A case of isolated ACTH deficiency who developed autoimmune-mediated hypothyroidism and impaired water diuresis during glucocorticoid replacement therapy

A case of isolated ACTH deficiency who developed autoimmune-mediated hypothyroidism and still showed impaired water diuresis during glucocorticoid replacement therapy is reported. A 45-year-old woman was initially admitted for nausea, vomiting, and general malaise. Her serum sodium and plasma osmolality, ACTH and cortisol values were low, but her urine osmolality was high. Other pituitary hormone levels, thyroid hormone levels, and a computed tomogram of the pituitary gland were normal. The patient was treated with hydrocortisone and followed in the outpatient clinic; however, she was lost to follow up 18 months after admission. Three years later she presented with hypoglycemia and hyponatremia. Her serum or plasma ACTH, FT3, FT4, cortisol levels were low and her serum TSH level was high. Pituitary stimulation tests revealed a blunted response of ACTH to CRH and an exaggerated response of TSH to TRH. Plasma ADH was inappropriately high, and a water-loading test revealed impaired water diuresis and poor suppression of ADH. Although ADH was suppressed, impaired water diuresis was observed in the water loading test after hydrocortisone supplementation. Thyroxine supplementation completely normalized the water diuresis. Her outpatient clinic medical records revealed a gradual increase in TSH levels during follow up, indicating that she had developed hypothyroidism during glucocorticoid replacement therapy. The hyponatremia on the first admission was due to glucocorticoid deficiency, whereas the hyponatremia on the second admission was due to combined deficiencies of glucocorticoid and thyroid hormones.     

Hyperresponsiveness of TSH and prolactin and impaired responsiveness of GH in Japanese patients with isolated ACTH deficiency]

Two hundred and forty-one cases of isolated ACTH deficiency have been reported in Japan since 1969. Pituitary hormone responsiveness to stimulation tests before and after hydrocortisone supplementation was investigated in these cases. Plasma ACTH level showed no or little change in response to lysine vasopressin, metyrapone, CRF or insulin-induced hypoglycemia in 97.3-100% of the cases. Serum GH level changed little or not at all in response to GRF, insulin-induced hypoglycemia, glucagon, 1-dopa and arginine in 26.9, 29.3, 40.0, 50.0 and 56.1%, respectively. Serum TSH and prolactin (PRL) levels showed hyperresponse to TRH in 34.7 and 35.6%, respectively. After hydrocortisone therapy, GH secretion was more responsive than before therapy in 78.9% of the cases. After supplementation, TSH level was less responsive to TRH stimulation than before therapy in 59.3% of the cases. After hydrocortisone supplementation, TSH response to TRH decreased in 75% of ACTH-deficient patients without primary hypothyroidism but did not decrease in more than half of those with primary hypothyroidism. TSH response to TRH decreased after supplementation in 76.5% of the patients with TSH hyperresponsiveness before therapy, and increased after therapy in 66.7% of those with normal TSH responses before therapy. After supplementation, PRL response to TRH was less than that before therapy in 43.5% of ACTH--deficient patients, and greater than that before therapy in 30.4%. PRL response to TRH decreased after therapy in 66.7% of the patients with PRL hyperresponsiveness before therapy, and increased in 63.6% of those with normal PRL response before therapy. Primary hypothyroidism and Hashimoto's thyroiditis were complicated in 21.6 and 11.6%, respectively, of the 241 patients with isolated ACTH deficiency. In patients who had TSH hyperresponsiveness and/or high basal TSH levels and PRL hyperresponsiveness and/or high basal PRL levels, primary hypothyroidism was complicated in 58.4 and 42.3%, respectively. Hashimoto's thyroiditis was complicated in 29.8 and 20.5%, respectively, of these patients. Pituitary cell antibody (PCA) was detected in 36.6% of ACTH-deficient patients who were examined. Pituitary cell surface antibody (PCSA) to AtT-20 cells and GH3 cells was detected in 50.0 and 28.0% of the examined cases, respectively. The prevalence of PCA and PCSA did not differ between TSH-hyperresponsive patients and those with normal TSH basal levels and response, whereas PCA and PCSA were significantly more prevalent in PRL-hyperresponsive patients than in those with normal PRL levels and response. An empty sella was found in 30.2% of the examined case.(ABSTRACT TRUNCATED AT 400 WORDS)     

