1/31. Cosecretion of estrogen and inhibin B by a feminizing adrenocortical adenoma: impact on gonadotropin secretion. We describe the first reported case of a feminizing adrenocortical adenoma cosecreting estrogens and inhibin B. A 39-yr-old man, with no previous history of disease and free of treatment, complained of gynecomastia without any clinical abnormality. plasma E2 and T were 496 pmol/liter and 8.7 nmol/liter, respectively. Testicular echography was normal, and abdominal computed tomography scan showed a 28-mm right adrenal tumor. hCG (5000 IU, im) induced a rise in plasma T levels (20.7 nmol/liter) without any change in plasma E2 levels. Basal plasma LH and FSH levels were undetectable. GnRH (100 microg, i.v.) induced an increase in plasma LH levels without a change in plasma FSH levels. The mean plasma inhibin B level was 330 /- 45 pg/ml (normal range, 94-327). Pulsatile GnRH administration (20 microg/pulse every 90 min for 3 d) stimulated LH secretion, whereas FSH secretion remained blunted. The patient underwent surgery to remove a 12-g adrenal adenoma. Six months later, plasma E2 and T levels were normalized. LH showed a spontaneous pulsatile pattern, and the mean plasma FSH level was 4.8 U/liter. The secretion of both gonadotropins was stimulated during a pulsatile GnRH administration performed in the same manner as before surgery. The mean plasma inhibin B level was 210 /- 25 pg/ml. Immunohistochemical studies revealed the presence of aromatase in clusters of tumor cells. Incubation of tumor sections with anti-beta(B)-inhibin antibody revealed intense staining in groups of cells that were also labeled with anti-alpha-inhibin antibody. These data show that the tumor cosecreted E2 and inhibin B, which were both responsible for inhibition of gonadotropin secretion. Tumor secretions appeared to be much more potent in suppressing FSH than LH levels. ( info) |
2/31. Progestin binding in testes from three siblings with the syndrome of male pseudohermaphroditism with testicular feminization. We have found a specific binding protein for synthetic progestins 6,7-[3H]methyltrienolone (R1881) and 17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione (R5020) and in the testis cytosol from three "sisters" with the complete form of the testicular feminization syndrome. The binding component sediments in the 8S region of sucrose gradients. It is saturable. The apparent affinity constant (Ka) for R5020 was determined in two cases and found to be 1.8 and 0.6 X 10(8) M-1. The number of binding sites calculated from Scatchard plots is relatively high: 572 and 826 fmol/mg protein. Competition studies indicate that this putative receptor is specific for natural and synthetic progestins but not for 5 alpha-dihydrotestosterone and cortisol. Similar progestin binding could not be found in normal human and rat testes. ( info) |
3/31. Major hyperestrogenism in a feminizing adrenocortical adenoma despite a moderate overexpression of the aromatase enzyme. A 30-year-old male was referred for the rapid development of gynecomastia, and dramatic hyperestrogenemia was assessed: plasma estrone, estradiol but also cortisol were not suppressed by high-dose dexamethasone, while gonadotropin pulsatility was completely abolished. A 60-mm right adrenal tumor was evidenced on computed tomography-scan, and the patient underwent adrenalectomy. The tumor was found to express a moderate increase in aromatase activity compared with adjacent non-neoplastic adrenal tissue. Quantitative RT-PCR also showed a weak and non-significant increase in total aromatase mRNA in the tumor compared with normal adrenal tissue. Aromatase transcripts were mainly promoter PII-derived, but different patterns of aromatase minor transcripts were found: promoter I.3- and I.6-derived transcripts were identified in the tumor, while only promoter I.4-derived transcripts were found in normal adrenal. This case report demonstrates that a sharp aromatase overexpression is not a prerequisite for clinical and biochemical hyperestrogenism, and further characterizes the aromatase promoter utilization in this feminizing adrenocortical tumor and in the normal adrenal cortex. ( info) |
