Adenylate cyclase in human ovarian cancers: sensitivity to gonadotropins and nonhormonal activators

Adenylate cyclase activity in particulate preparations of ovarian tumors from 47 women was determined by measuring the conversion of phosphorus 32-labeled adenosine triphosphate to phosphorus 32-labeled cyclic adenosine monophosphate. Ovarian cancers typically exhibited an active adenylate cyclase which was stimulated by 50 mumol/L 5'-guanylylimidodiphosphate and 10 mmol/L of sodium fluoride. This activity was comparable to that in particulates of normal postmenopausal ovaries and was independent of the class of tumor. There was no significant increase in adenylate cyclase activity in any epithelial or germinal tumor in the presence of either 250 nmol/L of human chorionic gonadotropin or 333 nmol/L human follicle-stimulating hormone. However, cyclic adenosine monophosphate production by two sex cord stromal tumors was stimulated by follicle-stimulating hormone, but not by human chorionic gonadotropin. Follicle-stimulating hormone stimulated a threefold increase in activity in the granulosa-theca cell tumor, with an activation constant (57 nmol/L) similar to that in follicle-stimulating hormone-responsive rat ovaries. Prostaglandin E1 (50 mumol/L) increased cyclic adenosine monophosphate production by epithelial tumors more than twofold. These data suggest that sex cord stromal tumors, unlike the more common epithelial tumors, can be modulated directly by gonadotropin.     

Ectopic hormone production by ovarian neoplasms

Ovarian neoplasms, producing ectopic hormones, other than struma ovarii, are extremely rare. We review such tumors that have been reported in the world's literature during the last 15 years. Most patients presented with a clinical picture which was typical of the excess hormone produced. The clinical syndromes associated with ovarian neoplasms are: the Zollinger-Ellison syndrome, hypoglycemia, hyperthyroidism, hypercalcemia, Cushing's syndrome, hyperprolactinemia, hypertension related to renin or aldosterone production, and ectopic production of human chorionic gonadotropin. The clinical characteristics of these patients, as well as the pathologic findings, are described. In most of these cases the tumor was not localized preoperatively and the patients underwent unnecessary extensive operative procedures. Regardless of benign or malignant histology, complete excision of the tumor practically offers cure to these patients. Although rare, the possibility of ectopic hormone production by ovarian neoplasms should be kept in mind when investigating a patient with a nonlocalized hormone-secreting tumor. A review of ovarian neoplasms producing ectopic hormones is herein presented along with the diagnostic and therapeutic dilemmas characterizing this entity.     

Gonadotropin-like substance in the preimplanted rabbit blastocyst.

The presence of a gonadotropin-like substance in preimplanted rabbit blastocyst fluid was determined bu radioreceptorassay of human chorionic gonadotropin (hCG)/luteinizing hormone (LH), using receptors prepared from bovine corpus luteum, rat testis, and rat ovaries. An average of 16.6 microliter of fluid containing 0.83 ng of luteotropic material was recovered from each blastocyst. An intense fluorescence was exhibited by the trophoblastic cells of the blastocysts treated with fluorescein-conjugated gamma-globulin isolated from antiserum raised against human chorionic gonadotropin. Serum concentrations of LH as well as estradiol, progesterone, and 17 alpha-hydroxyprogesterone up to day 6 after mating were determined in pregnant rabbits and compared with those in pseudopregnant and normal rabbits. In pregnant rabbits after mating, a surge of 62 +/- 15 ng of luteinizing hormone and 73 +/- 22 ng of progesterone/ml of serum occurred which returned to basal levels at 6 hours and on day 1, respectively. Secondary increases in serum luteinizing hormone of 26 +/- 12 to 36 +/- 16 ng/ml on days 3 and 5 and in serum progesterone of 16 +/- 4 and 14 +/- 5 ng/ml on days 5 and 6, respectively, were observed in pregnant rabbits.     

