Plasma cortisol was analyzed every 20 minutes for 24 hours in six psychotically depressed patients and eight normal persons. The depressives, while ill, secreted substantially more cortisol, had more secretory episodes, and more minutes of active secretion; throughout day and night, cortisol concentration was markedly elevated both at the beginning and end of secretory episodes, and cortisol was actively secreted during late evening and early morning hours when normally secretion is minimal. After treatment, the patients' secretory patterns normalized. Biological half life of cortisol remained normal throughout. The data suggest an abnormal disinhibition during depressive illness of the neuroendocrine centers regulating adrenocorticotrophic hormone release. Such neuroendocrine activation has been produced in animals following depletion of brain biogenic amines; a similar mechanism may be involved in the hypersecretion of cortisol in certain depressed patients.

Disrupted 24-hour patterns of cortisol secretion in psychotic depression.

OBJECTIVE An increased prevalence of atherosclerosis has been shown among patients with hypopituitarism. The aim of the present study was to assess whether patients with hypopituitarism experience increased cardiovascular, in particular cerebrovascular, mortality.

DESIGN AND PATIENTS Retrospective cohort study of mortality, 1952–1992, in 344 patients, of whom 130 were female, receiving conventional hormone replacement for hypopituitarism following neurosurgery for pituitary tumours. The general population in the catchment area of southern Sweden from which the patients were recruited constituted the reference population. Expected mortality was obtained from cause, sex, calendar year, and 5-year age-specific death rates for the area.

RESULTS Increased mortality from cerebrovascular disease (standardized mortality ratio (SMR) 3.39; 95% CI 2.27–4.99) was the main contributor to the increased overall cardiovascular mortality (SMR 1.75; 95% CI 1.40–2.19). The increase in mortality from cardiac diseases was much smaller (SMR 1.41; 95% CI 1.04–1.88). The risk for cerebrovascular death was higher in women (SMR 4.91) than in men (SMR 2.64). The relative risk for cerebrovascular death was independent of the time interval since diagnosis of pituitary insufficiency, but was greater in subjects diagnosed at an earlier age (<55 years). No increased mortality in malignant tumours was observed (SMR 0.95; 95% CI 0.60–1.48).

CONCLUSION The increased cerebrovascular mortality may be due to GH deficiency, or to long-term lack or inadequacy of substitution for other pituitary hormones. The observations that an early onset of pituitary insufficiency and female sex are predictors for a high risk for cerebrovascular mortality merit particular attention when treating this group of patients.

Increased cerebrovascular mortality in patients with hypopituitarism

An analysis of 235 patients with galactorrhea (5.5 per cent males) showed that 20 per cent of all patients, and 34 per cent of women with associated amenorrhea, had radiologically evident pituitary tumors; these patients had the highest serum prolactin concentrations. The largest single group (32 per cent) consisted of women with idiopathic galactorrhea without amenorrhea; prolactin was normal in 86 per cent of these cases. Five patients had the empty-sella syndrome. Prolactin response was tested in selected patients by thyrotropin-releasing hormone, chlorpromazine, L-dopa, 24-hour sampling and other means. Tests with thyrotropin-releasing hormone were most useful in identifying patients with pituitary tumors. Surgery and radiotherapy lowered prolactin to a similar degree in patients with tumor, but galactorrhea and amenorrhea often persisted after treatment. The ergot derivatives, bromergocryptine and lergotrile mesylate, lowered prolactin in all 18 patients with idiopathic hyperprolactinemia or...

https://www.nejm.org/doi/pdf/10.1056/NEJM197703172961103?listPDF=true

Galactorrhea: A Study of 235 Cases, Including 48 with Pituitary Tumors

http://webs.wofford.edu/steinmetzkr/teaching/Thesis/Quervain%20-%20Cortisol%20-%202009.pdf

