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Insulin Resistance, Premature Adrenarche, and a Risk of the Polycystic Ovary Syndrome (PCOS)
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Insulin Resistance, Premature Adrenarche, and a Risk of the Polycystic Ovary Syndrome (PCOS) Lourdes Ibáñez, Neus Potau and Antonio Carrascosa
Timing of puberty and final height are usually normal in girls with a history of premature adrenarche. However, these patients show an increased frequency of ovarian hyperandrogenism, hyperinsulinism and dyslipemia at adolescence. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period, recommending long-term follow-up of these patients into adulthood.
L. Ibáñez and A. Carrascosa are at the Adolescent and Endocrine Unit and N. Potau is at the Hormonal Laboratory, Hospital Materno-Infantil Vall d’Hebron, Universitat Autònoma, Barcelona, Spain.
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In some cases of premature pubarche, normal androgen levels are found, suggesting increased peripheral sensitivity to preadrenarcheal levels of these hormones (Rosenfield et al. 1982). Enzymatic defects of steroidogenesis are other known causes of premature pubarche, with a variable reported frequency among populations (Temeck et al. 1987, Morris et al. 1989, Ibáñez et al. 1995a).
In the absence of enzymatic defects of adrenal steroidogenesis, and according to follow-up results in small groups of patients, the pubertal outcome of girls with premature adrenarche has been reported to be normal (Pang 1984). We undertook a study including 127 girls with isolated premature adrenarche from two European populations with similar ethnic characteristics, of whom 69 had entered puberty, 42 had reached menarche and 38 had attained final height (Ibáñez et al. 1992). Advanced bone age and tall stature were already present at diagnosis, persisted during the first years of follow-up, and subsequently waned (Ibáñez et al. 1992). The onset of gonadarche at age 9.7 ±0.9 years (mean ±SD) and the appearance of menarche at 12.0 ±1.0 years (mean ±SD) were comparable to maternal and population data (De la Puente et al. 1997). Furthermore, adult heights correlated with height prognosis rendered at diagnosis and at the onset of puberty, and final adult heights were generally above
97 90 Height percentile
Premature pubarche is defined as the early appearance of pubic hair, before eight years in girls and nine years in boys, with or without axillary hair and apocrine pubertal odor, and with no other signs of sexual development (Ibáñez et al. 1992). It occurs much more frequently in females than in males. In the majority of cases, premature pubarche is secondary to an early isolated maturation of the zona reticularis of the adrenal gland (premature adrenarche), with increased adrenal androgen secretion for chronological age (Korth-Schutz et al. 1976, Rosenfield et al. 1982, Pang 1984). Adrenal androgens, particularly dehydroepiandrosterone (DHEA) and androstenedione (D4-A) and testosterone are moderately increased for chronological age, but fall within the expected range according to the pubertal stage of pubic hair (Virdis et al. 1993, Ibáñez et al. 1995a and 1997a). Alternatively, some patients may present with DHEA-sulfate (DHEAS) levels exceeding those of pubertal controls with the same Tanner pubic hair stage (Virdis et al. 1993, Ibáñez et al. 1995a and 1997a).
Auxological Outcome and Pubertal Milestones of Girls with Premature Adrenarche
75 50
n = 38
25 10 3
Diagnosis
Onset of puberty
Actual final height
Height prognosis Figure 1. Final height in 38 girls with premature adrenarche. Comparison with the prediction of final height at premature adrenarche diagnosis and the prediction of final height at onset of puberty. Reproduced with permission from Ibáñez et al. (1992).
