The effects of o,p'-DDD on human adrenal steroid synthesis

In the present study, the effects of o,p'-DDD on plasma levels of pregnenolone, 17 alpha-hydroxypregnenolone, progesterone, 17 alpha-hydroxyprogesterone, 11-deoxycorticosterone, deoxycortisol, corticosterone, cortisol, androstenedione and testosterone were studied in 6 patients with adrenal carcinoma (3 with Cushing's syndrome, 2 with adrenogenital syndrome, one without clinical manifestation) and 6 with Cushing's disease. Plasma levels of these steroids were decreased in all of the patients with adrenal carcinoma. The decrement of progesterone and 17 alpha-hydroxyprogesterone was greater than that of pregnenolone and 17 alpha-hydroxypregnenolone. These results indicate that o,p'-DDD inhibits both cholesterol cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase system. Plasma levels of pregnenolone and 17 alpha-hydroxypregnenolone showed a twofold increase on the 7th day after consecutive administrations of o,p'-DDD in patients with Cushing's disease. Plasma levels of cortisol were decreased to normal one month after continuous o,p'-DDD treatment. Urinary 17-OHCS and 17-KS have been decreased out of proportion to the decrease in plasma cortisol in the first week of o,p'-DDD treatment. Such a disparity suggests that o,p'-DDD might affect the extra-adrenal metabolism of cortisol. However, no evidence was found for the inhibition of hepatic C17-20lyase and glucuronyl transferase. Regression of pulmonary metastases was observed in one case with Cushing's syndrome due to adrenal carcinoma, suggesting that o,p'-DDD causes necrosis of the metastatic adrenal carcinoma. A remission of the disease was obtained in one patient with Cushing's disease after 6 months of continuous o,p'-DDD treatment. The usefulness of o,p'-DDD for the treatment of adrenal carcinoma with metastases and Cushing's disease was confirmed.     

Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion.

Dehydroepiandrosterone sulfate (DS) concentration was measured in the sera of premature and full-term infants and in children throughout puberty. Panhypopituitary, Addisonian, and virilized children were also studied. DS decreased slowly during the first weeks of life from a high level in neonates to the low levels observed between one to five years. After five years of age, DS concentration started to rise. A steeper increase was observed with the onset of puberty, and adult DS concentrations were reached in late puberty. There was no sex difference in DS concentration at any pubertal stage or bone age. Day-to-day variations were small in childhood and during puberty, but were considerable in premature infants. DS concentrations measured at 0900 h were not significantly different from those at 1700 h. There was a positive correlation of serum DS concentrations with the excretion of urinary 17-ketosteroids in boys and girls (r=0.789). Premature infants had DS concentration in or above the late pubertal range. Five panhypopituitary patients and five Addisonian patients had DS concentrations below normal. DS was markedly elevated in patients with congenital adrenal hyperplasia and in one girl with adrenal carcinoma, and was suppressible with dexamethasone in the former. The ease of measurement and the small amount of blood required make serum DS determination a useful guide for adrenal androgen secretion.     

Corticotropin-releasing hormone- and adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing's disease.

A 53-yr-old man with Cushing's disease was found to have a pituitary carcinoma with metastases to the liver and lung which produced both CRH and ACTH simultaneously. Despite removal of the pituitary tumor, his Cushing's disease worsened. Endocrinological examination then demonstrated elevated plasma CRH and markedly elevated plasma ACTH, beta-lipotropin, and cortisol concentrations, increased urinary 17-hydroxycorticosteroid and 17-ketosteroid excretion, and no suppression of serum cortisol after low or high dose dexamethasone administration. Urinary 17-hydroxycorticosteroid excretion increased in response to metyrapone, and lysine vasopressin elicited a striking increase in plasma ACTH. A computed tomographic scan of abdomen revealed multiple hypodense areas in the liver and bilateral adrenal hyperplasia. Postmortem histological examination revealed a necrotic hemorrhagic pituitary carcinoma with metastases to the liver, lung, and olfactory bulb. Immunohistochemical staining, gel filtration, and Northern blot analysis of liver and lung metastases revealed evidence of the production of both CRH and ACTH in these metastases. We concluded that the patient's pituitary carcinoma produced both CRH and ACTH.     

