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Leydig cell hyperplasia and Leydig cell tumours of the ovary are rare. We present two cases in which patients had increased blood levels of testosterone and frank hirsutism. Imaging showed minimal abnormalities. After adrenal disease had been ruled out, they underwent a bilateral oophorectomy. One case showed a Leydig cell hyperplasia, the other a Leydig cell tumour. An androgen producing tumour should be excluded in every woman with evidence of hirsutism or frank virilization and markedly elevated testosterone levels. Adrenal disease with androgen hypersecretion can be suspected by detailed clinical, laboratory and radiologic imaging. Although DHEAS has a good sensitivity in the detection of adrenal origin of hyperandrogenism (and hence a good negative predictive value) it is not specific (specificity ranging from 85 to 98%). Imaging of the ovaries can be helpful but does not rule out ovarian disease if normal. Indeed, diffuse stromal Leydig cell hyperplasia and Leydig cell tumours (usually small) may escape imaging and in some cases diagnosis can only be made on pathology. As these clinical entities represent a diagnostic and therapeutic challenge, oophorectomy should be considered in postmenopausal women with hirsutism and elevated testosterone levels, after the exclusion of adrenal causes. The procedure is relatively safe and effective. Follow-up remains indicated.

Androgen-producing ovarian tumours can lead to assessment difficulties because of their small size. We present a case of virilising steroid cell ovarian tumour in a 41-year-old woman localised with Fluorine-18-Deoxyglucose Positron Emission Tomography/Computed Tomography ((18)FDG-PET/CT). Although the biochemical evaluation pointed to an ovarian source of androgen, diagnostic attempts to localise the source of hyperandrogenism with transvaginal ultrasound (US), and magnetic resonance imaging (MRI) of pelvis failed. Additional evaluation with (18)FDG-PET/CT showed an increased uptake in the right ovary. A laparoscopic right oophorectomy was performed and histopathology examination revealed a 1.2-cm Leydig cell tumour. The patient showed regression of clinical signs.

Transgenic (TG) mice, expressing the Simian Virus 40 T-antigen (Tag) under a 6-kb fragment of the murine inhibin alpha-subunit promoter (inh alpha p), develop gonadal tumors of granulosa/theca or Leydig cell origin. We showed previously that adrenocortical tumors develop if the TG mice are gonadectomized but never develop in intact animals. However, if functional gonadectomy was induced by GnRH antagonist treatment or by cross-breeding the TG mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared. Since the most obvious difference between the gonadectomized and GnRH-antagonist-treated or Tag/hpg double mutant mice is the elevated gonadotropin secretion in the first group, we examined whether the adrenal tumorigenesis would be gonadotropin-dependent. Surprisingly, both the adrenal tumors and a cell line (C alpha 1) derived from one of them expressed highly functional LH receptors (LHR), as assessed by Northern hybridization, immunocytochemistry, ligand binding, and human CG (hCG)-stimulated cAMP and steroid production. No FSH receptor expression was found in the adrenal tumors by RT-PCR. hCG treatment of the C alpha 1 cells stimulated their proliferation, as measured by [3H]thymidine incorporation. This effect was related to hCG-stimulated steroidogenesis since progesterone, testosterone, and estradiol, at physiological concentrations, also stimulated the C alpha 1 cell proliferation. Different adrenocortical cells expressed initially LHR and Tag, whereas both were highly expressed in the tumor cells. In conclusion, the high level of functional LHR in the adrenal tumors indicates that this receptor can function as tumor promoter when ectopically expressed and stimulated by the ligand hormone.

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 ability of human choriogonadotropin (hCG) to regulate its receptors and target cell responses has been studied in a clonal strain of cultured Leydig tumor cells (MA-10). Exposure of the MA-10 cells to hCG results in decrease in hCG binding activity which is dependent on time and the concentration of hCG. This decrease is due to a change in the number of receptors rather than in the affinity of the receptors, and it is accompanied by a corresponding reduction in the ability of hCG to stimulate steroidogenesis. Exposure of the MA-10 cells to hCG also resulted in a reduction of the steroidogenic responses to cholera toxin and 8-Br-adenosine cyclic 3',5'-monophosphate. The hCG-induced loss of steroidogenic responses to these stimuli seems to be due to the stimulation of steroidogenesis rather than to the decrease in hCG receptors because it also can be induced when steroidogenesis is stimulated with cholera toxin or 8-Br-adenosine 3',5'-monophosphate under conditions such that the number of hCG receptors is not reduced.

The clinical and pathological features of 207 ovarian Sertoli-Leydig cell tumors from our consultation and hospital files were reviewed. The patients ranged in age from 2 to 75 (average 25) years. Seventy-five percent of them were 30 years of age or younger and less than 10% were over 50 years of age. One-third of the patients presented because of unequivocal evidence of androgen excess, and an additional 10% had a history suggesting androgen excess; most of the remaining patients complained of abdominal swelling or pain. At operation, 97.5% of the tumors were Stage I, 1.5% were Stage II, and 1% were Stage III. Both ovaries were involved in 1.5% of the cases. The tumors ranged from microscopic to 51 cm in diameter (average 13.5 cm); 15% of them were ruptured. Thirty-eight percent of the tumors were solid, 58% were solid and cystic, and 4% were cystic. The solid tissue was typically lobulated and yellow. On microscopic examination, 11% of the tumors were well differentiated, 54% were of intermediate differentiation, 13% were poorly differentiated, and 22% contained heterologous elements according to the criteria of the World Health Organization; a prominent retiform pattern was present in 15% of them. Follow-up was obtained for 164 patients. The tumor was clinically malignant in 18% of them. The prognosis correlated most meaningfully with the stage and degree of differentiation of the tumor. The high-stage tumors were all clinically malignant. All the well-differentiated tumors were benign, but 11% of those of intermediate differentiation, 59% of the poorly differentiated tumors, and 19% of those with heterologous elements were malignant. In a few cases radiation therapy, chemotherapy, or a combination of the two, in addition to surgical excision, was of benefit in the management of the malignant tumors.