Peak left ventricular systolic pressure/end-systolic volume ratio: a sensitive detector of left ventricular disease.

The purpose of this study was to evaluate $\text{peak pressure}\text{systolic volume}$ ratio as a detector of cardiac disease. To validate that tracings obtained through fluid-filled catheters were accurate for this purpose, in 35 patients left ventricular pressure-volume loops were constructed from tracings recorded with a micromanometer-tipped angiographic catheter. Comparisons were made between the peak ratio of left ventricular pressure to volume (E_max) using the micromanometer-tipped angiographic catheter and the ratio between peak left ventricular pressure before angiography and end-systolic volume during angiography ($\text{peak pressure}\text{systolic volume}$ ratio) using the fluid-filled lumen of the same catheter. The relations of E_max and that of $\text{peak pressure}\text{systolic volume}$ ratio to ejection fraction were similar and curvilinear. $\text{Peak pressure}\text{systolic volume}$ ratio was approximately 10 percent higher than E_max, with a correlation coefficient between 0.99 of the two ratios. Therefore, $\text{peak pressure}\text{systolic volume}$ ratio, which is easily obtained in clinical practice, can be used instead of E_max.Retrospective analysis of the $\text{peak pressure}\text{systolic volume}$ ratio and ejection fraction was made from routine diagnostic catheterization data obtained using fluid-filled catheters in 115 subjects, of whom 17 were normal, 60 had coronary artery disease without asynergy, 23 had aortic valve disease and 15 had mitral valve disease. In subjects with a normal ejection fraction (more than 60 percent) the $\text{peak pressure}\text{systolic volume}$ ratio separated those groups with a diseased heart from those with a normal heart. Those with a diseased heart had a greater end-systolic volume than normal subjects. Thus, the $\text{peak pressure}\text{systolic volume}$ ratio is more sensitive than ejection fraction in detecting subtle changes in myocardial function in human beings.     

Comparative studies on the steroid metabolism in mammals. I. Characterization of 17 beta-hydroxysteroid dehydrogenase from monkey liver.

17β-Hydroxysteroid dehydrogenase preparation was obtained from soluble fraction of monkey liver by ammonium sulfate fractionation and heat-treatment. The activity of 17β-hydroxysteroid dehydrogenase was localized in the 50–80% ammonium sulfate fraction and was found to be stable at 37° for 25 hr. This enzyme preparation catalyzed the reduction of dehydroepiandrosterone (DHEA) to androst-5-ene-3β, 17β-diol (Adiol), estrone (E₁) to estradiol-17β (E₂), and androstenedione (A) to testosterone (T). The Michaelis constants (K_m) for each substrate were: DHEA, 50 μM; E₁, 20 μM; and A, 13 μM. The activity of 17β-hydroxysteroid dehydrogenase was activated by either NADH or NADPH, NADPH, however, was found to be more effective than NADH. The K_m values for NADPH were 170, 120, and 30 μM, respectively, for the reduction of the 17-oxo group of DHEA, E₁, and A. NADP inhibited the activity of 17β-hydroxysteroid dehydrogenase for all three substrates. Both DHEA and E₁ served as competitive substrates for the enzyme. The inhibitor constants were 26 μM for DHEA and 50 μM for E₁. A acted as a competitive inhibitor of the enzyme for DHEA, but it acted as a noncompetitive inhibitor of the enzyme for E₁.     

Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women

To investigate the adrenal cause of hyperandrogenism in peri- and postpubertal hirsute women, baseline and ACTH-stimulated serum concentrations of delta 5-17-hydroxypregnenolone (delta 5-17P), dehydroepiandrosterone (DHEA) and its sulfate, 17-hydroxyprogesterone (17-OHP), cortisol, delta 4-androstenedione, and testosterone were determined in 116 women with hirsutism or acne of peri- and postpubertal onset with or without menstrual abnormalities. The results were compared with the same steroid concentrations in 30 normal age-matched women. Sixteen of the 116 women with hirsutism whose ACTH-stimulated 17-OHP levels (mean +/- SD, 5404 +/- 3234 ng/dl; normal, 334 +/- 194) were markedly elevated while their ratios of delta 5-17P to 17-OHP (0.4 +/- 0.2; normal, 3.4 +/- 1.5) were low were diagnosed as having nonclassical symptomatic 21-hydroxylase deficiency. Seventeen other hirsute women, including 3 siblings, had very high responses of delta 5-17P (2276 +/- 669 ng/dl; normal, 985 +/- 327) and DHEA (2787 +/- 386 ng/dl; normal, 1050 +/- 384) to ACTH stimulation, with significantly elevated ratios of delta 5-17P to 17-OHP (11 +/- 2.0; normal, 3.4 +/- 1.5) and DHEA to delta 4-androstenedione (7.5 +/- 2.3; normal, 4.6 +/- 1.5). In these hirsute women, the morning serum delta 5-17P and DHEA concentrations were elevated, had a diurnal variation, and were suppressed with dexamethasone administration. We propose that partial adrenal 3 beta-hydroxysteroid dehydrogenase deficiency is the cause of hirsutism in these women. This may represent an allelic variant at the genetic locus for 3 beta-hydroxysteroid dehydrogenase deficiency similar to that reported for symptomatic nonclassical 21-hydroxylase deficiency producing peripubertal excess androgen syndrome.     

Impaired 3,5,3'-triiodothyronine (T3) production in diabetic patients.

Serum concentrations of thyroxine (T₄), 3,5,3′-triiodothyronine (T₃), and 3,3′,5′-triiodothyronine (RT₃) were measured in 50 patients with diabetes mellitus. The mean concentrations of serum T₄, T₃, and RT₃ were 8.5 ± 3.7 (SD) μg/dl, 134 ± 41 ng/dl, and 30 ± 13 ng/dl, respectively, which were not significantly different from values of 33 normal control subjects. The serum $\text{T}{}_3\text{T}{}_4$ ratio showed a significant inverse correlation with the level of fasting blood sugar (FBS) (p < 0.01). Turnover studies were carried out in seven normal control subjects and in 5 insulin-independent diabetic patients on T₄ replacement. T₄ turnover was similar in both groups. The T₃ metabolic clearance rate of the diabetic patients was also normal (20.7 ± 4.0 liter/day/70 kg), but the T₃ disposal rate was reduced when compared to that of normal control subjects (17.0 ± 5.6 vs. 40.6 ± 4.8 μg/day). The RT₃ metabolic clearance rate (80.6 ± 20.2 vs. 105.0 ± 14.0 liter/day/70 kg) and the RT₃ disposal rate (29.4 ± 10.8 vs. 49.4 ± 11.6 μg/day) were both reduced in the diabetic patients. In five other diabetic patients on 3 wk of oral T₄ replacement, the serum $\text{T}{}_3\text{T}{}_4$ ratio was below the normal range (0.0059 ± 0.0041 vs. 0.0152 ± 0.0011) and remained unchanged during insulin infusion during 10 hr. The $\text{T}{}_3\text{T}{}_4$ ratio increased but remained below the normal range after 10 days of dietary and insulin treatment (0.0083 ± 0.0032; p < 0.05). Our results suggest that T₃ production from peripheral T₄ monodeiodination is impaired in uncontrolled diabetic patients. This impairment in T₃ production is correlated with the impairment of glucose utilization.     

Direct inhibitory effect of estrogen on LH-stimulated androgen synthesis by ovarian cells cultured in defined medium