VIRILIZING ADRENAL ADENOMA IN AN ADULT WITH THE BECKWITH-WIEDEMANN SYNDROME: PARADOXICAL RESPONSE TO DEXAMETHASONE

An adult woman with Beckwith-Wiedemann syndrome, hemihypertrophy and an androgen-secreting adrenal adenoma is described. She presented with a 7-year history of progressive virilization and was found to have high plasma levels of testosterone and dehydroepiandrosterone (DHEA) sulphate and elevated levels of urinary metabolites of testosterone and its precursors. Administration of dexamethasone was associated with progressive rises in plasma 17 alpha OH progesterone, 11 beta-desoxycortisol, DHEA sulphate, androstenedione and testosterone, together with increased urinary excretion of androsterone, 11 beta OH androsterone, etiocholanolone, DHEA, and 16 alpha OH DHEA. Hormone levels fell to normal following removal of the tumour.     

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.     

An infant with Cushing's disease due to an adrenocorticotropin-producing pituitary adenoma.

An 8-month old male with Cushing's disease is presented; his clinical presentation and appearance were typical of infants with glucocorticoid excess. Concentrations of cortisol, 17-hydroxyprogesterone, and adrenal androgens were strikingly elevated. High doses of dexamethasone did not suppress the excretion of urinary free cortisol or 17-hydroxycorticoids, and administration of ACTH elicited no further rise in plasma cortisol. Responses of LH, FSH, and PRL to iv LRF and TRF were appropriate for age, but neither TSH nor ACTH rose significantly. Plasma ACTH values were elevated to 700 pg/ml. An intracranial mass lesion superior and anterior to the sella turcica was demonstrated by computerized axial tomography and angiography. An inoperable pituitary adenoma was a massive surrounding fibroblastic reaction was found at craniotomy. The pathological diagnosis of an ACTH-producing pituitary adenoma was confirmed by immunohistochemistry and by the in vitro secretion of ACTH by cells cultured from the tumor.     

Late diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia results from 21-hydroxylase deficiency in more than ninety percent of cases. The classical form of 21-hydroxylase deficiency presents in the neonatal period with virilization or adrenal insufficiency, with or without concurrent salt wasting. We report on a rare case of classic 21-hydroxylase deficiency diagnosed in late adulthood. A 39-year-old male patient presented for workup of infertility. Urologic investigation revealed small testes, bilateral testicular masses, and asthenozoospermia. The patient's steroid metabolism showed markedly increased levels of adrenal androgens, in particular of 17-hydroxyprogesterone amd 21-deoxycortisol. The gas chromatographic-mass spectrometric (GC-MS) urinary steroid profile was dominated by metabolites of 17-hydroxyprogesterone, while the endogenous glucocorticoid production was subnormally low. ACTH levels in plasma were elevated. These hormonal findings were consistent with 21-hydroxylase deficiency. Therapy with dexamethasone was initiated. The CTP21A2 gene analysis revealed the mutation I172N (ATC --> AAC) in exon 4 of allele 1 and a large gene deletion in allele 2. Cases of 21-hydroxylase deficiency diagnosed in late adulthood are rare; however, clinicians should be alert of this possibility.     

Lack of correlation between gonadotropin and adrenal androgen levels in agonadal children.

To evaluate the relationship between the secretion of gonadotropins and adrenal androgens, patients with gonadal agenesis were evaluated by (a) administering human luteinizing hormone (hLH) for 5 days with or without estrogen pretreatment to agonadal patients who had prepubertal LH levels; (b) correlating circulating gonadotropin levels with adrenal androgens in 45 patients; and (c) comparing adrenal androgens with gonadotropins after long-term administration of estrogen or androgens. Results are as follows: (a) No alteration in serum concentrations of dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), estrone (E1), testosterone (T), or in excretion of urinary 17-ketosteroid (17 KS) occurred after the administration of hLH. (b) No clearcut relationship between endogenous level of LH or FSH and DHA OR DHAS was demonstrated although a coincident increase of all hormones with age occurred. (c) Administration of estrogen to patients with gonadal agenesis did not affect their levels of DHA and DHAS although those patients given androgen developed higher DHAS, but not DHA, levels. Hence, increasing gonadotropin concentrations would not appear to be a primary etiologic factor in the maturation of the adrenal.     

