Hirsutism: A Clinico-investigative Study.

BACKGROUND: Hirsutism is a common clinical condition characterized by presence of terminal hair at body sites under androgenic influence. Inspite of the significant worldwide prevalence of hirsutism, studies on hirsutism from India are not many.
OBJECTIVE: To assess the etiology of hirsutism and correlate its severity with underlying causes and various hormone levels.
MATERIALS AND METHODS: In this prospective study, 40 patients of hirsutism enrolled on first come basis were included. All patients underwent detailed clinical assessment and transabdominal ultrasonography. Free and total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, luteinizing hormone, follicle stimulating hormone, prolactin, free tri-iodothyronine, free tetra-iodothyronine, and thyroid stimulating hormone, and sex hormone binding globulin were estimated. Forty age-matched controls without features of hyperandrogenemia were included for the comparison.
RESULTS: Thirteen (32.5%) patients had mild, 52.5% had moderate whereas 15% had severe hirsutism. Positive family history was documented in 42.5% patients. The clinical features found to be associated with hirsutism included acne (55%), menstrual irregularities (40%), acanthosis nigricans (37.5%), obesity (37.5%), and androgenetic alopecia in 27.5% of patients. Polycystic ovarian syndrome (PCOS) was the underlying cause in 70%, non-classical congenital adrenal hyperplasia and hypothyroidism in 7.5% each whereas idiopathic hirsutism was found in 15% patients.
CONCLUSION: PCOS was the most common cause of hirsutism found in the instant study. Further, there was positive correlation between severity of hirsutism and free testosterone levels.

INTRODUCTION

Hirsutism is defined as presence of excessive terminal hair in androgen-dependent areas in a female over face, chest, abdomen, upper thigh, and areole.[1] In these areas, hair growth is usually minimal or absent. Hirsutism can be caused by abnormally high androgen levels secreted from ovaries/adrenal gland or because of hair follicles being more sensitive to normal androgen levels.[2] The increased hair growth is often observed in patients with endrocrine disorders characterized by hyperandrogenism. The signs and symptoms that may accompany hyperandrogenism are acanthosis nigricans, obesity, virilization, Cushing's syndrome, acne, alopecia, and pelvic mass. Hence, it is important to evaluate every patient who complains of unwanted facial or body hair. In this study, we have tried to analyze the underlying causes for hirsutism along with the associated clinical manifestations.

MATERIALS AND METHODS

In this prospective study, 40 consecutive untreated hirsute patients with modified Ferriman-Gallwey (mFG) score of >8, between 15 and 45 years of age, who presented to the Dermatology and Endocrinology departments of Dr. Ram Manohar Lohia Hospital, New Delhi between September 2009 and December 2010 were included. Patients already on oral hormonal treatment, anti-androgens, or insulin sensitizers were excluded. The control group included an equal number of age-matched females with no signs of hirsutism and/or hyperandrogenism.

A detailed medical history along with physical examination was undertaken in all patients. History was obtained from each patient using a proforma which included age of onset of hirsutism, duration, rate of progression of disease, marital status, parity, age at menarche, menstrual irregularities and presence of symptoms of virilization, i.e., deepening of voice, increased muscularity, thinning of scalp hair, seborrhea, decreased breast size, and oligomenorrhea. Patients were examined for clinical evidence of acne, androgenetic alopecia (AGA), acanthosis nigricans, signs of virilization including loss of female body contours and atrophy of breast. Body mass index (BMI) was also measured. The degree of hirsutism was assessed by mFG scoring system.[3] Hirsutism was classified as mild (mFG score 9-16), moderate (mFG score 17-25), and severe (mFG score 26-36).

The blood samples were drawn at 08:00-09:00 h after overnight fasting between 5th and 6th day of menstrual cycle. Free and total testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogestrone (17-OHP) levels were measured using enzyme-linked immunosorbent assay (ELISA)[4] and luteinizing and follicle stimulating hormone (LH/FSH ratio), Prolactin, free tri-iodothyronine (fT3), free tetra-iodothyronine (fT4), and thyroid stimulating hormone (TSH) levels were measured by chemiluminiscence.[5] Adrenocorticotrophin hormone (ACTH) stimulation test was performed in five patients with 17-OHP levels between 2 and 8 ng/ml to rule out late onset/non-classical congenital adrenal hyperplasia (NCAH). Pelvic ultrasound for ovaries was carried out between day 3 and 5 of menstrual cycle in all patients. Modified National Institute of Health Criteria[6] was used for diagnosis of polycystic ovarian syndrome (PCOS). The polycystic ovarian morphology was defined by the presence of 10 or more intermediate follicles each measuring 2-9 mm in diameter and/or increased ovarian volume of more than 10 ml on transabdominal ultrasound.

