The dexamethasone-modified adrenal scintiscan in hyporeninemic aldosteronism (tumor versus hyperplasia). A comparison with adrenal venography and adrenal venous aldosterone

The dexamethasone-modified adrenal scintiscan, a noninvasive procedure, is described for the preoperative distinction between primary aldosteronism (aldosterone-producing ademona) and idiopathic aldosteronism (bilateral hyperplasia) and for the preoperative localization of aldostersone-producing adenomas. This procedure has been carried out on 17 subsequently proved cases of primary aldosteronism and nine cases (four unexplored) of idiopathic aldosteronism. In the tumor cases, it indicated correctly the side of the tumor in 88 per cent. It was correct in predicting the existence of bilateral hyperplasia in all of the five cases explored. It produced the same response in four more cases believed to have bilateral hyperplasia, in which surgical exploration has not been carried out. Many of the same patients had, in addition, standard adrenal scintiscans (SS), adrenal venography, and determinations of aldosterone in adrenal venous blood. These results are compared with those of the dexamethasone scintiscan (DS). In tumor localization, the 88 per cent figure for the DS was only moderately better than that of the other three (71 per cent, SS; 80 per cent, venography; 80 per cent, adrenal venous aldosterone levels). However, in predicting bilateral hyperplasia, the DS was 100 per cent correct, as were the levels of aldosterone in adrenal venous blood. The SS and adrenal venography failed in bilateral hyperplasia and gave many false-positive results indicating tumor. The DS, a relatively simple outpatient procedure, appears to be at least as effective, both in lateralizing tumors and distinguishing between tumor and bilateral hyperplasia, as the more difficult, expensive, and sometimes hazardous invasive procedure of bilateral adrenal vein catheterization.     

Congenital adrenal hyperplasia presenting as massive adrenal incidentalomas in the sixth decade of life: report of two patients with 21-hydroxylase deficiency

Divergent recommendations exist regarding the evaluation of adrenal incidentalomas. Recent data have indicated a prevalence of adrenal tumors of 71% in nonclassical congenital adrenal hyperplasia (CAH) and unmasked heterozygotes. These data expand the differential diagnosis of such incidental tumors and substantially modify the approach to their evaluation. We present two patients, female pseudohermaphrodites with the simple virilizing form of CAH and 21-hydroxylase deficiency, who functioned successfully as married phenotypic males. Both came to medical attention in the sixth decade by virtue of massive adrenal incidentalomas encountered in the evaluation of recurrent urinary tract infections. Each had a 46, XX karyotype, no palpable testes, and markedly elevated baseline levels of 17-hydroxyprogesterone (17-OH Prog) of 6086 ng/dL and 6750 ng/dL. Both responded appropriately to dexamethasone suppression with reduction of 17-OH Prog, androgens and, in the second patient, ACTH to normal or near normal levels. Histologic and autopsy examination of the first patient's tumor and computed tomographic characteristics of the second revealed a benign adenoma and myelolipoma respectively. We extend and confirm previous recommendations that CAH be included in the differential diagnosis of adrenal incidentaloma and that baseline 17-OH Prog. levels be obtained, with ACTH stimulation if necessary, to diagnose the presence of nonclassical CAH.     

Radioisotopic study of the adrenal glands using 131I-19-iodocholesterol

Scintigraphy of the adrenal gland with 131I-19-iodocholesterol has recently been added to radiological techniques in adrenal imaging and has been used successfully to demonstrate anatomical and functional disorders of the adrenals in a variety of clinical situations. A review of the authors' experience stresses the diagnostic value of this method. Radiological findings and results of scintillation imaging are complementary: their comparison improves and clarifes indications for scintigraphy. Hyperadrenal cortical diseases always gave satisfactory scintigrams, the most interesting results being obtained in adrenal cortical hyperplasia and unilateral hyperfunctioning adenomas. In these cases the evaluation of the response to stimulation or suppression tests was very useful. On the other hand scintigraphy was less valuable in demonstrating malignant and non malignant tumours.     

