22 adult females with therapy-resistant acne vulgaris were treated for 12 months with Diane, a drug containing cyproterone acetate and ethinylestradiol. Treatment was withdrawn in 7 patients because of side-effects of lack of of effect. In the remaining 15 patients, the treatment had extremely promising results, from 70 to 90% improvement of the acne. In a remarkably high number of patients, the androgen production, measured by the urinary excretion of fractional <em>17</em>-<em>ketosteroids</em>, was elevated. None of these patients had signs of endocrinological diseases, in particular no cases of hirsutism of Stein-Leventhal syndrome were found. The current concept of the course of acne is that the conversion in the skin of testosterone to dehydrotestosterone is increased. The finding of an elevated urinary excretion of androgenic substances in this group of acne patients indicates that the pathogenesis is far more complicated.

BACKGROUND

The height growth pattern in 24 patients with the salt-wasting from of congenital adrenal hyperplasia was retrospectively evaluated from the neonatal period to attainment of adult height.

METHODS

All patients were on mineralcorticoid therapy and received hydrocortisone (mg/m2 body surface and day. Mean +/- SD): 34.53 +/- 8.2 during the first year of life, 22.83 +/- 4.1 from then to the puberty onset and 21.83 +/- 3.6 during puberty. Height was measured every 3-4 months and compared with that of the normal age- and sex-matched controls.

RESULTS

Height differences with respect to reference population (M +/- SD) were: +0.38 +/- 0.82 in the neonatal period; -2.21 +/- 1.1 at one year of age; -0.76 +/- 1.25 at three years of age; -0.45 +/- 0.99 at the onset of puberty and -1.34 +/- 0.79 at attainment of adult height. Adult height differed significantly (p < 0.01) from control values and in girls from those of their mothers (p < 0.05). Hyperandrogenism, evaluated through urinary <em>17</em>-<em>ketosteroids</em>, testosterone, delta 4 androstenedione and DA-S, was not documented during prepuberty and puberty.

CONCLUSIONS

Our patients showed a lower growth rate than those of the control population during the two periods of higher growth potentiality: the first year of life and puberty, and this results in adult height impairment.

The absence of uterus has been regarded by a number of authors as a condition for the diagnosis of testicular feminization, although cases with a rudimentary uterus have been reported. However, their number within the framework of this syndrome cannot be exactly determined. In the present report on a 22 year-old patient with testicular feminization and uterus bicornis solidus a double uterus malformation identical with that described in the Mayer-Rokitansky-küster syndrome was found. Forms of testicular feminization with rudimentary uterus in genetically-male individuals may be explained by the absence of androgens, or the absence of reactivity on the part of the target organ, and a simultaneous disturbance (lessening) of the function of the so-called X-factor (oviduct repressor) during early embryonal development. Our own observations, as well as reports in the literature, suggest a theory according to which testicular feminization may be regarded as a series of morphological variants, from male-oriented forms with vaginal aplasie, hypertrophy of the clitoris and male distribution of pubic hair, to female-orientated ones with a vagina of normal length and a rudimentary uterus. The absence of a uterus as a condition for the definition of the syndrome can be maintained only so far as no cases have, as yet been observed with a normally-developed uterus in a typical position. The karyogram showed a small Y-chromosome. Functional anomalies may only be surmised, since Y-anomalies are frequent (3% in a random collection). The morphology of the testes mirrored the functional embryonal insufficiency (pre-pubertal, undifferentiated testicular tissue with a varying amount of stroma and Leydig cells); the basal excretion of testosterone, <em>17</em>-<em>ketosteroid</em> fractions and pregnane in the 24-hour urine was within the normal range for males. Oestrogen production over and above the "adrenal values" was also present. The values for plasma testosterone, which are in accordance with those of males of a similar age, are considered as indicating the importance of "androgen resistance in the periphery" as a factor in the aetiology of testicular feminization.

