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Retinol-binding protein 4, leptin, and insulin resistance in idiopathic hirsutism and hirsute women with polycystic ovary syndrome

El-Barbary, Rasha A.H.a; El-Said, Enas E.b; Ahmad, Fayzac; Al-Wakeel, Mervat E.S.d

Journal of the Egyptian Women's Dermatologic Society: May 2013 - Volume 10 - Issue 2 - p 94–100
doi: 10.1097/01.EWX.0000424171.02538.56
Original articles
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Background Idiopathic hirsutism (IH) and polycystic ovary syndrome (PCOS) are the most common causes of hirsutism. Many studies have examined the relationship between retinol-binding protein 4 (RBP4), leptin, and insulin resistance (IR) in patients with PCOS and the association of IR and leptin with IH. To our knowledge, there are no published data on the role of RBP4 in IH.

Objective To evaluate the possible role of RBP4, leptin, and IR in IH compared with PCOS and healthy controls.

Patients and methods The study included 14 patients with IH (group I) and 11 hirsute patients with PCOS (group II), and 13 healthy women serving as a control group. Serum RBP4 and leptin were measured by enzyme-linked immunosorbent assay. IR was determined using homeostasis model assessment-insulin resistance (HOMA-IR). Hormonal assessment was carried out for all patients.

Results The RBP4 level was significantly higher in each patient of group I and group II compared with the controls (P<0.001 for each). No significant difference was detected in HOMA-IR between group I (IH) and the control group, whereas group II (PCOS) had significantly more HOMA-IR than the control group (P<0.001). Leptin levels in groups I and II did not show a significant difference compared with the control group. There was no significant difference in these three parameters between groups I and II. The RBP4 levels of group II (PCOS) were correlated positively with both age and BMI. Leptin levels were correlated negatively with testosterone in group I (IH) and with BMI in group II (PCOS).

Conclusion RBP4 may be involved in the pathogenesis of IH as PCOS. Patients with IH, similar to PCOS, may need to be strict in decreasing their body weight.

Departments of aDermatology and Venereology

bClinical Pathology

cObstetric and Gynecology

dEndocrinology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Correspondence to Rasha A.H. El-Barbary, MD, Department of Dermatology and Venereology, Faculty of Medicine for Girls, Al Azhar University, 113611 Cairo, Egypt Tel: +20 100 172 0388; e-mail: dr_rashaderma@yahoo.com

Received June 20, 2012

Accepted November 6, 2012

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Introduction

Hirsutism is the excessive growth of terminal hairs in androgen-dependent areas of a woman’s body where terminal hair is not normally found. Hirsutism results from the transformation of vellus hairs into terminal hairs because of the effect of androgens. Excess androgen may be the result of overproduction by the ovaries or the adrenal gland, under the production of sex hormone-binding globulin by the liver or enhanced conversion of circulating testosterone into more potent dihydrotestosterone. Pituitary causes and drugs may also be causes of hirsutism 1. However, a significant proportion of hirsute patients have a normal serum androgen concentration, a condition usually termed as idiopathic hirsutism (IH). IH and polycystic ovary syndrome (PCOS) are the most common causes of hirsutism. The pathogenesis of IH is not clear, but might be related to a putative increase in the sensitivity of the hair follicle to androgens, resulting from abnormalities in the androgen signal transduction system in the skin. Increased peripheral 5α-reductase activity has also been postulated to explain the pathogenesis of this disorder 2. PCOS affects about 70–80% of hirsute women. It presents clinically with menstrual irregularities, infertility, and signs of hyperandrogenism such as hirsutism, acne, or androgenetic alopecia 3. Metabolic disturbances in PCOS including insulin resistance (IR), impaired glucose tolerance, hyperlipidemia, and obesity can also occur 4.

Adipose tissue has been considered as an active endocrine organ that releases a large number of bioactive mediators (collectively referred to as adipokines) such as leptin, adiponectin, visfatin, retinol-binding protein 4 (RBP4), and resistin. These adipokines have been shown to facilitate changes in carbohydrate and lipid metabolism, thereby involved in the pathogenesis of IR 5.

RBP4 is one of adipokines that belongs to the lipocalin family of proteins, secreted from the liver and adipose tissue. RBP4 acts as a carrier for retinol (vitamin A) from the liver to the peripheral tissues. At the level of peripheral tissues, RBP4 may act directly by binding to cell surface receptors 6 or through retinoic acid on retinoic acid receptors and retinoic acid-X receptors 7. Retinoids have been shown to affect the hair follicle growth cycle in mice, with topical application increasing the length of the anagen phase and decreasing time in telogen 8. Although RBP4 is a promising marker of IR in mice, its role in humans remains unclear 9.

