Adele Mangiantini

Two different pathogenetic mechanisms may play a role in acne and in hirsutism

OBJECTIVE Acne is one of the most common skin disorders. Androgens are known to play an important and possibly central role. Androgens secreted from ovaries and adrenal glands (androstenedione, dehydroepiandro‐sterone and its sulphate, testosterone) and target tissue‐produced androgens (testosterone and its 5α‐reduced metabolite, dihydrotestosterone) have been implicated. Although the sebaceous gland and the hair follicle form a single morphological entity, the pilosebaceous unit, acne and hirsutism do not always appear concomitantly, thus leading to the supposition that these two structures may have different degrees of sensitivity to similar androgenic stimulation.

Lack of correlation between sex hormone binding globulin, adrenal and peripheral androgens in precocious adrenarche

Sex hormone binding globulin (SHBG) is a specific steroid-binding plasma glycoprotein regulated by several different factors. Sex steroids are currently considered to be the main physiological regulators of this protein. Testosterone (T) in adults seems to be the main hormone active in lowering SHBG. The role of dihydrotestosterone (DHT) in such regulation, particularly in the prepubertal age, is not well understood, and no data exist about the role of 3α-androstanediol (3Aα) and its glucuronide. In adulthood, in addition to T, 5-ene steroids seems to play a role in the regulation of SHBG plasma concentration. To assess the effect of adrenal and peripheral androgens in modulating SHBG levels in the prepubertal age, we studied subjects with precocious pubarche secondary to precocious adrenarche (PA). PA represents, in fact, a good model of study as it is characterized by an increased production and action of adrenal androgen in females under 8 yr of age and in males under 9. Sixty-five subjects (55 females and 10 males; chronologic age: 3.6 - 8.2 yr (6.9+1.3, SD); bone age: 3.6 -11 yr (7.6±1.9); BMI 17.9±3 kg/m2) were studied. Fifteen age-matched normal children (BMI 15.2±0.8 kg/m2) were studied as controls. Androste-nedione (A), dehydroepiandrosterone (DHA) and its sulphate (DHA-S), T, DHT, 3Ad and its glucuronide (3AG) and SHBG were evaluated in all subjects. In PA cases serum SHBG levels (50±27 nM) were significantly lower (p<0.05) with respect to normal prepubertal patients. Glandular androgens, as expected, were significantly higher with respect to controls (p<0.001 for A and DHA; p<0.02 for T; p<0.05 for DHA-S). Peripheral androgens were also significantly higher in PA patients (p<0.001 for DHT and 3Ad; p<0.01 for 3AG). No correlation was found between SHBG and steroids, whereas SHBG correlated inversely with BA (p<0.01) and with BMI (p<0.02). In conclusion, our results in PA i) confirm previous observations about the lack of correlation between SHBG and adrenal steroids, ii) point out the lack of correlation between SHBG and peripheral androgens, iii) led to the conclusion that other factors, such as nutritional state and growth can be considered as playing a major role in regulating SHBG levels in the prepubertal age.

Changes in steroid pattern following acute and chronic adrenocorticotropin administration in premature adrenarche

