Gross and histopathologic effects of medroxyprogesterone acetate and progesterone on the mammary glands of adult beagle bitches

Adult beagle bitches received 0.2 to 75 mg/kg doses of medroxyprogesterone acetate (MPA) once every 3 months for 1 to 1.5 years. Doses greater than 2.0 mg/kg prevented the recurrence of ovarian cycles; lower doses did not. MPA (10 and 75 mg/kg) induced a dose-related development of multiple, large (greater than 5 mm diameter) mammary nodules that occurred earlier in older dogs than in younger dogs. MPA-induced mammary hyperplasia and nonnodular dysplasias were also noted. Most of the large (5 to 110 mm in diameter) MPA-induced nodules were, in nearly equal numbers, nodules of lobular hyperplasia, simple adenomas, or complex adenomas. Such benign mammopathies all appear to have histopathologic counterparts in human breast disease. However, simple adenomas are uncommon in both humans and dogs. Some of the MPA-induced nodules were benign mixed tumors with cartilaginous metaplasia. No malignant tumors were found. Induction of mammary tumors by 75 mg MPA/kg was not affected by prior ovariectomy but was reached by prior hypophysectomy, suggesting involvement of pituitary secretion in MPA-induced mammary gland disease.     

Progesterone receptors in endometrial carcinoma and their response to medroxyprogesterone acetate

Progesterone receptors (PR) were measured in 18 cases of endometrial carcinoma using the dextran-coated charcoal assay. The histological changes and PR levels of the endometrial carcinoma after the medroxyprogesterone acetate (MPA) treatment were studied. A higher PR levels were observed in well-differentiated tumors. After treatment with MPA, the PR content was reduced and histological appearance similar to normal endometrium was noticed. The histological changes of the tumor was closely related to the receptor levels.     

The influence of high doses of oral medroxyprogesterone acetate on glucose tolerance, serum insulin levels and adrenal response to ACTH. A study of 17 patients under treatment for endometrial cancer

Seventeen women aged 55 to 76 years who had been treated for endometrial cancer by surgery or radiotherapy or a combination of both were given 300 mg of medroxyprogesterone acetate (MPA) daily by mouth. Before treatment and again during the 3rd week of treatment an oral glucose tolerance test (with measurement of serum insulin levels) and an ACTH-stimulation test were done. All blood glucose levels tended to be higher with MOA therapy and serum insulin levels were significantly increased 3 h after a glucose load. The rise of serum cortisol 30 min after ACTH-stimulation was significantly less with MPA therapy. Oral MPA thus appeared to have a glucocorticoid-like action.     

Inhibin A and inhibin B producing ovarian fibrothecoma revealed by suppression of follicle stimulating hormone (FSH) in a post-menopausal woman: report of the first case

In this report, we describe the first case ever reported in the literature, of an inhibin-A (INHA) and inhibin-B (INHB) producing fibrothecoma. A post-menopausal woman was referred to our unit because of follicle stimulating hormone (FSH) level below the reference interval for postmenopausal women. By contrast luteinizing hormone, hCG, and estradiol levels were within normal range. This discrepancy suggested the secretion of FSH inhibitory factors. INHB and INHA levels were markedly elevated for age, 475?pg/mL and 100?pg/mL, respectively. Ultrasonography and MRI showed a pelvic mass of indeterminate nature. Abnormal inhibin secretion is generally observed in granulosa cell tumors. In this case this etiology was unlikely because of low estradiol and AMH levels. Surgical exploration revealed a 10?cm mass of the left ovary proven histologically to be an ovarian fibrothecoma (OFT). After tumor removal, INHB and INHA levels decreased rapidly. Only three cases of OFT with an important secretion of INHB have been reported to date. INHA secretion has never been associated with OFT. There is a need to develop coupled hormone and imaging strategies to diagnose the source of INH secretion in case of FSH/LH discrepancy.     

Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome.

Several studies have been performed during recent years to investigate the existence of a possible endocrine cause for premenstrual syndrome (PMS); the results reported are often discordant. Great interest has been raised around allopregnanolone, which could be involved in the determination of mood disorders reported by PMS patients. During the luteal phase, lower levels of this hormone have been detected in PMS patients. The aim of our study was to evaluate estradiol, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, total and free testosterone, cortisol, pregnenolone and allopregnanolone levels in 20 patients suffering from PMS and to compare them with those found in 20 fertile healthy women in the follicular and the luteal phases. Adrenocorticotropic hormone (ACTH) tests after dexamethasone suppression were performed in 10 patients of each group during the follicular and the luteal phases. In the PMS group, significantly lower allopregnolone levels were found in the luteal phase, while progesterone was lower in the PMS group in both phases. In the PMS group, higher free testosterone levels were found during the luteal phase and higher DHEA levels in both the follicular and the luteal phases. The present data confirm reduced allopregnanolone levels in the luteal phase in PMS patients, together with higher levels of DHEA and free testosterone. It is possible to conclude that, in addition to the previously described reduced luteal secretion of allopregnanolone, the adrenal gland production of this steroid in PMS sufferers is also impaired in the luteal phase. Considering the specific actions of these hormones on the control of mood and behavior, this specific hormonal milieu may contribute to the cyclic occurrence of anxiety, aggressiveness and irritability reported by PMS patients.     

