74) 1325 (254–4400) 1.91 (0.85–3.45) 61 (23–105) 75 (62–111) 9.5 (4.37–14) 10252.5 (72–13950) 3349 (1470–6570) 1.7 (0.9–8.3)
NS NS NS NS < 0.05 NS NS NS < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
AUC, area under the curve; BMI, body mass index; DHEAS, dehydroepiandrosterone; FPG, fasting plasma glucose; FSH, follicular stimulating hormone; HOMA-IR, homeostasis model assessment-insulin resistance; LH, lutenising hormone; NS, not significant; SHBG, sex hormone binding globulin. Table 3 Hormonal and insulin resistance parameters in women with androgenetic alopecia (AGA) (excluding impaired glucose tolerance and diabetes mellitus patients) and control subjects. Values were reported as median (min–-max))
FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR FSH (mIU/mL) LH (mIU/mL) Oestradiol (pg/mL) Free testosterone (pg/mL) DHEAS (ng/mL) Androstenedione (ng/mL) SHBG (nmol/L)
Patients with AGA (n = 70)
Controls (n = 20)
P
92 (16–111) 11 (1–69) 13500 (8805–22215) 6868 (1299–91575) 2.5 (0.1–18.1) 6.65 ± 2.32 4.4 (1.49-20.9) 63.3 (12.2–150) 1.69 (0.73–4.2) 1611 (1.74–8616) 2.71 (0.31–71) 47.5 (2–416)
75 (62–111) 9.5 (4.37-14) 10252.5 (72–13950) 3349 (1470–6570) 1.7 (0.9-8.3) 5.69 ± 2.02 4.13 (2.07–10.41) 82.5 (31–198) 1.5 (1.05–2.11) 1325 (254–4400) 1.91 (0.85–3.45) 61 (23–105)
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NS NS < 0.05 NS NS < 0.05 < 0.05
AUC, area under the curve; FPG, fasting plasma glucose; FSH, follicular stimulating hormone; HOMA-IR, homeostasis model assessmentinsulin resistance; LH, lutenising hormone; NS, not significant. Table 4 Insulin resistance parameters in women with androgenetic alopecia (excluding patients with hyperandrogenemia) and controls. Values were reported as median (25–75%)
FPG (mg/dl) Basal insulin (mU/L) AUC glucose (mg/dl, 120 min) AUC insulin (mU/L, 120 min) HOMA-IR
Patients with androgenetic alopecia (n = 45)
Controls (n = 20)
P
92 (87.5–100) 10.75 (8.5–15.8) 14175 (12637.5–15900) 6941.2 (3295–9504.6) 2.9 (1.9–4)
75 (62–111) 9.5 (4.37–14) 10252.5 (72–13950) 3340 (1470–6570) 1.7 (0.9–8.3)
< 0.05 NS < 0.05 < 0.05 < 0.05
AUC, area under the curve; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment-insulin resistance; NS, not significant.
described by Achard and Thiers in 1921 when it was called diabetic-bearded women.14 The relationship between polycystic ovary syndrome (PCOS) and IR has previously been shown and PCOS and AGA involve the same alleles on the gene that regulates androgen secretion and activation.15–20 Matilainen and colleagues evaluated women aged 63 years with AGA.21 The authors used a basal insulin meas© 2015 The Australasian College of Dermatologists
urement and OGTT to detect IR. In our study, FBG, basal insulin, AUC glucose, AUC insulin and HOMA scores were used to detect IR. Our findings suggest that IR is present in AGA. We recruited young patients since use of prescription drugs at advanced age and comorbid systemic diseases might affect IR. In a study by Hirsso and colleagues 105 women aged 63 with Ludwig grades II–III AGA were
Androgenetic alopecia, insulin resistance compared with 225 patients with Ludwig grades 0–I AGA. The authors used The quantitative insulin-sensitivity check index (QUICKI), glucose level at 2 h after glucose load and basal insulin level to detect IR and found that their QUICKI index was significantly higher.22 Although our study and that of Hirsso used different tests for the evaluation of IR, both studies support the presence of IR in patients with AGA. In another study, Ekmekçi and colleagues evaluated IR in 41 non-obese women aged 22–44 years, with Ludwig grades I–II AGA and 25 healthy women.23 The authors investigated IR by assessing OGTT, basal insulin, HOMA score and the QUICKI index. They concluded that AGA is associated with IR. The larger sample size in our study makes our results more meaningful when compared to the other studies. The main limitations of studies in the literature were the absence of hormonal levels due to advanced age or the failure to detect hyperandrogenism by laboratory findings in younger age groups. In the present study, the patients were assessed by both hormone profile and abdominopelvic sonography. We found hyperandrogenemia in 30 patients with AGA, but without any other clinical findings of hyperandrogenism. This result suggests that AGA may be the sole manifestation of hyperandrogenemia and it might be due to the polymorphism of the androgen receptor. In the study by Ekmekçi and colleagues hyperandrogenism was excluded using only clinical findings. However, our results show that hyperandrogenism may not be completely reflected in a clinical presentation; thus, patients should be evaluated by their hormone profile. There are several studies confirming that hyperandrogenism causes IR. In our study, when we repeated our analyses by excluding patients with hyperandrogenemia in the patient group, it was found that IR still persisted. Thus, IR was notable in female patients with AGA regardless of hyperandrogenemia. The association of AGA and IR is independent of hyperandrogenemia. Further studies are needed to clarify the association between AGA and IR.
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