To examine androgenic potential of polycystic ovaries (PCO), slices of follicular and stromal tissues from the same ovary obtained by wedge resection from two markedly, two moderately and one slightly enlarged PCO were incubated separately with [1-14C] acetate. Incorporation into progestins, androgens and estrogens was assessed by reverse dilution technique with recrystallization to constant specific activity. Although the greatest incorporation into androstenedione with much lesser incorporation into testosterone and dehydroepiandrosterone was observed with all the five follicles, the amount of incorporation into the three steroids increased gradedly with histologically defined magnitude of thecal cell hyperplasia in atretic follicles. Only the stromal tissues from two markedly enlarged PCO produced androgens with a similar pattern of 14C distribution among the steroids, thereby incorporation into the three androgens remaining 5.5% or less of that by the follicles from the same ovary. Preoperative levels of plasma androstenedione and urinary <em>17</em>-<em>ketosteroids</em> were shown to increase in four patients with PCO containing atretic follicles with thecal cell hyperplasia, but not in one patient with slightly enlarged PCO containing atretic follicles without thecal cell hyperplasia. It is inferred that atretic follicles with thecal cell hyperplasia is a significant source of androgen overproduction by PCO.

The aim of this research was to study both insulin secretion and insulin resistance index (IRI) in seventeen females, aged 16-30, affected by polycystic ovarian syndrome. The diagnosis was made using clinical, hormonal, radiological and echographic criteria. Eight healthy women, carefully matched with our patients for age and for statistical obesity incidence, were studied as controls. Both glycemic and insulinemic curves, areas, insulinemic/glycemic area ratio (IRI) were studied by tolbutamide test (1 g i.v.). Areas were assessed by planimeter, blood glucose by Trinder method, blood insulin by a RIA method, statistical study by t Student test and correlation coefficients. These latter were determined by comparing individual plasma testosterone, FSH, LH and LH/FSH ratio values together with urinary total <em>17</em>-<em>ketosteroid</em> and delta HEA output values on the one hand and insulin areas and IRI values on the other. Increased glycemic areas, insulinemic peaks and areas, associated with markedly increased IRI values, were observed in the patients. A correlation exists between hyperinsulinism, insulin resistance on the one hand and increased urinary androgens output on the other. delta HEA resulted particularly increased over other androgenic fractions.

Dexamethasone suppression (DS) adrenal cortical scintigraphy has been shown to be useful in the detection of the adrenal pathology in women with hyperandrogenism. However, a relationship between adrenal cortical uptake of I-131 6 beta-iodomethylnorcholesterol (NP-59) and the level of adrenal androgen secretion has not been established. A retrospective analysis of DS adrenal scintiscans has been performed on 39 women with hirsutism and hyperandrogenism. In 14 patients with normal patterns of imaging, in vivo adrenal gland iodocholesterol uptake, calculated using a semi-operator-independent-computer algorithm, did not correlate with the excretion of urinary <em>17</em>-<em>ketosteroids</em> (<em>17</em>-KS). In contrast, in 20 patients demonstrating abnormal bilateral early imaging patterns, adrenal gland NP-59 uptake correlated significantly with the level of urinary <em>17</em>-KS excretion (r = 0.65, P less than 0.05). To date seven of these 20 patients have had confirmatory procedures documenting the adrenal glands as contributing sites of androgen secretion. A similar correlation with urinary <em>17</em>-KS excretion was seen in five other patients with unilateral imaging patterns (r = 0.94, P less than 0.005), due to androgen-secreting adrenal cortical adenomas. No correlation between adrenal NP-59 uptake and plasma testosterone or dehydroepiandrosterone sulphate levels was observed in any of the groups. Thus, adrenal gland uptake of NP-59 under DS reflects a measure of androgen secretion in women with androgen excess.

An adrenal medullary ganglioneuroma containing Leydig cells and revealed by a virilizing syndrome in a 56-year old woman is presented. The syndrome, associating with masculinization an elevated serum testosterone level and a normal urinary <em>17</em> <em>ketosteroids</em>, is uncommon in adrenal tumours. The tumour was located by computed tomographic (CT) scan and treated by right adrenalectomy. Microscopic examination showed typical features of an adrenal medullary ganglioneuroma containing Leydig cells with Reinke crystalloids. Positive immunohistochemical study confirmed the testosterone secreting nature of the cells. The presence of Leydig cells in the adrenal gland is discussed according embryogenic studies: 1. the common origin of the gonad and the adrenal cortex from the coelomic epithelium, 2. the vicinity of adrenocortical gland and gonad during embryogenesis, 3. the thecal metaplasia of mesenchymal cells, 4. the development of Leydig cells from Schwann cells. Fourth case published in the world literature.