Gonadotropin (LH,FSH) levels in serum and cyst fluid in epithelial tumors of the ovary

Objectives The aim of this work was to determine gonadotropin (LH, FSH) levels in serum and cyst fluid in various type of ovarian epithelial neoplasms (benign, borderline, malignant) and to compare them with levels in benign cysts. Additionally we decided to estimate if there were some significant correlations between serum and ovarian cyst fluid in gonadotropin levels in all investigated groups.Materials and methods The study group included 74 patients before (n=36) and after (n=38) menopause, divided into four groups depending on the histopathologic diagnosis. Serum and cyst fluid levels of LH and FSH were determined in all patients.Results We found statistically significant differences concerning LH and FSH levels in serum and cyst fluid between malignant and borderline tumors, between malignant tumors and benign cystadenomas and between malignant tumors and non-neoplastic cysts. We also found statistically significant correlations between serum and cyst fluid as to FSH and LH levels in patients with borderline tumors. There were no statistically significant correlations between serum and cyst fluid as to FSH and LH levels in patients with malignant epithelial tumors (group 1) and in patients with benign cystadenomas (group 3).Conclusions High FSH and LH levels in cyst fluid of malignant epithelial tumors of the ovary are in line with the gonadotropin theory of tumor growth. Simultaneous determination of various types inhibin levels appears to be an interesting topic for our future research.     

Human chorionic gonadotropin, follicle-stimulating hormone, and luteinizing hormone in patients with epithelial ovarian carcinoma

Plasma levels of human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were studied in patients with epithelial ovarian carcinoma prior to and during chemotherapy. Blood samples were drawn for radioimmunoassay at monthly intervals. Plasma concentrations were compared to those of three different control groups: healthy post-menopausal women (PM), fertile women in the follicular phase of the menstrual cycle (FPh), and postmenopausal women with nongynecologic disseminated malignant disease (DMD). The hCG level was elevated in women with great tumor burden, such as large tumor volume, FIGO stage IV, and histologic type V. LH and FSH levels showed the reverse pattern. hCG concentration decreased during chemotherapy, whereas LH increased. Initial plasma concentrations were not found to have prognostic importance. We discuss the possibility that hCG is produced by the tumor, which stimulates steroid hormone production by the stroma, which, in turn, exerts negative feedback on FSH production by the pituitary.     

The role of tumor markers in gynecologic oncology.

Human chorionic gonadotropin is a highly sensitive and specific tumor marker for gestational trophoblastic neoplasia that accurately reflects tumor volume and the clinical course of disease. In women with endodermal sinus tumors and embryonal carcinomas, alpha-fetoprotein usually is a reliable marker, and it accurately predicts the presence of yolk sac elements in mixed germ cell tumors. CA 125 is the most widely utilized tumor marker presently available for use in patients with epithelial ovarian cancer. It has utility in monitoring therapy and differentiating benign from malignant pelvic masses. Measurement of serial CA 125 levels in postmenopausal women may facilitate screening for occult early stage disease. In the future, monoclonal antibodies that recognize tumor-associated antigens may prove useful for radionuclide imaging.     

Use of combined exogenous gonadotropins and pulsatile gonadotropin-releasing hormone in patients with polycystic ovarian disease: a new approach to induction of ovulation

A combined regimen based on exogenous gonadotropins followed by pulsatile gonadotropin-releasing hormone was attempted in order to induce ovulation in a group of patients with polycystic ovarian disease. The women were selected on the basis of previous unsuccessful treatment with clomiphene citrate, gonadotropin and pulsatile gonadotropin-releasing hormone used separately. At our first attempt at application of this new approach, in all patients follicular growth was recorded and ovulation was induced with exogenous chorionic gonadotropin, without hyperstimulation. Two clinical pregnancies were established. Retrospective hormonal evaluation showed the presence of two premature luteinizations. Pulsatile gonadotropin-releasing hormone administration following follicular recruitment with exogenous gonadotropin may therefore be considered an effective therapy for polycystic ovarian patients resistant to conventional treatment.     

Low leptin level in an obese hyperandrogenic woman--potential marker for androgen-secreting tumor.

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.     

Low leptin level in an obese hyperandrogenic woman – potential marker for androgen-secreting tumor

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.     