Das hypophysäre Koma

Pituitary coma is a rare case of emergency and primarily due to ACTH and TSH deficiency. Pituitary coma occurs more often in patients with well-known pituitary deficiency than in patients with intrasellar tumor. Clinical manifestations are hypotonia, bradycardia, decreased skin and nipple pigmentation, muscle weakness, vomitus, nausea, obstipation, hypothermia, and hypoventilation. A postpartal agalactia is often the first sign of Sheehan's syndrome. Unlike primary adrenal insufficiency (Addison's disease) ACTH deficiency does not cause hyperpigmentation, hyperkalemia, or salt loss. The suspicion of pituitary coma requires replacement with 100 mg hydrocortisone iv, 200 mg hydrocortisone iv/24 h, 500 micro g levothyroxine iv and fluid substitution. Since thyroxine accelerates the degradation of cortisol and can precipitate adrenal crisis in patients with limited pituitary reserve, hydrocortisone replacement should always precede levothyroxine therapy. ACTH stimulation test, CRH stimulation test and insulin tolerance test (optional) should be performed after therapeutic compensation to determine pituitary function.     

Suppression of the TSH response to TRH by thyroxine therapy in differentiated thyroid carcinoma patients.

Absent response of serum thyrotrophin (TSH) after stimulation with 200 micrograms synthetic thyrotrophin-releasing hormone (TRH) was used as a criterion of adequate suppression of TSH in the treatment of thyroid carcinoma patients with thyroxine. The mean causing total suppression of the response was 223 micrograms of thyroxine per day. At this dose level about 40% of the patients had serum thyroxine concentrations above the upper reference interval and only 10% had elevated triiodothyronine concentrations. In some patients the TSH response to TRH varied between absent and low normal when tested at long intervals. The ideal dose of thyroxine is obviously slightly higher than the smallest one causing total suppression of the TSH response to TRH, i.e. about 250 micrograms a day. The individual dose must be found using the TRH stimulation test because serum thyroid hormone levels cannot be used as a guideline for adequate dosage. In some patients the thyroid remnant of apparently normal thyroid tissue was not totally suppressed although the thyroxine dose was definitely above the level causing suppression of the response to TRH.     

Acute and chronic effects of high glucocorticoid levels on hypothalamic-pituitary-thyroid axis in man.

It is known that glucocorticoids can influence anterior pituitary hormones other than ACTH. Their effects on the hypothalamic-pituitary-thyroid axis are controversial. To further investigate this issue, the acute and chronic effects of high plasma cortisol levels on TSH secretion were evaluated in 20 normal subjects and in 14 patients with Cushing's syndrome. In normals, high plasma cortisol levels were obtained by giving ACTH 250 micrograms or CRH 100 micrograms iv as a bolus or by an hydrocortisone 500 mg infusion over 1 h. Acute cortisol increase produced no effect both on basal and TRH-stimulated TSH secretion. In patients with Cushing's syndrome, basal TSH levels, low or suppressed, showed an impaired response to TRH, inversely correlated with urinary cortisol values. After successful surgery, TSH and its response to TRH became normal in concomitance with the normalization of plasma and urinary cortisol levels. Our data show the lack of an acute inhibitory effect of high plasma cortisol levels on TRH-TSH axis. However, after long-term exposure to high plasma cortisol levels, i.e. Cushing's syndrome, inhibition of both basal and TRH-stimulated TSH secretion was demonstrated. These findings indicate that only prolonged hypercortisolism does interfere with pituitary TSH secretion. The underlying mechanisms are still unclear.     

Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases

OBJECTIVE: Addison's disease is frequently a component of autoimmune polyendocrinopathies while secondary adrenal insufficiency associated with autoimmune disorders is believed to be a rare event. We present a series of patients with secondary adrenal insufficiency coexisting with autoimmune diseases and/or antithyroid autoantibodies. DESIGN AND PATIENTS: Among a group of 102 patients with secondary adrenal failure of unknown origin diagnosed at the Department of Endocrinology of the Centre for Postgraduate Medical Education (Warsaw, Poland) we have identified a group with associated autoimmune disorders. Thyroid abnormalities occurred most frequently. Other diseases included insulin-dependent diabetes mellitus, pernicious anaemia, vitiligo, premature ovarian failure and autoimmune thrombocytopaenia. There were 23 women and one man aged 17-72 years at the time of investigation. Additionally, we included a woman with Addison's disease in whom the ACTH deficiency appeared 18 years after the onset of primary adrenal hypofunction. MEASUREMENTS: Pituitary-adrenal function tests comprised urinary excretion of 17-hydroxycorticosteroids in basal conditions and during a 2-day tetracosactrin test, plasma concentrations of ACTH and cortisol, and a 2-day metyrapone test (in eight cases). Thyroid function and immunity tests were: TSH, thyroxine, the antithyroglobulin, antimicrosomal and anti-peroxidase autoantibodies. Other endocrine studies included: serum LH, FSH and PRL. RESULTS: The 17-hydroxycorticosteroid values, both basally and during stimulation tests were consistent with a diagnosis of secondary adrenal insufficiency. Serum cortisol and plasma ACTH concentrations were low. In 14 patients primary hypothyroidism was confirmed by low T4 levels. In three patients subclinical primary hypothyroidism was revealed (elevated TSH levels). Three patients who had a past history of Graves' disease were euthyroid at the time of investigation. Twenty-three patients had antibodies against peroxidase. Most patients had gonadotrophins and PRL values within normal limits. CONCLUSIONS: The co-existence of autoimmune disorders with secondary adrenal insufficiency suggests an autoimmune aetiology for the ACTH deficiency.     

Effect of carbenoxolone on the plasma renin activity and hypothalamic–pituitary–adrenal axis in congenital adrenal hyperplasia due to 21-hydroxylase deficiency*

OBJECTIVE: To test the hypothesis that carbenoxolone, an inhibitor of 11beta-hydroxysteroid dehydrogenase, might augment the ACTH-suppressing and mineralocorticoid activities of hydrocortisone without a corresponding increase in peripheral hydrocortisone effects, we assessed the effects of carbenoxolone in patients with congenital adrenal hyperplasia. DESIGN AND PATIENTS: Six patients with classic 21-hydroxylase deficiency (5 salt-losing, 1 nonsalt-losing) were enrolled in this study. The study protocol involved 3 treatment periods (except for patient 3): phase 1, hydrocortisone and fludrocortisone; phase 2, hydrocortisone, fludrocortisone and carbenoxolone; phase 3, hydrocortisone and carbenoxolone. Patient 3 was not treated with fludrocortisone at baseline, so she participated only in phase 1 (hydrocortisone only) and phase 2 (hydrocortisone and carbenoxolone). Hydrocortisone and fludrocortisone dosages were kept the same during the study except for the discontinuation of fludrocortisone during phase 3. MEASUREMENTS: Plasma adrenal androgens or their precursors (androstenedione, 17-hydroxyprogesterone, and testosterone, and urine pregnanetriol); plasma cortisol, cortisol-binding globulin, ACTH, apparent cortisol metabolic clearance, 24-h urine 17-hydroxysteroids, and urine free cortisol; mineralocorticoid activity, as measured by plasma renin activity, body weight, plasma potassium, and mean blood pressure; fasting insulin/glucose ratio, protein balance, % eosinophils in peripheral blood, and total urine pyridinoline and deoxypyridinoline; TRH stimulation of TSH and pyridostigmine/GHRH stimulation of growth hormone. RESULTS: Compared to phase 1, the addition of carbenoxolone (with or without concurrent fludrocortisone administration) produced statistically significant decreases of 20-50% in mean plasma 17-hydroxyprogesterone, androstenedione, and renin activity. Since carbenoxolone also decreased the apparent metabolic clearance rate of cortisol by 20%, other measures of systemic glucocorticoid activity were examined. Carbenoxolone did not produce a cushingoid appearance or increase body weight, blood pressure, blood glucose or plasma insulin levels. Carbenoxolone also did not suppress stimulated GH levels, but did decrease TRH-stimulated TSH levels by approximately 20% (P < 0.05). CONCLUSION: Carbenoxolone can augment the adrenal androgen-suppressing activity of hydrocortisone in patients with 21-hydroxylase deficiency. These observations support the hypothesis that selective inhibition of enzymes that metabolize cortisol may lead to new approaches to improve the treatment of congenital adrenal hyperplasia.     

