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Hyperandrogenism in the Adolescent Female
Hyperandrogenism in the adolescent female Vincenzo Toscano,* Rina Balducci,† Adele Mangiantini,† Paolo Falasca,* and Francesco Sciarra* *III Endocrinologia, Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Universita` La Sapienza and †Clinica Pediatrica, Dipartimento di Sanita` Pubblica e Biologia Cellulare, Universita` Tor Vergata, 00100 Roma, Italy Hirsutism in adolescent girls commonly starts as an esthetic problem in young women and is later complicated by the development of infertility and polycystic ovary syndrome, which are frequent consequences of prolonged hyperandrogenism. To ascertain whether particular prepubertal clinical manifestations may predict the development of adolescent hirsutism, we followed 70 girls with precocious pubarche (PP) with or without prepubertal hypertrichosis (PH) until 3 years (mean age 14.8 6 0.9 years) after menarche. Similar follow-up was carried out in six girls with PP secondary to 21 hydroxylase deficiency (NC-CAH), treated with hydrocortisone. In addition, a retrospective study on the incidence of precocious pubarche was performed in 139 hirsute teenagers (mean age 17 6 1.8 years). Testosterone, androstenedione, dehydroepiandrosterone sulphate, 17a-hydroxyprogesterone (basal and after ACTH), luteinizing hormone and follicle-stimulating hormone were evaluated by radioimmunoassay or immunoradio metric assay in the early follicular phase, in cycling subjects. Pelvic ultrasonography was also performed. In the 139 hirsute teenagers, 29 had a history of PP (21% vs. 0.6% in the general Italian population). Of these 139 patients, NC-CAH was diagnosed in 8 (6%), 5 of whom (63%) had PP. Of the 70 girls with PP, hirsutism was present in 44 (63%). PH was present in 37 of 44 patients (84%) with hirsutism, but only in 9 of 26 (35%) without hirsutism. Our results showed that 1) PP represents a risk factor for the development of postpubertal hirsutism; 2) the association with PH seems to increase the risk probability; and 3) patients with hirsutism due to NC-CAH have a higher incidence of PP compared with other hirsute patients, but glucocorticoid treatment in such patients prevents the development of hirsutism. Whether early treatment in the other PP patients may prevent the development of hirsutism remains to be established. (Steroids 63:308–313, 1998) © 1998 by Elsevier Science Inc.
Keywords: hirsutism; precocious pubarche; prepubertal hypertrichosis
Introduction Hirsutism, defined as the presence of excessive hair growth in women, is a common presenting complaint in adolescence. Androgen production in females begins around 6 – 8 years of age at adrenarche followed by a gradual increase throughout adolescence, when the ovaries start to contribute to the circulating androgen pool. Hirsutism usually begins around menarche and gradually progresses over the teenage years.1,2 It is an effect of androgen excess, but its presence is dependent also on race, skin sensitivity, and on duration of exposure to and level of hyperandrogenemia. Idiopathic hirsutism may thus reflect a combination of mildly increased androgen production from adrenals and/or ovaries and increased skin sensitivity to androgens. Adrenal causes of hyperanAddress reprint requests to Vincenzo Toscano, MD, III Endocrinologia, Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Universita` La Sapienza, 00161 Rome, Italy. E-mail: [email protected] Steroids 63:308 –313, 1998 © 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
drogenism include unusual forms of Cushing syndrome and the nonclassic forms of congenital adrenal hyperplasia (NC-CAH), of which 21-hydroxylase deficiency is the most common cause.1,2 Polycystic ovary syndrome (PCO) is the most frequent cause/consequence of abnormal androgen production; weight gain and, in some cases, inherited predisposition to insulin resistance worsens the hyperandrogenism and subsequent development of hirsutism.3–5 The end-result of long-lasting hyperandrogenism is not only hirsutism but also oligoamenorrhea, anovulation, and infertility, leading to a serious medical problem in terms of both treatment and of treatment cost. Premature pubarche (PP) is defined as the appearance of pubic and/or axillary hair before 8 years of age, and may be the first clinical manifestation of hyperandrogenism in females. It may reflect an adrenal enzyme deficiency or, more frequently, a benign process caused by early adrenal maturation or increased peripheral sensitivity to adrenal hormones.6,7 Similarly, prepubertal hypertrichosis (PH) may 0039-128X/98/$19.00 PII S0039-128X(98)00032-4
Hyperandrogenism in the adolescent female: Toscano et al. represent another benign prepubertal process caused by an increased skin sensitivity to circulating androgens.8 The aim of the present investigation was to evaluate if prepubertal clinical manifestations of increased hair growth may constitute predictive markers for the development of hirsutism in adolescent girls. Two groups of patients were studied: the first group was of hirsute females, all very young, who presented with or without history of a PP (a retrospective study). The second group comprised patients diagnosed as having PP or PH, followed up 3 years after menarche (a prospective study).
Experimental Patients The retrospective study included 139 hirsute patients (mean age 17 6 1.8 years). All were asked for the age at which their first pubic hair appeared, and only those with an exact record were included in the study. The prospective study included 70 girls with PP with or without PH and 6 girls with PP secondary to nonclassic congenital adrenal hyperplasia due to 21 hydroxylase deficiency (NC-CAH) diagnosed at the age of 6.7 6 0. 9 years and at age of 6.6 6 0.4 years, respectively and followed up for 3 years after menarche (mean age 14.8 6 0.9 years at the end of study). The NC-CAH patients were all treated with glucocorticoids (hydrocortisone at doses from 12 to 20 mg/m2 body surface), because at some stage of management bone age/chronological age ratio was greater than one.