Selenium concentrations in serum, hair and tumor tissue from patients with ovarian tumors

Selenium (Se) concentration was determined in 150 samples of serum, 135 samples of hair and 96 samples of ovarian tissue from patients with malignant or benign ovarian tumors and normal subjects. The serum Se level in patients with malignant ovarian tumors was significantly lower than that in patients with benign ovarian tumors and normal subjects. No difference of Se concentrations of hair among different groups was observed. Se level in malignant ovarian tumor tissue was significantly higher than that in benign ovarian tumor tissue and normal ovarian tissue. The low serum Se level in patients with malignant ovarian tumors was probably the result of protective migration of Se from blood to the cancer tissue.     

Anovulation with estrogen production: receptor disorders?

Receptor antibodies have been implicated in the pathogenesis of several autoimmune disorders such as Graves disease. The authors hypothesized that serum antibodies against the luteinizing hormone (LH) receptor existed in women with chronic anovulation syndrome and continuously stimulated the ovaries. Twenty patients with the clinical diagnosis of anovulation with estrogen production were studied. The effects of serum globulins on the binding of 125I-labeled human chorionic gonadotropin (hCG) to ovarian receptors in the patients were compared with the effects in age-matched controls. These studies did not demonstrate significant inhibition of 125I-hCG binding to ovarian receptors by immunoglobulins of patients with anovulation and estrogen production in comparison with those of control subjects. This finding suggests that the cause of anovulation with estrogen production is not an autoimmune phenomenon involving the LH receptor of the human ovary.     

Combined ovarian vein catheterization with ovarian stimulation in the diagnosis of androgen overproduction.

A 28-year-old woman was evaluated for late onset secondary amenorrhea, progressive hirsutism and an elevated serum testosterone concentration. Her serum cortisol, androstenedione, dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were normal. Bilateral ovarian and adrenal vein catheterization demonstrated mild elevated testosterone and androstenedione levels in the right ovarian vein. Fifteen minutes after administering the intravenous injection of 5,000 IU human chorionic gonadotropin, there was a six and a half to sevenfold increase in the level of these two hormones in the right ovarian vein with no significant change in hormone levels from other sources. Based on the ovarian peripheral vein gradients obtained during venography following ovarian stimulation, the diagnosis of right ovarian hyperthecosis was made. This diagnosis could not have been reached without the combination of selective ovarian vein catheterization and ovarian stimulation. We recommend that this combined test, which may provide additional information on the source of the androgens in women with hyperandrogens, be performed in selected cases, when a virilizing tumor is suspected.     

Serum lactic dehydrogenase as a tumor marker in dysgerminoma

Dysgerminoma is the most common malignant germ cell tumor in young women. The management of advanced-stage dysgerminoma challenges the gynecologic oncologist to achieve maximal survival, while maintaining childbearing potential. Radiation therapy has been extremely successful in curing dysgerminoma, but ovarian conservation is usually not possible. In contrast, various chemotherapeutic regimens have achieved high cure rates with continued ovarian function. Diagnosing recurrent dysgerminoma promptly so that salvage therapy can be initiated is important when conservative management has been employed. While alpha-fetoprotein and human chorionic gonadotropin have proven useful as tumor markers in some types of germ cell tumors, they have not been useful in patients with dysgerminoma. Serum lactic dehydrogenase (LDH) levels are known to be elevated in some patients with dysgerminoma. We treated a patient with Stage IIIC dysgerminoma whose initial serum LDH level was markedly elevated. After unilateral salpingo-oophorectomy with pelvic and paraaortic lymphadenectomy, followed by four cycles of VAC chemotherapy, her LDH level returned to normal. Her LDH level rose with disease recurrence and returned to normal again with salvage BEP chemotherapy. This is the first report to document the utility of serial LDH measurements in detecting disease recurrence in patients with ovarian dysgerminoma.     