Acute adrenal crisis complicating hypertensive congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency

In its classical form, congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is characterized by hypertension and abnormal sexual development. Suppression of ACTH secretion by means of administering glucocorticoids fulfills the therapeutic goal of reducing blood pressure and decreasing androgen production. The present report describes the case of a patient suffering from congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency who developed an acute adrenal crisis, unprovoked by stress, following interruption of glucocorticoid replacement therapy. It is suggested that patients on a suppressive dose of glucocorticoids for adrenal hyperplasia are at increased risk for acute adrenal insufficiency if therapy is interrupted, and that deoxycorticosterone (DOC) in the absence of a glucocorticoid is insufficient to prevent manifestations of adrenal crisis.     

Assessment of adrenal glucocorticoid function. Which tests are appropriate for screening?

The rapid cosyntropin stimulation test offers a simple means for detecting adrenal insufficiency. In contrast, assessment of suspected hypercortisolism (Cushing's syndrome) is difficult because cortisol levels fluctuate with intermittent release of corticotropin from the pituitary or from tumors. Also, a number of medications affect cortisol levels, leading to false-positive or false-negative results. The classic low-dose followed by high-dose dexamethasone test is cumbersome, and other, simpler studies, such as the overnight high-dose dexamethasone suppression test, may prove more practical and cost-effective. With both high and low levels of adrenal glucocorticoids, awareness and early recognition of the symptoms are important. An endocrinologist should be consulted when the overnight dexamethasone suppression test or the 24-hour urine cortisol collection is abnormal or if clinical suspicion is high despite normal results on screening tests.     

Pre-operative localization of aldosterone-secreting adrenal adenomas

Techniques for pro-operative localization of aldosterone-secreting adrenal adenomas were studied in thirty-seven patients, each with hypertension and biochemical evidence of primary hyperaldosteronism and each later having adrenal surgery (thirty-two adenomas, five bilateral hyperplasia). Bilateral adrenal vein catheterization was attempted in all cases; it was successful on the left side in all patients and in 92% of cases on the right. Adrenal vein plasma samples were obtained from the left side in 92% and from the right in 73% of cases. Adrenal vein plasma aldosterone measurements correctly indicated the presence of tumour in twenty-eight cases but falsely predicted unilateral adenoma in two cases of bilateral adrenal hyperplasia. Adrenal venography also correctly predicted unilateral adrenal adenomas in twenty-six cases but falsely suggested the presence of tumour in three cases of bilateral adrenal hyperplasia. Computed tomography (CT) was used in the last eight cases. In seven instances the predictions (six adenomas, one bilateral adrenal hyperplasia) were confirmed at surgery. However, the remaining patient harboured an adenoma 20 mm in diameter which was not detected by CT although diagnosed both by adrenal venography and adrenal vein aldosterone measurements. Ultrasound detected adenoma in only three of twenty-two cases examined. Although further comparative studies of the type described here are required, the results of computed tomography are promising and suggest that this non-invasive technique might well become the first choice procedure in localizing aldosterone-secreting adenomas.     

The localization of aldosterone-producing adenoma on computed tomography--a comparative study with adrenal scintigraphy and plasma aldosterone concentration in the adrenal or renal vein