Materials and methods Testosterone, androstenedione, dehydroepiandrosterone sulphate, and 17a-hydroxyprogesterone (basal and 1 h after 0.25 mg of Synacthen®) were evaluated by radioimmunoassay; luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated by immunoradio metric assay in the early follicular phase as described previously.6,9 In the same phase of the menstrual cycle, pelvic ultrasonography was also performed in all patients. Results are reported as mean 6 SD. Statistical analysis was performed byANOVA to compare the results between groups and x2 to compare the distribution of menstrual irregularities or ultrasonographic results.
Table 1 Patients with Idiopathic Hirsutism and Normal Cycles Patients (92)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (11)
NP (81)
Controls (25)
49 6 18* 254 6 117* 415 6 233* 60 6 36
45 6 16 202 6 86* 313 6 147* 55 6 33
41 6 11 141 6 44 161 6 52 45 6 12
106 6 42
99 6 46
/
8.4 6 2.0 5.0 6 1.0 1.7 6 1.2 8.4 6 3.1
6.1 6 2.0 3.7 6 1.0 1.3 6 0.6 7.7 6 3.1
6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
*p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
menarche lower (10.1 6 1.1 vs. 11.3 6 1.4, n.s.). Oligo- or amenorrhea was present in the 45% of the cases with PP and in 63% of the remaining cases, again not statistically significant. Hormonal data. Testosterone, androstenedione, dehydroepiandrosterone sulphate, unstimulated and stimulated 17 a-hydroxyprogesterone, LH, FSH, and LH/FSH ratios are reported in Tables 1–3.
Patients with PP (a prospective study) Clinical data. The 70 patients with precocious idiopathic pubarche (mean age of onset 6.7 6 0.9 years) showed menarche at a mean age of 11.8 6 0.93 years, compared with the age of mother’s menarche (12.2 6 2.62 years) and within the range of the normal Italian population (12.4 6 1 years).10 By three years after menarche (14.8 6 0.9 years), 44 (63%) of these patients had developed hirsutism; 37 (84%) of these 44 cases showed PH at first presentation, present in only 9 (35%) of the 26 patients who did not develop hirsutism. Oligo- or amenorrhea was present in 17
Results Patients with hirsutism (a retrospective study) Clinical data. Of the 139 hirsute patients, 131 had idiopathic hirsutism and 8 had NC-CAH. Twenty four (19%) had a history of PP. The degree of hirsutism was comparable in patients with PP and the other patients (7.8 6 1.9 vs 7.6 6 0.4, respectively), whereas age at menarche was significantly lower (p , 0.001) in patients with PP (10.6 6 1.4 vs. 11.8 6 1.4 years). PCO was present in 14 of 24 (58%) patients with PP and 26 of 115 (23%) of the remaining patients (p , 0.001). Oligo- or amenorrhea was present in 53% of the cases with PP and in 25% of the remaining cases (p , 0.001). Of the eight patients with NC-CAH, five showed the history of PP, an incidence substantially higher than patients with idiopathic hirsutism (p , 0.001). The degree of hirsutism tended to be higher in patients with PP than in those without (9.8 6 3 vs 7.8 6 2, n.s.) and the mean age at
Table 2 rhea
Patients with Idiopathic Hirsutism and Oligoamenor-
Patients (39)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (13)
NP (26)
Controls (25)
46 6 27 210 6 40* 365 6 104* 46 6 28
49 6 25 220 6 36* 355 6 124* 55 6 27
41 6 11 141 6 44 161 6 52 45 6 12
102 6 12
102 6 12
10 6 2.0* 4.7 6 0.8 3.1 6 0.3* 8.4 6 3.6
12 6 3* 4.4 6 1.2 3.1 6 0.5* 8.1 6 3.0
/ 6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
*p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
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309
Steroids in maturity dicted height (BP) (149.3 6 5.64, p , 0.05) at the time of presentation.
Table 3 Patients with Hirsutism Due to NC-CAH Patients (8)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (5)
NP (3)
Controls (25)
48 6 11 294 6 60* 317 6 215* 851 6 240*
70 6 30§ 339 6 107* 362 6 214* 1198 6 672*
41 6 11 141 6 44 161 6 52 45 6 12
4250 6 1150
5285 6 1425
/
9.8 6 3.0 6.9 6 5.8 1.9 6 1.0 9.8 6 3.0
8.8 6 5.0 4.6 6 1.4 1.9 6 1.0 7.8 6 2.0
6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
Hormonal data. Testosterone, androstenedione, dehydroepiandrosterone sulfate, unstimulated and stimulated 17 a-hydroxyprogesterone, LH, FSH and LH/FSH ratios at diagnosis, menarche and 3 years later are reported in Tables 4–6.