Leptin, another adipokine, is associated with the regulation of body fat stores. In rodents, leptin contributes toward the regulation of energy balance and reduces the percentage of body fat. In humans, however, leptin resistance is involved in the development of obesity-induced IR 10. In vitro, leptin seems to antagonize some actions of insulin by attenuating the phosphorylation of insulin receptor-1 (IRS-1) and increasing the association of IRS-1 with phosphatidyl-inositol 3-kinase 11. Moreover, leptin receptors have been reported in the pancreas, suggesting that leptin may also regulate insulin release as part of an adipo-insular feedback 12.

IR leads to compensatory hyperinsulinemia. The pathophysiology that links adiposity, IR, and hyperandrogenism is not fully understood. At the central level, insulin seems to be involved in the dysregulation of luteinizing hormone (LH) secretion. At a peripheral level, insulin promotes ovarian androgen secretion by enhancing cytochrome P450c17α activity and by stimulating insulin-like growth factor 1 secretion 13.

The aim of the present study was to evaluate the possible role of RBP4, leptin, and IR in IH compared with PCOS and healthy controls.

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Patients and methods

The current study was carried out on 38 women between November 2010 and March 2011. The study included 25 hirsute women, 14 patients with IH (group I) and 11 hirsute patients with PCOS (group II), and 13 healthy age-matched and BMI-matched women serving as a control group. The patients were recruited from the Outpatient Clinics of Dermatology, Gynecology or Endocrinology of Al-Zahraa University Hospital, Cairo, Egypt. Controls were recruited from among workers of Al-Zahraa University Hospital. Informed written consent was obtained from all participants after taking the approval of Research Ethics Committee of the Faculty of Medicine for Girls, Al-Azhar University. IH was defined as the presence of hirsutism, normal ovulatory function, and normal androgen profile without features suspicious for other causes of hirsutism 2. The diagnosis of PCOS was made according to the revised diagnostic criteria (Rotterdam 2003 consensus criteria) 14 of PCOS when two of the following three features were present: oligo-ovulation and/or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound examination.

Women between 20 and 40 years of age were included (patients and controls). Women with Cushing’s syndrome, congenital adrenal hyperplasia, hyperprolactinemia, thyroid dysfunction, virilizing tumors, diabetes mellitus, hepatic or renal dysfunction, and hypertension were excluded. None of the patients or controls had used any medication known to interfere with carbohydrate metabolism and hirsutism. After obtaining informed consent, all groups were subjected to the following:

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I. Clinical evaluation

Full assessment of history including onset of hirsutism and its relation to puberty, menstrual history (i.e. regularity, amenorrhea), infertility, drug intake (e.g. oral contraceptive pills), and a positive family history of hirsutism, acne, androgenic alopecia, or infertility.

Complete general examination with anthropometric measurements including weight (kg) and height (m); then, BMI was calculated according to the following formula: weight in kilograms divided by height in meters square. Those with BMI of at least 25 kg/m2 were considered obese.

Dermatological examination was carried out to detect other signs of hyperandrogenism such as acne and androgenetic alopecia.

Scoring of the degree of hirsutism was carried out using the modified Ferriman–Gallwey Score, which evaluated the presence of terminal hair in nine body areas (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back, and thighs). Hirsutism was scored from absent (Score 0) to severe (Score 4) and the numbers were added to a maximum count of 36. Scores of 8 and higher were consistent with the diagnosis of hirsutism 8.

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II. Imaging studies

Ultrasonographic evaluation of the ovaries was carried out. The presence of at least 12 follicles measuring 2–9 mm in diameter and/or ovarian volume of at least 10 cm3 was considered to indicate polycystic ovaries 15.

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III. Laboratory investigations

After 6–8 h of fasting, 5 cc venous blood was collected between 08:00 and 10:00 a.m. at the third to fifth day of the menstrual cycle (early follicular phase) for patients with normal cycles and for normal control women. For patients with amenorrhea, blood samples were collected irrespective of the duration of the cycle. The samples were centrifuged within 30 min of collection. Then, serum from all blood samples was separated and used to assess the following:

  • Levels of LH, follicle-stimulating hormone (FSH), and total testosterone and dehydroepiandrosterone sulfate by chemiluminescent immunoassay using an Immulite 2000 analyzer (Siemens Healthcare Diagnostics Inc., West Sacramento, California, USA).
  • Glucose level by an enzymatic colorimetric assay using a Cobas C-311 autoanalyzer (Roche Diagnostics, Indianapolis, Indiana, USA).
  • Insulin level by a chemiluminescent immunoassay using an Immulite 2000 analyzer (Siemens Healthcare Diagnostics Inc.). IR, defined by the homeostasis model assessment IR (HOMA-IR), was calculated using the following equation: HOMA-IR=fasting insulin (µU/l)×fasting glucose (mmol/l)/22.5 16.
  • RBP4 serum level was measured by ELISA using a SLT Spectra ELISA reader (SLT Lab Instruments, Salzburg, Austria) with the Quantikine Human RBP4 ELISA Kit supplied by R&D Systems Inc. [Minneapolis, Minnesota, USA (Cat. no. DRB400, Lot no.293307)].
  • Leptin serum level was measured by ELISA using an ELISA reader SLT Spectra (SLT Lab Instruments) with AccuDiag ELISA Kit supplied by Diagnostic Automation/Cortez Diagnostics, Inc. [Ref. no. 1742-6, Lot. no. 45k012; Calabasas, California, USA].
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IV. Statistical analysis