The direct inhibitory effect of estrogen on ovarian androgen synthesis was investigated. When primary cultures of rat ovarian theca-interstitial cells were grown in defined medium with LH there was a marked increase in androgen synthesis of which 98% was androsterone (control = 11 ± 2 ng; LH = 1219±217 ng/ml/10⁶ cells). Diethylstilbestrol (DES), estrone (E₁), estradiol (E₂), and estriol (E₃) inhibited LH-stimulated androsterone synthesis by 81%, 81%, 81%, and 47%, respectively. The ED₅₀'s of the estrogens were: DES = 4.2±2.l × 10^?9M; E₁ = E₂ = 9.5±2.4 × 10^?8 M; and E₃ = 3.8±2.6 × 10^?7 M. The estrogen effect was very rapid ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ = 10 min) and long-lasting. Metabolic studies revealed that estrogen inhibited androsterone, androstenedione, 5α-androstane-3α, 17β-diol, and testosterone accumulation by 80%, dehydroepiandrosterone and 17α-hydroxypregnenolone by 40%, 17α-hydroxyprogesterone by 30%, while pregnenolone and progesterone were unchanged. These results prove, for the first time, that estrogen can directly inhibit LH-stimulated androgen production in ovarian theca-interstitial cells and suggest that mechanism involves, at least in part, a rapid selective inhibition of the 17α-hydroxylase/C_17–20 desmolase activities.     

Biosynthesis and secretion of testosterone by adrenal tissue from the North American opossum, Didelphis virginiana, and the effects of tropic hormone stimulation.

The synthesis and secretion of corticosteroids and testosterone by the adrenal cortex of the North American opossum Didelphis virginiana has been studied. In vitro, tissue from adult females has the capacity to synthesise testosterone from $\text{[}{}^3\text{H}\text{]}$ pregnenolone and $\text{[}{}^{14}\text{C}\text{]}$ progesterone in yields similar to those of cortisol. From endogenous precursors, values for testosterone production, measured by RIA, were about $\text{1}\text{30th}$ of those for total corticosteroid as measured by CPB. Testosterone output from endogenous precursors was stimulated by the addition of FSH or LH to the incubation media, whereas ACTH had no effect. Corticosteroid output was stimulated by both ACTH and LH, but not by FSH. In vivo, circulating levels of both corticosteroid and testosterone were decreased by dexamethasone treatment. ACTH treatment, on the other hand, stimulated corticosteroid levels but was without effect on testosterone. PMS treatment gave increased testosterone concentrations after 1 day's treatment although this was not sustained following further treatments on the 2 subsequent days. Cortisol was unaffected. Neither control values for testosterone nor those obtained in stimulated animals were significantly affected by ovariectomy. The results suggest that the adrenal cortex is the source of circulating testosterone in the adult female opossum and that the synthesis and secretion of testosterone may be enhanced by stimulation with gonadotropin. In nearly all respects there is a striking similarity between these results and those obtained with another marsupial, the Australian brush-tailed possum (Trichosurus vulpecula). The results are discussed in relation to the functional zonation of the mammalian adrenal cortex.     

Determination of left ventricular diastolic chamber stiffness and myocardial stiffness in patients with congenital heart disease

Left ventricular diastolic indexes were derived in 13 patients aged 5 to 21 years. Three had a normal heart, three had lesions causing volume overload and seven had coarctation of the aorta, including one whose main lesion was severe endocardial fibroelastosis. At cardiac catheterization simultaneous high fidelity pressure (P) and left ventricular volume (V) measurements were obtained and several points in one diastolic cycle taken. With use of a monoexponential formula (P = ae^bv) for P versus V, $\text{dP}\text{dv}$ and the operant chamber stiffness b were obtained. Similarly, with use of σ = αe^β?, $\text{dσ}\text{d?}$, elastic stiffness (E) and the muscle stiffness constant K_E were obtained. Values for b were 0.0273 ± 0.0065 in normal subjects, 0.017 ± 0.0043 in those with volume overload, 0.0369 ± 0.0173 in those with coarctation (without endocardial fibroelastosis) and 0.0192 in the child with endocardial fibroelastosis. The plot of P versus V for coarctation was to the left and steeper than normal and the patients with volume overload had a flattened rightward curve, whereas the curve for those with endocardial fibroelastosis was extremely rightward. The stress-radii curves of the normal subjects and those with coarctation were similar whereas the curves for patients with volume overload and endocardial fibroelastosis were rightward of normal. The value for K_E was 8.92 ± 0.87 for the normal subjects, 8.26 ± 0.75 for those with volume overload, 9.2 ± 2.5 for those with coarctation and 22.75 for those with endocardial fibroelastosis.Thus, the pressure-loaded ventricle is stiffer than the normal, which in turn, is stiffer than the volume-loaded ventricle. This response, due to hypertrophy, appears to be appropriate in that diastolic stress was normalized and muscle stiffness was not increased except in the patient with endocardial fibroelastosis.     