Estrogen receptors in human uterine adenocarcinoma: correlation with tissue differentiation, vaginal karyopycnotic index, and effect of progestogen or anti-estrogen treatment

Estrogen receptor levels were measured in the cytosol of uterine adenocarcinomas obtained by endometrial biopsy in 37 postmenopausal women. The karyopycnotic index was determined individually by vaginal smear. It was considered estrogenic when superior to 5% (KI⁺). The histologic characteristics of the tumors were classified as well (D⁺) or poorly (D^?) differentiated. The receptor level was highest in D⁺KI^? tumors (103 ± 19 (SEM) fmole/mg protein), intermediate in D⁺KI⁺ tumors (44 ± 12), and lowest in D^? tumors (25 ± 10). During medroxyprogesterone acetate (MPA) treatment, the receptor level dropped rapidly in D⁺ tumors (from 87 ± 14 to 16 ± 5) and remained low in D^? tumors (25 ± 10 to 1 ± 1). Tamoxifen (T) treatment also produced a reduction in the receptor levels: in D⁺ tumors to 1 ± 1 and in D^? tumors to 6 ± 2. In conclusion, high receptor levels in cytosol of D⁺ tumors as well as the significant reduction under MPA or T treatment suggest the persistence in these tumors of hormonal regulatory mechanisms. Estrogenic impregnation of the patient should, however, be taken into account to differentiate between the hormone-sensitive D⁺KI⁺ tumors and the receptor-poor D^? tumors.     

The medroxyprogesterone acetate serum level following various medroxyprogesterone acetate dose schedules in gynecologic oncology

Medroxyprogesterone acetate (MPA) is used as an adjuvant hormonal medication in patients with different kinds of carcinomas. Since adequate serum levels are thought to be essential we determined the individual, postoperative MPA levels in 36 patients with endometrial carcinoma over a period of 12 weeks. The patients received either an oral dose of 3 X 100 mg MPA or a weekly changing scheme with 2 X 10 mg Tamoxifen and 3 X 100 mg MPA. An additional small group of 4 patients with ovarian carcinoma was enrolled receiving an oral dose of 1000 mg MPA daily. The peripheral serum levels of MPA exhibit enormous inter- and intraindividuell variations and only the high dosage schemes yield levels above 90 ng/ml which are claimed necessary by some authors. The cortisol concentration measured at the same time were within the normal range and did not correlate with the MPA values.     

LOH of chromosome 6q compared with LOH of 17q and 18q in ovarian cancers: relationship to p53 expression and clinicopathological findings

In 41 ovarian epithelial tumors (7 borderline and 34 invasive), loss of heterozygosity (LOH) of chromosomes 6q, 17q, and 18q was examined using 4 microsatellite markers: ER (6q 25–1), BRCA1 (17q21), DCC (18q21), and D18S58 (18q23). The LOH was compared with clinicopathological findings, including p53 and ER expression. In borderline tumors, LOH and p53 expression were never found, while in invasive carcinomas LOH and p53 were found in 71% and 59% of cases, respectively. In particular, in invasive carcinomas 6q LOH represented a marker distinguishing two groups of tumors; those with 6q LOH were only of serous histotype and at advanced stages (III/IV). No significant difference was found for any of genes in 5-year survival of the patients. No correlation was found between ER expression and ER LOH, as well as between biological aggressiveness and 17q and/or 18q LOH.
We conclude that p53 and LOH of the investigated loci distinguish borderline from invasive ovarian carcinomas; moreover, the comparison of these results with clinicopathological parameters suggests that the presence of 6q LOH may be a factor accounting for greater biologic aggressiveness independent of the histologic subtype.     