ACTH and prolactin deficiency

A 35 year old woman suffering from ACTH and prolactin (Prl) deficiency is described. Her symptoms of adrenal insufficiency appeared gradually after her first pregnancy in 1970; however, she conceived twice more and delivered healthy babies in 1972 and 1974, which she could not breast feed due to lack of milk. During an episode of pneumonia in 1977 she suffered acute adrenal insufficiency, after which she began treatment with hydrocortisone. Her pituitary reserve for TSH, GH, LH and FSH was normal, but her ACTH and Prl levels were undectable and did not respond to acute iv challenges of corticotrophin-releasing factor (CRF) and TRH, respectively. Autoantibodies, including antilactotroph titres, were negative, except for a positive pituitary immunofluorescence to ACTH. There was also no ACTH stimulation to a prolonged infusion of CRF followed by an acute iv bolus. These results, together with the gradual onset of symptoms which worsened after each pregnancy, suggest a possible autoimmune aetiology of her pituitary ACTH and Prl deficiencies.     

Do we still need the TRH stimulation test?

OBJECTIVE: To evaluate the diagnostic value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnosis of central hypothyroidism in patients with Sheehan's syndrome. DESIGN: TRH stimulation test was performed in 72 patients with Sheehan's syndrome. Basal free triiodothyronine (fT(3)) and free thyroxine (fT(4)) levels were measured. Serum thyrotropin (TSH) concentration was determined before and 30, 60, 90, and 120 minutes after 200 mug TRH IV bolus injection. The peak TSH values <5.5 microIU/ml were defined as inadequate response. A peak TSH at 60 minutes or later was considered as delayed response. If TSH (60 minutes after peak), was more than 40% of the peak value it was considered as prolonged response. The diagnosis of central hypothyroidism (CH) was made if either serum fT(4) concentration was subnormal with an inappropriately low serum TSH concentration or inadequate response to TRH stimulation test and/or a delayed or prolonged response to TRH stimulation test. MAIN OUTCOME: Fifty-six (77.7%) of the patients had low serum fT(4) and fT(3) levels with an inappropriately low serum TSH levels were defined as CH (CH0 group). Ten (13.8%) patients with normal and low-normal fT(4) levels had no response and/or delayed or prolonged response to TRH stimulation test (CH1group). Six (8.3%) patients had fT(3), fT(4), and TSH levels within normal limits and peak TSH responses >/=5.5 microIU/ml consistent with euthyroidism (euthyroid group). Thus, 66 (91.6%) of 72 patients with Sheehan's syndrome had CH. Although fT(4) levels were within normal reference range, TRH stimulation test revealed that 10 (13.8%) of these had CH. CONCLUSION: TRH stimulation test is useful in the diagnosis of central hypothyroidism, especially in whom fT(4) and/or TSH is low-normal and known to have hypothalamo-pituitary pathology.     

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by rathke's cleft cyst: a case report

We report a case of a seventy-year-old woman with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by Rathke's cleft cyst. She experienced nausea, vomiting, diarrhea, and headache and disturbance of consciousness induced by hyponatremia at a serum sodium level of 100 mEq/l. In spite of severe hyponatremia, urinary sodium excretion was not suppressed and serum osmolality (270 mOsm/kg) was lower than urine osmolality (304 mOsm/kg), and arginine vasopressin (AVP) remained within normal range. SIADH was diagnosed because she was free from other diseases known to cause hyponatremia such as dehydration, cardiac dysfunction, liver dysfunction, renal dysfunction, hypothyroidism, and adrenal insufficiency. Cranial computed tomographic (CT) scan and cranial magnetic resonance (MR) imaging showed a cystic lesion of approximately 2 cm in diameter in the pituitary gland. These images suggested that the cystic lesion was a Rathke's cleft cyst, which was the cause of SIADH. Water restriction therapy normalized her serum sodium concentration and improved her symptoms. After one year, she suffered from general fatigue, appetite loss, fever, and body weight loss (5 kg/2 months). She had neither hypotension nor hypoglycemia, but her serum sodium level was low and serum cortisol, ACTH, and urine free cortisol were very low. Therefore, secondary adrenal insufficiency was suspected and diagnosed by stimulation tests. After start of hydrocortisone replacement therapy (10 mg/day), her symptoms disappeared. In conclusion, Rathke's cleft cyst should be kept in mind as a potential cause in a patient with SIADH, hypopituitarism, and/or adrenal insufficiency.     

