Cushing's syndrome and pregnancy: aetiologies and prognosis in twenty-two patients.

OBJECTIVE: The association of an active Cushing's syndrome and pregnancy is a rare event which raises specific diagnostic difficulties and bears poor maternal and foetal prognoses. We report our series of 22 patients. PATIENTS: Age range was 19-34 (mean +/- SEM = 27.3 +/- 1.5) the onset of hypercorticism occurred before the pregnancy (n = 2), during the pregnancy (n = 15) or in the early post-partum (n = 5). The diagnosis was made during the pregnancy of 4 patients and in the post-partum of 18. RESULTS: Cushing's syndrome was revealed by the local manifestations of an adrenocortical tumour in 3 patients and by the clinical features of hypercorticism in 19 patients: mainly morphological changes (n = 19), high blood pressure (n = 12), and/or accelerated hair growth (n = 7). Aetiological distribution was noteworthy by the unusual predominance of primary adrenocortical tumours (n = 16) especially adrenocortical carcinomas (n = 8). Cushing's disease was present in only 4 patients and in 2 an ectopic ACTH secretion was observed. This association implied a high rate of complications for the mother: high blood pressure (n = 12), diabetes (n = 3), preeclampsy (n = 3) and pulmonary embolism (n = 1) and for the infant: prematurity (n = 16), hypotrophy (n = 4), adrenal insufficiency (n = 1), virilization (n = 1), stillbirth (n = 1). During their pregnancy 18 patients had a symptomatic treatment while only 4 patients (3 with adrenocortical carcinoma and one with an ACTH-secreting phaeochromocytoma) had a unilateral adrenalectomy. CONCLUSION: This condition is difficult to recognize: the diagnosis of Cushing's syndrome may be obscured by normal hormonal modifications of the pregnant state; it also forbears particular severity because of maternal and foetal complications, the unusual prevalence of malignant tumours and the particular difficulty in curing or merely controlling the hypercorticism.

Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy.

Adrenocortical carcinoma is a rare tumor, and only limited information is available about its natural history and the effects of therapy. We studied 105 patients (75 female and 30 male; mean age, 46 years) with adrenocortical carcinoma who were referred to us between 1963 and 1987. The average duration of symptoms before diagnosis was 8.7 months. At the time of diagnosis, 68 percent of the patients had endocrine symptoms, and 30 percent had distant metastases. Hormonal studies showed that 79 percent of the tumors were functional. Eighty patients underwent surgery, and 59 also received the adrenal cytotoxic agent mitotane. The median disease-free interval after surgery was 12.1 months (range, 1 to 175). Tumor dissemination occurred in 82 percent of the patients, most commonly to the lung, liver, and adjacent organs. The median survival time was 14.5 months (range, less than 1 to 175), and the five-year survival was 22 percent. Age over 40 years and the presence of metastases at the time of diagnosis were the only factors recognized as indicating a poor prognosis. Mitotane controlled hormonal secretion in 75 percent of the patients. Eight mitotane-treated patients had partial tumor regression, but the drug did not have a significant effect on survival. We conclude that adrenocortical carcinoma carries a poor prognosis. Mitotane therapy may offer transient benefits, particularly in controlling endocrine symptoms.

[Short term effects of ketoconazole in Cushing's syndrome]. / Effets à court terme du ketoconazole dans les syndromes de Cushing.

The effects of Ketoconazole (600 mg/day) were evaluated in 10 patients with Cushing's syndrome during a mean period of 4.5 weeks (range 1-12). The urinary free cortisol excretion (UFC) decreased by 21 +/- 15% (mean +/- SEM) (p less than 0.01) on day 1; 54 +/- 8% (p less than 0.0001) on day 2; 60 +/- 15% (p less than 0.0001) on day 3 and 87 +/- 3% (p less than 0.0001) on day 8 compared to baseline. Salivary cortisol at 0800 h decreased similarly. On day 3, 7 patients showed normal UFC values and on day 8, only 1 patient, with the ectopic ACTH syndrome, had persistent hypercortisolism. The cortisol decrease was associated with an increase in desoxycorticosterone values (p less than 0.01) and a decrease in dehydroepiandrosterone sulfate (p less than 0.001), delta 4 androstenedione (p less than 0.05) and testosterone (p less than 0.05). No significant variations were observed in ACTH, 11 desoxycortisol, aldosterone, plasma renin activity, corticosteroid-binding globulin and sex hormone-binding globulin. Side effects were few: mild clinical adrenal insufficiency (n = 5), oedema (n = 3) and reversible hepatic toxicity (n = 1). We conclude that Ketoconazole is an effective inhibitor of cortisol and androgens synthesis. It is well tolerated, rapidly effective and its efficacy persists unchanged for at least one month in all forms of Cushing's syndromes. For these reasons Ketoconazole may be a valuable drug for preoperative treatment of Cushing's syndrome.