Effects of growth hormone administration on dehydroepiandrosterone sulphate, androstenedione, testosterone and Cortisol metabolism during nutritional repletion

This study evaluated whether pharmacological doses of recombinant human growth hormone (hGH) influences androgen or cortisol metabolism during nutritional repletion following prolonged illness. Stable hospitalized adults (three males, seven female) receiving constant calorie and protein intake were studied. An initial control week was followed by a treatment period during which hGH (10 mg/day s.c.) was administered daily. Prior to hGH treatment, serum and 24-h urinary concentrations of dehydroepiandrosterone sulphate (DS) were below the normal range; serum androstenedione and testosterone concentrations were within the lower limit of normal. In contrast, serum cortisol (F) and 24-h urinary F excretion were normal. During hGH treatment, nitrogen balance became positive and plasma insulin-like growth factor I (IGF-I) concentrations rose five to seven-fold. However, serum DS, androstenedione, testosterone and F, and urinary F excretion did not change, while 24-h urinary DS excretion fell significantly. Growth hormone administration markedly stimulated protein anabolism but did not increase the low concentrations of circulating androgens or alter the disassociation between adrenal androgen and F release in stable hospitalized males and females. Thus, hGH does not appear to function as a cortical adrenal androgen stimulating hormone (CASH) or regulate adrenal cortisol or gonadal androgen release in this clinical setting.     

THE EFFECT OF o,p''-DDD ON ADRENAL STEROID REPLACEMENT THERAPY REQUIREMENTS

Two patients with adrenal carcinoma treated with 2,2-bis (2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) as adjuvant therapy were studied. Both patients developed hypoadrenalism while on o,p'-DDD and apparently adequate dexamethasone replacement therapy. The hypoadrenalism was overcome by increasing steroid replacement therapy. Dexamethasone levels were measured in the serum by radioimmunoassay and shown to be lowered by o,p'-DDD therapy. A study of the absorption and disappearance of dexamethasone from the circulation in response to a (1 mg oral dose indicated that the steroid was absorbed normally but was cleared more rapidly from the circulation of these two patients than from normal controls. This may be due to a change in the type of metabolites excreted. It is suggested that many of the reported side-effects of o,p'-DDD may be due to hypoadrenalism and may be controlled by greatly increasing the steroid replacement dose. The adequacy of corticosteroid replacement therapy may best be assessed by monitoring the levels of ACTH.     

The protracted effect of o,p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo

We hereby present a patient with Cushing's disease who became pregnant while being treated with o,p'-DDD and underwent a therapeutic abortion in view of the known embryotoxicity and placental transfer of this drug. Biopsy of adipose tissue in this patient showed it to be the storage site of considerable quantities of o,p'-DDD. Serum levels of o,p'-DDD determined in this patient initially four months after withdrawal of treatment and in another similar case three months after withdrawal were about 20 times higher than those found in untreated patients and reached control values only about 20 months later. Repeated evaluation of plasma and urinary free cortisol failed to reveal any correlation with the serum levels of o,p'-DDD, suggesting that the drug blood values cannot be used as a reliable indicator of the therapeutic effect on the adrenal gland. The histopathological examination of the embryo, aged about 42 days, revealed a dysmorphogenic event in the cortical primordia characterized by pycnotic sympathoblasts. It is suggested that such a toxic effect of o,p'-DDD on the embryonic cortical cells may act indirectly, affecting the viability of the migrating sympathoblasts.     

APPARENT MINERALOCORTICOID EXCESS AND DEFICIENT 11β-OXIDATION OF CORTISOL IN A YOUNG FEMALE

A 19-year-old female, known to have had hypertension and hypokalemic alkalosis since the age of 9 months, was found to have suppressed renin, negligible plasma and urinary aldosterone and low plasma levels of other known sodium-retaining steroids. Despite the normal plasma cortisol the urinary excretion of 17-oxosteroids and 17-oxogenic steroids was low as was the cortisol secretion rate, suggesting a diminished metabolic clearance of cortisol. This was confirmed by the demonstration of a prolonged t 1/2 of 14C-cortisol. The abnormally high urinary excretion ratios of cortisol to cortisone, tetrahydracortisol to tetrahydrocortisone and 11-hydroxy-aetiocholanolone to 11-oxy-aetiocholanolone indicate that the diminished cortisol breakdown is the result of deficient 11 beta-oxidation. Moreover, the urinary excretion of free cortisol was elevated, probably due to diminished tubular reabsorption of cortisol. Hypokalemic alkalosis did not respond to spironolactone, but was partly corrected by amiloride. No response to dexamethasone was observed, but dexamethasone combined with aminogluthetimide normalized blood pressure and serum K. These findings support the involvement of a sodium-retaining, kaliuretic steroid in this rare syndrome.     