© 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00014-9
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Ovarian Function in Girls Diagnosed with Premature Adrenarche
Although data on the auxological outcome appeared to be reassuring, an increased incidence of hirsutism and polycystic ovary syndrome (PCOS) in peripubertal and pubertal premature adrenarche girls, although not well documented, have been pointed out by some authors (Yen 1980, Ibáñez et al. 1990). PCOS as a Form of Functional Ovarian Hyperandrogenism PCOS is the most common cause of hyperandrogenism in reproductive age women, with an incidence of 3% in both adolescents and adults (Rosenfield and Lucky 1993, Ibáñez et al. 1994). In its fully developed form, PCOS is characterized by menstrual abnormalities, hirsutism, obesity, hyperandrogenemia, elevated plasma luteinizing hormone (LH) concentrations and ultrasonographic evidence of polycystic ovaries (Yen 1980, McKenna 1988, Barbieri 1991). However, it is clinically, histologically and biochemically heterogeneous; some women with the typical clinical picture have been considered to have PCOS in the absence of polycystic ovaries or abnormalities of gonadotropin secretion (Goldzieher and Green 1962), and that has contributed to considerable controversy surrounding the pathogenesis and diagnostic criteria of the syndrome (Hall 1993, Ehrmann et al. 1995, Homburg 1996, Ibáñez et al. 1996a, Rosenfield 1997). In adult women with well-defined PCOS, masculinized pituitary–gonadal responses to gonadotropin-releasing hormone (GnRH) agonist (nafarelin) TEM Vol. 9, No. 2, 1998
Premature Adrenarche and Functional Ovarian Hyperandrogenism Postpubertal follow-up of premature adrenarche girls has revealed an increased incidence of FOH at adolescence (45% versus 3% in the normal adolescent population) (Ibáñez et al. 1993). The entity seems to occur more frequently in girls with elevated DHEAS and/or D4-A levels at premature adrenarche diagnosis (Ibáñez et al. 1993) (Figure 2). The studies of the ovarian steroid secretion in these patients throughout puberty indicate that girls diagnosed with premature adrenarche have an exaggerated ovarian androgen synthesis compared with Tanner-stage and body age-matched controls (Ibáñez et al. 1997d). The ovarian androgen hyper-responsiveness is already detectable early in puberty, is most
evident during mid and late puberty and is characterized by higher basal, peak and incremental responses of most steroid intermediates to GnRH agonist challenge (Ibáñez et al. 1997d). These data are suggestive of abnormal regulation of ovarian cytochrome
A 325
17-OHP (ng dl−1)
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testing have been found (Barnes et al. 1989). Significant increases in D4-A and, principally, 17-hydroxyprogesterone (17-OHP) following GnRH agonist stimulation suggested abnormal regulation (dysregulation) of ovarian cytochrome P450c17α activity in these patients (Barnes et al. 1989, Ehrmann et al. 1992 and 1995). Dysfunction of individual thecal cells escaping from downregulation of steroidogenesis, predominantly at the level of 17α-hydroxylase, and mainly 17,20 lyase activities of cytochrome P450c17α would produce overactive steroidogenesis, resulting in what has been called ‘functional ovarian hyperandrogenism’ (FOH) (Ehrmann et al. 1995). Several lines of evidence suggest that PCOS is a form of FOH (Ehrmann et al. 1992 and 1995). As recently reported, this entity would include patients with the abnormal ovarian PCOS-type responses to a GnRH agonist, regardless of whether elevated LH levels or polycystic ovaries are present (Ehrmann et al. 1992 and 1995, Rosenfield 1997). This pattern of ovarian-steroidogenic response appears to be particularly frequent in both hyperandrogenic women and adolescents (Ehrmann 1992, Ibáñez et al. 1994 and 1995b).
260
195 r = 0.67 p < 0.001 130
65
50 110 170 230 290 350 410 D4-A (ng dl−1)
B 325
17-OHP (ng dl−11)
midparental heights, following the secular trend still present in both populations (Figure 1) (Ibáñez et al. 1992). Therefore, premature adrenarche appears to cause a transient acceleration in growth and bone maturation with no negative effects on the onset and progression of puberty and final height.
260
195 r = 0.47 p < 0.005
130
65
75
150
225
300
DHEAS (µg dl−1) Figure 2. Correlation between baseline androstenedione (D4-A; A) and dehydroepiandrosterone-sulfate (DHEAS; B) levels at the diagnosis of premature adrenarche and 17-hydroxyprogesterone (17-OHP) values after leuprolide acetate challenge. Modified from Ibáñez et al. (1993).
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P450c17α and support a pubertal onset of FOH. As the same cytochrome catalyzes the 17α-hydroxylase and 17,20 lyase enzymatic activities in the adrenals (Miller 1988), it has been hypothesized that, in premature adrenarche girls, dysregulation of this androgen-forming enzyme might begin in the adrenal during the prepubertal period, causing premature adrenarche development, and might subsequently occur in the gonads, provoking FOH (Ibáñez et al. 1993). •
Premature Adrenarche and Hyperinsulinemia
Hyperinsulinemia, insulin resistance and adrenal hyperandrogenism are common features both in obese and lean women and adolescents with PCOS and FOH (Lucky et al. 1986, Jialal et al. 1987, Dunaif et al. 1989, Nestler et al. 1989, O’Meara et al. 1993, Rittmaster et al. 1993, Apter et al. 1995, Ibáñez et al 1995b, Morales et al. 1996). The defects producing insulin resistance in PCOS appear to be genetic, involving the early steps of insulin receptor-mediated signaling, and are associated with increased kinaseinduced serine phosphorylation of the insulin receptor (Dunaif 1995). It has been proposed that hyperinsulinemia per se might cause both ovarian and adrenal hyperandrogenism (Dunaif 1992, Rosenfield 1996). Hyperinsulinemia and Ovarian Hyperandrogenism Hyperinsulinemia increases ovarian androgen production, acting either through the ovarian insulin receptors or through the ovarian insulin-like growth factor I (IGF-I) receptors (Cara and Rosenfield 1988, Poretsky and Piper 1994), and decreases IGF-Ibinding protein (IGFBP-1) and sex hormone-binding globulin (SHBG) concentrations (Suikkari et al. 1988, Nestler 1993). Moreover, insulin has been well documented to enhance the androgenic response of ovarian thecal cells to LH, and the folliclestimulating hormone (FSH)-mediated induction of LH responsiveness in granulosa cells (Barbieri et al. 1986, Willis et al. 1996).