The evaluation of computed tomography (CT) for detecting aldosterone-producing adenoma in primary aldosteronism was performed by comparison with adrenal scintiscan; determination of aldosterone in adrenal or renal veins, retroperitoneal pneumography and adrenal venography was reliable for diagnosis of adrenal tumors in pheochromocytoma or Cushing's syndrome, but not so effective for small adenoma of primary aldosteronism. An abdominal CT scan was performed on six patients with primary aldosteronism, one with idiopathic hyperaldosteronism and one with glucocorticoid responsive hyperaldosteronism; in an attempt to evaluate the utility of this noninvasive procedure. Diagnosis of hyperaldosteronism was made by demonstrating the elevated plasma aldosterone concentration and aldosterone secretion rate, normal excretion rate of urinary 17-OHCS and 17-KS, and low plasma renin activity. The CT scan correctly predicted unilateral adrenal adenoma in all the patients with primary aldosteronism of which the findings were identical to those demonstrated by surgery. The diameter of these tumors ranged from 10 X 7 X 6 to 19 X 17 X 14 mm. Also the CT scan in idiopathic hyperaldosteronism and glucocorticoid responsive hyperaldosteronism showed bilateral adrenal hyperplasia and bilateral normal adrenal glands, respectively. The pathological findings in these two cases disclosed the adrenal hyperplasia of zona glomerulosa and adrenal hyperplasia of zona subglomerulosa accompanied by a normal thickness of the adrenal gland, respectively. The precision of the CT scan, adrenal scintigraphy and determination of plasma aldosterone in the adrenal or renal veins were almost equal to the diagnosis of the localization of adrenal adenoma. It is concluded that the CT scan is a noninvasive and most useful method for the localization of aldosterone-producing adenoma and helpful in distinguishing adrenal adenoma from adrenal hyperplasia.     

A virilizing Leydig cell tumor of the ovary associated with stromal hyperplasia under gonadotropin control

A 34-yr-old nulliparous black woman presented with hair loss, facial hirsutism, irregular menses and infertility associated with greatly increased serum total testosterone levels. The adrenal glands and the ovaries were normal on radiological and ultrasonographic investigation. Catheterization of the veins draining from the adrenal glands and the ovaries yielded testosterone levels of 20.3 nmol/L and 20.0 nmol/L in the right and the left adrenal veins, respectively, and 17.9 nmol/L and 27.4 nmol/L in the right and left ovaries venous plexus, respectively. Sequencial dexamethasone and ethynyl estradiol suppression test showed a decrease in cortisol level with no change in total testosterone level on dexamethasone while an increase in testosterone from 10.5 nmol/L to 20.1 nmol/L was observed ten days after ethynil estradiol had been associated to dexamethasone. When a gonadotropin-releasing hormone agonist (gonadorelin 3.5 mg i.m.) was administered for 2 months, serum gonadotropins levels decreased to less than 2 IU/L, total testosterone to 3.8 nmol/L and estradiol to less than 36 pmol/L. The patient was submitted to a pelvic exploratory laparotomy and a left salpingo-oophorectomy was performed. A solid and circumscribed ovarian tumor of 1.0 cm in diameter was found. The pathological diagnosis was a Leydig cell tumor with surrounding stromal hyperplasia. These findings may suggest that this tumor was gonadotropin-dependent being indirectly stimulated by ethynil estradiol, through a sensitization of the pituitary gonadotropes and increase in gonadotropin levels and suppressed by a gonadotropin-releasing hormone agonist.     

The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome

Patients cured from endogenous Cushing syndrome usually develop postoperative adrenal suppression in the year ensuing surgery. To define whether the pituitary corticotroph is the rate limiting step in the postoperative recovery of this secondary/tertiary form of adrenal insufficiency, we examined surgically cured patients with Cushing syndrome 10 days, 3 months, and 6-12 months after surgery, by administering ovine CRH (oCRH) iv at the dose of 1 microgram/kg.h over 24 h. The pituitary corticotroph of these patients responded vigorously to oCRH, with ACTH concentrations reaching above the normal range at all three times of testing. Parallel measurements of cortisol in nonadrenalectomized patients demonstrated subnormal adrenal responsiveness at 10 days and 3 months and normalization at 6-12 months after surgery. The circadian rhythm of ACTH was maintained postoperatively at 10 days and 6-12 months, and the circadian rhythm of cortisol was also present at 6-12 months after surgery, in spite of the constant infusions of pharmacological doses of oCRH, suggesting that factors other than CRH secretion regulate this rhythm. We conclude that the corticotroph is not the rate limiting step in the recovery of the hypothalamic-pituitary-adrenal axis from glucocorticoid-induced adrenal suppression, and that the locus of the defect resides in the hypothalamic CRH neuron and/or its higher regulatory inputs.     