Biochemically adrenarche is characterized by increased production of 5-ene steroids, in particular Dehydroepiandrosterone (DHA) and its sulphate (DHA-S). It is still not clear if ACTH is responsible for this adrenal steroid production. The aim of the present study was to evaluate the effect of acute and chronic ACTH administration, without dexamethasone pretreatment, on hormonal patterns in 20 patients (5 males aged between 6 8/12 and 7 10/12 years and 15 females aged between 5 9/12 and 7 6/12 years) with idiopathic premature adrenarche. Pregnenolone (5P), DHA, DHA-S, 17-hydroxyprogesterone (17-OHP), androstenedione (A), 11-deoxycortisol (S) and cortisol (F) have been determined by Radioimmunoassay. The results of the hormonal evaluation (means +/- standard error) showed high plasma levels of DHA [329.2 +/- 41.7 ng/100 ml (dl)] and DHA-S (169.1 +/- 54 micrograms/dl) and slightly increased levels of 5P (74.4 +/- 7.1 ng/dl), of A (45.4 +/- 4.6 ng/dl) and 17-OHP (69.3 +/- 11.3 ng/dl) in comparison to those of controls, thus indicating a decrease in 3 beta-hydroxysteroid dehydrogenase activity and an increase in 17-20-lyase and 17-hydroxylase activities, characteristic for adrenarche. Acute and chronic ACTH stimulation did not amplify the characteristic basal hormonal pattern, but they induced a shift of adrenal steroid metabolism to 4-ene pathway, suggesting that the basal hormonal pattern in premature adrenarche may be independent or, at least, not exclusively dependent on ACTH control.

Hyperandrogenism in the Adolescent Female

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 +/- 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 +/- 1.8 years). Testosterone, androstenedione, dehydroepiandrosterone sulphate, 17 alpha-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.

Effect of hCG or hCG + treatments in young thalassemic patients with hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism (HH) is common (40%) in beta-thalassemic patients. Taking into consideration that in HH non-thalassemic patients we obtained good results in pubertal development using hCG treatment (1500 IU every 6 days), 10 HH thalassemic subjects (14 5/12 -17 yr, all with bone age greater than 13 6/12) were treated with the same regimen. In 5 of these patients purified FSH (75 IU every 3 days) was added to hCG in order to evaluate the FSH effect on testosterone (T) response (Group 1 was given hCG alone, Group 2 hCG + FSH: Profasi HP and Metrodin Serono). To evaluate the kinetics of testosterone response, plasma level of T was determined basally and 1, 2, 4 and 6 days after hCG injection. This dynamic study and a clinical examination were carried out at the beginning of treatment and at the 4th and 12th month after. Results obtained in the first group confirmed our previous data from non-thalassemic HH patients: in fact, after 12 months of therapy a stage G2-G3 was reached. In the second group, however, testis size and testosterone secretion were significantly higher than in the first group. At the 4th month, in Group 1 and in Group 2 testis size and the area under the T response curve were 3.18 ± 0.18ml and 13,364 ± 1047 ng/dl vs 4.62 ± 0.25 ml (p < 0.02) and 18,045 ±1110 ng/dl (p < 0.016), respectively. At the 12th month testis size and area under T response curve were increased to 6.12 ± 0.25 ml and 24,017 + 1176 ng/dl in Group 1 and 8.12 ± 0.6 ml (p < 0.01) and 33,924 ± 2181 ng/dl (p < 0.01) in Group 2. After 12 months, a significant comparable increase in growth velocity, without bone age acceleration, was observed in both groups. Our results demonstrate that hCG or hCG + FSH treatments are able to induce a satisfactory sexual development in thalassemic HH patients; moreover FSH in addition to hCG seems to improve not only testis size as expected, but also testosterone production.