Discussion Our study on the follow-up of PP and on the evaluation of its incidence in hirsute patients clearly demonstrates that PP represents a prepubertal manifestation of hirsutism and cannot be considered a benign condition not requiring treatment. PH, which may complicate or precede PP, is clearly associated with an increased incidence of hirsutism and PCO development in adolescent girls. As already reported by Ibanez,11 PP did not cause precocious menarche in our patients, although in our retrospective study on hirsute patients with a history of PP, the age of menarche was significantly lower than in the remainder. The inevitable imprecision of data based on patients’ recall may account for this difference, even if the data collection was equivalent in both groups (hirsute patients with or without a history of PP). The possibility that hyperandrogenic status could induce mild advancement of bone age and of the pubertal development has to be considered, especially when androgen levels were particularly high. This seems to be confirmed by the small group of patients with hirsutism due to NC-CAH and PP, for whom the age of menarche was even lower. Oligo- or amenorrhea and/or dysfunctional bleeding was present in PP patients independent of the development of hirsutism, whereas PCO as expected was higher in patients developing hirsutism than in others.12,13 In patients with hirsutism, in contrast, the incidence of both PCO and oli-
§p , 0.02 vs. controls. *p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
of 70 patients (24%); in hirsute patients the percentage was 25%, and 26% if only hirsute patients with PH are considered. PCO was present in 16 out of 70 (23%), in 13 out of 44 hirsute patients (30%), and in 12 out of 37 patients with hirsutism and PH (32%). These patients reached a final height of 158.6 6 5.9, in keeping with both target (159.2 6 4.3, p , 0.001) and predicted (BP) height (160.3 6 5.7, p , 0.001) at first presentation. The six patients with PP due to NC-CAH (mean age of onset 6.6 6 0.4 years), treated with glucocorticoids to keep bone age with chronological age, reached menarche at a mean age of 12.6 6 1.8 years. Three years after menarche (15.5 6 1.2 years), none of these had developed hirsutism. Oligo- or amenorrhea was present in one of the seven patients, and none developed PCO. These patients reached a final height of 156.1 6 5.9, in keep with target height (157 6 5.1, p , 0.01), and significantly greater than pre-
Table 4 Patients with Precocious Idiopathic Pubarche Patients (70) at diagnosis H (44) T (ng/dL) 27 6 16* A (ng/dL) 95 6 64* DEHA-S (mg/dL) 134 6 45* 17a-OHP (ng/dL) unstimulated 61 6 29* 17a-OHP (ng/dL) stimulated 95 6 32 LH (mIU/mL) / FSH (mIU/mL) / LH/FSH / Age (years) 6.7 6 1.0 Bone age (years) 7.9 6 1.9 Final height (cm) / Degree of hirsutism /
at Menarche
NH (26)
H (44)
NH (26)
H (44)
NH (26)
19 6 8 82 6 43* 134 6 64* 58 6 26* 98 6 28 / / / 6.9 6 0.7 7.8 6 1.2 / /
37 6 15*† 143 6 23*† 215 6 105 75 6 31 115 6 25 6.8 6 1.2*† 3.1 6 0.8 1.3 6 0.5 11.9 6 0.9 / / /
20 6 7 110 6 25 205 6 93 68 6 21 110 6 22 5.1 6 0.9 3.3 6 1.2 1.1 6 0.6 11.9 6 0.9 / / /
51 6 25*† 231 6 65*† 245 6 112 85 6 24 125 6 22 8.0 6 1.0*† 4.6 6 1.2*† 1.6 6 1.1 / / 158 6 4.9 6.3 6 1.2
24 6 10 152 6 73§ 240 6 120 88 6 28 112 6 18 6.9 6 2.0* 3.9 6 1.1* 1.2 6 0.9 / / 158 6 6.1 /
§p , 0.05 vs. controls. *p , 0.001 vs. controls. †p , 0.001 vs. NH. H, patients developing hirsutism; NH, patients not developing hirsutism.
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3 Years after menarche
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Controls (34) Prepub (14) Pub (20) 14 6 3 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
Hyperandrogenism in the adolescent female: Toscano et al. Table 5 Patients with Precocious Idiopathic Pubarche and Prepubertal Hypertricosis Patients (46) at diagnosis
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Age (years) Bone age (years) Final height (cm) Degree of hirsutism
at Menarche
3 Years after menarche
Controls (34)
H (37)
NH (9)
H (37)
NH (9)
H (37)
NH (9)
Prepub (14)
Pub (20)
28 6 17‡ 96 6 77* 145 6 46* 60 6 45* 108 6 32 / / / 7.0 6 1.1 8.2 6 1.1 / /
18 6 8.7 79 6 55‡ 109 6 69§ 70 6 33* 122 6 37 / / / 7.0 6 0.3 8.1 6 0.9 / /
37 6 18*† 152 6 20*† 206 6 42 85 6 32 110 6 45 5.9 6 1.2 2.6 6 0.9 1.1 6 0.7 12 6 0.9 / / /
21 6 6.0 112 6 28 187 6 53 68 6 12 110 6 22 6.1 6 1.3 3.1 6 1.1 1.4 6 1.1 12 6 1.0 / / /
48 6 24*† 228 6 67*† 315 6 85* 99 6 45 120 6 47 8.0 6 1.0* 4.6 6 1.2‡ 1.6 6 1.1 / / 158 6 4.6 6.3 6 1.2
19 6 5.0 152 6 74§ 309 6 89* 60 6 28 112 6 18 7.1 6 2.1* 4.2 6 1.9‡ 1.3 6 0.9 / / 159 6 3.9 /
14 6 3.0 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
§p , 0.05 vs. controls. ‡p , 0.01 vs. controls. *p , 0.001 vs. controls. †p , 0.001 vs. NH. H, patients developing hirsutism; NH, patients not developing hirsutism.
