Urinary 17-ketosteroids Research Articles

Insulin resistance and secretion in polycystic ovarian disease.

In order to verify the relationship between insulin resistance and hyperandrogenism in Polycystic ovary disease (PCOD), circulating levels of insulin in response to oral glucose tolerance test (OGTT) were assessed in 23 PCOD patients and 10 matched control subjects without obesity, acanthosis nigricans and impaired glucose tolerance. In PCOD patients serum total testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), LH and LH/FSH ratio were significantly higher than in control subjects; whereas urinary 17-ketosteroids (17-KS) and glycemic response to OGTT were not different. PCOD patients were clearly hyperinsulinemic before and during OGTT compared to the control group: mean +/- SD basal insulin (Io) (23.4 +/- 10.3 vs 11.3 +/- 4.6 microU/ml, p less than 0.001) and the sums of insulin levels (sigma I) during OGTT (341.4 +/- 148.9 vs 162.2 +/- 56 microU/ml, p less than 0.001). In the two groups serum T, but not DHEA-S, LH, urinary 17-KS and the degree of obesity, was strongly associated with Io (r = 0.458, p less than 0.01) and sigma I (r = 0.419, p less than 0.02), as well as with insulin resistance as assessed by basal (r = 0.425, p less than 0.02) and postglucose challenge (r = 0.384, p less than 0.05) insulin to glucose ratio. These results confirm that the hyperinsulinism and insulin resistance in PCOD is not related to obesity and suggest that the hyperandrogenism may be partially responsible of the observed imbalance in glucose-insulin homeostasis.

Endocrine effects of high-dose ketoconazole therapy in advanced prostatic cancer.

The endocrine effects of ketoconazole (400 mg orally every 8 h) were studied in 9 previously untreated patients with advanced prostatic cancer. Five of these patients were followed for 12 months. A rapid fall in the serum concentration of testosterone was noted in all patients studied. Minimal values were observed on day 4 of treatment but thereafter serum testosterone increased slowly. The effect of the drug on unbound testosterone was relatively more important, since sex hormone binding globulin increased markedly during treatment. An increase in progesterone and LH was observed in all patients. This suggests that ketoconazole limits the conversion of C21-precursors into androgens. This block is compensated in part by activation of the hypothalamo-hypophyseal feedback system. Urinary 17-ketosteroids were decreased but 17-hydroxysteroids were unaffected by the treatment. In 5 patients followed monthly over a period of 12 months the mean testosterone concentration ranged from 69 ng/100 ml in one patient to 428 ng/100 ml in another. An excellent inverse correlation could be demonstrated between the mean serum concentration of testosterone and the mean concentration of ketoconazole. The change of serum dehydroepiandrosterone sulphate also correlated inversely with the mean ketoconazole level. Increased concentrations of oestradiol were noted in 2 patients with slight gynaecomastia. It is concluded that long-term suppression of androgen production can be realized by high-dose ketoconazole treatment and that the degree of suppression is proportional to the serum levels of the drug.

Lack of relationship of hypogonadism to muscle wasting in myotonic dystrophy.

Myotonic dystrophy is frequently associated with testicular atrophy. Since androgens may play a role in the maintenance of muscle mass, we have studied the levels of plasma testosterone and gonadotropins and of urinary 17-ketosteroids in 22 men with myotonic dystrophy, 36 normal men, and 16 men (control group) with muscle wasting. Results were correlated with muscle mass as estimated by creatinine excretion and total body potassium. Patients with myotonic dystrophy had significantly lower testosterone and higher gonadotropin levels than normal, and these changes were progressive in longitudinal studies. Testosterone levels were also lower than normal in disease control subjects. There was no correlation between low testosterone levels and diminished muscle mass in either myotonic dystrophy or disease control patients. The low plasma concentration of testosterone in men with myotonic dystrophy and other neuromuscular diseases does not appear to be directly related to their muscle wasting. This study does not exclude the possibility that an alteration in testosterone receptor or tissue effects may contribute to a loss of muscle tissue.