醋酸甲羟孕酮增强顺铂对人卵巢癌耐药细胞抗癌作用的研究

目的:观察醋酸甲羟孕酮(MPA)对人卵巢癌CoC1/cDDP细胞移植瘤的生长抑制作用及对DDP的耐药逆转作用,并分析其作用机制。方法:建立人卵巢癌裸鼠皮下移植瘤模型,随机分为4组,每组5只。(1)对照组:腹腔注射等体积生理盐水;(2)DDP治疗组:每只每次腹腔注射DDP 3mg/kg。(3)MPA治疗组:每只每次灌胃30mg/kg;(4)联合治疗组:每只每次灌胃MPA 30mg/kg,1h后每只每次腹腔注射DDP 3mg/kg,每隔2天给药1次,共4次,于治疗第1、5、10、15、20天分别测瘤体积,20天后处死裸鼠,完整剥出瘤组织,称瘤重,计算抑瘤率;通过流式细胞仪检测亚G1期细胞及AnnexinV+/PI-细胞鉴定细胞凋亡,分析移植瘤细胞周期;用半定量RT-PCR法检测移植细胞组织Survivin-ΔEx3、caspase-3、P21WAF1/CIP1及GST-π4基因mRNA表达。结果:(1)MPA组、MPA+DDP组治疗第10天起皮下移植瘤体积明显小于DDP组和对照组,且进行性缩小(P<0.01);抑瘤率分别为51.63%、62.21%,均明显大于DDP组的6.84%(P<0.01),并且两组间有显著差异(P<0.01);(2)流式细胞仪分析显示,移植瘤出现亚G1期峰及AnnexinV+/PI-细胞均证实MPA能诱导CoC1/cDDP细胞凋亡,并显著高于对照组及DDP组,并出现G1期阻滞;与DDP合用除出现G1期阻滞外又出现G2/M期阻滞,S期明显减少,亚G1期细胞及AnnexinV+/PI-细胞进一步上升;(3)半定量RT-PCR检测显示,MPA组Survivin-ΔEx3、GST-πmRNA下调,而P21WAF1/CIP1、caspase-3 mRNA上调,与DDP合用后,对Survivin-ΔEx3、P21WAF1/CIP1及GST-πmRNA的表达无协调作用,而对caspase-3 mRNA有协同上调作用。结论:MPA通过阻滞G0/G1期明显抑制了CoC1/cDDP移植瘤生长,并有很强的致凋亡作用,同时下调GST-πmRNA,从而逆转对顺铂耐药。     

Circulating lipid and lipoprotein concentrations during danazol and high-dose medroxyprogesterone acetate therapy of endometriosis

In a study on endometriosis, ten patients were treated with danazol (200 mg three times a day) and ten patients with high-dose medroxyprogesterone acetate (MPA) (100 mg a day) for 6 months. The circulating high-density lipoprotein-cholesterol concentration decreased significantly in the danazol (53%) and in the MPA groups (26%); the change in the danazol group was significantly higher than that in the MPA group. Danazol also significantly increased the low-density lipoprotein-cholesterol levels (37%), whereas MPA had no significant effect. Danazol (29%) and MPA (12%) decreased the apolipoprotein A-1 levels significantly. The decrease caused by danazol was significantly greater. Danazol also significantly decreased the apolipoprotein A-2 levels (12%) and significantly increased the apolipoprotein B levels (17%), whereas MPA had no significant effects on them. Three months after the end of medication, all values were at the pretreatment levels. The circulating cholesterol, triglyceride, and very low-density lipoprotein concentrations remained unchanged during both treatments. Danazol and high-dose MPA induced a similar significant regression of peritoneal endometriotic implants in relation to placebo. Our present results, showing that danazol, to a greater extent than high-dose MPA, is associated with changes in lipoprotein metabolism that expose the individual to an increased risk of cardiovascular diseases, suggest that high-dose MPA is preferable to danazol in the long-term treatment of endometriosis.     

Plasma medroxyprogesterone acetate levels following intramuscular or oral administration in patients with endometrial adenocarcinoma.

The concentration of medroxyprogesterone acetate (MPA) in plasma samples taken 24 h after intramuscular or oral administration of 100 mg daily doses of the drug to patients with endometrial adenocarcinoma was measured by radioimmunoassay. In general, a plasma level of about 4 ng/ml was found 24 h after the dose, independent of the route of drug administration. However, in three of the patients to whom intramuscular MPA was given, considerably higher values were found. A maximal plasma level was achieved three hours after ingestion of 100 mg MPA. This was followed by a rapid decline to 20-25% of the peak value after about 12 h. A rather small day-to-day intraindividual variation was found in daily blood samples taken just before administration of the next dose. However, considerable differences were found between individuals and it is concluded that this variation in plasma levels may be reflected in the clinical efficacy of the treatment. Thus further studies in which plasma values and clinical effectiveness are correlated seem to be indicated.     