Ultrasonographic detection of adrenal gland tumors in two ferrets

Hyperadrenocorticism is recognized as a common medical condition in middle- to old-aged ferrets. Because diagnosis of adrenocortical tumors in ferrets, using results of adrenocorticotropic hormone stimulation or dexamethasone suppression tests, is unreliable, ultrasonography was used as an alternative to laparotomy for the detection of tumors in 2 ferrets. The diagnosis was confirmed by surgical excision and histologic examination of the adrenal gland. In a typical manifestation of the condition, clinical signs in 1 ferret included vulvar swelling and serous to mucopurulent vaginal discharge, which resolved after the adrenalectomy.     

Selection of patients for clomiphene citrate therapy

Ninety-three infertile women were treated with clomiphene citrate alone or in combination with human chorionic gonadotropin (hCG) for absent or infrequent ovulation. The patients were divided into eight categories according to the diagnosis obtained: ovarian androgenic hyperplasia, adrenal androgenic hyperplasia, mixed ovarian and adrenal androgenic hyperplasia, hypothalamic anovulation, postpill anovulation, follicular phase defect, luteal phase defect, and amenorrhea-galactorrhea syndrome. Each group was analyzed individually to compare the ovulation and conception rates and the complications involved. A survey of the data presented in this study shows that the best response was noted in patients with ovarian androgenic hyperplasia. Patients with a functional pathologic adrenal component responded favorably when dexamethasone was used as an adjuvant to clomiphene therapy. Those with hypothalamic anovulation responded better when hCG was added to clomiphene therapy. Women with postpill anovulation as well as those with follicular phase defect were found to be good candidates for clomiphene therapy. In properly selected patients with poor luteal phase defect, hCG secured excellent results both in ovulation and conception. Patients with lactation amenorrhea failed to ovulate when treated with clomiphene alone.     

Laparoscopic surgery of adrenal glands: indications and limits

Over the last four years it has been demonstrated that laparoscopy can be used successfully for adrenalectomy, providing certain advantages over conventional open surgery. The aim of this study was to determine the indications for laparoscopic approach in adrenal surgery. From June 1994 to June 1996 laparoscopic transabdominal flank approaches were proposed in patients with a unilateral 8 cm or less, non-malignant tumors of the adrenal gland. For tumors under 4 cm in diameter only secreting tumors were removed. Among 77 patients requiring ablation of the adrenal gland, 50 (65%) underwent a laparoscopic procedure: 29 Conn adenomas, 10 Cushing adenomas, 6 Pheochromocytomas, 4 incidentalomas. One patient had Cushing's disease and underwent bilateral resection. Mean tumor size was 26 mm (7-75 mm). Malignancy was demonstrated in 2 tumors: one cortisone secreting tumor and one leiomyosarcoma. Conversion was required in 4 cases (8%). Mean operative time for unilateral adrenalectomies was 147 minutes (50-300'). There were no deaths. Morbidity included: one hemorrhage via the trocar orifice requiring reoperation, one infarction of the spleen which regressed spontaneously, one parietal hematoma, and one case of phebitis of the lower limb. The endocrinopathy was successfully cured in all patients with secreting tumors. The 27 other patients underwent open adrenalectomy. Laparoscopic approach was not proposed due to suspected malignancy in 13 cases, previous surgery in 8 cases and multiple, bilateral and/or extra adrenal tumors in 6 cases. Laparoscopic approach to the adrenal gland is the procedure of choice in patients with Conn adenomas, Cushing adenomas and in most cases of pheochromocytomas. It is not indicated for malignant and large tumor (> 8 cm). Currently two-thirds of our patients requiring and adrenalectomy are operated laparoscopically.     