ADRENAL STEROIDOGENESIS IN HIRSUTE WOMEN

Adrenal steroidogenesis has been studied in vivo in ten hirsute and ten normal women. Serum levels of nine steroids on the biosynthetic pathway: the Δ⁵3 β-hydroxysteroids, pregnenolone (Pe), 17α-hydroxypregnenolone (17 Pe), dehydroepiandrosterone (DHEA), androstenediol (Adiol), and their Δ⁴3 keto counterparts, progesterone (Po), 17α-hydroxyprogesterone (17 Po), androstenedione (Adione), and testosterone (T), as well as cortisol, were measured following ACTH stimulation from a dexamethasone-suppressed state. The results are complicated by the finding of marked heterogeneity in the adrenal steroid response between different subjects in the normal population. One of the ten normal women had a much greater increment of Po and 17Po than the others following ACTH stimulation, suggesting that she has reduced 21-hydroxylase activity. A similar heterogeneity was also seen in the hirsute women, three of the ten having an exaggerated 17Po response to ACTH. Two of the same hirsute women also had greater Adione responses than normal. Adrenal steroidogenesis was normal in most of the hirsute women, while a subtle adrenal variant, possibly of 21-hydroxylase, has been demonstrated in a minority as in normal individuals; we do not yet know whether this is of aetiological importance. Our data do not support previous suggestions that adrenal 3β-hydroxysteroid dehydrogenase activity is reduced in hirsute women.     

Urinary free cortisol excretion during growth and aging: correlation with cortisol production rate and 17-hydroxycorticosteroid excretion

Urinary free cortisol (UFC) values in normal subjects have been determined for various age groups ranging from 4 mo to 50 yr. Mean values for $\text{UFC}\text{24}\text{hr}$ increased with age until approximately 20 yr, after which a relatively stable level of excretion was maintained. Correction of UFC for body surface area (per sq m), body weight (per kg), or muscle mass, i.e., creatinine excretion (per g creatinine), did not resolve the differences in all of the age groups studied. Regardless of the correction parameter used (surface area, etc.), a minimum in cortisol excretion was found in the 11–20-yr age group. Guidelines for the interpretation of cortisol production rate (CPR) and 17-hydroxycorticosteroid (17-OHCS) excretion in the same age groups are also provided. There was a significant positive correlation between UFC and both CPR (r = 0.71) and 17-OHCS (r = 0.87) during growth and maturation. Taking into account the variation in excretion of UFC with age, the data provides reference standards for the use of UFC in the diagnosis of adrenocortical disorders in children and adults.     

Inadequately low serum levels of steroid hormones in relation to interleukin‐6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis

Objective

To compare levels of steroid hormones in relation to cytokines and to study levels of cortisol or dehydroepiandrosterone (DHEA) in relation to other adrenal hormones in untreated patients with early rheumatoid arthritis (RA) and reactive arthritis (ReA) compared with healthy controls.

Methods

In a retrospective study with 34 RA patients, 46 ReA patients, and 112 healthy subjects, we measured serum levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF), adrenocorticotropic hormone (ACTH), cortisol, 17‐hydroxyprogesterone (17‐OH‐progesterone), androstenedione (ASD), DHEA, and DHEA sulfate (DHEAS).