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Hyperinsulinemia and Adrenal Hyperandrogenism Experimental hyperinsulinemia acutely suppresses adrenal 17,20 lyase function, resulting in relative increases in 17-OHP levels, and acutely reduces serum DHEA and DHEAS concentrations (Nestler et al. 1992, Jakubowicz et al. 1995). Insulin, together with IGF-I and IGF-II, has been shown to augment adrenal steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture (L’Allemand et al. 1996, Mesiano et al. 1997). In hyperandrogenic women, hyperinsulinemia, within the high physiological range, potentiates ACTHstimulated steroidogenesis, causing an increase in 17α-hydroxylase activity and a relative impairment in 17,20 lyase activity, suggested by the finding of increased ACTH-stimulated 17hydroxypregnenolone:DHEA and 17OHP:D4-A ratios after insulin infusion (Moghetti et al. 1996). This pattern of adrenal-steroidogenic response, which has been called functional adrenal hyperandrogenism (FAH), resembles an exaggeration of adrenarche (Ehrmann et al. 1995). Hyperinsulinemia as a Common Link for the Frequent Coexistence of Functional Adrenal and Ovarian Hyperandrogenism To explain the frequent coexistence of adrenal and ovarian hyperandrogenism in women with androgen excess, it has been postulated that a common mechanism results in dysregulation of androgen formation by 17α-hydroxylase and 17,20 lyase, involving cytochrome P450c17α, in both the adrenal glands and ovaries (Ehrmann et al. 1995, Rosenfield 1996). The adrenal secretory abnormality is particularly prominent in the D5 pathway and the ovarian abnormality in the D4 pathway (Ehrmann et al. 1995, Rosenfield 1996). A major candidate as the cause of both adrenal and ovarian dysregulation is hyperinsulinemia (Rosenfield 1996). Insulin and the Peripubertal Onset of PCOS/FOH Puberty has been associated with increasing fasting and glucose-
stimulated insulin concentrations and a decrease in insulin sensitivity (Caprio et al. 1989, Amiel et al. 1991, Potau et al. 1997). The insulin resistance during puberty is restricted to peripheral glucose metabolism, and is associated with concomitant increases in plasma growth hormone, IGF-I and IGFBP-3 levels and a decrease in IGFBP-1 and SHBG concentrations (Holly et al. 1989, Amiel et al. 1991, Potau et al. 1997). The transient hyperinsulinemia and increased IGF-I activity during puberty have been proposed as inducing factors in the development of PCOS/FOH in susceptible subjects (Nobels and Dewailly 1992). Although after puberty the insulin and IGF-I levels progressively decline in most individuals, in some cases, hyperinsulinemia and/or other factors (genetic or environmental) may act as a trigger for the eventual development of ovarian hyperandrogenism (Nobels and Dewailly 1992). Patterns of Insulin Secretion in Premature Adrenarche Hyperinsulinemia in response to an oral glucose load is a common feature in postpubertal girls with a history of premature adrenarche (Ibáñez et al. 1996c). Although the increased insulin levels appear to be more frequent in those patients who develop FOH, up to 27% of premature adrenarche girls with no signs and symptoms of androgen excess also show mean serum insulin levels well above the upper normal limit for controls (Ibáñez et al. 1996c). Mean serum insulin levels are directly related to the degree of ovarian hyperandrogenism (assessed by an abnormal 17-OHP response to GnRH agonist challenge) in FOH patients, and to the free androgen index (equivalent to free testosterone) both in FOH and non-FOH subjects (Ibáñez et al. 1996c). Fifty per cent of these girls also show an ACTHstimulated pattern of adrenal androgen secretion suggestive of FAH (Ibáñez et al. 1997b). Recent studies indicate that the hyperinsulinism can already be detected in the prepubertal period and throughout all stages of pubertal TEM Vol. 9, No. 2, 1998
development (Ibáñez et al. 1997c) (Figure 3). The increased insulin levels are often accompanied by an increased early insulin response to glucose and glucose uptake rate in peripheral tissues, elevated free androgen indexes and decreased IGBP-1 and SHBG levels (Ibáñez et al. 1997c). •