Elevated serum progesterone levels during pituitary suppression may signify adrenal hyperandrogenism

OBJECTIVE: To investigate whether elevated serum P levels after pituitary down-regulation signify adrenal enzyme defects or hyperandrogenism. DESIGN: Prospective study. SETTING: Assisted reproduction unit in a university medical center. PATIENT(S): Two hundred twenty-seven IVF patients treated by the long down-regulation protocol. INTERVENTION(S): Oral dexamethasone (DEX) administration if P level exceeded 0.8 ng/mL (conversion factor to SI unit, 3.180) after pituitary suppression. MAIN OUTCOME MEASURE(S): Serum concentrations of P, E2, LH, DHEAS, and 17 alpha-hydroxyprogesterone and ACTH stimulation tests. RESULT(S): In eight patients (3.5%), serum P levels exceeded 0.8 ng/mL and E2 and LH levels confirmed pituitary down-regulation. Mean DHEAS levels in the patients in this group were significantly higher than in the other patients. All eight patients demonstrated a significant decrease in serum P level after DEX administration. In five patients the ACTH stimulation test suggested an adrenal defect. Five pregnancies were achieved after the addition of DEX to the treatment protocol. CONCLUSION(S): High serum P levels after pituitary down-regulation appear to be of adrenal origin and may be the first indication of an adrenal enzyme defect. Further investigation such as an ACTH stimulation test is recommended, followed by treatment with DEX if indicated.     

Adrenocorticotrophin-independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide

The aetiology of ACTH-independent macronodular adrenal hyperplasia (AIMAH) is uncertain. We examined a 55 year old man with Cushing's syndrome due to AIMAH, whose cortisol levels increased after stimulation with lysine-8-vasopressin (LVP) in vitro as well as in vivo. Abdominal MRI revealed nodular enlargement of both adrenal glands. No adenoma was evident on pituitary MRI. 131I-adosterol scintigraphy exhibited marked uptake into both adrenal glands. Although baseline plasma cortisol levels were within normal limits, urinary free cortisol excretion was 3-fold higher than the upper limit of the normal range. Plasma ACTH levels were undetectable. Oral dexamethasone failed to suppress plasma cortisol levels irrespective of dose, and administration of corticotrophin releasing hormone failed to increase plasma ACTH and cortisol levels. LVP injection failed to increase plasma ACTH levels, but elicited an increase in plasma cortisol levels. The direct stimulatory effect of LVP on cortisol secretion was confirmed in vitro in cultured adrenocortical cells from macronodules obtained at surgery. Food intake, gastric inhibitory polypeptide (GIP), or octreotide administration, which were reported to regulate cortisol release in patients with AIMAH, failed to affect plasma cortisol levels. In conclusion, plasma cortisol responsiveness to LVP, GIP, and octreotide is heterogeneous in patients with AIMAH.     

Prenatal molecular genetic diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH), in its severe forms, produces virilization of the external genitalia of the affected female fetus. Early treatment with dexamethasone of the pregnant mother at risk of a fetus with 21-OH deficiency avoids the masculinization of the affected female fetus. We present a pregnant mother, where the prenatal diagnosis was established by DNA analysis of a chorionic villous sample obtained in the 9th week of gestation. Molecular analysis showed the female fetus to be affected of 21-OH deficiency. Maternal treatment with dexamethasone started on the 6th week of gestation has prevented the virilization of the affected baby. No significant side effects have been encountered. Prenatal diagnosis and treatment for 21-OH deficiency is effective and safe, as is described in the literature. This is the first case in Spain where both prenatal molecular diagnosis and treatment for 21-OH deficiency have been reported.     

Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome

Primary bilateral adrenocortical diseases are rare entities that have recently been appreciated as potential causes of Cushing syndrome. They include (i) primary pigmented adrenocortical disease (PPNAD), also known as "micronodular adrenal disease", which is a genetic disorder that is often associated with Carney complex, and (ii) massive macronodular adrenocortical disease (MMAD), a rare disorder of unknown etiology that affects older adults. Carney complex is a multiple endocrine neoplasia (MEN) syndrome that affects not only the adrenal cortex, but also the pituitary, thyroid, and gonads. It is associated with pigmentation abnormalities as well as myxomas and other mesenchymal and neural crest neoplasms. The inheritance of the complex is autosomal dominant, and genetic mapping has shown that at least two loci are involved in its pathogenesis. MMAD appears to be an isolated finding in most cases, and a genetic defect has not yet been defined. Ectopic expression of hormone receptors has been implicated in several cases of MMAD, but an underlying deficit has not been detected. Bilateral adrenocortical hyperplasia has also been described in McCune-Albright syndrome and MEN type-1, but this finding is not always associated with hypercortisolism. The genetic defects for these diseases are known, but their role in adrenal cortex pathophysiology has not been fully elucidated. Identification of the molecular defects responsible for bilateral adrenocortical disorders is expected to shed light on many aspects of early adrenal gland differentiation and tumorigenesis.     