Results

RA patients had higher serum levels of IL‐6, TNF, cortisol, and DHEA compared with ReA patients and healthy subjects, but no difference was noticed with respect to ACTH and DHEAS. However, in RA and ReA patients compared with healthy subjects, levels of ACTH, cortisol, ASD, DHEAS, and 17‐OH‐progesterone were markedly lower in relation to levels of IL‐6 and TNF. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL‐6 in RA (R_Rank = −0.582, P = 0.001) and, to a lesser extent, in ReA (R_Rank = −0.417, P = 0.011). In RA patients, the mean grip strength of both hands was positively correlated with the ratio of serum cortisol to serum IL‐6 (R_Rank = 0.472, P = 0.010). Furthermore, in these untreated patients with RA and ReA, there was a relative decrease in the secretion of 17‐OH‐progesterone, ASD, and DHEAS in relation to DHEA and cortisol. This indicates a relative predominance of the nonsulfated DHEA and cortisol in relation to all other measured adrenal steroid hormones in the early stages of these inflammatory diseases.

Conclusion

This study indicates that levels of ACTH and cortisol are relatively low in relation to levels of IL‐6 and TNF in untreated patients with early RA and ReA compared with healthy subjects. The study further demonstrates that there is a relative increase of DHEA and cortisol in relation to other adrenal hormones, such as DHEAS. This study emphasizes that adrenal steroid secretion is inadequately low in relation to inflammation. Although changes in hormone levels are similar in RA and ReA, alteration of steroidogenesis is more pronounced in RA patients than in ReA patients.

     

CUSHING'S SYNDROME, NODULAR ADRENAL HYPERPLASIA AND VIRILIZING CARCINOMA

A 48-year-old hypertensive diabetic woman rapidly became virilized. Urine 17-oxo-and oxogenic steroids and plasma testosterone, androstenedione, DHEA, DHEA-sulphate and androstenediol were greatly elevated. Plasma cortisol was constantly high and was not suppressed by dexamethasone. Circulating immunoreactive ACTH was consistently detectable at 18–24 ng/l. A 450 g carcinoma arising from a nodular hyperplastic right adrenal gland was resected. Production by the tumour of 17α-hydroxypregnenolone, 17α-hydroxyprogesterone and five C-19 steroids, but very little prenenolone, progesterone or cortisol, was shown by blood sampling, tumour culture and dramatic falls after operation. The plasma cortisol fell to half, with no diurnal variation, consistent with persistent Cushing's syndrome, and the plasma ACTH rose to 55 ng/l. She died 3 months later from a myocardial infarction. Autopsy revealed a pituitary basophil adenoma at a site where radiologically there had been an indentation in the fossa floor for at least 7 years. The left adrenal gland showed nodular hyperplasia. Therefore we conclude that mild pituitary-dependent Cushing's syndrome may have been present for many years before development of a virilizing carcinoma. This case demonstrates that adrenal carcinoma in man can sometimes develop as a consequence of nodular adrenal hyperplasia which may in turn be due to long-standing trophic hyper-stimulation.     

ADRENAL AND GONADAL STEROIDS IN GIRLS DURING SEXUAL MATURATION

The peripheral venous plasma concentrations of gonadotrophins (LH and FSH), prolactin (Prl), cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone-sulphate (DHA-S), pregnenolone (Δ₅P), progesterone (P), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and oestradiol (E₂) were measured in girls at different stages of sexual development (from P1 to P4–5 according to Tanner, 1962). Both gonadotrophins increase progressively during sexual maturation, to reach the highest concentrations in P4–5. However, the FSH values were significantly lower in these P4–5 pre-menarchal girls than those found in adult women in the early follicular phase. No significant changes were found in plasma Prl, cortisol and 17P levels during pubertal development; in contrast, plasma concentrations of DHA tripled from P1 to P4–5, reaching adult levels. A progressive rise was also found in DHA-S plasma levels. A significant, but less evident increase was found in Δ₅P and P plasma concentrations, from group P1 to P4–5. A, T and DHT levels rose progressively and significantly from P1–2 to the end of sexual maturation. In the case of E₂, only a moderate increase was found during pubertal development. All these data indicate that during pubertal development, there is a progressive reduction in the sensitivity towards oestrogen of the hypothalamic centres controlling gonadotrophin secretion. Prl does not seem to be involved in human sexual maturation, while important changes have been found in adrenal androgens. The constant levels of 17P and cortisol, in comparison with the behaviour of DHA, DHA-S, T and A, seem to indicate that during this period of life, the adrenal gland is stimulated by unknown factors other than ACTH, acting on the adrenal androgen-producing cells and responsible for the reported rises in plasma adrenal androgens.     