Nodular adrenal hyperplasia with elevated adrenocorticotropic hormone levels

Micronodular adrenal hyperplasia is an uncommon adrenal disorder characterized by failure of urinary corticosteroid excretion to be suppressed by high-dose dexamethasone therapy. Thus, micronodular adrenal hyperplasia demonstrates dexamethasone suppressibility that resembles primary adrenal neoplasia. However, since some cases have been reported to have measurable plasma adrenocorticotropic hormone (ACTH) levels, it is unclear whether this disorder arises primarily in the pituitary-hypothalamic region or in the adrenal gland. Our patient had clinical features of Cushing's syndrome and elevated urinary corticosteroid excretion that did not suppress with even high doses of dexamethasone; however, ACTH levels were elevated and were suppressible with high-dose dexamethasone therapy. At operation, enlarged adrenal glands with multiple micronodules were found. This case is compatible with the hypothesis that hypothalamic-pituitary hyperfunction precedes the development of micronodular adrenal disease in some cases.     

11β-Hydroxylase deficiency: management of a difficult case by laparoscopic bilateral adrenalectomy

A 14-year-old girl presented with short stature and progressive virilization. She had not undergone the menarche. On investigation, she had elevated testosterone, androstenedione, dihydroepiandrosterone sulphate and 17α-hydroxyprogesterone levels, which were all suppressed by overnight dexamethasone to within their normal ranges. An initial diagnosis of 21-hydroxylase deficiency was revised to 11β-hydroxylase deficiency after a tetracosactrin stimulation test, which showed only a modest rise in 17α-hydroxyprogesterone level (from 92 nmol/l at baseline to 133 nmol/l at 60 minutes) and measurement of the basal 11-deoxycortisol, which was grossly elevated. Treatment with dexamethasone 0.5 mg nocte resulted in suppression of androgens in the daytime, but not in the evening, particularly androstenedione. Treatment with hydrocortisone 10 mg b.d. failed to suppress testosterone or androstenedione over a 24-hour period. Addition of cyproterone and oestrogen supplements had no effect and significant virilization persisted. Laparoscopic bilateral adrenalectomy was therefore performed as definitive treatment and resulted in remarkable clinical and biochemical improvement. This case illustrates difficulties in correct diagnosis, choice of appropriate steroid regimen and monitoring efficacy of treatment in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. More aggressive management with earlier bilateral adrenalectomy may be appropriate in selected cases.     

Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate

A 57-year-old woman presented with an apparently obvious diagnosis of iatrogenic virilization. At the age of 51, she began a 4-year treatment with prednisone or cyclosporine, which are known to promote hair growth, for Beh?et disease. At the age of 56, osteoporosis was overtreated with the anabolic steroid nandrolone. Insignificant inhibition by dexamethasone of the extremely high serum concentrations of testosterone and less high concentrations of weak androgens prompted us to search for a virilizing tumor. Computed tomography showed a 2.3 x 1.5 cm nodule in the right adrenal gland. As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors.     

Differential diagnosis of hyperandrogenism in women with polycystic ovary syndrome

According to the Androgen Excess and Polycystic Ovary Syndrome Society (AE&PCOS), the main feature of PCOS is clinical hyperandrogenism or laboratory hyperandrogenaemia. Therefore, in diagnosing PCOS one must always exclude other causes of androgen excess. In a woman with hyperandrogenism, the diagnosis of PCOS can usually be made according to the patient's history and careful clinical examination. Signs of mild hyperandrogenaemia usually start after the menarche and cycles continue to be anovulatory in adult life. Non-classical congenital adrenal hyperplasia (NCCAH) can be another cause of hyperandrogenism with oligomenorrhea. This can be diagnosed in a patient with elevated basal or ACTH stimulated serum 17OH-progesterone (17-OHP) levels or in a case of a significant decrease in serum testosterone (TST) and dehydroepiandrosterone sulphate (DHEA-S) in a two day dexamethasone suppression test. Cushing's disease (ACTH producing pituitary adenoma) is a rare cause of hyperandrogenaemia in women with recent onset of hyperandrogenism. However, it must always be taken into the consideration in a patient with accompanying signs of hypercortisolism. It can usually be excluded by performing an overnight dexamethasone suppression test or the measurement of 24 h urinary free cortisol levels. Severe signs of hyperandrogenism which lead to virilization should always lead to the exclusion of androgen secreting tumors of ovarian or adrenal origin. These are very rare but should be always taken into the account in a patient with recent onset of severe signs of androgen excess and very high serum androgen levels. Mild signs of hyperandrogenaemia in a woman with recent oligomenorrhea should always lead to the exclusion of hyperprolactinaemia.     