All data were analyzed using the Statistical Package for the Social Sciences for Microsoft Windows, version 18.0 (SPSS Inc., Chicago, Illinois, USA). Normally distributed data (parametric data) were presented as mean±SD and compared using Student’s t-test. Nonparametric results were presented as median–interquartile range and compared by the Mann–Whitney test. The correlations were assessed using Spearman’s correlation coefficient. P-value up to 0.05 was considered statistically significant.

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Results

The study included 14 women with IH (group I) and 11 hirsute women with PCOS (group II), mean age 29.57±6.82 and 27±5.21 years, respectively, and BMI 29.71±3.52 and 31.64±5.66 kg/m2, respectively. Thirteen healthy age-matched and BMI-matched women were enrolled as controls (control group), mean age 30.77±4.6 years and BMI 29.46±4.27 kg/m2.

In terms of the clinical assessment and other laboratory tests performed, no statistically significant difference was detected in any of the measured parameters between group I and group II, apart from the LH/FSH ratio, which was significantly higher in group II (PCOS) (P<0.001) (Table 1).

Table 1

Table 1

On comparing the three groups, we found that RBP4 was significantly higher in groups I and II compared with the control group (P<0.001 for each). HOMA-IR was significantly higher in group II (PCOS) compared with the control group (P<0.001), but it did not show any significant difference between group I (IH) and the control group. Leptin did not show any significant difference between the three groups. On comparing groups I and II, we did not found any significant difference in RBP4, leptin, or IR (Table 2).

Table 2

Table 2

By correlating the three parameters studied with the clinical and laboratory data of groups I and II, we found that there was a significant positive correlation between RPB-4 levels in group II (PCOS) and both age (r=0.76, P=0.006) and BMI (r=0.64, P=0.032) (Table 3) (Figs 1 and 2). In addition, leptin showed a significant negative correlation with testosterone in group I (IH) (Table 4) (r=−0.57, P=0.032) and with BMI (r=−0.67, P=0.023) in group II (Figs 3 and 4). No significant correlation could be found between HOMA-IR and any of the parameters studied.

Table 3

Table 3

Figure 1

Figure 1

Figure 2

Figure 2

Table 4

Table 4

Figure 3

Figure 3

Figure 4

Figure 4

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Discussion

Several studies have examined the relationship between RBP4, leptin, and IR in patients with PCOS 17–20. However, few data have reported the association of IH with IR 21,22 and leptin 23. To our knowledge, there are no published data investigating the role of RBP4 in IH. The aim of the present study was to evaluate the possible role of RBP4, leptin, and IR in IH compared with PCOS and healthy controls.

In our study, we found significantly higher RBP4 levels not only in hirsute women with PCOS but also in patients with IH compared with the age-matched and BMI-matched healthy controls. Previous studies 9,24,25 have reported conflicting results. Whereas some studies have found RBP4 levels of PCOS patients and controls not to differ significantly 9,24, others have reported an increased RBP4 level in PCOS, suggesting RBP4 as an additional pathogenic factor 25, which is consistent with our data. Interestingly, in the PCOS group, RBP4 is positively correlated with BMI and age, which is in agreement with previous studies 26–29 that have suggested an association between adiposity, especially visceral, with increased levels of circulating and adipose tissue RBP4 levels and have reported higher RBP4 levels in women older than 50 years of age compared with those younger than 50 years of age 30.

It was suggested that circulating levels of adipokines may be related to the direct effects of sex hormones on adipocyte expression and secretion 31. Furthermore, previous studies 32,33 have found a correlation between RBP4 and serum levels of testosterone, DHEA-S, FSH, and LH in women with PCOS. This possible mechanism is not supported by Santoro et al.34 as serum RBP4 levels are similar in pubertal and prepubertal individuals who have significantly different levels of circulating sex hormones. In agreement with this, we did not find any correlations between RBP4 and hormonal parameters. The current study did not find a significant difference between hirsute PCOS and IH in the RBP4 level. Therefore, we suggest that RBP4 may be associated with hirsute women irrespective of whether they have PCOS or IH.