Dyslipemia and Premature Adrenarche
Prospective epidemiological studies suggest that hyperinsulinemia may be an independent risk factor for the development of cardiovascular disease, playing a major role in the genesis of dyslipemia in subjects with both normal and impaired glucose tolerance (Laakso et al. 1990, Després et al. 1996). The cluster of highly atherogenic metabolic abnormalities of syndrome X [hyperinsulinemia, glucose intolerance, increased very low-density lipoproteins (VLDL) and triglycerides, decreased high-density lipoprotein cholesterol (HDL-C) and hypertension] are likely to be secondary to the basic abnormality of insulin resistance (Orchard et al. 1983, Reaven 1988, Haffner et al. 1992, Després 1993). Recent clinical studies in children have provided evidence that the genesis of an atherogenic pattern of risk factors may start in childhood (Arslanian and Suprasongsin 1996). In adult women with PCOS, insulin resistance is usually associated with an
atherogenic lipid profile, characterized by increased triglyceride and lowdensity lipoprotein cholesterol (LDL-C) levels, and decreased HDL-C concentrations (Wild et al. 1992, Robinson et al. 1996). The lipid disturbances seem to be associated more with the hyperinsulinemia than with the degree of androgen excess (Wild et al. 1992). Insulin resistance and dyslipemia seem to account for the higher incidence of premature cardiovascular disease in these patients (Talbott et al. 1995, Birsdall et al. 1997). The study of lipid patterns in premature adrenarche girls has revealed that, in addition to hyperinsulinemia, from childhood, these patients show higher serum triglyceride, VLDL and LDL-C:HDL-C ratios than normal girls (Ibáñez et al. 1996b). These data support the idea that the cluster of highly atherogenic abnormalities of syndrome X may start in childhood, and suggest that premature adrenarche patients might be at a higher risk for premature cardiovascular disease development (Ibáñez et al. 1996b). •
Conclusions
Premature adrenarche is not necessarily a benign condition. Long-term follow-up of these patients is highly recommended owing to the increased incidence of ovarian hyperandrogenism, hyperinsulinemia and dyslipemia. Prospective studies of prema-
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*
*
MSI (mIU l−1)
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0 B1
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Figure 3. Mean (+SE) serum insulin (MSI) levels after an oral glucose load in girls with a history of premature adrenarche throughout all stages of pubertal development, (open bars), compared with normal bone age- and body mass index-matched controls. (closed bars). B1–B5, Tanner breast stages 1 to 5; *, significantly different from controls. Modified from Ibáñez et al. (1997c).
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Insulin Resistance, Premature Adrenarche, and a Risk of the Polycystic Ovary Syndrome (PCOS) Lourdes Ibáñez, Neus Potau and Antonio Carrascosa
Timing of puberty and final height are usually normal in girls with a history of premature adrenarche. However, these patients show an increased frequency of ovarian hyperandrogenism, hyperinsulinism and dyslipemia at adolescence. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period, recommending long-term follow-up of these patients into adulthood.
L. Ibáñez and A. Carrascosa are at the Adolescent and Endocrine Unit and N. Potau is at the Hormonal Laboratory, Hospital Materno-Infantil Vall d’Hebron, Universitat Autònoma, Barcelona, Spain.
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In some cases of premature pubarche, normal androgen levels are found, suggesting increased peripheral sensitivity to preadrenarcheal levels of these hormones (Rosenfield et al. 1982). Enzymatic defects of steroidogenesis are other known causes of premature pubarche, with a variable reported frequency among populations (Temeck et al. 1987, Morris et al. 1989, Ibáñez et al. 1995a).