Identification of nonclassical 21-hydroxylase deficiency in girls with precocious pubarche.

Recent studies have described mild adrenal enzymatic defects in patients presenting with precocious pubarche. In order to identify these defects we have evaluated basal and ACTH- (25 IU iv) stimulated serum adrenal steroid levels in 19 girls, 2- to 8.3-year-old, with precocius pubarche (pubic hair Tanner II-III). Two patients had clitorial enlargement. Bone age was moderatly advanced in 10 patients and 2 to 3.7 yr in four others. Four patients had high basal serum levels of 17-hydroxyprogesterone (17OHP) (525 + 202 ng/dl, mean +SD), compatible with the diagnosis of nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH-21OH), which was confirmed by an increased response of 17OHP to ACTH (3425 +/- 953 ng/dl). Fifteen patients had moderately elevated basal 17OHP levels (56 + 38 ng/dl) but a normal 170HP response (191 +/- 71 ng/dl) to ACTH, compatible with the diagnosis of idiopathic precocious pubarche (IPP). The cortisol response to ACTH was normal in both groups. Basal values of DHEA-S were 651 +/- 256 and 506 + 462 ng/ml and of DHEA 380 +/- 24 ng/dl and 205 +/- 102 ng/dl, in NCCAH-210H and IPP, respectively. We conclude that: i) clinical findings and baseline levels of DHEA-S and DHEA in IPP can be indistinguishable from the late onset 21 hydroxylase deficiency; ii) baseline levels of 17OHP are sufficient for the diagnosis of NCCAH-21OH; iii) the ACTH stimulation test is indicated only when baseline levels of 17OHP are moderately elevated (100-300 ng/dl).     

Radioimmunoassay of steroids produced by cultured chick embryonic gonads: differences according to age, sex, and side.

Embryonic gonads from White Leghorn chick embryos 7.5–18 days old were cultured on synthetic medium for 24 hr. Radioimmunoassys after ether extraction of the homogenized organs and their corresponding media allowed us to determine qualitatively and quantitatively the amount of secreted steroids. Steroid production by the explant is confirmed because the relative amount of each steroid present in the cultures (explants + media) is higher than the initial hormonal content of the gonads before explanation. Estradiol (E₂), testosterone (T), and dehydroepiandrosterone (DHA) are mainly found in the culture media, whereas progesterone (P), DHA, and estrone (E₁) remain more or less in the gonads. Total steroid production increases during development for gonads of both sexes, with significant higher levels in females. A preferential relative production according to the sex is obvious. The absolute or relative production of estrogens (E₁ + E₂) is always more abundant in female gonads than in male gonads. For testosterone, the production by pairs of gonads is higher in females than in males until 15 days, after which it is the contrary. The relative secretion is higher in males and shows a maximum value at 10 days which may be correlated with the regression of the Müllerian ducts. $\text{T}\text{E}{}_2$ is always > 1 in testes and < 1 in the left ovary, but in right female gonads it reaches 1.61 at 10 days of incubation. DHT is mainly secreted by male gonads and also shows a peak at 10 days. For female gonads, a quantitative as well as a qualitative difference in steroid secretion appears between left and right gonads; these latter, even though fated to rudimentation, are not devoid of steroidogenic capability.     