We further evaluated another adipokine, leptin, which was linked to obesity, and insulin action and assumed to be elevated in PCOS 23. Unfortunately, this was not supported by our data, as we did not find a significant difference in leptin levels between either hirsute PCOS patients or IH compared with the controls, in agreement with other studies 35,36. The difference in the results may be because of the small patient numbers and different BMI. Moreover, there was no significant difference in leptin levels between hirsute PCOS patients compared with IH patients. The leptin of the PCOS group was correlated negatively with BMI. Other authors 37,38 have found a correlation between BMI and serum leptin concentrations not only in PCOS but also in IH patients. It was proposed that leptin is also a sex-affected adipokine and a negative correlation has been reported between leptin and LH concentrations in PCOS patients, but not in ovulatory women with IH 19,23. In contrast, we did not find any correlation between leptin and LH in our groups. This insignificant correlation may be attributed to the pulsatile manner of LH, as in the other studies 19, 24-h mean LH was used. However, the role of leptin in ovarian function or in the reproductive system remains unclear 26. Laughlin et al.19 and Petermann et al.35 proposed that leptin is involved neither in the hypersecretion of LH nor in the regulation of LH pulsatility.

The role of androgens in the regulation of leptin secretion is controversial 17. A hypothesis of an inhibitory action of androgens on plasma leptin concentrations has been suggested. This hypothesis is supported by the inverse correlation observed between serum leptin and testosterone concentrations in men 39. Carmina et al.40 have reported a negative correlation between leptin and dehydroepiandrosterone levels in PCOS women, suggesting that androgens may play a role in suppressing serum leptin in these women. However, Upadhyaya et al.17 and Rouru et al.20 have found a positive correlation between leptin and free testosterone in PCOS patients. However, we observed a significant negative correlation between total testosterone and leptin, which was evident for IH, but not for PCOS patients. Our findings of insignificant associations between leptin and testosterone levels in PCOS are in agreement with some studies 19,26.

Although not universal, IR and hyperinsulinemia have been found in women with PCOS. The pathophysiology that links adiposity, IR, and hyperandrogenism is not fully understood 13. Furthermore, there are no enough data showing whether patients with IH have IR 22; we investigated the presence of IR using HOMA-IR. Hirsute PCO patients have significantly more HOMA-IR than controls, but we did not find significant difference between the IH group compared with the control or the PCOS group. In agreement with our results, several studies have also found that there was a significant difference in serum insulin level and HOMA-IR in hirsute women with PCO than in the control group 22,40, but HOMA-IR was significantly higher in IH than in controls in their results 41. Sheikholeslami et al.42 showed that serum insulin level and HOMA-IR in the PCO group was significantly higher in comparison with that in the IH group. Möhlig et al.43 suggested that the pathogenesis of PCOS may be a kind of a vicious cycle involving both hyperandrogenemia and IR/hyperinsulinemia, as high levels of insulin are considered to stimulate ovarian androgen production, leading to hirsutism, menstrual problems, and anovulation 44. However, hyperandrogenemia may enhance IR and metabolic dysregulation seen in PCOS 45. However, in our results, we did not find any correlations between IR and clinical, and hormonal parameters in either PCOS or IH. This in contrast with the result of Landay et al.46, who found associations between the Ferriman–Gallwey Score, HOMA-IR, and BMI, and concluded that insulin may have a direct effect on the severity of hirsutism. In the present study, the hirsutism score did not correlate with any of the parameters studied.

Many studies have shed some light on the possible role of insulin and/or IR in modulating leptin gene expression 47,48 and a correlation between IR and RBP4 in PCOS has been found 27–29. Furthermore, it was proposed that leptin is increased in obesity and directly stimulates RBP4 expression in human adipocytes 31. In contrast to the previous finding, we failed to find a significant correlation between the levels of three studied parameters, RBP4, leptin, and HOMA-IR, in either hirsute PCOS patients or IH patients. In agreement with our results, several studies 9,18,46–48 have found that RBP4 is not a useful marker of IR in PCOS.

The conflicting results may be because of the difference in the methodology or the reduced patient number in this study. RBP4 levels can be influenced by the collection method and plasma anticoagulants in collecting tubes. Furthermore, the design of the immunoassays itself can significantly influence the results 27. Leptin is also known to be secreted in a pulsatile manner 23. Neither hormonal abnormality nor IR seems to explain the higher RBP4 in hirsute PCOS women in our study, as RBP4 levels have also been increased in IH patients.

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Conclusion

IH and PCOS are associated with increased serum levels of RBP4. This adipokine may be involved in the pathogenic process of hirsutism. A large-scale study is recommended to clarify the relationship between the adipokines, mainly RBP4, and IH. This may require that patients with IH, similar to PCOS, are strict in following a healthy life style with pharmacological aid to decrease their body weight.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

hirsutism; idiopathic hirsutism and polycystic ovary syndrome; insulin resistance; leptin; retinol-binding protein 4

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