A 31-year-old woman with infertility and polycystic ovaries diagnosed with non-classic congenital adrenal hyperplasia due to a novel CYP21 mutation

A 31-yr-old woman presenting with a history of hirsutism, amenorrhea, and infertility was previously assumed to have polycystic ovary syndrome. A new gynecological-endocrine evaluation demonstrated elevated testosterone/SHBG ratio, serum 17-hydroxyprogesterone (17-OHP), and urinary pregnantriol. She was diagnosed with non-classic congenital adrenal hyperplasia. In spite of treatment with dexamethasone and fludrocortisone in doses that suppressed adrenal androgens and 17-OHP into normal range or below, she did not ovulate. Clomiphene citrate and then FSH/hCG treatment in several cycles gave no consistent ovulation. Progesterone levels remained elevated throughout the cycles indicating a possible contribution from the adrenals. Oral glucose tolerance was normal, but the homeostasis model assessment index indicated insulin resistance. With metformin 1500 mg daily the index decreased remarkably from 2.77 to 0.96 with a few ovulations but no pregnancy occurred. Three cycles of IVF treatment thereafter were unsuccessful. Three months after the last in vitro fertilization (IVF) cycle, still on dexamethasone, fludrocortisone, and metformin, her menstruations became regular and she thereafter became pregnant. During pregnancy metformin was discontinued and dexamethasone replaced with prednisolone. Mild gestational diabetes developed and insulin was given. A healthy boy was born at term by elective Cesarean section. A CYP21- gene analysis had not indicated any of the known mutations but after gene sequencing a novel mutation was found, namely R233G. This case confirms the necessity of adding an analysis of 17-OHP when evaluating women with hirsutism and menstrual disturbances and if an elevated value is found, the advantage of performing a mutation analysis to facilitate counseling and decisions on treatment.     

Cortisol secretion by an incidentally discovered nonfunctional adrenal adenoma

We describe a middle-aged man with late-onset multiple sclerosis and an incidentally discovered asymptomatic adrenal mass. He had no symptoms or signs of hypercortisolism. A 24-h profile revealed fluctuating serum cortisol values (between 15.1 and 4.7 micrograms/dl) and inappropriately low plasma ACTH values. Urinary cortisol excretion was 89 and 106 micrograms/day on two occasions. After a 4-h ACTH infusion, serum cortisol rose from 6.3 to 108 micrograms/dl. The serum dehydroepiandrosterone level, 33 ng/dl before ACTH stimulation, did not change. During dexamethasone administration, the lowest daily urinary cortisol excretion was 37 micrograms/day, and 17-ketosteroid excretion was 8 mg/day. The response to metyrapone showed a rise of serum 11-deoxycortisol to 25.6 micrograms/dl and of ACTH to 169.5 pg/ml. After removal of the tumor, most likely an adenoma, the circadian pattern of cortisol and ACTH was normal. During a 4-h ACTH infusion, the serum cortisol level rose from 10 to 27 micrograms/dl, and dehydroepiandrosterone rose from 62 to 90 ng/dl. During dexamethasone administration, daily urinary cortisol excretion decreased to 12 micrograms/day, and 17-ketosteroid excretion dropped to 3.9 mg/day. These data show that while the tumor appeared clinically to be nonfunctional, it was producing cortisol and possibly androgens autonomously, albeit at levels too low to cause complete suppression of the pituitary-adrenal axis.     

Virilizing adrenal adenoma stimulated by dexamethasone in a middle-aged woman.

In a middle-aged woman with virilizing adenoma, 2 mg dexamethasone increased urinary excretion of 17-ketosteroids (17-KS) and 17-hydroxycorticosteroids, whereas 8 mg dexamethasone increased urinary excretion only of 17-KS. With discontinuation of dexamethasone, 17-KS excretion returned to the predexamethasone level. Dexamethasone depressed the basal level of cAMP synthesis and basal testosterone production by the normal adrenal tissue in vitro. Dexamethasone also depressed the increase of cAMP produced by ACTH in the normal tissue. In contrast, dexamethasone increased basal cAMP synthesis and stimulated testosterone secretion in the tumor tissue. ACTH and dexamethasone were additive in their effects on cAMP and testosterone in the tumor tissue. It is suggested that dexamethasone acted directly on the adrenal tumor to stimulate steroid secretion in this patients.     

Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus

BACKGROUND: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones. OBJECTIVE: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon. METHODS: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured. RESULTS: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5-10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters. CONCLUSIONS: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.