In the absence of enzymatic defects of adrenal steroidogenesis, and according to follow-up results in small groups of patients, the pubertal outcome of girls with premature adrenarche has been reported to be normal (Pang 1984). We undertook a study including 127 girls with isolated premature adrenarche from two European populations with similar ethnic characteristics, of whom 69 had entered puberty, 42 had reached menarche and 38 had attained final height (Ibáñez et al. 1992). Advanced bone age and tall stature were already present at diagnosis, persisted during the first years of follow-up, and subsequently waned (Ibáñez et al. 1992). The onset of gonadarche at age 9.7 ±0.9 years (mean ±SD) and the appearance of menarche at 12.0 ±1.0 years (mean ±SD) were comparable to maternal and population data (De la Puente et al. 1997). Furthermore, adult heights correlated with height prognosis rendered at diagnosis and at the onset of puberty, and final adult heights were generally above
97 90 Height percentile
Premature pubarche is defined as the early appearance of pubic hair, before eight years in girls and nine years in boys, with or without axillary hair and apocrine pubertal odor, and with no other signs of sexual development (Ibáñez et al. 1992). It occurs much more frequently in females than in males. In the majority of cases, premature pubarche is secondary to an early isolated maturation of the zona reticularis of the adrenal gland (premature adrenarche), with increased adrenal androgen secretion for chronological age (Korth-Schutz et al. 1976, Rosenfield et al. 1982, Pang 1984). Adrenal androgens, particularly dehydroepiandrosterone (DHEA) and androstenedione (D4-A) and testosterone are moderately increased for chronological age, but fall within the expected range according to the pubertal stage of pubic hair (Virdis et al. 1993, Ibáñez et al. 1995a and 1997a). Alternatively, some patients may present with DHEA-sulfate (DHEAS) levels exceeding those of pubertal controls with the same Tanner pubic hair stage (Virdis et al. 1993, Ibáñez et al. 1995a and 1997a).
Auxological Outcome and Pubertal Milestones of Girls with Premature Adrenarche
75 50
n = 38
25 10 3
Diagnosis
Onset of puberty
Actual final height
Height prognosis Figure 1. Final height in 38 girls with premature adrenarche. Comparison with the prediction of final height at premature adrenarche diagnosis and the prediction of final height at onset of puberty. Reproduced with permission from Ibáñez et al. (1992).
© 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00014-9
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Ovarian Function in Girls Diagnosed with Premature Adrenarche
Although data on the auxological outcome appeared to be reassuring, an increased incidence of hirsutism and polycystic ovary syndrome (PCOS) in peripubertal and pubertal premature adrenarche girls, although not well documented, have been pointed out by some authors (Yen 1980, Ibáñez et al. 1990). PCOS as a Form of Functional Ovarian Hyperandrogenism PCOS is the most common cause of hyperandrogenism in reproductive age women, with an incidence of 3% in both adolescents and adults (Rosenfield and Lucky 1993, Ibáñez et al. 1994). In its fully developed form, PCOS is characterized by menstrual abnormalities, hirsutism, obesity, hyperandrogenemia, elevated plasma luteinizing hormone (LH) concentrations and ultrasonographic evidence of polycystic ovaries (Yen 1980, McKenna 1988, Barbieri 1991). However, it is clinically, histologically and biochemically heterogeneous; some women with the typical clinical picture have been considered to have PCOS in the absence of polycystic ovaries or abnormalities of gonadotropin secretion (Goldzieher and Green 1962), and that has contributed to considerable controversy surrounding the pathogenesis and diagnostic criteria of the syndrome (Hall 1993, Ehrmann et al. 1995, Homburg 1996, Ibáñez et al. 1996a, Rosenfield 1997). In adult women with well-defined PCOS, masculinized pituitary–gonadal responses to gonadotropin-releasing hormone (GnRH) agonist (nafarelin) TEM Vol. 9, No. 2, 1998
Premature Adrenarche and Functional Ovarian Hyperandrogenism Postpubertal follow-up of premature adrenarche girls has revealed an increased incidence of FOH at adolescence (45% versus 3% in the normal adolescent population) (Ibáñez et al. 1993). The entity seems to occur more frequently in girls with elevated DHEAS and/or D4-A levels at premature adrenarche diagnosis (Ibáñez et al. 1993) (Figure 2). The studies of the ovarian steroid secretion in these patients throughout puberty indicate that girls diagnosed with premature adrenarche have an exaggerated ovarian androgen synthesis compared with Tanner-stage and body age-matched controls (Ibáñez et al. 1997d). The ovarian androgen hyper-responsiveness is already detectable early in puberty, is most
evident during mid and late puberty and is characterized by higher basal, peak and incremental responses of most steroid intermediates to GnRH agonist challenge (Ibáñez et al. 1997d). These data are suggestive of abnormal regulation of ovarian cytochrome
A 325
17-OHP (ng dl−1)
•
testing have been found (Barnes et al. 1989). Significant increases in D4-A and, principally, 17-hydroxyprogesterone (17-OHP) following GnRH agonist stimulation suggested abnormal regulation (dysregulation) of ovarian cytochrome P450c17α activity in these patients (Barnes et al. 1989, Ehrmann et al. 1992 and 1995). Dysfunction of individual thecal cells escaping from downregulation of steroidogenesis, predominantly at the level of 17α-hydroxylase, and mainly 17,20 lyase activities of cytochrome P450c17α would produce overactive steroidogenesis, resulting in what has been called ‘functional ovarian hyperandrogenism’ (FOH) (Ehrmann et al. 1995). Several lines of evidence suggest that PCOS is a form of FOH (Ehrmann et al. 1992 and 1995). As recently reported, this entity would include patients with the abnormal ovarian PCOS-type responses to a GnRH agonist, regardless of whether elevated LH levels or polycystic ovaries are present (Ehrmann et al. 1992 and 1995, Rosenfield 1997). This pattern of ovarian-steroidogenic response appears to be particularly frequent in both hyperandrogenic women and adolescents (Ehrmann 1992, Ibáñez et al. 1994 and 1995b).