Anterior pituitary dysfunction during the luteal phase following ovarian hyperstimulation

The capacity of the pituitary to secrete prolactin (PRL) and gonadotropins was investigated during the luteal phase of eight normally menstruating tubal infertility patients after ovarian stimulation with clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin. The baseline values of PRL were significantly higher (P less than 0.025), those of luteinizing hormone unchanged, and those of follicle-stimulating hormone lower (P less than 0.025) during the treatment than in the control cycles. The maximal response of PRL to the dopamine antagonist metoclopramide was increased (P less than 0.01), whereas the maximal responses of luteinizing hormone (P less than 0.025) and follicle-stimulating hormone (P less than 0.001) to gonadotropin-releasing hormone were lowered in the treatment cycles. The current results indicate that ovarian hyperstimulation with clomiphene citrate/human menopausal gonadotropin/human chorionic gonadotropin may induce luteal phase pituitary dysfunction, which may affect the luteal phase functions of the corpus luteum.     

Lactic dehydrogenase, alkaline phosphatase and human chorionic gonadotropin in a pure ovarian dysgerminoma

Pure dysgerminoma is considered to be a nonsecretary ovarian tumor. In this study serum lactic dehydrogenase, human chorionic gonadotropin, and alkaline phosphatase levels were highly elevated in a 21-year-old woman with unilateral ovarian pure dysgerminoma and fell sharply to normal levels after removal of the tumor. In order to establish the source of these elevated serum enzymes and hormone, the tumor was homogenized and the level of these substances was found to be several times higher than that of normal homogenized ovarian tissue. In addition, the presence of lactic dehydrogenase and alkaline phosphatase in the dysgerminoma cells was shown by histochemical methods. This is the first report providing evidence that pure dysgerminoma contains and secretes enzymes and hormones which may constitute tumor markers useful for the diagnosis and follow-up of patients with this type of neoplasm.     

Glutathione S-transferases P1-1 and A1-1 in ovarian cyst fluids

PURPOSE: The purpose of the present study was to determine the gluthathione S-transferases (GST) P1-1 and A1-1 levels in cyst fluid from malignant, borderline, and benign ovarian tumors. The clinical relevance of these enzymes in cyst fluid was investigated, including the possible relation with resistance to chemotherapy. METHODS: A total of 90 ovarian cysts were punctured for cyst fluid collection. GSTP1-1 and GSTA1-1 concentrations were determined by ELISA in cyst fluid from 23 malignant, 9 borderline, and 51 benign primary ovarian tumors, and levels were correlated with histopathological data. RESULTS: Significantly higher GSTP1-I concentrations were found in cyst fluid from malignant (median: 477 ng/ml), compared with benign (median: 52 ng/ml) ovarian cysts (p < 0.0001), as well as in fluid from borderline (median: 366 ng/ml) compared with benign cysts (p < 0.0001). No significant differences were found in cyst fluid GSTA1-1 concentrations between the histologic subgroups. In cyst fluid from malignant tumors higher GSTPI-1 and lower GSTAI-1 concentrations were found in patients with worse prognostic factors: FIGO II-III-IV, grade 2-3, residual tumor > 2 cm, presence of ascites, patients with recurrent disease, and survival, but differences were not significant. In the subgroup of patients that received cisplatin-based chemotherapy (n = 14) significantly higher GSTP1-1 (p = 0.01) concentrations were found in patients with recurrence compared with patients without recurrence. Considering only FIGO stage I patients, a differentiation could be made between patients with or without recurrence based on cyst fluid GSTP I - I concentrations. CONCLUSIONS: Determination of glutathione S-transferases P 1-1 in cyst fluid samples from ovarian tumors can be of additiona] value in the differentiation between histologic subgroups. In case of possible low malignant potential cysts where sampling of the most representative tissue can be an issue, determination of GSTP- I concentrations in cyst fluid may optimise histopathologic classification. Cyst fluid GSTP1-1 seems to be a good marker for aggressiveness of the ovarian tumor, and it may predict response to chemotherapy.     