Effect of acute hypercalcemia on thyrotropin (TSH) and triiodothyronine responses to TSH-releasing hormone in man

In chronic hypercalcemia, basal TSH has been found to be low, with normal serum circulating concentrations of T3 and T4. This observation suggested a potentiation by hypercalcemia of the thyroid secretory response to TSH. The present study was undertaken to assess the possible influence of hypercalcemia on the T3 secretory response to TSH. Since T3 secretion was studied after stimulation of endogenous TSH by TRH, it was first necessary to find a protocol enabling us to study the effect of calcium on T3 release without affecting TSH secretion. Eighteen subjects underwent two TRH tests, with and without simultaneous calcium infusion, at 2-week interval and in a randomized order. In group A (five subjects) calcium infusion started 1 min after TRH, in group B (five subjects) 10 min after TRH, and in group C (eight subjects) 20 min after TRH. In groups A and B, TSH secretion was markedly blunted by hypercalcemia. In contrast, when calcium infusion was started 20 min after TRH (group C), the TSH secretion profile was no longer different from that in the control study. However, in this situation the increments of T3 and free T3 120 and 180 min after TRH were significantly higher when the subjects were rendered hypercalcemic than in the control study. These findings suggest that calcium might act at two different levels, to enhance the thyroid secretory response to TSH and decrease TSH secretion by acting directly on the pituitary gland. Both effects would produce the association of low serum TSH and normal levels of T3 and T4 observed in chronic hypercalcemia.     

A case of Addison's disease confirmed with low dose cosyntropin stimulation test

An eighty-year-old man who had complained of skin pigmentation and weight loss was referred to our hospital. Upon physical examination, marked hyperpigmentation was found on the whole body including oral mucosa, tongue and fingernails. Endocrinological findings showed increased ACTH (126 pg/ml) and normal serum cortisol (15.4 microg/dl). First, we used a 250 microg cosyntropin stimulation test which is valid to diagnose Addison's disease, resulting in an adequate cortisol response. Second, we performed 1 microg cosyntropin stimulation test, and the cortisol response was blunted. Since the diagnosis of Addison's disease was fairly certain, he was treated with hydrocortisone 15 mg/day, and improvement of his skin pigmentation and an increase in body weight were observed. To our knowledge, this is the first report that 1 mug cosyntropin stimulation test was helpful to make diagnosis as having Addison's disease rather than the 250 microg cosyntropin stimulation test, although it is established that the 1 mug cosyntropin stimulation test is useful in secondary or relative adrenal insufficiency.     

Aberrant luteinizing hormone-releasing hormone-stimulated adrenocorticotropic hormone secretion in a patient with pituitary hyperplasia due to primary hypothyroidism

We report a patient with primary hypothyroidism associated with an aberrant ACTH response to the LH-RH test. A 40-year-old woman was admitted to our hospital displaying headache, nausea, and numbness on the left side of her face, upper limbs, and tips of her toes. Computed tomography and magnetic resonance imaging revealed a mass-like lesion in the pituitary. A high serum TSH concentration with concomitant low thyroid hormone concentrations resulted in a diagnosis of primary hypothyroidism. To exclude the possibility of a coexisting pituitary tumor including a TSH-secreting tumor, we performed dynamic TSH secretion tests. TRH testing showed an excessive, delayed TSH response, typical of primary hypothyroidism. Serum TSH decreased not only after administration of CRH, octreotide, or L-DOPA, but also after administration of LH-RH. In this case, LH-RH testing induced ACTH secretion. To determine if aberrant ACTH secretion in response to LH-RH loading is a common phenomenon in severe primary hypothyroidism, we performed the LH-RH test on 4 additional patients with pituitary enlargement due to primary hypothyroidism. Two patients demonstrated aberrant ACTH secretion in response to LH-RH loading, but the others did not. To our knowledge, this is the first report of aberrant LH-RH-stimulated ACTH secretion in primary hypothyroidism.     