Secretion of vascular endothelial growth factor in ovarian cancer.

Vascular endothelial growth factor (VEGF) is an important regulator of vascular endothelial cell function during vasculogenesis and tumor growth and is believed to play a major role in peritoneal fluid accumulation in ascites tumors. High VEGF production from primary tumors has been reported to correlate with increased metastatic spreading and worse prognosis compared to low VEGF secreting tumors. In addition, VEGF secretion has recently been proposed as one of the major factors responsible for defective immune function in cancer patients. In order to evaluate whether ovarian carcinomas actively secrete VEGF, in this study we have analyzed and quantified VEGF secretion in several fresh and established human ovarian carcinoma cell lines in vitro using a sensitive enzyme-linked immunosorbent assay (ELISA). In addition, VEGF levels were also evaluated in the ascitic fluids and plasma of six ovarian cancer patients. All fresh tumors secreted high levels of VEGF (mean = 5,046, range between 1,760 and 7,780 pg/ml/10(5) cells/48 hr) when compared to established ovarian carcinoma cell lines (mean = 493, range between 160 to 1,120 pg/ml/10(5) cells/48 hr) (p <0.02). Importantly, high grade malignancies were found to secrete larger amounts of VEGF (mean = 6,660 pg/ml) when compared to lower grade tumors (mean = 1,820 pg/ml) (p <0.01). Ascitic fluids from all patients were rich in VEGF (mean = 5,483, range between 1,300 and 11,200 pg/ml) and plasma levels of VEGF in ovarian cancer patients were significantly higher (mean = 408, range between 160 and 810 pg/ml) when compared with healthy individuals (mean = 46, range between 35 and 60 pg/ml) (p <0.01). Taken together, these data demonstrate that ovarian cancers secrete large amounts of VEGF in vitro and in vivo. This findings therefore suggest that this factor may play a crucial role in the genesis of ascitic fluid accumulation, angiogenesis and tumor induced immunosuppression in ovarian cancer patients. The design of anti-angiogenic treatment directed at blocking the action of VEGF may be a reasonable novel therapeutic approach in the treatment of ovarian cancer.     

Nucleolar organizer regions as a prognostic indicator in epithelial cancers of the ovary.

Recent studies have shown that quantification of silver-stained nucleolar organizer region associated proteins (AgNORs) is correlated with ploidy and proliferative activity in several neoplasms. The prognostic value of this marker, however, has not been well defined in epithelial ovarian carcinomas (EOCs). We studied 84 cases of EOCs in an attempt to assess the potential prognostic significance of AgNORs and to compare the results with other prognostic factors in EOCs. Clinical, operative and treatment details, and follow-up data were recorded for each case. In univariate analysis, a highly significant correlation of AgNOR count with clinical stage (p < 0.01), histologic grade (p < 0.05), response to chemotherapy (p < 0.05), and biologic behavior (p < 0.01) was found. High AgNOR counts were observed in late stage (III and IV) tumors, grade 3 carcinomas, tumors in patients with partial response to chemotherapy, progressive disease, recurrence, or death from tumor. In multivariate analysis, AgNOR count at cut off 3.5 was found to be the third prognostic variable after response to therapy and stage. These observations suggest that AgNOR count holds promise for prediction of tumor aggressiveness in EOCs. However, its role as an independent prognostic variable of patient survival remains questionable.     

Effects of progesterone, progestogens, and danazol on the specific cortisol binding in human plasma

The interaction of medroxyprogesterone acetate (MPA) with cortisol binding to corticosteroid-binding globulin (CBG) was studied with the use of an aqueous two-phase system with polyethylene glycol and dextran for equilibrium partition. Competitive binding analyses were also performed for progesterone (P), levonorgestrel, norethisterone, danazol, and tamoxifen. P and danazol were found to exert cortisol displacing activity, whereas MPA and the other tested compounds had no such effect. The glucocorticoid effects reported for MPA could not be explained by displacement. In general, P serum concentrations are lower than those of cortisol, and most binding sites on CBG are occupied by the glucocorticoid. At high P levels displacement and an increase in free cortisol may occur. Danazol displacement of cortisol is hampered by its pronounced albumin binding. In conclusion, none of the tested compounds should increase free and biologically active cortisol during normal clinical treatment.     