Glucocorticoids and the regulation of memory in health and disease

For a given body mass index (BMI), mortality is higher in patients with central compared to generalized obesity. Glucocorticoids play an important role in determining body fat distribution, but circulating cortisol concentrations are reported to be normal in obese patients. Our recent studies show enhanced conversion of inactive cortisone (E) to active cortisol (F) through the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in cultured omental adipose stromal cells; the autocrine production of F may be a crucial factor in the pathogenesis of central obesity. We have now analyzed F metabolism in subjects with BMIs between 20-25 kg/m2 (group A), 25-30 kg/m2 (group B), and more than 30 kg/m2 (group C; n 12 in each group; six males and six premenopausal females; aged 23-44 yr). Glucose/insulin were measured using a 75-g oral glucose tolerance test, and each subject had total body and regional fat (scapular, waist, hip, and thigh) quantified using dual energy x-ray absorptiometry. Urinary total F metabolites (measured by gas chromatography/mass spectrometry) were increased in subjects with obesity [group A, 11,176 +/- 1,530 microg/24 h (mean +/- SE); group C, 13,661 +/- 1,444], although not significantly so (P = 0.08). There was a significant reduction in the urinary tetrahydrocortisol (THF) +/- 5alpha-THF/tetrahydrocortisone (THE) and the cortol/cortolone ratio in obesity (group A vs. C, 1.06 +/- 0.08 vs. 0.84 +/- 0.04 and 0.41 +/- 0.03 vs. 0.34 +/- 0.03, respectively; both P < 0.05). Urinary free F (UFF) excretion was similar in all three groups, as was the UFF/urinary free E (UFE) ratio. The 0900 h circulating F, E, and ACTH pre- and postovernight 1-mg dexamethasone suppression values were similar in all three groups, but a reduction in the generation of serum F from dexamethasone-suppressed values after oral cortisone acetate (25 mg) was evident in both obese groups [e.g. 546 +/- 37 nmol/L in group A vs. 412 +/- 40 in group B (P < 0.05) and 388 +/- 38 in group C (P < 0.01) 180 min post-E]. Insulin resistance was present in groups B and C, but regression analysis revealed no relationship between F metabolites or the THF +/- 5alpha-THF/THE ratio and insulin action (homeostasis model assessment analysis and insulin values in the oral glucose tolerance test). There was, however, a highly significant relationship between the THF +/- 5alpha-THF/THE ratio and BMI (t = -3.44; P < 0.01) and total body fat (t = -2.27; P < 0.05). Stepwise regression analyses indicated an inverse relationship between THF+/-5alpha-THF/THE and scapular and waist fat (t = -2.25; P = 0.03) and a direct relationship with hip and thigh fat (t = 2.42; P = 0.02) in both sexes. The fall in the THF + 5alpha-THF/THE ratio but unchanged UFF/UFE ratio together with impaired F concentrations after oral E indicates inhibition of 11betaHSD1 in subjects with obesity. This results in an increased MCR for F, explaining the increased F secretion rate in obesity in the face of normal circulating F concentrations. 11BetaHSD1 activity is highly related to body fat distribution, with android or central obesity, but not gynoid obesity, associated with reduced activity in both sexes. This reduction in 11betaHSD1 activity raises new questions as to the primary role of 11betaHSD1 in the pathogenesis of insulin resistance and central obesity.

/pdf/cortisol-metabolism-in-human-obesity-impaired-cortisone-3o45vmnfqb.pdf

Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity.

Prolactin secretion in normal adults is characterized by periods of episodic secretion which increase in magnitude during sleep. In this study, we report the 24-h mean prolactin concentrations, prolactin secretory patterns, and associated pituitary hormone function in nine patients (seven women and two men) with hyperprolactinemia of diverse etiologies. Four of the women and one of the men had clinically demonstrable pituitary tumors, one boy had a hypothalamic tumor, and the three other women had "functional" hyperprolactinemia. The 24-h mean prolactin concentrations derived from averaging the 20-min interval samples for 24 h ranged from 28.6 to 1,220 ng/ml. The plasma prolactin patterns in these patients showed persistence of episodic secretion in all and loss of the normal sleep-wake difference in plasma prolactin in seven of nine. Three of the patients with galactorrhea and comparable 24-h mean prolactin concentrations (58.3, 59.7, and 64.3 ng/ml) showed similar prolactin secretory patterns despite different etiologic mechanisms. Evaluation of the secretory patterns of luteinizing hormone (LH) in these patients showed loss of normal pulsatile LH release and a low 24-h mean LH concentration in the patient with the pituitary tumor, while the two patients without clinically demonstrable pituitary tumors ("post-pill" galactorrhea and "idiopathic" galactorrhea) showed normal LH secretory patterns and 24-h mean LH concentrations. The 24-h mean cortisol concentrations and secretory patterns were normal in five of the seven patients who had these parameters measured. The patient with the hypothalamic tumor had a low 24-h mean cortisol concentration and production rate and absent response to metyrapone. The patient with "idiopathic" galactorrhea had an elevated 24-h mean cortisol concentration but normal cortisol production rate and urinary 17-hydroxycorticoid excretion. Growth hormone secretion was abnormal in four of the patients (one with the hypothalamic tumor and three with pituitary tumors). Thyrotropin-releasing hormone (TRH) administration in four patients resulted in normal TSH release in two patients (one of whom developed galactorrhea after the test), an absent response in the patient with the hypothalamic tumor, and a blunted response in one of the women with a pituitary tumor. The two men had low 24-h mean plasma testosterone concentrations (69 and 30 ng/100 ml) and symptoms of impotence and loss of libido. Five of the women (four with pituitary tumors and one with Chiari-Frommel syndrome) had either low 24-h mean LH concentrations, abnormal LH secretory patterns, or both. These data indicate that patients with hyperprolactinemia encompassing a varied etiological range frequently show loss of the normal sleep-associated increase in prolactin secretion as well as abnormalities in the regulation of the other hypothalamic pituitary-regulated hormones. The finding that the abnormalities in LH, growth hormone, thyrotropin, and cortisol (adrenocorticotrophic) secretion were almost uniformly confined to the patients with the clinically demonstrable hypothalamic or pituitary tumors suggests that the size of the lesion is the critical factor.