Evening urinary free corticoids: a screening test in Cushing's syndrome and incidentally discovered adrenal tumours.

In this study, we investigated the usefulness of the determination of evening urinary free corticoids/creatinine in samples collected from 20.00 to 24.00 h as a screening test in Cushing's syndrome. In controls (N = 61) the ratio values ranged from 1.1 to 9.4 mumol/mol, whereas in patients with Cushing's syndrome (N = 20), they ranged from 27.5 to 855.5 mumol/mol. However, in 28% of patients with major obesity (greater than 50% overweight) and no hypercortisolism, the ratio values were between 9.4 to 27.8 mumol/mol. A short (10 days) hypocaloric diet induced a decrease in the values in 75% of these patients; the normal range was reached in 50% of them. In addition, the evening urinary free corticoids/creatinine was slightly abnormal in 8 out of 10 patients with incidentally discovered 'silent' adrenal adenomas, whereas it was normal in all 6 with other adrenal masses. In conclusion, evening urinary free corticoids/creatinine is easy to obtain and it reaches a higher sensitivity (100%) and specificity (97%) than the 24 h urinary free corticoids. In the case of borderline values, the presence of overweight should be taken into account.

Transsphenoidal pituitary surgery for the treatment of Cushing's disease: results in 64 patients and long term follow-up studies.

Transsphenoidal pituitary surgery was performed in 64 patients with Cushing's disease in search of a corticotroph adenoma. In 4 patients, profuse local bleeding prevented completion of the exploration. Of the 60 patients who had an adequate exploration, 4 could not be followed after surgery. Short term assessment of the surgical outcome (3-6 months postoperatively) was performed on 60 patients, including the 4 who had incomplete pituitary exploration. Forty-two patients (70%) were judged as immediate successes [urinary cortisol excretion, less than 90 micrograms (less than 248 nmol)/day]; the mean urinary cortisol excretion and plasma ACTH level fell from 463 +/- 70 (+/- SE) to 26.7 +/- 3.6 micrograms/day (1277 +/- 193 to 74 +/- 10 nmol/day; n = 33) and from 111 +/- 33 to 36 +/- 14 pg/mL (24 +/- 7 to 8 +/- 3 pmol/L; n = 23) in patients who had both measurements pre- and postoperatively. Eighteen patients (30%) were judged as immediate failures; neither urinary cortisol excretion nor plasma ACTH levels changed significantly in patients who had both measurements pre- and postoperatively. The preoperative epidemiological, clinical, hormonal, and radiological characteristics of the 2 groups were similar. Histological examination of pituitary fragments removed in 58 of the 60 patients evaluated postoperatively revealed the presence of tumoral tissue in a higher percentage of patients in the immediate success group (72%) than in the immediate failure group (24%; P less than 0.01). The 42 patients in the immediate success group were followed from 6 months to 7 yr (median, 2 yr); 6 patients had recurrences from 2-3 yr after operation. Actuarial analysis indicates that the probability of a patient remaining well 6 yr after surgery is 72 +/- 20% (95% confidence limit). Most of the patients in the immediate success group had transient ACTH deficiency preceding a progressive return to normal pituitary-adrenal function.

Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function.

The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.

Hormonal consequences of orchidectomy for carcinoma of the prostate. With special reference to the measurement of free testosterone in saliva and prostatic dihydrotestosterone levels.

22 patients with metastatic carcinoma of the prostate were treated by subcapsular orchidectomy and followed by regular determinations of plasma testosterone, dihydrotestosterone, delta 4-androstenedione, dehydroepiandrosterone sulfate and testosterone estradiol-binding globulin as well as salivary testosterone, which reflects free plasma testosterone. Subcapsular orchidectomy constantly induced a dramatic and stable decrease in testicular androgens without modification of adrenal androgens or testosterone estradiol-binding globulin. Free testosterone levels vary widely for a given value of plasma testosterone, probably due to individual variations of testosterone estradiol-binding globulin. Salivary testosterone is preferable to plasma testosterone for monitoring hormonal therapy for metastatic carcinoma of the prostate. In another group of orchidectomized stage-D2 patients, obstructive symptoms motivated transurethral resection of the prostate allowing the assay of intraprostatic dihydrotestosterone which was constantly below the dihydrotestosterone level of androgen-independent tissues (below 2.5 ng/g).

[Male hypertestosteronemia]. / Hypertestostéronémie masculine.