Evaluation of thyroid functions with respect to iodine status and TRH test in chronic autoimmune thyroiditis

Objective: Chronic autoimmune thyroiditis (CAT) is the most common form of thyroiditis in childhood and a frequent cause of acquired hypothyroidism. The objective of this study was to evaluate the thyroid status of childrenand adolescents with CAT with respect to iodine status and diagnostic values of thyrotropin-releasing hormone (TRH) test. Methods: Seventy-one children (mean age: 11.6 years) were studied in a retrospective analysis. Free thyroxine (T4), thyrotropin (TSH), TSH response to TRH test, thyroid autoantibodies, thyroid sonography, and urinary iodine excretion (UIE) were evaluated. Results: At diagnosis, 8.5% of patients had overt hypothyroidisim and 36.6% subclinical hypothyroidism; 5.6% had overt hyperthyroidisim and 8.5% had subclinical hyperthyroidism. Of them, 40.8% were euthyroid. Median UIE was 51 mg/L in overt hypothyroidism and 84 mg/L in subclinical hypothyroidism. The values were 316 mg/L and 221 mg/L in overt and subclinical hyperthyroidism, respectively. Basal TSH showed a strong correlation with peak TSH level on TRH test. Thirty-four percent of patients with normal basal TSH level showed an exaggerated TSH response. Conclusion: Iodine deficiency was seen more in cases with hypothyroidism, while excess of iodine was observed to be more frequent in hyperthyroid patients. Iodine status was a strong predictorof the thyroid status in CAT. TRH test may be helpful in further delineating patients with subclinical hypothyroidism. Conflict of interest:None declared.     

Delirium and neuromuscular symptoms in an elderly man with isolated corticotroph-deficiency syndrome completely reversed with glucocorticoid replacement

A 68-yr-old man had developed intractable vomiting soon after recovering from a flu-like illness. The use of Compazine as an antiemetic produced classic dystonic manifestations which resolved rapidly after discontinuation and treatment with Artane. However, he later developed a variety of neurobehavioral disturbances which led to his admission to the hospital. Extensive diagnostic procedures failed to identify any gastrointestinal or neurological causes. His condition unceasingly worsened until hypocortisolemia was serendipitously discovered, and all of his symptoms disappeared rapidly and completely with glucocorticoid replacement. Over the course of hospitalization, other than a single episode of orthostatic hypotension, the patient did not manifest any signs of adrenal insufficiency or endocrinopathy. Although detectable, his plasma ACTH level was markedly low in the presence of hypocortisolemia. His adrenal function was subnormal in the cortisol response to ACTH stimulation. His renin-angiotensin-aldosterone system and catecholamine levels were normal. He had normal pituitary responses to GnRH, TRH, and insulin, with rises in plasma levels of LH, FSH, TSH, PRL, and GH, but no stimulation of ACTH. Repeated CRH tests revealed no stimulation of ACTH and cortisol. No circulating anti-ACTH, antiadrenal, or antipituitary antibody was detected. We conclude that this elderly patient had a rare syndrome of selective corticotroph dysfunction which resulted in secondary adrenal failure and exacerbated his mental and neuromuscular abnormalities. To our knowledge, these symptoms, which clearly relate to hypocortisolism, have not been previously reported.     

A case of partial Addison's disease activated with the administration of rifampicin (RFP)

The patient was a 76 year-old female with tuberculous tendonitis, treated with anti-tuberculous drugs including rifampicin (RFP). About two weeks after the start of RFP, she noticed general malaise and started vomiting, and the laboratory data showed severe hyponatremia. Because of mild liver dysfunction, RFP was discontinued and her symptoms gradually improved. Abdominal X-ray and CT showed swellings and calcifications of adrenal glands bilaterally. Serum ACTH level was high and cortisole, 17-OHCS, and 17-KS levels were normal. Her response to rapid ACTH stimulation was blunted significantly. After another trial of RFP, she started to vomit and complain general malaise again. We diagnosed her as partial Addison's disease and administered hydrocortisone with RFP. After this treatment her improvement was rapid. It has been known that RFP causes induction of enzymes in hepatic microsomes which increase the catabolism of glucocorticoids. To avoid the risk of adrenal insufficiency, patients with insufficient adrenal hormone reserve should receive compensatory hydrocortisone while they are taking RFP.     

Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion

Six patients with idiopathic isolated deficit of TSH secretion were examined and reported on. Their clinical symptoms and routine biochemical data were unclear and were not specific for hypothyroidism. Serum triiodothyronine, free thyroxine and TSH levels were slightly low or low-normal. Basal metabolic rate and thyroidal (123)I-uptake were also slightly low or low-normal. The response of serum TSH to TRH stimulation was blunted in all patients. No nocturnal surge of serum TSH level could be seen in any of the patients. Empty sella was revealed in three patients, and pituitary microadenoma in one patient via magnetic resolution imaging. Antihuman pituitary cytosol antibody was seen in five patients. Autoimmunity may have played a role in the pathogenesis of idiopathic isolated TSH deficiency. Routine examination of thyroid function cannot easily detect this disease. TSH response to TRH stimulation and nocturnal surge of TSH should be examined when this disease is suspected.     

Adrenal insufficiency caused by primary aggressive non-Hodgkin's lymphoma of bilateral adrenal glands: report of a case and literature review

 A 64-year-old woman was hospitalized because of poor general condition, gastrointestinal upset, unexplained fever, electrolyte imbalances, and an incidental finding of bilateral huge adrenal masses on computerized tomography (CT) of the abdomen. Non-Hodgkin's lymphoma (NHL) of B-cell origin was proven by ultrasound-guided aspiration biopsy of the left adrenal gland. Meanwhile, primary adrenal insufficiency was confirmed by her low serum cortisol level, high ACTH level, and inadequate adrenal response to the rapid ACTH stimulation test. The diagnosis of primary adrenal NHL was supported by detailed physical examinations, bone marrow examination, and such imaging studies as CT scan and sonography. She received three courses of chemotherapy with cyclophosphamide, vincristine, and prednisolone and there was an initial transient response, but she died of sepsis and progression of NHL three and a half months later. Received: September 14, 1998 / Accepted: November 24, 1998     

Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene

BACKGROUND: One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. OBJECTIVE: To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. PATIENTS: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. METHODS: GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. RESULTS: Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. CONCLUSION: In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.     

RECOVERY OF ADRENAL FUNCTION AFTER TREATMENT OF ADRENOCORTICAL CARCINOMA WITH o,p''-DDD

The adrenolytic agent, 2,2-bis[2-chlorophenyl-4-chlorophenyl] 1,1 dichloroethane (o,p'-DDD), was used over a 20-month period following surgery in a 2 3/12-year-old girl for treatment of adrenocortical carcinoma. The child remained free of disease and was maintained on glucocorticoid and mineralo-corticoid supplements for 7 years. Hormonal evaluation was undertaken at 9 9/12 years of age to determine remaining adrenal steroidogenic capacity. Following discontinuation of both hydrocortisone and 9 alpha-fludrocortisone, she remained stable and asymptomatic. Immediately after discontinuing 9 alpha-fludrocortisone, the adrenal glomerulosa was able to respond to stimulation by the renin-angiotensin system as shown by the ability to achieve renal sodium conservation on a restricted sodium intake (less than 10 mEq/d for 5 d). The response of the adrenal fasciculata to ACTH stimulation showed a slower recovery. Baseline levels of cortisol were in the low normal range, but there was no increase in plasma cortisol or urinary 17-hydroxysteroids following stimulation with ACTH. The responses of cortisol, deoxycorticosterone, and corticosterone to ACTH stimulation gradually improved to achieve normal stimulated levels 18 months after stopping medications. Serum testosterone and delta 4-androstenedione were initially increased for level of puberty, while levels of dehydroepiandrosterone were prepubertal. Testosterone and delta 4-androstenedione did not suppress with dexamethasone (2 mg/d for 2 d; 4 mg/d for 2 d), and dehydroepiandrosterone decreased only slightly. However, administration of norethindrone (Norlutin) (10 mg orally, three times a day for 3 d) resulted in suppression while human chorionic gonadotrophin (hCG; 5000 U i.m. daily for 3 d) produced stimulation of testosterone, delta 4-androstenedione and dehydroepiandrosterone. Thus the androgens were felt be predominantly of ovarian origin. Dehydroepiandrosterone rose to low normal levels by 18 months after discontinuation of hydrocortisone. We thus demonstrate for the first time that both the adrenal glomerulosa and fasciculata have the capacity to recover normal function following treatment with o,p'-DDD. Further, we suggest that early exposure to excess adrenal androgens may result in mild alteration of gonadal function.