gomenorrhea was higher in patients with a history of PP, suggesting that PCO may be a consequence of a more severe and probably long-lasting hyperandrogenism and that the menstrual cycle disturbances may also be correlated. Exaggerated adrenarche has been considered14 to trigger the onset of PCO by providing the substrate from which excess estrone arises; PP thus seems to be more a harbinger of adult androgen excess than of the early onset of a normal process, as previously suggested.15 In support of this interpretation is the recent finding that children with premature adrenarche are at high risk of developing a PCOS-like type of functional ovarian hyperandrogenism at puberty.11 It has been postulated that a common mechanism is
responsible for the dysregulation of androgen formation by 17a-hydroxylase and 17,20 lyase, primarily involving cytochrome P450c17, in both the adrenal glands and ovaries16 –22. Ibanez et al. have suggested that the increased P450c17 activity might begin in the adrenal during childhood to cause PP, and subsequently occur in the ovary provoking functional ovarian hyperandrogenism.12 Prepubertal hypertrichosis (a condition that usually precedes the development of PP and in which adrenal and ovarian hyperfunction can be completely excluded, despite the significant increase in DHT plasma we have documented; Reference 8) represents a risk factor for the development of postpubertal functional ovarian hyperandrogenism and thus has led us to suggest
Table 6 Patients with Precocious Pubarche Due to NC-CAH Patients (6) at diagnosis H (0) T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Age (years) Bone age (years) Final height (cm) Degree of hirsutism
NH (6) 103 6 61* 565 6 174* 182 6 65* 2592 6 1072* / / / / 6.4 6 0.5 11 6 1.2 / /
at Menarche H (0)
NH (6) 58 6 25* 310 6 49* 215 6 58 1857 6 720* / 6.3 6 1.2* 4.1 6 0.9† 1.2 6 0.5 13 6 1.8 / / /
3 Years after menarche H (0)
Controls (34)
NH (6)
Prepub (14)
Pub (20)
61 6 16* 434 6 163* 288 6 125† 2016 6 348* / 7.8 6 1.4* 3.2 6 1.1 1.6 6 0.9 / / 156 6 5.9 /
14 6 3.0 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
†p , 0.01 vs. controls. *p , 0.001 vs. controls. H, patients developing hirsutism; NH, patients not developing hirsutism.
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Steroids in maturity that dysregulation of P450c17 is more a consequence of increased peripheral androgen production than as primary synthetic defect.23 Patients with PP secondary to 21OH-CAH treated early with glucocorticoids did not develop hirsutism or PCO; patients with hirsutism secondary to this enzymatic defect show a high incidence of PP, significantly different to idiopathic hirsutism, which strongly supports our hypothesis that PH with functional ovarian hyperandrogenism is the consequence of prolonged exposure to elevated androgen levels. Hyperinsulinemia and modest insulin resistance have been described in all the conditions we have examined,12,24 and some authors12 consider this metabolic alteration as the primary cause of both adrenal and ovarian functional hyperandrogenism. This hypothesis, however, is not supported by the present data, which accord with our previous observation that hyperinsulinemia and the modest insulin resistance is contributory to rather than causative of abnormal adrenal and/or gonadal steroidogenesis9; in turn it appears to be the consequence of long-lasting hyperandrogenism, which similarly seems to trigger the induction of PCO and menstrual cycle disturbances, as our findings in 21OH-CAH strongly suggest. The recent results of Moghetti et al.25 that antiandrogen (spironolactone, flutamide) treatment partially reversed the peripheral insulin resistance, regardless of which antiandrogen was used, further support this hypothesis. In a few cases of hyperandrogenism associated with obesity and acanthosis nigricans hyperinsulinemia may be the prime mover in the induction of PCO in such patients, but such a mechanism is limited to very small group of hirsute patients. The hormonal results in the retrospective study showed no differences between hirsute patients with or without a history of PP. In contrast, patients in the prospective study followed 3 years from menarche who have developed hirsutism showed significantly higher values of T and A than either controls or patients with no hair overgrowth; these latter patients showed significantly increased values of A with respect to controls, suggesting that this group may be at risk of hirsutism in the future. This is again consistent with hirsutism being an evolving syndrome, in which the clinical manifestations strictly correlate with the severity of hyperandrogenism and the length of exposure to high circulating androgens. No differences are observed between groups when hirsutism has already developed, as observed in our two groups of hirsute patients with or without a history of PP in the retrospective study. We were thus unable to find at the time of diagnosis any hallmark among PP patients of those at higher risk of developing hirsutism postpubertally. A history of PH clinically manifest from birth in patients with PP is a clear predictor of hirsutism postpubertally. Plasma levels of testosterone higher than in controls in the perimenarchal period should alert the clinician to the possibility of the development of hirsutism. Given the large number of patients with idiopathic pubarche who develop hirsutism, the possibility that these patients need to be treated, by analogy with 21OH-CAH, must be approached with caution, and the treatment of choice is matter of debate. Spironolactone has been proposed as effective treatment for patients with PH,26 and inhibitors of 5a-reductase type I, when available, may
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be of interest in the light of our previous results showing significantly higher levels of DHT in these patients.8 In conclusion, PP represents a risk factor for the development of postpubertal hirsutism, and an association with PH seems to further increase the probability. Patients with hirsutism due to 21OH-CAH have a higher incidence of PP compared with other hirsute patients, although glucocorticoid treatment prevents the development of hirsutism. Patients with hirsutism and a history of PP show a higher incidence of PCO and menstrual cycle disturbances than other hirsute patients, a finding suggesting that hirsutism may be an evolving syndrome and that pharmacological treatment may stop its evolution. Further studies are necessary to establish the treatment of choice and which cases in particular may profit from the treatment.