Leydig cell function in Klinefelter's syndrome

The two major secretion products of the normal testes were measured in peripheral plasma of eight patients with Klinefelter's syndrome; two agonadal, one castrate, one patient with isolated gonadotropin deficiency, and one patient with unclassified primary hypogonadism. Plasma testosterone and 17-α-hydroxyprogesterone were very low in all but the Klinefelter's patients. Testosterone values markedly varied, but were generally subnormal in Klinefelter's, ranging from $\text{25–425 mμg}\text{100 ml}$, 187 ± 160. The 17-α-hydroxyprogesterone (17-OHP), however, was elevated in three and within the normal range in five [Klinefelter's 120 ± 63 (SD) vs. normal $\text{97 ± 21 (SD) m μg}\text{100 ml}$, respectively]. The 17-OHP values are inappropriate when considered with the subnormal testosterone values. One of the youngest patients studied had a subnormal testosterone but a plasma 17-OHP that was three times the mean for a normal adult male. The 17-OHP in Klinefelter's was of testicular origin, since dexamethasone had minimal effect, but testosterone almost completely reduced plasma 17-OHP. The marked circadian variation of 17-OHP in normal males was not present in Klinefelter's, although noncyclic fluctuations were observed. LH in the form of chorionic gonadotropin produced a variable response. Some of the patients exhibited a rise in plasma 17-OHP and testosterone despite already elevated 17-OHP levels. The studies indicate the presence of a disorder involving Leydig cell steroidogenesis in Klinefelter's syndrome.     

Hyperosmolar nonketotic diabetic coma: a complication of propranolol therapy

A 46-yr-old hypertensive man treated for 1 yr with apresoline 200 mg and propranolol 240 mg daily, was admitted in deep coma, severely dehydrated, serum glucose $\text{1130}\text{mg}\text{100}\text{ml}$ without ketonemia, normal serum CO₂, blood pH 7.52, serum osmolarity 357 mOsm/kg, fever of 105.6°F, and central venous pressure of less than 1 cm. The plasma free fatty acid was 270 μeg/liter, insulin 16 μU/ml and growth hormone 2.5 ng/ml. He responded excellently to 100 units regular insulin and 8 liters of hypotonic infusions. Seven months later he had a similar episode despite addition of 1 g tolbutamide daily in the interim. When studied without any medication he had fasting hyperglycemia of $\text{175–200}\text{mg}\text{100}\text{ml}$. An intravenous tolbutamide test was diabetic. When repeated following intravenous propranolol, 10 mg, the insulin response to tolbutamide was diminished. Without propranolol or hypoglycemic therapy, fasting hyperglycemia increased over 5–6 wk to $\text{630}\text{mg}\text{100}\text{ml}$, with traces of ketonemia, FFA level of 1350 μeq/liter and serum osmolarity of 305 mOsm/kg. The study was later repeated with the addition of oral propranolol 240 mg daily. Uncontrolled diabetes was again clinically manifest, although glucose levels rose more slowly. Despite fasting glucose levels reaching $\text{930}\text{mg}\text{100}\text{ml}$, no sign of ketosis occurred when the patient was taking propranolol. FFA level at this time was only 640 μeq/liter and serum osmolarity had risen to 335 mOsm/kg. His diabetes is now satisfactorily treated with insulin injections, to avoid the disturbances of carbohydrate metabolism caused by propranolol. These studies indicate that large amounts of propranolol may precipitate hyperosmolar nonketotic coma in an untreated diabetic by a blockade of lipolysis and/or impairment of insulin response.     

LACK OF EFFECT OF OESTROGENS ON ADRENAL ANDROGEN SECRETION IN CHILDREN AND ADOLESCENTS WITH A COMMENT ON OESTROGENS AND PUBIC HAIR GROWTH