Virilizing Adrenocortical Tumors in Childhood: Eight Cases and a Review of the Literature

Eight cases of adrenocortical tumor are presented with a review of the literature. Although such tumors are rare, they are important causes of inappropriate virilization and Cushing's syndrome in childhood. Clinical virilization with or without hypercortisolism was found in all eight children, who were 5 years old or younger. Excessive linear growth was noted, despite evidence of hypercortisolism. Serum levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and cortisol were elevated in all cases tested and appear to be useful diagnostic alternatives to the more traditional determinations of urine 17-ketosteroids and 17-hydroxycorticosteroids. Abdominal sonography and computed tomography have proven to be reliable tools for tumor localization. Surgical resection was the definitive therapy in all patients, and perioperative steroid replacement was essential. Histologic diagnosis appeared to have little bearing on prognosis, and the majority of pediatric patients have had clinically benign disease. At a mean follow-up of 3 years, seven of the eight children were alive and had no evidence of tumor recurrence.

Primary acquired hypoaldosteronism

Primary acquired hypoaldosteronism

Reduced adrenal androgens in patients with myotonic dystrophy.

Endocrine disturbances associated with myotonic dystrophy (MD) include testicular atrophy, hyperinsulinemic glucose intolerance, thyroid abnormalities, and low or low normal urinary 17-ketosteroid (17-KS) excretion. Since the major circulating precursors of urinary 17-KS are dehydroepiandrosterone sulfate (DHAS) and dehydroepiandrosterone (DHA), a decrease in adrenal androgen production has been suggested. This possibility was studied in 19 MD patients and 19 age- and sex-matched normal subjects. Each patient had a 24-h urine collection for 17-KS and cortisol determinations, a 4-h iv infusion of 25 micrograms tetracosactrin with serial measurements of serum DHAS, DHA, and cortisol, and an insulin-induced hypoglycemia test. Sixteen patients had 0800 and 2400 h serum collections for cortisol estimations. Serum DHAS [1.0 +/- 0.5 (+/- SD) vs. 3.9 +/- 1.9 mumol/liter; P less than 0.0005] and DHA (5.9 +/- 2.7 vs. 11.0 +/- 7.1 nmol/liter; P less than 0.005) levels were significantly lower in MD patients than in normal subjects; cortisol levels were higher (540 +/- 222 vs. 394 +/- 128 nmol/liter; P less than 0.01), almost certainly a reflection of stress. A normal diurnal cortisol rhythm was found in all 16 subjects. Cortisol responses to insulin-induced hypoglycemia were normal, increasing from 345 +/- 243 nmol/liter to a maximum of 831 +/- 282 nmol/liter. Urinary 17-KS excretion was low or low normal, while urinary cortisol levels were normal in 18 and mildly elevated in 1 patient. There was a significant correlation between 17-KS and DHAS levels (r = 0.46; P less than 0.05). DHAS, DHA, and cortisol responses to tetracosactrin infusion were similar in patients and normal subjects. It is concluded that 1) in MD patients, serum DHAS and DHA concentrations are significantly lower than those in normal subjects, explaining the frequent reports of low or low normal 17-KS excretion; 2) the reduced DHAS and DHA concentrations are most likely due to decreased production rather than increased clearance; and 3) glucocorticoid production is normal.

Cushing’s disease: clinical and laboratory response to bromocriptine therapy

Four patients with Cushing's disease were treated with bromocriptine, administered three times daily, in doses ranging from 7.5 to 15 mg/day, during an average period of 80 days. Daily urinary 17-hydroxycorticosteroids (17-OHCS) and 17-ketosteroids (17-KS) excretion was measured during dynamic tests and at two-week intervals. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were also assayed before and after therapy. A marked clinical and laboratory improvement was noted in two patients, in another some clinical and laboratory improvement was obtained only after bromocriptine dosage was increased to 15 mg/day. There was no effect in the fourth patient. Thus, at least for a short period of time, bromocriptine may be useful therapy for some patients with Cushing's disease.