4/31. Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings. Familial hyperestrogenism is a rare clinical condition of unknown etiology in which patients present excessive androgen to estrogen conversion. Excessive aromatization is primarily ascribed to abnormalities in the CYP19. mice that lack steroid 5alpha-reductase type 1 also exhibit hyperestrogenism due to an increased availability of androgen precursors. Here we studied two adult siblings, born to unrelated parents, who presented clinical and hormonal evidence of estrogen excess. The man was treated with topical dihydrotestosterone, which promoted adequate virilization. The woman was treated with anastrazole, a potent aromatase inhibitor, with normalization of menstrual cycles. genetic linkage to the steroid 5alpha-reductase type 1 gene (SRD5A1) was ruled out in this family. A similar analysis did not rule out linkage to CYP19, although no mutation was identified in the coding region of this gene. Aromatase mRNA was at least 10-fold more abundant in the female patient's skin fibroblasts vs. the control. Southern analysis of genomic dna did not reveal rearrangements or amplification of the coding region of CYP19. We conclude that the phenotype of familial hyperestrogenism includes prepubertal gynecomastia, hypogonadism, and short stature in men, and precocious thelarche, macromastia, enlarged uterus, and menstrual irregularities in women. Topical dihydrotestosterone is an efficient alternative treatment in men with hyperestrogenism; in addition, second generation aromatase inhibitors are useful in both sexes. ( info) |
5/31. Studies of the diurnal pattern of plasma corticosteroids and gonadotropins in two cases of feminizing adrenal carcinoma: measurements of estrogen and corticosteroid production. Two adult men with feminizing adrenal cortical carcinoma had measurements of their 24-h plasma corticosteroid and gonadotropin patterns as well as 24-h mean hormone levels of estradiol, estetrol, 11-desoxycortisol, DHEA-S, DHEA and testosterone. Cortisol, 11-desoxycortisol and estrogen production rates were also measured. The 24-h corticosteroid patterns showed preservation of the normal 24-h episodic and circadian patterns, albeit at higher levels. The cortisol production rates were markedly elevated despite only moderate elevation of the 24-h mean cortisol level. There were elevated plasma 11-desoxycortisol levels and a markedly elevated 11-desoxycortisol production rate in one patient and THS excretion in the other. The plasma estradiol levels, urinary excretion and production rates were markedly elevated. In addition, there was a decrease in the specific activity of estriol compared with estrone and estradiol as well as measurable levels of estetrol in both patients. These latter observations coupled with the urinary immunoassayable hCG in one patient suggest that these tumors may be functioning like trophoblastic tissue. The possibility that estetrol may serve as an additional marker for tumors of trophoblastic origin is of additional interest. ( info) |
6/31. Mechanism of feminization in primary liver cancer. Primary liver cancer occasionally presents with feminization. The mechanism is unknown. We studied a young man with primary liver cancer associated with feminization that disappeared after removal of the tumor. Before operation, the serum estrone level was markedly (1113 pg per milliliter) and estradiol and estriol levels were slightly elevated. Human placental lactogen was also increased (0.52 microng per milliliter). luteinizing hormone, follicle-stimulating hormone and prolactin levels were normal, and testosterone reduced. Beta subunits of human chorionic gonadotropin were not detected in the serum. in vitro assay of tumor tissue showed estrogenic activity and high levels of these subunits. With a reversed isotope dilution technic with crystallization to constant specific activity, we showed the tumor tissue to convert dehydroepiandrosterone sulfate and dehydroepiandrosterone to estrone and estradiol. Production of beta subunits of chorionic gonadotropin and raised serum levels of placental lactogen provided further evidence that the tumor was functioning as trophoblastic tissue. ( info) |
7/31. Familial adrenal feminization probably due to increased steroid aromatization. 5/10 members of a North African family (father, 2 male and 2 female siblings) had gynaecomastia, early growth and short final stature. The 8-year-old propositus had advanced bone age, facial acne, gynaecomastia, pubic hair and prepubertal testicular volume. Basal oestrone (E1) was elevated (670 pmol/l) and increased with adrenocorticotropic hormone (ACTH; 826 pmol/l). After human chorionic gonadotropin stimulation testosterone (T) responded normally whereas E1 and oestradiol (E2) remained unchanged. ACTH-dependent adrenal feminization was confirmed by a transient reduction of breast tissue following dexamethasone or cypropterone acetate treatment. testolactone increased T/E2 (from 5.6 to 20.3) and A/E1 (from 3.4 to 31.4) ratios and temporarily reduced the breast tissue. In conclusion, this is a familial type of adrenal feminization with increased adrenal androgen aromatization. This is the first time that male-to-male and male-to-female transmission has been reported. ( info) |