In normal females, androstenedione from both the adrenal cortex and ovary, as a result of peripheral conversion, is the source of the majority of biologically active testosterone in the circulation. The control of the secretion of precursor steroid and androgenic hormone (testosterone) in females is not clear at this time. There are a number of possibilities to explain various types of hirsutism and virilization. The presence of true virilization indicates a significant disorder and requires complete investigation. The presence of increased amounts of <em>17</em>-<em>ketosteroids</em> in the urine implicates the adrenal cortex as a source of the pathologic manifestations. The suppressibility of elevated <em>17</em>-<em>ketosteroids</em> with cortisol analogues aids in distinguishing between adrenal hyperplasia and autonomous neoplasm of the adrenal cortex. By far the most common entity in this area is simple hirsutism without virilization. Although our knowledge of this disorder is quite incomplete, conservative management is indicated. Further progress in this field is rapidly occurring. An informed clinician can do an adequate job of diagnosis and treatment with the clinical and laboratory tools generally available.

We examined the effect of medical adrenalectomy on the clinical and hormonal responses in 50 men with disseminated prostatic carcinoma. Patients refractory to initial hormonal therapy were treated with aminoglutethimide and hydrocortisone (AG-HC) and evaluated by the criteria of the National Prostatic Cancer Project. Eight patients showed a partial response (PR), and <em>17</em> remained stable while receiving these medications. Survival times for these two groups averaged 87.8 and 38 weeks, respectively. In contrast, <em>17</em> men were unresponsive to this therapy, exhibiting progressive disease with a mean survival time of 18 weeks. Eight patients could not tolerate the drug regimen or were lost to follow-up. Serum and urinary hormone profiles determined serially during AG-HC therapy revealed that all measured serum androgens and estrogens were significantly lowered by AG-HC treatment; however, specific hormones, including free testosterone, dihydrotestosterone, estrone, and estradiol were suppressed to a greater degree in responders (R) as compared with nonresponders (NR). Urinary excretion of <em>17</em>-<em>ketosteroids</em> did not change during AG-HC therapy, but specific androgen metabolites, including testosterone glucuronide and androstanediol glucuronide, were suppressed by 50% during AG-HC therapy. We showed modest clinical benefit of AG-HC therapy in advanced prostatic cancer. That greater hormonal suppression was associated with greater responsiveness to this therapy raises the hope that further manipulations directed against suppression of extratesticular androgens may be a useful approach as second-line treatment of advanced prostatic cancer.

In order to ascertain the usefulness of urinary <em>17</em>-<em>ketosteroids</em> (<em>17</em>-KS) in the evaluation of hirsutism, 28 paired determinations of <em>17</em>-KS and serum androgens were performed in 26 hirsute women before (control) and after (post Dex) 7 days of dexamethasone (Dex) administration. Upper normal control and post Dex urinary <em>17</em>-KS and serum steroid levels were as follows: <em>17</em>-KS, 15 and 5 mg/24 hour urine collection; dehydroepiandrossterone sulfate (DHEA-S), 2500 and 400 ng/ml serum; testosterone (T), 0.5 and 0.3 ng/ml; dihydrotestosterone (DHT), 0.35 and 0.2 ng/ml; androstenedione (A), 2.3 and 1.6 ng/ml; androst-5-ene-3beta-<em>17</em>beta-diol (delta5-diol), 1.6 and 0.4 ng/ml; and cortisol (F), 140 and 40 ng/ml. In 5 of the 28 tests, control <em>17</em>-KS levels were elevated. In these 5 tests, control serum levels of one or more androgens were also elevated. DHEA-S was the only steroid of which the serum levels were elevated in all these 5 patients. Control <em>17</em>-KS were within normal limits in 23 tests. Of these, 19 had elevated serum androgens. Nine patients with elevated post Dex urinary <em>17</em>-KS also had elevated post Dex levels of serum androgens. Of 19 patients with normal post Dex <em>17</em>-KS, 14 had elevated post Dex serum androgen levels. These data indicate that 1) urinary <em>17</em>-KS determinantions do not reliably identify patients with elevated serum androgens; 2) Dex suppression of <em>17</em>-KS does not correlate well with Dex suppression of serum androgens; and 3) for the evaluation of hyperandrogenism, measurements of serum androgens give a better understanding of the type of androgens involved and the source of hyperandrogenism.