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Keywords: hirsutism; precocious pubarche; prepubertal hypertrichosis
Introduction Hirsutism, defined as the presence of excessive hair growth in women, is a common presenting complaint in adolescence. Androgen production in females begins around 6 – 8 years of age at adrenarche followed by a gradual increase throughout adolescence, when the ovaries start to contribute to the circulating androgen pool. Hirsutism usually begins around menarche and gradually progresses over the teenage years.1,2 It is an effect of androgen excess, but its presence is dependent also on race, skin sensitivity, and on duration of exposure to and level of hyperandrogenemia. Idiopathic hirsutism may thus reflect a combination of mildly increased androgen production from adrenals and/or ovaries and increased skin sensitivity to androgens. Adrenal causes of hyperanAddress reprint requests to Vincenzo Toscano, MD, III Endocrinologia, Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Universita` La Sapienza, 00161 Rome, Italy. E-mail: [email protected] Steroids 63:308 –313, 1998 © 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
drogenism include unusual forms of Cushing syndrome and the nonclassic forms of congenital adrenal hyperplasia (NC-CAH), of which 21-hydroxylase deficiency is the most common cause.1,2 Polycystic ovary syndrome (PCO) is the most frequent cause/consequence of abnormal androgen production; weight gain and, in some cases, inherited predisposition to insulin resistance worsens the hyperandrogenism and subsequent development of hirsutism.3–5 The end-result of long-lasting hyperandrogenism is not only hirsutism but also oligoamenorrhea, anovulation, and infertility, leading to a serious medical problem in terms of both treatment and of treatment cost. Premature pubarche (PP) is defined as the appearance of pubic and/or axillary hair before 8 years of age, and may be the first clinical manifestation of hyperandrogenism in females. It may reflect an adrenal enzyme deficiency or, more frequently, a benign process caused by early adrenal maturation or increased peripheral sensitivity to adrenal hormones.6,7 Similarly, prepubertal hypertrichosis (PH) may 0039-128X/98/$19.00 PII S0039-128X(98)00032-4
Hyperandrogenism in the adolescent female: Toscano et al. represent another benign prepubertal process caused by an increased skin sensitivity to circulating androgens.8 The aim of the present investigation was to evaluate if prepubertal clinical manifestations of increased hair growth may constitute predictive markers for the development of hirsutism in adolescent girls. Two groups of patients were studied: the first group was of hirsute females, all very young, who presented with or without history of a PP (a retrospective study). The second group comprised patients diagnosed as having PP or PH, followed up 3 years after menarche (a prospective study).
Experimental Patients The retrospective study included 139 hirsute patients (mean age 17 6 1.8 years). All were asked for the age at which their first pubic hair appeared, and only those with an exact record were included in the study. The prospective study included 70 girls with PP with or without PH and 6 girls with PP secondary to nonclassic congenital adrenal hyperplasia due to 21 hydroxylase deficiency (NC-CAH) diagnosed at the age of 6.7 6 0. 9 years and at age of 6.6 6 0.4 years, respectively and followed up for 3 years after menarche (mean age 14.8 6 0.9 years at the end of study). The NC-CAH patients were all treated with glucocorticoids (hydrocortisone at doses from 12 to 20 mg/m2 body surface), because at some stage of management bone age/chronological age ratio was greater than one.
Materials and methods Testosterone, androstenedione, dehydroepiandrosterone sulphate, and 17a-hydroxyprogesterone (basal and 1 h after 0.25 mg of Synacthen®) were evaluated by radioimmunoassay; luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated by immunoradio metric assay in the early follicular phase as described previously.6,9 In the same phase of the menstrual cycle, pelvic ultrasonography was also performed in all patients. Results are reported as mean 6 SD. Statistical analysis was performed byANOVA to compare the results between groups and x2 to compare the distribution of menstrual irregularities or ultrasonographic results.
Table 1 Patients with Idiopathic Hirsutism and Normal Cycles Patients (92)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (11)
NP (81)
Controls (25)
49 6 18* 254 6 117* 415 6 233* 60 6 36
45 6 16 202 6 86* 313 6 147* 55 6 33
41 6 11 141 6 44 161 6 52 45 6 12
106 6 42
99 6 46
/
8.4 6 2.0 5.0 6 1.0 1.7 6 1.2 8.4 6 3.1
6.1 6 2.0 3.7 6 1.0 1.3 6 0.6 7.7 6 3.1
6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
*p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
menarche lower (10.1 6 1.1 vs. 11.3 6 1.4, n.s.). Oligo- or amenorrhea was present in the 45% of the cases with PP and in 63% of the remaining cases, again not statistically significant. Hormonal data. Testosterone, androstenedione, dehydroepiandrosterone sulphate, unstimulated and stimulated 17 a-hydroxyprogesterone, LH, FSH, and LH/FSH ratios are reported in Tables 1–3.