Sexual and gonadal dysfunction in adrenal disorders

Among various diseases of the adrenals, major disorders that cause sexual and gonadal disturbances are congenital adrenal hyperplasia(CAH) and Cushing's syndrome, and the others include virilizing or feminizing adrenocortical tumors. CAH was reviewed based on the recent advances in molecular genetics. The most striking discovery was steroidogenic acute regulatory protein, mutations of which produce lipoid adrenal hyperplasia that was previously attributed to P-450scc deficiency. Reversible amenorrhea or impotence is found in patients with Cushing's syndrome. Low plasma estrogen and testosterone levels are associated with female and male patients, respectively. Elevated adrenal androgen accounts for mild virilization in female patients with ACTH-dependent subtypes. The sites of action at which hypercortisolemia suppresses the hypothalamic-pituitary-gonadal axis were discussed.     

Home monitoring of 17 hydroxyprogesterone levels in congenitx127drenal hyperplasia with filter paper blood samples

OBJECTIVE: The purpose of this study was to evaluate the usefulness of 17 hydroxyprogesterone (17OHP) determination in dried filter paper blood samples from patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. It was hypothesized that these home samples would enhance patient treatment. STUDY DESIGN: Results of 17OHP determination in simultaneously collected venous and dried filter paper blood samples were compared to establish assay reliability. Thereafter, parents mailed dried filter paper blood samples collected before each hydrocortisone dose. RESULTS: The 17OHP levels in wet and dried blood samples correlated well (r = 0.98). Results did not change when stored for 2 weeks under various conditions. Blood sampling at different times of the day provided insights into the patterns of 17OHP secretion and identified times of inadequate adrenal suppression. Dose adjustments were then made considering the time of day when adrenal suppression was inadequate. CONCLUSION: Home monitoring of 17OHP is a reliable and practical approach for assessing adrenal steroid activity in patients with congenital adrenal hyperplasia. Considering the time of day of 17OHP elevations also facilitates hydrocortisone dosing adjustment.     

The effect of dexamethasone administration at different stages of gestation on maternal plasma steroid concentrations in the baboon (Papio cynocephalus)

Dexamethasone administration at different stages of gestation in the baboon was studied for its effect on maternal steroid hormone concentrations. Dexamethasone (2 mg i.m. at 12 h intervals for three doses) was administered at early (days 37-39), mid (days 76-85) or late (days 112-123) gestation and morning blood samples were collected before, during and after dexamethasone suppression for 6 consecutive days. Dexamethasone treatment, at all stages of pregnancy, resulted in a significant decline in maternal serum cortisol concentrations, which rapidly return to normal concentrations after treatment. Progesterone concentrations were not affected by dexamethasone at any stage of gestation. Serum concentrations of oestradiol, testosterone and androstenedione were unchanged following dexamethasone administration in early pregnancy. A trend toward lower serum oestradiol was observed following dexamethasone administration in both mid and late gestation, but this was not significant. Both testosterone and androstenedione were significantly decreased following dexamethasone in both mid and late pregnancy and recovered to pretreatment concentrations within a few days after cessation of treatment. These results confirm other studies which demonstrate that adrenal precursors (maternal or fetal) are a major contributor to maternal serum concentrations of oestradiol. They also demonstrate that these adrenal precursors increase serum concentrations of testosterone and androstenedione in the pregnant baboon. Since these changes are only evident after that time (>40 days) when the fetal adrenal is steroidogenically competent, a role for fetal adrenal involvement in maternal serum androgen concentrations is suggested.