Primary aldosteronism due to adrenal carcinomas.

In the present study two patients with aldosterone-producing adrenal carcinomas are reported. The clinical features were characterized by hypertension and severe hypokalemia with muscular weakness, flaccid paralysis of arms and legs, diarrhea and polyuria. In both cases excessively high plasma aldosterone levels and suppressed plasma renin activity were found. In contrast to most other cases with aldosterone-secreting tumours plasma cortisol, urinary free cortisol excretion, 17-hydroxy- and 17-ketosteroids were in the normal range. There was no clinical evidence of oversecretion of sex hormones. After adrenalectomy blood pressure and serum potassium normalized and the clinical symptoms disappeared. Plasma aldosterone and urinary aldosterone secretion returned to normal, while plasma renin activity remained low. Three and a half and 6 months later primary aldosteronism and the associated clinical symptoms reappeared due to hormonally active metastases. After introducing the antitumour drug o,p'-DDD in patient 1 aldosterone secretion normalized and the clinical status of the patient markedly improved. However, 10 months after diagnosis the patient died due to a haemorrhage from a liver metastasis. In patient 2 tumour-invaded regional lymph nodes were surgically removed with only minor changes in the hormone pattern.

The relationship of I-131 6 beta-iodomethyl-19-norcholesterol (NP-59) adrenal cortical uptake to indices of androgen secretion in women with hyperandrogenism.

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 17-ketosteroids (17-KS). In contrast, in 20 patients demonstrating abnormal bilateral early imaging patterns, adrenal gland NP-59 uptake correlated significantly with the level of urinary 17-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 17-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.

Ovarian Leiomyoma With Hilus Cell Hyperplasia That Caused Virilization

A 68-year-old woman had noted gradual virilization and depression for 3 years. Examination revealed a 10-cm right pelvic mass. Plasma testosterone was substantially elevated (1,082 ng/dl), but urinary ketosteroid and ketogenic steroid excretion was normal. Laparotomy revealed a 10-cm mass that replaced the right ovary and weighed 210 g. Histologic analysis revealed a leiomyoma and proliferation of hilus cells in the periphery of the mass. The plasma testosterone decreased postoperatively to 45 ng/dl. We believe that this is the first report of an ovarian leiomyoma associated with hilus cell hyperplasia that caused virilization.

Endocrine profiles in pediatric andrology. III. Human chorionic gonadotropin stimulation test in cryptorchid boys.

Serum testosterone (T) concentration and urinary 17-ketosteroid (17-KS) excretion were measured under basal conditions and after stimulation with human chorionic gonadotropin (hCG) in 36 prepubertal males (10 normal children and 26 cryptorchid patients). As a function of hCG stimulation, the increase in serum T level was evident in both groups, although the magnitude of the rise was higher in the control group than in cryptorchid boys. No significant differences in serum T or urinary 17-KS were observed between patients with unilateral and bilateral undescended testis, either before or after hCG stimulation. In spite of the wide individual variations in testicular response in all subjects, the test is valuable in assessing Leydig-cell function and in prognosis for virilization at puberty.

Role of androgens in menstrual disorders of nonhirsute and hirsute women, and the effect of glucocorticoid therapy on androgen levels in hirsute hyperandrogenic women