Patients with PP (a prospective study) Clinical data. The 70 patients with precocious idiopathic pubarche (mean age of onset 6.7 6 0.9 years) showed menarche at a mean age of 11.8 6 0.93 years, compared with the age of mother’s menarche (12.2 6 2.62 years) and within the range of the normal Italian population (12.4 6 1 years).10 By three years after menarche (14.8 6 0.9 years), 44 (63%) of these patients had developed hirsutism; 37 (84%) of these 44 cases showed PH at first presentation, present in only 9 (35%) of the 26 patients who did not develop hirsutism. Oligo- or amenorrhea was present in 17
Results Patients with hirsutism (a retrospective study) Clinical data. Of the 139 hirsute patients, 131 had idiopathic hirsutism and 8 had NC-CAH. Twenty four (19%) had a history of PP. The degree of hirsutism was comparable in patients with PP and the other patients (7.8 6 1.9 vs 7.6 6 0.4, respectively), whereas age at menarche was significantly lower (p , 0.001) in patients with PP (10.6 6 1.4 vs. 11.8 6 1.4 years). PCO was present in 14 of 24 (58%) patients with PP and 26 of 115 (23%) of the remaining patients (p , 0.001). Oligo- or amenorrhea was present in 53% of the cases with PP and in 25% of the remaining cases (p , 0.001). Of the eight patients with NC-CAH, five showed the history of PP, an incidence substantially higher than patients with idiopathic hirsutism (p , 0.001). The degree of hirsutism tended to be higher in patients with PP than in those without (9.8 6 3 vs 7.8 6 2, n.s.) and the mean age at
Table 2 rhea
Patients with Idiopathic Hirsutism and Oligoamenor-
Patients (39)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (13)
NP (26)
Controls (25)
46 6 27 210 6 40* 365 6 104* 46 6 28
49 6 25 220 6 36* 355 6 124* 55 6 27
41 6 11 141 6 44 161 6 52 45 6 12
102 6 12
102 6 12
10 6 2.0* 4.7 6 0.8 3.1 6 0.3* 8.4 6 3.6
12 6 3* 4.4 6 1.2 3.1 6 0.5* 8.1 6 3.0
/ 6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
*p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
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309
Steroids in maturity dicted height (BP) (149.3 6 5.64, p , 0.05) at the time of presentation.
Table 3 Patients with Hirsutism Due to NC-CAH Patients (8)
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Degree of hirsutism
PP (5)
NP (3)
Controls (25)
48 6 11 294 6 60* 317 6 215* 851 6 240*
70 6 30§ 339 6 107* 362 6 214* 1198 6 672*
41 6 11 141 6 44 161 6 52 45 6 12
4250 6 1150
5285 6 1425
/
9.8 6 3.0 6.9 6 5.8 1.9 6 1.0 9.8 6 3.0
8.8 6 5.0 4.6 6 1.4 1.9 6 1.0 7.8 6 2.0
6.3 6 2.8 5.3 6 2.1 1.1 6 0.3 /
Hormonal data. Testosterone, androstenedione, dehydroepiandrosterone sulfate, unstimulated and stimulated 17 a-hydroxyprogesterone, LH, FSH and LH/FSH ratios at diagnosis, menarche and 3 years later are reported in Tables 4–6.
Discussion Our study on the follow-up of PP and on the evaluation of its incidence in hirsute patients clearly demonstrates that PP represents a prepubertal manifestation of hirsutism and cannot be considered a benign condition not requiring treatment. PH, which may complicate or precede PP, is clearly associated with an increased incidence of hirsutism and PCO development in adolescent girls. As already reported by Ibanez,11 PP did not cause precocious menarche in our patients, although in our retrospective study on hirsute patients with a history of PP, the age of menarche was significantly lower than in the remainder. The inevitable imprecision of data based on patients’ recall may account for this difference, even if the data collection was equivalent in both groups (hirsute patients with or without a history of PP). The possibility that hyperandrogenic status could induce mild advancement of bone age and of the pubertal development has to be considered, especially when androgen levels were particularly high. This seems to be confirmed by the small group of patients with hirsutism due to NC-CAH and PP, for whom the age of menarche was even lower. Oligo- or amenorrhea and/or dysfunctional bleeding was present in PP patients independent of the development of hirsutism, whereas PCO as expected was higher in patients developing hirsutism than in others.12,13 In patients with hirsutism, in contrast, the incidence of both PCO and oli-
§p , 0.02 vs. controls. *p , 0.001 vs. controls. PP, precocious pubarche; NP, normal pubarche.