Male hypogonadism is characterized by a lowering of plasma testosterone level below the lower limit of physiological variations. Conversely, some adult males, apparently eugonadic, have a plasma testosterone level much higher than normally. In most cases, male hypertestosteronaemia - defined by a plasma testosterone level above 13 ng/ml and due to various physiopathological mechanisms - is part of a wider pathological context. It betrays hyperandrogenism (elevated free testosterone) during treatment with androgens or chorionic gonadotropic hormone. In other cases, it seems to underlie a relative hypoandrogenism with rise of testosterone bound to transport proteins and/or excess of oestrogens. Hypertestosteronaemia therefore appears as a biochemical sign not to be ignored, but it also suggests that men with abnormally high testosterone levels present with new pathology and that aetiological investigations are necessary.

Hormonal consequences of orchidectomy for carcinoma of the prostate. With special reference to the measurement of free testosterone in the saliva.

22 patients with metastatic carcinoma of the prostate were treated by subcapsular orchidectomy and followed by regular determinations of plasma T, DHT, D4A Dione, SDHEA, and TeBG as well as salivary T which measures the free Testosterone. Subcapsular orchidectomy constantly induced a dramatic and stable decrease of testicular androgens or TeBG. Free Testosterone levels vary widely for a given value of plasma T, probably due to individual variations of TeBG. Therefore salivary T should be used preferably to plasma T to monitor hormonal therapy of metastatic carcinoma of the prostate.

[The hormonal state of pregnancy: modification of cortisol and testosterone]. / Etat hormonal de la grossesse: modification du cortisol et de la testostérone.

The pattern of cortisol and testosterone levels during the normal pregnancy was investigated by measuring these hormones in the same 19 healthy pregnant women at 11th to 19th, 24th to 29th and 34th to 39th week post amenorrhea. We noted the well-known increase in total plasma cortisol and testosterone, due to the elevated concentration of their transport protein, i.e., Corticosteroid Binding Globulin (CBG) and Testosterone Estradiol Binding Globulin (TeBG), consecutive to the increase in plasma oestrogens. Morning (8h) and evening salivary cortisol (20 h) values, which are a good reflect of free plasma cortisol, were found increased since the second trimester of pregnancy, with a conserved circadian cycle. 24 h urinary free cortisol was slightly increased since the first trimester, yet remaining within the normal range; in the late pregnancy it reached sometimes higher levels. "Vesperal" urinary cortisol measured on a collected urine sample between 20 h and 24 h was higher in pregnant women since the beginning of pregnancy as compared to that of non pregnant women. Levels of salivary free testosterone measured in a few patients appeared similar to that of non-pregnant controls. We also report the data obtained in two pregnant women with Cushing's syndrome due to an adrenocortical carcinoma which showed a strong elevation of urinary and salivary free cortisol while a pregnant woman with a luteoma had a lower level as compared to normal pregnant. Moreover these three patients had a marked increase in free salivary testosterone opposite to normal pregnant women.

[Discordance between the short and standard metyrapone tests in isolated corticotropin insufficiency]. / Discordance entre les tests à la métopirone court et standard au cours d'une insuffisance corticotrope isolée.

A 71-year-old man presented with clinical and common biological features of secondary adrenal insufficiency. Basal ACTH level was in the normal range. As it has been previously reported in ACTH deficiency, cortisol response to ACTH-test was normal. A single-dose metyrapone test, performed to confirm the diagnosis of adrenal insufficiency, gave unexpectedly normal results. However 11-desoxycortisol (compound S) response to standard-metyrapone test was subnormal ascertaining the diagnosis of ACTH-deficiency. Thus normal responses to single-dose metyrapone test do not imperatively exclude secondary adrenal failure.

Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

Cyproterone acetate lead-in prevents initial rise of serum testosterone induced by luteinizing hormone-releasing hormone analogs in the treatment of metastatic carcinoma of the prostate.

Luteinizing hormone-releasing hormone (LH-RH) analogs are an effective treatment of metastatic carcinoma of the prostate. However, they induce an initial rise in serum testosterone responsible for 10-30% of diseases flares. The efficacy of the antiandrogen cyproterone acetate (CPA) was tested in 15 patients with metastatic carcinoma of the prostate. 10 patients were given 100 mg CPA t.i.d. from day 1 to 14 in association with the LH-RH analog Buserelin, 500 micrograms t.i.d., from day 7 to 14.5 patients were given CPA and Buserelin at the same doses from day 1 to 7. Serum testosterone determinations were obtained on days 1-7, 8, 11 and 14, at 08.00 h, and on days 8, 11, 1 h after each analog injection in group 1, and on days 1, 4 and 7 at 08.00 h and 1 h after each analog injection in group 2. All the patients were then treated by orchidectomy. Pretreatment with CPA blunted the initial rise of testosterone which never rose above pretreatment levels. Simultaneous treatment had no demonstrable effects on the rise of serum testosterone. It is concluded that pretreatment with CPA allows a safer use of LH-RH analogs in the treatment of metastatic carcinoma of the prostate.