The question of hormonal dysregulation in patients with CRPS I in whole was investigated very scantily. There are only a few studies concerning catecholamines, oestrogens and endorphins independently. Other hormones were studied in patients with different other chronic pain conditions. Considering the accumulation of sufficient knowledge about the role of disadaptation processes in CRPS I pathogenesis and the role of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in the process of adaptation it was logical and consistent to define the role of hormonal dysregulation of these systems in patients with CRPS I.

Our objective was to determine the role of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of complex regional pain syndrome type I (CRPS I) in women.

We investigated the pituitary gonadotropic function and the function of sex glands in women with CRPS I and healthy volunteers by measuring the plasma levels of estradiol (E2 ), follicle-stimulating hormone, luteinizing hormone, prolactin, adrenocorticotropic hormone, and cortisol, and urinary excretion of <em>17</em>-<em>ketosteroids</em>, <em>17</em>-oxycocorticosteroids, epinephrine and norepinephrine.

Women with CRPS I were characterized by the decreased content of oestrogens in the blood plasma and increased pituitary gonadotrophic function. The disturbed ratio of anabolic and catabolic steroids in women with CRPS I was detected due to lower adrenal cortex function.

In patients with CRPS I endocrine status is characterized by hormonal imbalances of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems. The changes in reproductive and adaptation homeostasis characterize CRPS I as a form of the disease of disadaptation.

This study determined the role of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of CRPS I.

We conducted a study to determine the effect of exogenous cortisol on circadian blood pressure changes in patients with hypopituitarism. Under replacement with hydrocortisone of 15 to 25mg either once (8:00) or twice a day (8:00 and 20:00), and with prednisolone of 3.75 to 5mg once a day, the patients underwent non-invasive ambulatory blood pressure monitoring for 24 hours. The average 24-hour blood pressure before hydrocortisone replacement was 92.9 +/- 1.0 (systolic)/53.2 +/- 0.8mmHg (diastolic), while that after hydrocortisone replacement once or twice a day and prednisolone replacement significantly increased to 108.2 +/- 1.4/63.5 +/- 0.9mmHg, 109.1 +/- 1.6/62.3 +/- 1.0mmHg, and 105.4 +/- 1.2/62.3 +/- 0.9mmHg, respectively. Hydrocortisone replacement once a day showed a significant increase in day-night differences of blood pressure, while hydrocortisone replacement twice a day did not. There were no differences in nocturnal decrease in pulse rate between these two replacements. The daytime and nighttime urinary excretions of <em>17</em>-hydroxycorticosteroids in hydrocortisone replacement once a day were 7.7mg/12hr (daytime) and 1.4mg/12hr (nighttime), respectively, while those in hydrocortisone replacement twice a day were 3.9mg/12hr (daytime) and 3.6mg/12hr (nighttime), respectively. Urinary <em>17</em>-<em>ketosteroids</em>, epinephrine and norepinephrine did not show any differences between hydrocortisone replacement once and twice a day. These results suggest that hydrocortisone administration is one of the factors which modulate the circadian variation of blood pressure in patients with hypopituitarism, and may also suggest that the circadian change of cortisol secretion participates, at least in part, in the formation of an intrinsic circadian rhythm of blood pressure.

Clinical, biochemical and electrocardiographic parameters were studied in 10 patients with uncomplicated acute myocardial infarction with hyperglycemia (but normal glycosylated hemoglobin), and 15 age- and sex-matched patients with uncomplicated acute myocardial infarction without hyperglycemia. The magnitude of hyperglycemia correlated with the site and extent of the infarct, the magnitude of ST-segment elevation and the levels of <em>17</em>-<em>ketosteroids</em> in the urine.

To assess the validity of serum dehydroepiandrosterone sulphate (DS) radioimmunoassay instead of urinary total <em>17</em>-<em>ketosteroid</em> (<em>17</em>-KS) or individual metabolite (dehydroepiandrosterone + etiocholanolone + androsterone; D + E + A) determination to control adrenal androgen function, a comparative study has been performed. Mathematical analysis of simultaneous estimates revealed significant correlation when normal or above normal <em>17</em>-KS or D + E + A excretion relative to serum DS were considered. Poor correlation was observed when below normal metabolite excretion and serum DS were related. Furthermore, there was a significant correlation between estimates of <em>17</em>-KS (or D + E + A) and those of serum unconjugated D also determined by radioimmunoassay. The serum DS radioimmunoassay appeared to be a reliable tool to assess adrenal androgen function, at least in patients exhibiting normal or high <em>17</em>-<em>ketosteroid</em> values.