of 70 patients (24%); in hirsute patients the percentage was 25%, and 26% if only hirsute patients with PH are considered. PCO was present in 16 out of 70 (23%), in 13 out of 44 hirsute patients (30%), and in 12 out of 37 patients with hirsutism and PH (32%). These patients reached a final height of 158.6 6 5.9, in keeping with both target (159.2 6 4.3, p , 0.001) and predicted (BP) height (160.3 6 5.7, p , 0.001) at first presentation. The six patients with PP due to NC-CAH (mean age of onset 6.6 6 0.4 years), treated with glucocorticoids to keep bone age with chronological age, reached menarche at a mean age of 12.6 6 1.8 years. Three years after menarche (15.5 6 1.2 years), none of these had developed hirsutism. Oligo- or amenorrhea was present in one of the seven patients, and none developed PCO. These patients reached a final height of 156.1 6 5.9, in keep with target height (157 6 5.1, p , 0.01), and significantly greater than pre-
Table 4 Patients with Precocious Idiopathic Pubarche Patients (70) at diagnosis H (44) T (ng/dL) 27 6 16* A (ng/dL) 95 6 64* DEHA-S (mg/dL) 134 6 45* 17a-OHP (ng/dL) unstimulated 61 6 29* 17a-OHP (ng/dL) stimulated 95 6 32 LH (mIU/mL) / FSH (mIU/mL) / LH/FSH / Age (years) 6.7 6 1.0 Bone age (years) 7.9 6 1.9 Final height (cm) / Degree of hirsutism /
at Menarche
NH (26)
H (44)
NH (26)
H (44)
NH (26)
19 6 8 82 6 43* 134 6 64* 58 6 26* 98 6 28 / / / 6.9 6 0.7 7.8 6 1.2 / /
37 6 15*† 143 6 23*† 215 6 105 75 6 31 115 6 25 6.8 6 1.2*† 3.1 6 0.8 1.3 6 0.5 11.9 6 0.9 / / /
20 6 7 110 6 25 205 6 93 68 6 21 110 6 22 5.1 6 0.9 3.3 6 1.2 1.1 6 0.6 11.9 6 0.9 / / /
51 6 25*† 231 6 65*† 245 6 112 85 6 24 125 6 22 8.0 6 1.0*† 4.6 6 1.2*† 1.6 6 1.1 / / 158 6 4.9 6.3 6 1.2
24 6 10 152 6 73§ 240 6 120 88 6 28 112 6 18 6.9 6 2.0* 3.9 6 1.1* 1.2 6 0.9 / / 158 6 6.1 /
§p , 0.05 vs. controls. *p , 0.001 vs. controls. †p , 0.001 vs. NH. H, patients developing hirsutism; NH, patients not developing hirsutism.
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3 Years after menarche
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Controls (34) Prepub (14) Pub (20) 14 6 3 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
Hyperandrogenism in the adolescent female: Toscano et al. Table 5 Patients with Precocious Idiopathic Pubarche and Prepubertal Hypertricosis Patients (46) at diagnosis
T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Age (years) Bone age (years) Final height (cm) Degree of hirsutism
at Menarche
3 Years after menarche
Controls (34)
H (37)
NH (9)
H (37)
NH (9)
H (37)
NH (9)
Prepub (14)
Pub (20)
28 6 17‡ 96 6 77* 145 6 46* 60 6 45* 108 6 32 / / / 7.0 6 1.1 8.2 6 1.1 / /
18 6 8.7 79 6 55‡ 109 6 69§ 70 6 33* 122 6 37 / / / 7.0 6 0.3 8.1 6 0.9 / /
37 6 18*† 152 6 20*† 206 6 42 85 6 32 110 6 45 5.9 6 1.2 2.6 6 0.9 1.1 6 0.7 12 6 0.9 / / /
21 6 6.0 112 6 28 187 6 53 68 6 12 110 6 22 6.1 6 1.3 3.1 6 1.1 1.4 6 1.1 12 6 1.0 / / /
48 6 24*† 228 6 67*† 315 6 85* 99 6 45 120 6 47 8.0 6 1.0* 4.6 6 1.2‡ 1.6 6 1.1 / / 158 6 4.6 6.3 6 1.2
19 6 5.0 152 6 74§ 309 6 89* 60 6 28 112 6 18 7.1 6 2.1* 4.2 6 1.9‡ 1.3 6 0.9 / / 159 6 3.9 /
14 6 3.0 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
§p , 0.05 vs. controls. ‡p , 0.01 vs. controls. *p , 0.001 vs. controls. †p , 0.001 vs. NH. H, patients developing hirsutism; NH, patients not developing hirsutism.