RESULTS

Out of the 40 patients in the study, 25 patients (87.5%) were between 16 and 30 years old at the time of presentation. The mean age of presentation in the present study was 24.18 ± 5.61 years. Nineteen (47.5%) patients had hirsutism for ≤6 years, whereas 42.5% (n = 17) patients had hirsutism for >6 years. The mean duration of hirsutism before seeking medical advice was 6.1 ± 3.38 years. The majority of patients, i.e., 31 (77.5%) noticed hirsutism before 20 years of age, whereas in the remaining nine patients it manifested after the age of 20 years. A positive family history was present in 42.5% patients. The mean age of menarche was 13.3 years. 17.7% patients were married. A total of 13 (32.5%) patients had mild hirsutism (mFG score 9-16), 52.5% (n = 21) patients had moderate (mFG score 17-25) and remaining 6 (15%) patients had severe hirsutism (mFG score 26-36) [Table 1].

Table 1

Observations in study patients

In the associated medical conditions, acne was present in 22 patients (55%) and menstrual irregularities were present in 40% patients [Table 1]. They were associated with obesity (BMI >25) in 37.5% and AGA in 27.5% patients. Three (23.08%) out of 13 patients with mild hirsutism had acne, 13 (61.9%) out of 21 patients with moderate hirsutism had acne whereas 100% (6 out of 6) patients with severe hirsutism had acne. One patient (7.7%) out of 13 with mild hirsutism had AGA. Five patients (23.8%) out of 16 with moderate hirsutism had AGA whereas 5 (83.33%) out of 6 patients with severe hirsutism had AGA. The severity of hirsutism and its association with AGA was statistically significant (P < 0.01). No significant association was observed between severity of hirsutism and menstrual irregularity, obesity, and deepening of voice.

Nineteen out of 40 patients were overweight (BMI ≥23). Six (46.15%) among 13 patients with mild hirsutism had BMI ≥23 (overweight), 8 (38.09%) out of 21 patients with moderate hirsutism were overweight whereas 5 (83.33%) out of 6 patients of severe hirsutism were overweight. The association between the severity of hirsutism and BMI was found to be statistically significant (P < 0.05).

PCOS was found in 28 (70%) patients, NCAH and hypothyroidism in 3 (7.5%) patients each whereas idiopathic hirsutism was found in 6 (15%) patients [Table 2]. Sixteen (84.21%) out of 19 patients with BMI >25 had PCOS and there was significant association between BMI and PCOS (P < 0.05). Fifty percent of patients with PCOS had irregular menstrual cycles whereas 16.67% had irregular menses without the evidence of PCOS. The relationship between PCOS and menstrual irregularities was significant. LH/FSH ratio was found to be raised (>2) in 78.57% hirsute patients with PCOS whereas LH/FSH ratio was raised in only 16.67% patients without PCOS. The relation between these two was significant.

Table 2

Ultrasonographic findings in patients

The difference between the means of free testosterone, total testosterone, DHEAS, 17-OHP, LH, FSH, prolactin, and SHBG of cases was found to be statistically significant when compared with the control group by t-test (P < 0.05). However, TSH was not significantly raised in cases of hirsutism when compared with controls. Free testosterone levels were elevated in 18 (45%) patients. Out of these, 13 had PCOS, 3 had NCAH, and 2 patients had hypothyroidism. All six patients with severe hirsutism had elevated free testosterone level [Table 3]. The association between severity of hirsutism and free testosterone level was found to be significant (P < 0.05). Total testosterone was raised only in one patient who was having PCOS. DHEAS was raised in three patients and all three patients had PCOS. Twenty five (62.5%) patients had raised 17-OHP levels. Out of these, 19 had PCOS, 3 had NCAH, and 3 had hypothyroidism. SHBG was raised in 13 patients. There was no association between severity of hirsutism and total testosterone, DHEAS, 17-OHP, raised LH/FSH ratio, prolactin, and SHBG levels. Twenty (71.43%) patients with PCOS had biochemical hyperandrogenemia whereas 8 (28.57%) patients with PCOS had no hyperandrogenemia. Thus hyperandrogenemia is significantly associated with hirsuites with PCOS.

Table 3

Hormone levels in patients with different causes of hirsutism

DISCUSSION

Hirsutism is a common clinical condition that usually has a benign course. In rare cases, however, it may be the presenting feature of a serious underlying disease which needs proper etiological diagnosis and appropriate treatment. The severity of hirsutism in particular areas of the body varies in different patients and depends on the rate of androgen excess, or increased sensitivity of hair follicles to normal androgen levels in the serum.