Evidence for the hypothalamic origin of the polycystic ovary syndrome

The effect of suppression of gonadotropin secretion was evaluated in 21 patients with the polycystic ovary syndrome. Medroxyprogesterone acetate (MPA) was administered intramuscularly in a dose of 400 mg every 15 days for 9 months. A significant decrease in luteinizing hormone (LH) and testosterone levels (70 and 40%, respectively) was apparent after 3 months. At the end of the treatment period, the ovaries had become impalpable and hirsutism was markedly improved in 13 of 19 women. Side effects of treatment included local pain, vaginal spotting, galactorrhea, and hyperprolactinemia. Discontinuation of therapy was followed by a rapid return of follicle-stimulating hormone levels to baseline values, whereas LH and testosterone levels recovered only partially after more than 1 year. The improvement of hirsutism and ovarian shrinkage persisted for up to 2 years, and endometrial biopsy uniformly showed a pseudodecidual reaction in the stroma. After 1 year, prolactin levels declined to 52% of the baseline value and galactorrhea disappeared. The suppression of all the peripheral abnormalities of the reproductive system in polycystic ovary syndrome with MPA treatment suggests a primary hypothalamic disorder as the cause for the syndrome.     

GnRH-test after high-dose MPA in women with post-menopausal LH-preferential release

The association between post-climacteric LH-preferential release after GnRH-Test and the occurrence of benign or malignant estrogen dependent diseases makes the Authors evaluate the variations induced in such type of hypophyseal response by MPA, administered in the same doses as in the hormonal therapy of cancer. MPA lowered both the basal gonadotropin secretion and the amplitude of the response to the neurohormone, suggesting the hypothesis of a possible direct inhibitory action of the hormone on the hypophysis. The persistence of LH-preferential release after the ten day treatment with MPA 200 mg daily might be explained by the lack of modifications induced by the hormone on the levels of cytoplasmic E2-receptors, on which seems based LH-preferential release.     

Ovarian cancer stem cells: Are they real and why are they important?

The cancer stem cell hypothesis has been put forward as a paradigm to describe varying levels of aggressiveness in heterogeneous tumors. Specifically, many subpopulations have been clearly demonstrated to possess increased tumorigenicity in mice, broad differentiating capacity, and resistance to therapy. However, the extent to which these experimental findings are potentially clinically significant is still not clear. This review will describe the principles of this emerging hypothesis, ways in which it may be appropriate in ovarian cancer based on the clinical course of the disease, and how we might exploit it to improve outcomes in ovarian cancer patients.     

Placebo-controlled comparison of hormonal and biochemical effects of danazol and high-dose medroxyprogesterone acetate

The hormonal and biochemical effects of danazol (600 mg a day) and high-dose medroxyprogesterone acetate (MPA; 100 mg a day) were studied in a placebo-controlled, 6-month trial. Serum gonadotrophins and prolactin levels did not change during danazol and MPA treatments, whereas oestradiol and progesterone levels decreased significantly in relation to placebo without any difference between danazol and MPA. Both drugs significantly suppressed the sex hormone-binding globulin level (SHBG), and consequently, the free-androgen index (serum total testosterone nmol/l per SHBG nmol/l x 100) as compared with placebo, the effect of danazol being significantly stronger than that of MPA. Danazol, but not MPA, significantly increased serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and haemoglobin levels, and also thrombocyte counts, whereas MPA, but not danazol, increased the serum concentration of albumin in relation to placebo. Serum total bilirubin, conjugated bilirubin, gamma-glutamyl transferase, creatinine, alkaline phosphatase, sodium and potassium levels and leucocyte counts remained unchanged during both treatments. Danazol and high-dose MPA did not differ from each other in their ovarian and anterior pituitary effects, while the increase in androgenic activity induced by danazol was greater than that achieved with MPA. Danazol also had more biochemical effects than MPA. It interfered with the functions of the liver and the production of thrombocytes and haemoglobin, whereas MPA affected only albumin synthesis/release.     

Short-term effects of hormone therapy on serum C-reactive protein levels in postmenopausal women

Objectives: The aim of this study was to investigate the effects of tibolone and conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA) (CEE + MPA) on levels of serum C-reactive protein (CRP), an independent risk factor for cardiovascular disorders, in postmenopausal women. Study design: In this prospective randomized study, we randomly assigned 58 healthy postmenopausal women to CEE (0.625 mg/day) plus MPA (2.5 mg/day) (CEE + MPA) or tibolone (2.5 mg/day). The serum levels of CRP at 3 months after starting treatment were compared with baseline values for both therapies. Results: After 3 months of treatment the median CRP levels increased by 29% in the CEE + MPA group and by 5% in the tibolone group. But, these changes did not have statistical significance (P=0.15, P=0.06, respectively). Conclusions: Our findings show that neither tibolone nor CEE + MPA caused significant changes in serum CRP levels in postmenopausal women. The potential impact of hormone therapy on serum CRP levels should be investigated in ongoing clinical trials.     

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.