gomenorrhea was higher in patients with a history of PP, suggesting that PCO may be a consequence of a more severe and probably long-lasting hyperandrogenism and that the menstrual cycle disturbances may also be correlated. Exaggerated adrenarche has been considered14 to trigger the onset of PCO by providing the substrate from which excess estrone arises; PP thus seems to be more a harbinger of adult androgen excess than of the early onset of a normal process, as previously suggested.15 In support of this interpretation is the recent finding that children with premature adrenarche are at high risk of developing a PCOS-like type of functional ovarian hyperandrogenism at puberty.11 It has been postulated that a common mechanism is
responsible for the dysregulation of androgen formation by 17a-hydroxylase and 17,20 lyase, primarily involving cytochrome P450c17, in both the adrenal glands and ovaries16 –22. Ibanez et al. have suggested that the increased P450c17 activity might begin in the adrenal during childhood to cause PP, and subsequently occur in the ovary provoking functional ovarian hyperandrogenism.12 Prepubertal hypertrichosis (a condition that usually precedes the development of PP and in which adrenal and ovarian hyperfunction can be completely excluded, despite the significant increase in DHT plasma we have documented; Reference 8) represents a risk factor for the development of postpubertal functional ovarian hyperandrogenism and thus has led us to suggest
Table 6 Patients with Precocious Pubarche Due to NC-CAH Patients (6) at diagnosis H (0) T (ng/dL) A (ng/dL) DEHA-S (mg/dL) 17a-OHP (ng/dL) unstimulated 17a-OHP (ng/dL) stimulated LH (mIU/mL) FSH (mIU/mL) LH/FSH Age (years) Bone age (years) Final height (cm) Degree of hirsutism
NH (6) 103 6 61* 565 6 174* 182 6 65* 2592 6 1072* / / / / 6.4 6 0.5 11 6 1.2 / /
at Menarche H (0)
NH (6) 58 6 25* 310 6 49* 215 6 58 1857 6 720* / 6.3 6 1.2* 4.1 6 0.9† 1.2 6 0.5 13 6 1.8 / / /
3 Years after menarche H (0)
Controls (34)
NH (6)
Prepub (14)
Pub (20)
61 6 16* 434 6 163* 288 6 125† 2016 6 348* / 7.8 6 1.4* 3.2 6 1.1 1.6 6 0.9 / / 156 6 5.9 /
14 6 3.0 23 6 11 86 6 10 36 6 20 / / / / / / / /
22 6 7.0 110 6 34 183 6 45 100 6 45 / 5.0 6 1.0 3.0 6 0.7 1.2 6 0.9 / / / /
†p , 0.01 vs. controls. *p , 0.001 vs. controls. H, patients developing hirsutism; NH, patients not developing hirsutism.
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Steroids in maturity that dysregulation of P450c17 is more a consequence of increased peripheral androgen production than as primary synthetic defect.23 Patients with PP secondary to 21OH-CAH treated early with glucocorticoids did not develop hirsutism or PCO; patients with hirsutism secondary to this enzymatic defect show a high incidence of PP, significantly different to idiopathic hirsutism, which strongly supports our hypothesis that PH with functional ovarian hyperandrogenism is the consequence of prolonged exposure to elevated androgen levels. Hyperinsulinemia and modest insulin resistance have been described in all the conditions we have examined,12,24 and some authors12 consider this metabolic alteration as the primary cause of both adrenal and ovarian functional hyperandrogenism. This hypothesis, however, is not supported by the present data, which accord with our previous observation that hyperinsulinemia and the modest insulin resistance is contributory to rather than causative of abnormal adrenal and/or gonadal steroidogenesis9; in turn it appears to be the consequence of long-lasting hyperandrogenism, which similarly seems to trigger the induction of PCO and menstrual cycle disturbances, as our findings in 21OH-CAH strongly suggest. The recent results of Moghetti et al.25 that antiandrogen (spironolactone, flutamide) treatment partially reversed the peripheral insulin resistance, regardless of which antiandrogen was used, further support this hypothesis. In a few cases of hyperandrogenism associated with obesity and acanthosis nigricans hyperinsulinemia may be the prime mover in the induction of PCO in such patients, but such a mechanism is limited to very small group of hirsute patients. The hormonal results in the retrospective study showed no differences between hirsute patients with or without a history of PP. In contrast, patients in the prospective study followed 3 years from menarche who have developed hirsutism showed significantly higher values of T and A than either controls or patients with no hair overgrowth; these latter patients showed significantly increased values of A with respect to controls, suggesting that this group may be at risk of hirsutism in the future. This is again consistent with hirsutism being an evolving syndrome, in which the clinical manifestations strictly correlate with the severity of hyperandrogenism and the length of exposure to high circulating androgens. No differences are observed between groups when hirsutism has already developed, as observed in our two groups of hirsute patients with or without a history of PP in the retrospective study. We were thus unable to find at the time of diagnosis any hallmark among PP patients of those at higher risk of developing hirsutism postpubertally. A history of PH clinically manifest from birth in patients with PP is a clear predictor of hirsutism postpubertally. Plasma levels of testosterone higher than in controls in the perimenarchal period should alert the clinician to the possibility of the development of hirsutism. Given the large number of patients with idiopathic pubarche who develop hirsutism, the possibility that these patients need to be treated, by analogy with 21OH-CAH, must be approached with caution, and the treatment of choice is matter of debate. Spironolactone has been proposed as effective treatment for patients with PH,26 and inhibitors of 5a-reductase type I, when available, may
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be of interest in the light of our previous results showing significantly higher levels of DHT in these patients.8 In conclusion, PP represents a risk factor for the development of postpubertal hirsutism, and an association with PH seems to further increase the probability. Patients with hirsutism due to 21OH-CAH have a higher incidence of PP compared with other hirsute patients, although glucocorticoid treatment prevents the development of hirsutism. Patients with hirsutism and a history of PP show a higher incidence of PCO and menstrual cycle disturbances than other hirsute patients, a finding suggesting that hirsutism may be an evolving syndrome and that pharmacological treatment may stop its evolution. Further studies are necessary to establish the treatment of choice and which cases in particular may profit from the treatment.
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