The plasma concentrations of total testosterone, free testosterone index, androstenedione, 17β-estradiol, luteinizing hormone, follicle-stimulating hormone, prolactin, and urinary 17-ketosteroid and 17-ketogenic steroid excretion were measured in 48 nonhirsute and 119 hirsute patients. Hormone data were compared within and between groups according to whether the menstrual cycles were eumenorrheic, amenorrheic, or oligomenorrheic. Eleven hirsute women treated with prednisone were followed for 6 months. It was concluded that: (1) androstenedione, testosterone, free testosterone index, and adrenal androgens alone or in combination play a role in the pathogenesis of the hirsutism observed in eumenorrheic women and in the amenorrhea and oligomenorrhea of both hirsute and nonhirsute women; (2) body weight correlated with adrenal adrogens (17-ketosteroids) in nonhirsute women and with androstenedione in hirsute women; (3) prednisone significantly suppressed androstenedione and 17-ketosteroids (p < 0.05), with a decline of testosterone to 65% and luteinizing hormone to 51% of pretreatment values, with favorable clinical effects on the hirsutism, menstrual dysfunction, and infertility; (4) concentrations of 17β-estradiol were lower in amenorrheic than in eumenorrheic and oligomenorrheic women of both groups.

Adrenal and sex steroid hormone production by a virilizing adrenal adenoma and its diagnosis with computerized tomography

The presence of an androgen-secreting tumor in a 29-year-old woman was confimed and its location was determined by computerized axial tomographic (CAT) scanning. The hormone production from this virilizing adrenal adenoma was studied in vivo and in vitro. The major secretory products of the tumor (as compared to normal adrenal tissue) were testosterone (24-fold) and 17 β-estradiol (five-fold). Although the adenoma produced lesser amounts of dehydroepiandrosterone sulfate (DHEAS), the demonstration of elevated serum testosterone and DHEAS in serial samples was a better marker for an androgen-secreting adrenal tumor than were the urinary 17-ketosteroids, which remained in the upper limit of normal. The hormone production from the tumor depended neither on adrenocorticotropic hormone nor on human chorionic gonadotropin. The conclusions were that: (1) on the basis of serial measurements of serum testosterone and DHEAS, virilizing adrenal adenomas may be suspected when the concentrations of these hormones reach or exceed 200 ng/dl and 6,600 ng/ml, respectively; (2) the high-resolution CAT scanner can accurately localize these tumors; (3) cosmetic and menstrual dysfunction regressed after resection of the tumor; and (4) virilizing adrenal adenomas may produce both androgens and estrogens.

Diagnostic strategy in hyperandrogenic syndrome.

Plasma testosterone (T), androstenedione (A), follicle-stimulating hormone, (FSH), luteinizing hormone (LH), prolactin (PRL), and urinary 17-ketosteroids (17-CS) have been measured in 152 women complaining of acne and/or hirsutism. Mean plasma levels of T, A, LH, PRL, and urinary 17-CS were significantly increased as compared to controls. T and/or A were increased in 59% of the cases. T was higher in women with PRL greater than 16 micrograms/l as compared to women with PRL less than 13 micrograms/l. Hirsutism had markedly decreased in 64% and acne in 84% of patients treated with cyproterone acetate.

Endocrine and metabolic studies in unstable cor pulmonale.

Serum testosterone, follicle-stimulating hormone, luteinising hormone, and dihydro-epiandrosterone concentrations rose significantly in seven men studied during recovery from a severe exacerbation of chronic obstructive airways disease. Urinary 17-ketosteroids also rose significantly though serum androstenedione and prolactin concentrations did not. Our findings suggest that hypoxia in this condition suppresses the hypothalamus or pituitary or both and that such suppression is reversible. In view of previous reports of increase in total body potassium and intracellular water with recovery from cor pulmonale, we also carried out metabolic studies on our patients. Low body potassium concentrations in cor pulmonale fell further with recovery, in part reflecting a fall in lean body tissue. Intracellular water appeared to increase on recovery despite a fall in other lean body mass indices (the simplest and most reliable being skinfold thickness). We suspect this result to be spurious and due to problems with equilibration in isotope dilution. Alternatively it may reflect waterlogging of cells. A false figure for intracellular water could be responsible for an unexpectedly low estimated intracellular potassium concentration on recovery. Our results cast doubt on isotope dilution methods for measuring body water compartments in disease states likely to cause changes in cell permeability.

Significance of atretic follicles as the site of androgen production in polycystic ovaries.

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 17-ketosteroids 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.