In the instant study, a total of 13 (32.5%) patients had mild hirsutism, 21 (52.5%) patients had moderate and remaining 6 (15%) patients had severe hirsutism. These observations were similar to study by Adams et al.[7] who found mild hirsutism in 39%, moderate in 45%, and severe hirsutism in 11%. However, our findings were in disagreement with studies by Ansarin et al.[8] who reported mild hirsutism in 65%, moderate in 32.5%, and severe in only 2.5% of their patients. The relationship between duration and severity of hirsutism was found to be statistically significant in this study. These findings are corroborated by Rittmaster[9] who states that women tend to develop more body hair until menopause. This can be due to exposure to increased androgen levels for longer duration which in turn leads to increased number of body hair over androgen-dependent sites and thus, leading to increase severity of hirsutism with time. We also observed that acne and AGA were more commonly associated with severe hirsutism. Though numerous studies[8101112] have documented acne along with presence of hirsutism varying from 8% to 70%, the significance of its presence in mild to severe hirsutism has not been commented. Our study clearly establishes that acne is more commonly associated with severe hirsutism. This is likely to be due to hyperandrogenemia which will promote the development of both the acne and hirsutism.

Polycystic ovarian syndrome (PCOS) was diagnosed in 28 (70%) hirsute patients. Three patients (7.5%) each were diagnosed as NCAH and hypothyroidism whereas idiopathic hirsutism (IH) was diagnosed in 6 (15%) cases after the exclusion of other causes of hirsutism and these patients had normal levels of androgens with normal ovulatory functions. These findings are in disagreement with study by Ahmad et al.[13] who found IH in 80%, PCOS in 11.43%, hypothyroidism in 5.70%, and NCAH in 2.86% hirsute patients. Similarly, Malik et al.[11] found IH (47.3%) as the commonest cause of hirsutism, followed by PCOS (44.6%), hypothyroidism (4%), Cushing's syndrome (2.7%), and NCAH (1.3%). The reason for finding PCOS as the major cause of hirsutism in our study when compared with the above mentioned studies could be due increased number of obese patients in our study which is a commonly associated finding in PCOS. Secondly, we also included patients referred from endocrinology clinic who had severe hirsutism in whom there were less chances of finding normal androgen levels, hence, idiopathic hirsutism. Thirdly, the sample size of our study was smaller in comparison with the above-mentioned studies. The raised LH/FSH ratio in PCOS with hirsutism was found to be statistically significant in our study and was in agreement with the findings of Al-Khawajah et al.[14] and Malik et al.[11] At times LH/FSH ratio may be raised without underlying PCOS as has been seen in 2 (16.67%) patients in our study. The free testosterone levels in patients with PCOS was found to be raised in 13 (46.4%) out of 28 patients whereas 5 (41.6%) out of 12 patients with other causes of hirsutism had raised free testosterone level. The association between PCOS and free testosterone was not found to be significant in our study and since it could be raised with hirsutism in other causes the measurement of free testosterone could not be used to define PCOS. Similarly, Al-Khawajah et al.[14] also reported raised free testosterone in 30.6% hirsute women with PCOS and they also concluded no association between raised free testosterone and PCOS.

In this study, the difference between the means of free testosterone, total testosterone, DHEAS, 17-OHP, LH, FSH, Prolactin, and SHBG of cases was found to be statistically significant when compared with the control group by t-test. These findings were comparable with studies by Jahanfar and Eden[15] and Adams et al.[7] who found significant difference in total and free testosterone index and SHBG and LH between hirsute cases and control group. Similarly, Carmina and Lobo[16] found significantly elevated levels of free and total testosterone, DHEAS, and androstenedione but normal levels of LH and FSH.

In our study, the association between severity of hirsutism and free testosterone was found to be significant similar to the findings of Ruutiainen et al.[17] However, Souter et al.[18] in their study found out that serum levels of free testosterone did not correlate with the patient's mFG score. The reason for this dissimilarity could be that Souter et al. included patients with minimal unwanted hair growth whereas in our study the majority of the patients had moderate hirsutism. The association between severity of hirsutism and total testosterone and DHEAS levels was not found to be statistically significant similar to the studies by Ruutiainen et al.[17] and Souter et al.[18]

The association between severity of hirsutism and SHBG was not found to be significant which was not in accordance with the study by Ruutiainen et al.[17] who reported that serum SHBG was inversely correlated to the severity of hirsutism. The difference could probably be attributed to the different nature of patient profile in the western studies and the expertise/sensitivity of the investigational procedure involved.

In our study, 20 (71.43%) patients with PCOS had biochemical hyperandrogenemia whereas 8 (28.57%) patients with PCOS had no hyperandrogenemia. Six out of 12 (50%) patients with other causes of hirsutism had hyperandrogenemia. This observation was found to be significant similar to the study by Steinberger et al.[19] who demonstrated that women with PCOS had significantly higher serum androgen levels than women with no evidence of polycystic ovaries.

In summary, the commonest cause of hirsutism is PCOS which is in keeping with what is found in the medical literature.[715] The term idiopathic hirsutism is probably overused in the diagnosis of hirsutism, and it should therefore be reserved only for those patients who have negative findings after a thorough investigation. Hirsute women should be thoroughly investigated for the cause of problem. We believe such a workup will unravel a cause for the hirsutism in most if not all women afflicted with this problem. This will add to our understanding of hirsutism and may help us in a precise targeted approach for management of such patients.