260
195 r = 0.67 p < 0.001 130
65
50 110 170 230 290 350 410 D4-A (ng dl−1)
B 325
17-OHP (ng dl−11)
midparental heights, following the secular trend still present in both populations (Figure 1) (Ibáñez et al. 1992). Therefore, premature adrenarche appears to cause a transient acceleration in growth and bone maturation with no negative effects on the onset and progression of puberty and final height.
260
195 r = 0.47 p < 0.005
130
65
75
150
225
300
DHEAS (µg dl−1) Figure 2. Correlation between baseline androstenedione (D4-A; A) and dehydroepiandrosterone-sulfate (DHEAS; B) levels at the diagnosis of premature adrenarche and 17-hydroxyprogesterone (17-OHP) values after leuprolide acetate challenge. Modified from Ibáñez et al. (1993).
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P450c17α and support a pubertal onset of FOH. As the same cytochrome catalyzes the 17α-hydroxylase and 17,20 lyase enzymatic activities in the adrenals (Miller 1988), it has been hypothesized that, in premature adrenarche girls, dysregulation of this androgen-forming enzyme might begin in the adrenal during the prepubertal period, causing premature adrenarche development, and might subsequently occur in the gonads, provoking FOH (Ibáñez et al. 1993). •
Premature Adrenarche and Hyperinsulinemia
Hyperinsulinemia, insulin resistance and adrenal hyperandrogenism are common features both in obese and lean women and adolescents with PCOS and FOH (Lucky et al. 1986, Jialal et al. 1987, Dunaif et al. 1989, Nestler et al. 1989, O’Meara et al. 1993, Rittmaster et al. 1993, Apter et al. 1995, Ibáñez et al 1995b, Morales et al. 1996). The defects producing insulin resistance in PCOS appear to be genetic, involving the early steps of insulin receptor-mediated signaling, and are associated with increased kinaseinduced serine phosphorylation of the insulin receptor (Dunaif 1995). It has been proposed that hyperinsulinemia per se might cause both ovarian and adrenal hyperandrogenism (Dunaif 1992, Rosenfield 1996). Hyperinsulinemia and Ovarian Hyperandrogenism Hyperinsulinemia increases ovarian androgen production, acting either through the ovarian insulin receptors or through the ovarian insulin-like growth factor I (IGF-I) receptors (Cara and Rosenfield 1988, Poretsky and Piper 1994), and decreases IGF-Ibinding protein (IGFBP-1) and sex hormone-binding globulin (SHBG) concentrations (Suikkari et al. 1988, Nestler 1993). Moreover, insulin has been well documented to enhance the androgenic response of ovarian thecal cells to LH, and the folliclestimulating hormone (FSH)-mediated induction of LH responsiveness in granulosa cells (Barbieri et al. 1986, Willis et al. 1996).