Premature thelarche: a possible adrenal disorder.

Endocrine studies in girls with precocious thelarche were compared with those of normal girls of similar ages. Girls with precocious thelarche showed breast development and oestrogenised vaginal smears as the only signs of precocious sexual development. A few of the girls were tall and some had advanced bone ages but these two findings were not consistently present in the same patient. Hormones--such as serum oestradiol, oestrone, delta 4-androstenedione, progesterone, dehydroepiandrosterone (DHEA), follicle-stimulating hormone, luteinising hormone, and prolactin, and urinary 17-ketosteroids--were measured. Only DHEA was different, being higher in girls with precocious thelarche. It is suggested that the high DHEA level may serve as a precursor for conversion to oestrogens in target tissues, breast, and vagina. This mechanism for oestrogenisation had been reported in other patients.

Male Pseudohermaphroditism

Male pseudohermaphroditism is the condition of incomplete male differentiation of the external genitalia in an individual with a Y chromosome. The gonads of the male pseudohermaphrodite, when present, are either streak gonads or testes. A wide range of disorders and phenotypic presentations are encompassed by the term male pseudohermaphroditism. The following case describes a male pseudohermaphrodite who presented with ambiguous genitalia. However, as will be discussed in greater detail below, the external genitalia of male pseudohermaphrodites may be unambiguously female or may appear to be almost completely masculinized. CASE HISTORY The infant, a 9 lb 3 oz product of a full-term gestation, was born to a 23-year-old gravida 1, para O mother via normal spontaneous vaginal delivery. Pregnancy was uncomplicated and there was no history of maternal ingestion of medication. At birth, ambiguity of the external genitalia was noted with a 1-cm phallus, one opening on the perineum, and a small palpable mass in each of the large unfused labia. No uterus was palpable on rectal examination. Serial serum electrolytes remained normal. Genetic evaluation revealed a chromatinnegative buccal smear, with Y fluorescence. Karyotype analysis of peripheral lymphocytes revealed a 46, XY chromosomal complement. Radiologic studies included an excretory urogram revealing normal functioning kidneys with intact pelvocalyceal systems, ureters, and bladder, and a blind-ending vagina, with no evidence of cervical indentation. Base line 24-hour urinary 17-ketosteroid and 17-hydroxycorticosteroid determinations were all normal.

Effect of non-specific chromogens on the determination of the 17-ketosteroid content in rheumatoid arthritis

The excretion of total, neutral, 17-ketosteroids in rheumatoid arthritis has been determined photometrically by Zimmermann's reaction and by application of various procedures for the elimination of the effect of non-specific chromogens. Among the applied procedures the method including formaldehyde was the most practical and efficient for the estimation of the true content of urinary 17-ketosteroids. Thus, determining the exact content of 17-ketosteroids in rheumatoid arthritis a decreased excretion of the urinary metabolites of androgen hormones was established.

Growth Hormone and Adrenal Androgen Secretion

The effect of growth hormone (GH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 3/12-14 8/12 years. Plasma concentrations of dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and androstenedione (Δ4A), as well as urinary 17-ketosteroids and free cortisol were determined before, during short-term (2U/d×3) and after long-term (6 months) treatment with GH. The baseline, pretreatment plasma levels of DHEA-S were appropriate for the individuals' degree of skeletal maturation, whereas plasma DHEA and Δ4A were undetectable (<42ng/dl and < 27ng/dl, respectively) in 5/7 subjects. No significant change was noted in the plasma androgen values or in the urinary 17-ketosteroid and free cortisol concentrations during the short-term administration of GH. Despite a significant increase in growth velocity after 6 months of GH therapy, the pre- and post-treatment plasma and urinary steroid concentrations were not statistically different. These results fail to substantiate a role for GH in the secretion or metabolism of adrenal androgens. Thus, the delayed adrenarche and subnormal plasma adrenal androgen levels sometimes seen in GH deficient patients are not due to the absence of GH per se.