Plasma 3α-androstanediol glucuronide in precocious adrenarche

The aim was to study 3α-androstane-diol glucuronide (3AG) plasma levels and its relationship with 5-ene and 4-ene steroids in children with the benign form of precocious pubarche (precocious adrenarche). Sixty-five children with precocious adrenarche (PA), aged 3.6–8.2 yr (55 girls and 10 males) and 15 normal age-matched children were studied. We evaluated plasma androstenedione (A), dehydroepiandrosterone (DHA), its sulfate (DHA-S), testosterone (T), dihydrotestosterone (DHT), its glucuronide (DHTG), 3α-androstanediol (3Ad) and its glucuronide (3AG) in all subjects. All androgens are expressed as mean±SD. We found significantly higher plasma levels not only in glandular androgens but also in peripheral androgens (A, 2.4±1.5 nM vs 0.79±0.46 nM, p<0.001; DHA, 9.8±4.9 vs2.7±0J6 ng/dl, p<0.001; DHA-S, 3.4±2 μM vs 2.4±0.65 μM, p<0.05; T, 0.74±0.5 nM vs 0.4±0.1 nM, p<0.001; DHT, 0.36±0.13 nM vs 0.12±0.05 nM, p<0.001; 3Ad, 0.13±0.1 nM vs 0.054±0.03 nM, p<0.001; DHTG, 0.5±0.3 nM vs 0.26±0.09 nM p<0.01). As far as the plasma 3AG levels are concerned we found significantly higher values in PA with respect to controls (1.17±0.7 nM vsO.61±0.04 nM, p<0.01), suggesting that 3AG may be considered a marker of skin androgen utilization. 3AG plasma levels correlated better with serum A (p<0.002, r=0.42) and T (p<0.003, r=0.41) than with DHA (p<0.03, r=0.37), suggesting that both 4-ene and 5-ene androgens contribute to its production, but its plasma levels are better correlated with 4-ene than with 5-ene steroids. Furthermore 3AG plasma levels correlated with both 3Ad (p<0.01, r=0.4) and DHTG (p<0.001, r=0.47); no correlation was found with DHT, suggesting that in this condition 3AG may originate, in peripheral tissue either via the unconjugated pathway DHT→3Ad→3AG or via the conjugated pathway DHT→DHTG→3AG.

Two Different Pathogenetic Mechanisms May Play a Role in Acne and in Hirsutism

OBJECTIVE Acne is one of the most common skin disorders. Androgens are known to play an important and possibly central role. Androgens secreted from ovaries and adrenal glands (androstenedione, dehydroepiandrosterone and its sulphate, testosterone) and target tissue-produced androgens (testosterone and its 5 alpha-reduced metabolite, dihydrotestosterone) have been implicated. Although the sebaceous gland and the hair follicle form a single morphological entity, the pilosebaceous unit, acne and hirsutism do not always appear concomitantly, thus leading to the supposition that these two structures may have different degrees of sensitivity to similar androgenic stimulation. DESIGN AND PATIENTS To determine whether acne and hirsutism are the clinical expression of a different androgen metabolism at target tissue levels we studied 90 randomly selected patients who came to our Out-patient Department for diagnosis and treatment during the last 2 years with isolated acne of mild to severe degree and 52 patients with idiopathic hirsutism without acne or history of acne. Twenty-four women without acne or hirsutism and without a history of endocrine disease were studied as controls. MEASUREMENTS In both groups of patients, plasma levels of sex hormone binding globulin, of dihydrotestosterone, and of 3 alpha-androstanediol and of its glucuronide were evaluated. In all patients the percentage of free testosterone and the testosterone/sex hormone binding globulin ratio were also calculated. RESULTS Patients with acne and those with isolated hirsutism showed significantly decreased sex hormone binding globulin plasma levels. The values of the percentage free testosterone and those of the testosterone/sex hormone binding globulin ratio were, on the contrary, higher with respect to the controls, although there were no statistically significant differences between the two groups. Significantly increased plasma levels of dihydrotestosterone with respect to the controls were observed in patients with acne or in those with hirsutism. However, while all patients with hirsutism showed increased plasma values of 3 alpha-androstanediol and its glucuronide, all patients with acne showed plasma levels within the normal range, independently of the precursor plasma levels. CONCLUSIONS Our results demonstrate that dihydrotestosterone is further reduced to 3 alpha-androstanediol and its glucuronide only in hirsute patients but not in acne patients. These results suggest that dihydrotestosterone may undergo different metabolic pathways at skin levels and support the hypothesis that the two clinical manifestations may be the expression of the different metabolic fate of dihydrotestosterone itself. Moreover, our results demonstrate that 3 alpha-androstanediol and its glucuronide cannot be used as plasma markers of target-tissue produced androgens in all hyperandrogenic conditions.