Luteinizing hormone in peritoneal and ovarian cyst fluids: a predictor of ovarian carcinoma

Objective: The aim of this study was to define the role of luteinizing hormone (LH) as a tumor marker, specific for ovarian cancer. Methods: The study included 34 women with functional and benign ovarian cysts, 11 women with borderline ovarian tumors, 22 patients with advanced ovarian cancer and 15 patients with non-ovarian intraperitoneal malignancies. Serum, peritoneal fluid and ovarian cyst aspirates were obtained intraoperatively (laparoscopy or laparotomy) and were subjected to the LH analysis. Results: Peritoneal fluid LH levels were significantly increased in patients with ovarian cancer and those with borderline ovarian tumors as compared to patients with functional and benign ovarian cysts (P=0.005 and P=0.007, respectively). The patients with non-ovarian malignancies demonstrated the same peritoneal fluid LH levels as patients with benign ovarian tumors. There was no significant difference in the level of peritoneal fluid LH between ovarian cancer patients with and without ascites. The patients with functional and benign ovarian cysts demonstrated also significantly lower cyst fluid LH levels as compared to patients with malignant and borderline ovarian cysts (P=0.01 and P=0.03, respectively). Peritoneal and ovarian cyst fluid levels of LH were significantly increased in patients with fibrothecomas as compared to patients with other benign ovarian cysts. There were no significant differences in the serum LH levels comparing patients from all study groups. Conclusion: LH, detectable in peritoneal and ovarian cyst fluids, can be used as a tumor marker for identification of patients with borderline and malignant ovarian tumors.     

Effect of growth hormone administration on human ovarian function and steroidogenic gene expression in granulosa-luteal cells.

OBJECTIVE: To study the effect of growth hormone (GH) in combination with an ultrashort-term gonadotropin-releasing hormone analogue/human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) regimen in ovarian hyperstimulation for in vitro fertilization (IVF). DESIGN: Prospective randomized placebo-controlled study. SETTING: University-based IVF program. PATIENTS: Fifty-four normally cycling women (27 control and 27 GH-treated) participated in this study. INTERVENTIONS: Human recombinant GH (24 IU)/placebo was given intramuscularly on alternate days starting on cycle day 4 until the day of last hMG injection. RESULTS: Serum estradiol (E2) and progesterone (P) concentrations were slightly lower in the GH group than in the placebo group on the day of hCG injection and 1 day thereafter (P < 0.01 to 0.001). Serum luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone (T), and sex hormone-binding globulin did not differ between the groups. The follicular fluid (FF) concentration of T was higher in the GH group than in the placebo group (15.9 +/- 6.0 nmol/L versus 10.2 +/- 4.9 nmol/L, P < 0.005), and no differences were observed in the FF concentrations of E2, P, and insulin-like growth factor I between the groups. In granulosa cells isolated from patients who received GH treatment, the levels of 3 beta-hydroxysteroid dehydrogenase and aromatase messenger ribonucleic acid were significantly higher than in the patients receiving placebo. The number of hMG ampules needed for follicular development and the number of follicles and oocytes recovered were similar in both groups. CONCLUSIONS: These results indicate that GH administration modifies ovarian steroidogenic response to gonadotropins in IVF patients, suggesting a role for GH in the regulation of human ovarian function.     

Successful treatment of long-term unexplained infertility with gonadotropin-releasing hormone agonist analogue and human menopausal gonadotropin

Thirty-five couples with long-term unexplained infertility were treated in 98 cycles by giving gonadotropin-releasing hormone analogue, human menopausal gonadotropin and human chorionic gonadotropin for induction of superovulation. Pregnancy occurred in 24 cycles (24.5% per cycle and 68.6% per patient). All patients had been treated previously with clomiphene citrate and human menopausal gonadotropin in 110 cycles in conjunction with artificial insemination, but failed to achieve pregnancy. Pituitary suppression with gonadotropin-releasing hormone analogue followed by ovarian stimulation with human menopausal gonadotropin may correct the subtle abnormalities at the hypothalamic hypophyseal level that could be present in cases of unexplained infertility and it should be tried first for these patients before resorting to in vitro fertilization or gamete intrafallopian transfer.