8/31. Feminizing adreno-cortical carcinomas in male adults. A dire prognosis. Three cases in a series of 801 adrenalectomies and review of the literature. We describe the clinical presentation, biochemical features, diagnostic criteria, clinical course and differential diagnosis in three cases of feminizing adreno-cortical carcinoma (FACC) with a review of the literature. patients: From 1970 throughout December 2003 among a series of 801 adrenalectomies, three had been performed for FACC. RESULTS: Age at presentation was 74, 63 and 23 years. estradiol hypersecretion was observed in 3/3 patients, 17 OH progesterone was elevated in 2/3 patients and both of them had a diminution of testosterone, delta 4 androstenedione was elevated in 1/3 patients. Imaging studies suggested malignancy in 3/3 patients by the presence of necrosis, heterogeneity, calcifications, size of the tumor and compression of adjacent organs. All patients were stage III at presentation and had a Weiss score >or=6. Size and weight of the tumors were 30, 20, 15cm and 3750, 480 and 275g respectively. All 3 patients received mitotane and cortisone post-operatively and at follow up (7, 3 and 2 years) all 3 died of the disease. CONCLUSIONS: Feminizing adreno-cortical carcinomas in adults are exceedingly rare (1-2% of adreno-cortical carcinomas). Tumors are huge and even after surgery for cure their prognosis is worse than for other varieties of adreno-cortical carcinomas either secreting or non secreting. early diagnosis and treatment may improve overall prognosis. ( info) |
9/31. Feminizing adrenocortical tumor. Histological and ultrastructural study. A case of a feminizing adrenocortical tumor associated with Cushing's syndrome in a 29 year old male is presented. The ultrastructural features are compared with adrenal tumors secreting aldosterone, glucocorticoids of androgens. As in adrenal carcinomas, this tumor demonstrates nuclear pleomorphism with enlarged nucleoli and nuclear pseudoinclusions. The cytoplasmic organelles show some parallels between feminizing and androgen-secreting adrenal tumors. Different types of mitochondria occur with varying amounts of smooth endoplasmic reticulum. Numerous microbodies are present. Histological and ultrastructural signs indicating probably malignancy are discussed and it is noted that most of the feminizing adrenal tumors are carcinomata. Neither local recurrence nor distant metastases have yet been detected in this case, two years after excision of the tumor. ( info) |
10/31. Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing's syndrome. Inappropriate ACTH secretion with bilateral diffuse or macronodular adrenal hyperplasia is the most common cause of Cushing's syndrome. This report describes a patient with Cushing's syndrome and feminization due to ACTH-independent bilateral macronodular adrenal hyperplasia. A 47-yr-old black man presented with Cushingoid features, diabetes mellitus, hypertension, impotence, and gynecomastia. Urinary cortisol and 17-hydroxycorticosteroid excretion were 94 nmol/mmol creatinine (normal, less than 32) and 5.8 mumol/mmol creatinine (normal, 0.6-3.6), respectively. Both decreased by less than 30% after administration of dexamethasone (8 and 16 mg/day), and urinary 17-hydroxycorticosteroid excretion did not increase after metyrapone (750 mg, orally, every 4 h for six doses). plasma ACTH was undetectable (less than 1 pmol/L) and was not stimulated by administration of metyrapone or ovine CRH. serum testosterone was 5.2 nmol/L (normal, 7-30), FSH was 5 U/L (normal, 3-18), LH was 2.8 U/L (normal, 1.5-9.2), and estrone was 767 pmol/L (normal, 55-240). Both adrenal glands were enlarged, with a total weight of 86 g (normal, 8-10), and contained multiple nodules (diameter, greater than 0.5 cm) composed of two active cell types, one of which was also observed between the nodules. Cushing's syndrome with feminization due to ACTH-independent bilateral macronodular adrenal hyperplasia is an unusual process of unknown etiology that should be included with the other known causes of Cushing's syndrome. ( info) |