/pdf/hypothalamic-pituitary-function-in-diverse-qcmi4389gs.pdf

Hypothalamic-Pituitary Function in Diverse Hyperprolactinemic States

Four methods of measuring the daily cortisol production rate were intercompared in 49 patients with production rates varying between 2 and 60 mg per day: a. “Urinary” production rate by isotope dilution; b. “Urinary” production rate by quantitating the excretion of endogenous THF + ATHF + THE and multiplying their sum by an empirically derived constant; c. Plasma production rate by multiplying the MCR by the 24-hr mean plasma cortisol concentration; d. Plasma production rate by summation of incremental secretion, calculated from the episodic secretory peaks defined by the 72 sample 24-hr study technique previously reportd from this laboratory. It was found that these four methods yield values whose relationships, on the average, are completely predictable: a. The two “urinary” production rates yield identical values; b. Plasma production rate by summation of incremental secretion very slightly underestimates plasma production rate by MCR, because of the small proportion (less than 19%) of the dai...

Intercomparison of Four Methods for Measuring Cortisol Production

The pyrogenic effect of etiocholanolone.

It has been observed that discrepancies, and often pronounced ones, exist when apparent cortisol secretion rate is measured from each of 6 individual metabolites of cortisol. This study employed adrenalectomized patients maintained on dexamethasone. Unlabeled pure cortisol was infused episodically to simulate normal adrenal secretion. Cortisol-4-14C was infused at different times in relation to the measured plasma cortisol content. Urines were collected for 3 days and the specific activities were measured for cortol, cortolone, β-cortol, β-cortolone, tetrahydrocortisol and tetrahydrocortisone. The specific activities demonstrated that the tracer was not metabolized under any circumstance in precisely the same manner as the cumulative metabolism of the unlabeled cortisol. This is a sufficient reason for the discrepancies found in secretion rate measurements and no other mechanism need be invoked. Consideration is given to the validity of approximation of the true cortisol secretion rate. It was co...

Clarification of Discrepancies in Cortisol Secretion Rate

The metabolic fate of 11β-hydroxy-Δ4-androstene-3,17-dione has been studied in man under different levels of thyroid hormone. Several patients were studied at 2 levels of thyroid function. The metabolites derived in hyperthyroid subjects were qualitatively and quantitatively the same as those obtained in euthyroid subjects with 3α,11β-dihydroxyandrostan-17-one as the principal product. In hypothyroid subjects there was a decrease in the production of 3α,11β-dihydroxy-5β-androstan-17-one with a concomitant rise in the formation of 3,11β-dihydroxy-Δ4-androsten-17-ones. The amounts of the 5β-steroids produced were essentially the same in euthyroid, hyperthyroid and myxedematous subjects. It was concluded that the 5α-reductase and Δ4-3-hydroxysteroid dehydrogenase associated with 11β-hydroxy-Δ4-androstene-3,17-dione are responsive to low levels of thyroid hormone.

D. K. Fukushima

Papers

Hypothalamic-Pituitary Function in Diverse Hyperprolactinemic States

Intercomparison of Four Methods for Measuring Cortisol Production

The pyrogenic effect of etiocholanolone.

Clarification of Discrepancies in Cortisol Secretion Rate

Metabolism of 11 beta-hydroxy-delta 4-androstene-3,17-dione: effect of thyroid hormone.