True hermaphroditism: from female to male endocrine status.

True hermaphroditism was revealed by monthly intrascrotal bleeding in a 21-yr-old subject of male phenotype who had undergone surgical treatment for gonadal ectopy at the age of 7 yr. The presence of an ovary was demonstrated by the endocrine profile of an ovulatory menstrual cycle. Evidence for the presence of a testis was provided by a plasma testosterone increase after hCG administration (5000 IU/day for 3 days) and its spontaneous response to an endogenous preovulatory LH peak. Further endocrine studies revealed that both gonads were stimulated by endogenous gonadotropins. At surgery, a hemiuterus and an ovary with corpus luteum were found in the left hemiscrotum, and a testis and epididymis were found in the right hemiscrotum. After removal of the ovary, the subject passed from a predominantly female to a male endocrine status, which suggests that the endocrine secretion of the testis was inhibited by the negative feedback effect of ovarian steroids on gonadotropin secretion.

[Rapid beta 1-24-corticotropin test in the exploration of the corticotropic axis. 71 cases]. / Le test rapide à la beta 1-24 corticotrophine dans l'exploration de l'axe corticotrope. Soxiante et onze observations.

The reliability of the beta 1-24 corticotropin test, which is both cheap and safe, in the assessment of the hypothalamic-pituitary-adrenocortical function was re-evaluated by comparing its results with those of the metyrapone test in 71 subjects: 30 controls and 51 patients with suspected pituitary-adrenal dysfunction. Response to a 500 micrograms intramuscular injection of beta 1-24 corticotropin was evaluated by measuring the 60 min plasma cortisol levels; 4.5 g of metyrapone divided into 6 doses were then administered orally and response was evaluated by measuring plasma 11-desoxycortisol levels. A highly significant correlation (r = 0.79; p less than 0.001) was observed between plasma cortisol and plasma 11-desoxycortisol levels. The results were best interpreted by expressing the values obtained as plasma cortisol concentrations which, in normal subjects are at least 21 micrograms/100 ml. The rapid beta 1-24 corticotropin test was found to be very reliable (sensitivity 90%, specificity 100%) to detect adrenal insufficiency, irrespective of the organs affected on the hypothalamic-adrenocortical axis.

Effects of 10 days administration of percutaneous dihydrotestosterone on the pituitary-testicular axis in normal men.

Dihydrotestosterone (DHT) was administered percutaneously in a dose of 125 mg twice daily for 10 days to 12 normal men. Basal plasma levels of testosterone (T), 17 beta-estradiol (E2), and LH were measured every 2 days in these men and every 5 days in subjects from a control group receiving placebo. The daytime course of plasma hormone levels between two DHT applications was studied in six men. LRH tests were performed in nine men before and on day 10 of DHT administration. Plasma levels of free T and free E2, and T - E-binding globulin capacity and affinity were measured in six men before and on days 5 and 10 of DHT administration. Before DHT administration, there was no difference in basal plasma levels of T, DHT, E2, and LH between the control and the DHT-treated group. In the latter group, plasma DHT levels increased sharply from 0.52 +/- (+/- SE) to 3.70 +/- 0.92 ng/ml on day 2 (P less than 0.001) during DHT treatment. Plasma T, E2, and LH levels decreased significantly from 7.33 +/- 0.74 to 1.33 +/- 0.54 ng/ml (P less than 0.001), from 46 +/- 5 to 20 +/- 3 pg/ml (P less than 0.01), and from 7.8 +/- 1 to 4.2 mIU/ml (P less than 0.05), respectively. Except for a small decrease in plasma DHT (P less than 0.05) 12 h after the previous DHT application, hormone levels were stable during the time between the two DHT treatments. The responses of LH and FSH to LRH were not different before and on day 10 of DHT administration. Plasma levels of free T and free E2 as well as those of total T and E2 decreased; however, the percentages of unbound T and E2 were not different before and during DHT administration. T - E-binding globulin capacity and affinity were not modified by DHT administration. Changes in plasma DHT levels were negatively correlated with those in The results of this study demonstrate that 10-days DHT administration has an inhibitory effect on the hypothalamo-pituitary-testicular axis in normal men.