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Hyperinsulinemia and Adrenal Hyperandrogenism Experimental hyperinsulinemia acutely suppresses adrenal 17,20 lyase function, resulting in relative increases in 17-OHP levels, and acutely reduces serum DHEA and DHEAS concentrations (Nestler et al. 1992, Jakubowicz et al. 1995). Insulin, together with IGF-I and IGF-II, has been shown to augment adrenal steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture (L’Allemand et al. 1996, Mesiano et al. 1997). In hyperandrogenic women, hyperinsulinemia, within the high physiological range, potentiates ACTHstimulated steroidogenesis, causing an increase in 17α-hydroxylase activity and a relative impairment in 17,20 lyase activity, suggested by the finding of increased ACTH-stimulated 17hydroxypregnenolone:DHEA and 17OHP:D4-A ratios after insulin infusion (Moghetti et al. 1996). This pattern of adrenal-steroidogenic response, which has been called functional adrenal hyperandrogenism (FAH), resembles an exaggeration of adrenarche (Ehrmann et al. 1995). Hyperinsulinemia as a Common Link for the Frequent Coexistence of Functional Adrenal and Ovarian Hyperandrogenism To explain the frequent coexistence of adrenal and ovarian hyperandrogenism in women with androgen excess, it has been postulated that a common mechanism results in dysregulation of androgen formation by 17α-hydroxylase and 17,20 lyase, involving cytochrome P450c17α, in both the adrenal glands and ovaries (Ehrmann et al. 1995, Rosenfield 1996). The adrenal secretory abnormality is particularly prominent in the D5 pathway and the ovarian abnormality in the D4 pathway (Ehrmann et al. 1995, Rosenfield 1996). A major candidate as the cause of both adrenal and ovarian dysregulation is hyperinsulinemia (Rosenfield 1996). Insulin and the Peripubertal Onset of PCOS/FOH Puberty has been associated with increasing fasting and glucose-
stimulated insulin concentrations and a decrease in insulin sensitivity (Caprio et al. 1989, Amiel et al. 1991, Potau et al. 1997). The insulin resistance during puberty is restricted to peripheral glucose metabolism, and is associated with concomitant increases in plasma growth hormone, IGF-I and IGFBP-3 levels and a decrease in IGFBP-1 and SHBG concentrations (Holly et al. 1989, Amiel et al. 1991, Potau et al. 1997). The transient hyperinsulinemia and increased IGF-I activity during puberty have been proposed as inducing factors in the development of PCOS/FOH in susceptible subjects (Nobels and Dewailly 1992). Although after puberty the insulin and IGF-I levels progressively decline in most individuals, in some cases, hyperinsulinemia and/or other factors (genetic or environmental) may act as a trigger for the eventual development of ovarian hyperandrogenism (Nobels and Dewailly 1992). Patterns of Insulin Secretion in Premature Adrenarche Hyperinsulinemia in response to an oral glucose load is a common feature in postpubertal girls with a history of premature adrenarche (Ibáñez et al. 1996c). Although the increased insulin levels appear to be more frequent in those patients who develop FOH, up to 27% of premature adrenarche girls with no signs and symptoms of androgen excess also show mean serum insulin levels well above the upper normal limit for controls (Ibáñez et al. 1996c). Mean serum insulin levels are directly related to the degree of ovarian hyperandrogenism (assessed by an abnormal 17-OHP response to GnRH agonist challenge) in FOH patients, and to the free androgen index (equivalent to free testosterone) both in FOH and non-FOH subjects (Ibáñez et al. 1996c). Fifty per cent of these girls also show an ACTHstimulated pattern of adrenal androgen secretion suggestive of FAH (Ibáñez et al. 1997b). Recent studies indicate that the hyperinsulinism can already be detected in the prepubertal period and throughout all stages of pubertal TEM Vol. 9, No. 2, 1998
development (Ibáñez et al. 1997c) (Figure 3). The increased insulin levels are often accompanied by an increased early insulin response to glucose and glucose uptake rate in peripheral tissues, elevated free androgen indexes and decreased IGBP-1 and SHBG levels (Ibáñez et al. 1997c). •
Dyslipemia and Premature Adrenarche
Prospective epidemiological studies suggest that hyperinsulinemia may be an independent risk factor for the development of cardiovascular disease, playing a major role in the genesis of dyslipemia in subjects with both normal and impaired glucose tolerance (Laakso et al. 1990, Després et al. 1996). The cluster of highly atherogenic metabolic abnormalities of syndrome X [hyperinsulinemia, glucose intolerance, increased very low-density lipoproteins (VLDL) and triglycerides, decreased high-density lipoprotein cholesterol (HDL-C) and hypertension] are likely to be secondary to the basic abnormality of insulin resistance (Orchard et al. 1983, Reaven 1988, Haffner et al. 1992, Després 1993). Recent clinical studies in children have provided evidence that the genesis of an atherogenic pattern of risk factors may start in childhood (Arslanian and Suprasongsin 1996). In adult women with PCOS, insulin resistance is usually associated with an
atherogenic lipid profile, characterized by increased triglyceride and lowdensity lipoprotein cholesterol (LDL-C) levels, and decreased HDL-C concentrations (Wild et al. 1992, Robinson et al. 1996). The lipid disturbances seem to be associated more with the hyperinsulinemia than with the degree of androgen excess (Wild et al. 1992). Insulin resistance and dyslipemia seem to account for the higher incidence of premature cardiovascular disease in these patients (Talbott et al. 1995, Birsdall et al. 1997). The study of lipid patterns in premature adrenarche girls has revealed that, in addition to hyperinsulinemia, from childhood, these patients show higher serum triglyceride, VLDL and LDL-C:HDL-C ratios than normal girls (Ibáñez et al. 1996b). These data support the idea that the cluster of highly atherogenic abnormalities of syndrome X may start in childhood, and suggest that premature adrenarche patients might be at a higher risk for premature cardiovascular disease development (Ibáñez et al. 1996b). •
Conclusions
Premature adrenarche is not necessarily a benign condition. Long-term follow-up of these patients is highly recommended owing to the increased incidence of ovarian hyperandrogenism, hyperinsulinemia and dyslipemia. Prospective studies of prema-
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*
*
MSI (mIU l−1)
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ture adrenarche girls should be undertaken to clarify the pathogenetic link(s) between hyperandrogenism and hyperinsulinism.