To study the effect of oestrogen on adrenarche and adrenal androgen secretion we measured plasma concentrations of dehydroepiandrosterone-sulphate (DHEA-S), androstenedione (Δ⁴A) and oestradiol (E₂) in the following groups: children with premature adrenarche; agonadal patients before and after initiation of oestrogen replacement therapy; and, children exposed to increased concentrations of endogenous oestrogen at a precocious age. Fourteen of fifteen patients with premature adrenarche had plasma E₂ levels in the normal prepubertal range (> 10 pg/ml), despite a mean DHEA-S concentration that was significantly elevated for age (6–8 years: 72·5 ± 12·6 μg/dl v. 11·4 ± 2·9 μg/dl, P 0·002). DHEA-S and Δ⁴ A concentrations in fifteen patients with gonadal dysgenesis before and 2–14 months after initiation of oestrogen replacement therapy were not significantly different despite the appearance of oestrogen-induced secondary sex characteristics. Six of fifteen patients developed increased pubic hair during oestrogen therapy but had no increase in the concentrations of plasma DHEA-S. Two patients (aged 1 year 4 months and 4 years 10 months) with oestradrol secreting ovarian follicular cysts (plasma E₂ 11–796 pg/ml) and one patient (aged 6 years 10 months) who had had a granulosa cell tumour of the ovary maintained preadrenarchal DHEA-S levels (> 6·2 μg/dl) despite exposure to concentrations of circulating oestrogen that were high for their chronological age. We interpret the results as follows: (1) Initiation of premature adrenarche occurs without an increase into the early pubertal range of E₂ levels. (2) Administration of replacement doses of oestrogen does not increase adrenal androgen concentrations in adolescent patients with gonadal dysgenesis. (3) Elevated plasma concentrations of endogenous ovarian oestrogens at a precocious age did not increase adrenal androgen secretion in childhood. Thus, it appears that circulating oestrogens are either required for the activation or maintenance of adrenarche nor do they significantly affect the plasma concentrations of adrenal androgens in children and adolescents. (4) The pubic hair growth associated with the institution of oestrogen replacement in adolescent patients with gonadal dysgenesis is not mediated by an increase in adrenal androgen secretion and may result from a specific effect of oestrogen on androgen action at the target tissue (pubic skin).     

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche

To determine the adrenal contribution to elevated plasma androgens in 31 young hyperandrogenemic women with acne and/or hirsutism, we compared their responses to ACTH with those of 14 normal women. Each subject was given a low dose (10 micrograms/m2) of synthetic ACTH-(1-24) (Cortrosyn) after administration of 1.5 mg dexamethasone the night before the test. Thirty and 60 min responses of plasma 17 alpha-hydroxypregnenolone (17-Preg), 17 alpha-hydroxyprogesterone, (17-prog), dehydroepiandrosterone (DHEA), androstenedione, 11-deoxycortisol, and cortisol were measured. Eighteen (58%) patients had increased responses of at least one 17-ketosteroid or adrenal androgen precursor. All patients had cortisol responses within the range of those of the 14 normal subjects. Nine patients (29%) had evidence of steroid biosynthetic enzyme deficiencies, either mild congenital adrenal hyperplasia or the heterozygote state; after ACTH, 4 of these patients had elevated 17-prog in the range of values in heterozygote carriers of 21-hydroxylase deficiency, 2 had elevated levels of 11-deoxycortisol compatible with 11 beta-hydroxylase deficiency, and 3 had elevated levels of 17-Preg and DHEA, suggestive of 3 beta-hydroxysteroid dehydrogenase deficiency. Another 9 subjects (29%) had 17-ketosteroid (DHEA and/or androstenedione) hyperresponsiveness to ACTH with associated elevated 17-Preg responses. As a group, their patterns suggested relatively deficient 3 beta-hydroxysteroid dehydrogenase and relatively hyperactive C lyase without impairment of cortisol secretion. This pattern resembles exaggerated adrenarche, and we postulate that these 9 patients have hyperplasia of the zona reticularis. Neither basal levels of plasma androgens (free testosterone and DHEA sulfate) nor menstrual history predicted which patients would have abnormal ACTH responses. Although 5 of 11 (45%) patients with acne alone had abnormal responses to ACTH, 10 of 14 patients with acne and hirsutism (71%) had abnormal responses to ACTH. We conclude that an adrenal contribution is found in about half of hyperandrogenemic women with acne and/or hirsutism. This adrenal androgen hyperresponsiveness is heterogeneous. Some patients may have mild forms of congenital adrenal hyperplasia. However, functional androgenic hyperresponsiveness to ACTH, which resembles an exaggeration of adrenarche, is the most common abnormality found. Such findings may provide an explanation for the clinical observation of exacerbations of acne with stress.