* 40
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0 B1
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Figure 3. Mean (+SE) serum insulin (MSI) levels after an oral glucose load in girls with a history of premature adrenarche throughout all stages of pubertal development, (open bars), compared with normal bone age- and body mass index-matched controls. (closed bars). B1–B5, Tanner breast stages 1 to 5; *, significantly different from controls. Modified from Ibáñez et al. (1997c).
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Ibáñez L, Potau N, Georgopoulos N, Prat N, Gussinyé M, Carrascosa A: 1995b. Growth hormone, insulin-like growth factor-I axis, and insulin secretion in hyperandrogenic adolescents. Fertil Steril 64:1113–1119. Ibáñez L, Hall JE, Potau N, Carrascosa A, Prat N, Taylor AE: 1996a. Ovarian 17hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab 81:4103–4107. Ibáñez L, Chacón P, Potau N, López D, Gussinyé M, Carrascosa A: 1996b. Lipid patterns and their relation to insulin levels in girls with a history of premature pubarche [abst]. Horm Res 46(Supp 2):88. Ibáñez L, Potau N, Zampolli M, et al.: 1996c. Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 81:1237–1243. Ibáñez L, Potau N, Carrascosa A: 1997a. Androgens in adrenarche and pubarche. In Azziz R, Nestler JE, Dewailly D, eds. Androgen Excess Disorders in Women. Philadelphia, Lippincot-Raven, pp 73–84.
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polycystic ovary syndrome. Obstet Gynecol 84:613–621. Potau N, Ibáñez L, Riqué S, Carrascosa A: 1997. Pubertal changes in insulin secretion and peripheral insulin sensitivity. Horm Res 48:219–226. Reaven GM: 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607. Rittmaster RS, Deshwasl N, Lehman L: 1993. The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome. J Clin Endocrinol Metab 76:1295–1300. Robinson S, Henderson AD, Gelding SV, et al.: 1996. Dyslipemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol 44:277–284. Rosenfield RL: 1996. Editorial: Evidence that idiopathic functional adrenal hyperandrogenism is caused by dysregulation of adrenal steroidogenesis and that hyperinsulinemia may be involved. J Clin Endocrinol Metab 81:878–880. Rosenfield RL: 1997. Is polycystic ovary syndrome a neuroendocrine or an ovarian disorder? Clin Endocrinol 47:423–424. Rosenfield RL, Lucky AW: 1993. Acne, hirsutism, and alopecia in adolescent girls. Endocrinol Metab Clin North Am 22:507–532. Rosenfield RL, Rich BH, Lucky AW: 1982. Adrenarche as a cause of benign pseudopuberty in boys. J Pediatr 101: 1005–1009.
Suikkari AM, Koivisto VA, Rutanen EM, YkiJärvinen H, Karonen SL, Seppäla M: 1988. Insulin regulates the serum levels of low molecular weight insulin-like growth factor binding protein. J Clin Endocrinol Metab 66:266–272. Talbott E, Guzick D, Clerici A, et al.: 1995. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 15: 821–826. Temeck JM, Pang S, Nelson C, New MI: 1987. Genetic defects in steroidogenesis in premature pubarche. J Clin Endocrinol Metab 64:609–617. Virdis R, Zampolli M, Ibáñez L, Ghizzoni L, Street ME, Vicens-Calvet E: 1993. Il pubarca prematuro. Riv Ital Pediatr (IJP) 19:569–579. Wild RA, Alaupovic P, Parker IJ: 1992. Lipid and lipoprotein abnormalities in hirsute women. I. The association with insulin resistance. Am J Obstet Gynecol 166:1191–1197. Willis D, Mason H, Gilling-Smith C, Franks S: 1996. Modulation by insulin of folliclestimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 81:302–309. Yen SSC: 1980. Chronic anovulation caused by peripheral endocrine disorders. In Yenn SSC, Jaffe RB, eds. Reproductive Endocrinology. Philadelphia, Saunders, pp 441–499.
http://www.elsevier.com/locate/tto ◆ http://www.elsevier.nl/locate/tto Editor Adrian Bird, Institute for Cell and Molecular Biology at the University of Edinburgh Technical Tips Online publishes short, peer-reviewed, molecular biology techniques articles and related information in a unique Web-based environment. The articles describe novel methods or significant improvements to existing methods in any aspect of molecular biology.
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