Serum prolactin levels in women with gross cystic breast disease.

Serum prolactin (PRL) concentrations at baseline and after TRH stimulation were determined in 15 healthy women and in 51 premenopausal patients suffering from Gross Cystic Breast Disease. All women were in the luteal phase of the menstrual cycle and patients were divided into three groups according to cyst type at presentation. Basal hormone levels were within the normal range in the control group and in the three cystic breast disease groups. The maximum PRL response to TRH stimulation was significantly higher (p < 0.001) in patients with type I cysts (low Na+/K+ intracystic ratio and apocrine epithelium) than in patients with type II cysts (high Na+/K+ intracystic ratio and flattened epithelium), type III cysts (intermediate Na+/K+ intracystic ratio and mixed epithelium) and in normal women. Serum PRL concentrations corresponding to samples obtained 60 and 90 minutes after stimulation remained higher in the first group of patients. These results led us to consider the existence of an altered central regulation of PRL secretion in patients with type I cysts at presentation.     

Cohort study of association of risk of breast cancer with cyst type in women with gross cystic disease of the breast.

OBJECTIVE: To assess correlation between type of breast cyst and risk of breast cancer in women with gross cystic disease of the breast. DESIGN: Cohort study of women with breast cysts aspirated between 1983 and 1993 who were followed up until December 1994 for occurrence of breast cancer. SETTING: Major cancer prevention centre. SUBJECTS: 802 women with aspirated breast cysts. MAIN OUTCOME MEASURES: Type of breast cyst based on cationic content of cyst fluid: type I (potassium:sodium ratio > 1.5), type II (potassium:sodium ratio < 1.5), or mixed (both types). Subsequent occurrence and type of breast cancer. RESULTS: After median follow up of six years (range 2-12 years) 15 cases of invasive breast cancer and two ductal carcinomas in situ were diagnosed in the cohort: 12 invasive cancers (and two carcinomas in situ) among the 417 women with type I cysts, two cancers among the 325 women with type II cysts, and one among the 60 women with mixed cysts. The incidence of breast cancer in women with type I cysts was significantly higher than that in women with type II cysts (relative risk 4.62 (95% confidence interval 1.26 to 29.7)). These results were confirmed after adjustment for several risk factors for breast cancer (relative risk 4.24 (1.12 to 27.5)). CONCLUSIONS: The increased risk of breast cancer of women with breast cysts seems to be concentrated among women with type I breast cysts.     

Apolipoprotein D is the major protein component in cyst fluid from women with human breast gross cystic disease.

GCDFP(gross-cystic-disease-fluid protein)-24, a progesterone-binding protein present in large amounts in cyst fluid from human breast gross cystic disease, was purified in a one-step procedure by size-exclusion h.p.l.c. Peptide fragments obtained by trypsin digestion of the intact protein were purified by reverse-phase h.p.l.c. and analysed for their amino acid composition and subjected to automated Edman degradation. A search of the National Biomedical Research Foundation Data Bank revealed that all the sequenced tryptic peptides from protein GCDFP-24 matched perfectly with regions present in the amino acid sequence determined for human apolipoprotein D. Additional data on N-terminal sequence of the unblocked proteins, carbohydrate-attachment sites, amino acid composition and molecular-mass estimations supported the identity between both molecules. On the basis of this identity a possible role of apolipoprotein D in progesterone transport is proposed.     

The concentration of 16x-hydroxy androgens in serum and cyst fluid of women with gross cystic disease of the breast

The concentrations of 16 alpha-hydroxydehydroepi-androsterone sulfate (16 alpha-OHDHAS) and androst-5-ene-3 beta, 16 alpha-, 17 beta-triol-3-sulfate (A-TriolS) were measured in the plasma and breast cyst fluid (BCF) of women with gross cystic disease of the breast. In the 19 BCF samples analyzed, the 16 alpha-OHDHAS and A-TriolS concentrations ranged from 15 to 1130 ng/mL, and 12 to 871 ng/mL, respectively. However the concentrations of these steroids in the sera of these women were lower (15-179 ng/mL, 8-80 ng/mL, respectively). Estriol-3-sulfate (E3-3S) concentrations in the BCF samples ranged from barely detectable (0.2 ng/mL) to 3 micrograms/mL. In BCF or serum a positive linear correlation was observed in the concentration of 16 alpha-OHDHAS and A-TriolS (p less than 0.001 and 0.05, respectively). However, in the same patients no statistical significance was observed in the BCF vs serum concentrations of these two steroids. When the specimens from this and previous studies were combined, positive correlation was found between potassium ion concentration and E3-3S or 16 alpha-OHDHAS. The origin of the high concentration of E3-3S is still obscure. Although no linear correlation between 16 alpha-OHDHAS and E3-3S was observed, the possibility of a precursor-product relationship between the two is not elimnated.     

Levels of human chorionic gonadotropin in breast cyst fluid

The results of dosage of human chorionic gonadotropin (HCG) in 75 breast cyst fluids taken from 61 patients suffering from breast gross cystic disease (BGCD), 13 of which had multiple mono and/or bilateral cysts are discussed. The corresponding sera were also examined. Assays were carried out using the ELISA method. For comparison, HCG levels were also determined in 21 breast cyst fluids using RIA method. In 66.7% of the breast cyst fluids examined the hormone levels were higher than normal serum values. Corresponding sera showed HCG to be within the range of normal levels. In 5 patients the multiple and/or bilateral cysts showed widely differing hormone levels. The importance of these observations is discussed.     

Tumour markers in human breast cyst fluid in gross cystic breast disease (GCBD)

AIM: Parallel measurements of tumour markers in the serum and breast cyst fluid in a high risk group (GCBD) of breast cancer. The identification of individuals belonging to this group and their follow-up. MATERIALS AND METHODS: In the breast cyst fluid of 108 patients with GCBD (mean age 47 years) we measured the levels of CA 15-3, TPA, CEA and beta HCG completed by PCT determinations. Simultaneously, the serum CA 15-3 and TPA concentrations were also measured using the Luminescent Immunoassay techniques. RESULTS: Strikingly high TPA values were found in 98% of the patients. The CA 15-3 levels, however, were pathological only in 24%of them. The CEA and beta HCG levels showed hardly any rise and the PCT concentration remained normal. CONCLUSIONS: The lack of any rise in PCT concentration precludes the inflammatory origin of the cystic fluid and the normal serum arker levels exclude ultrafiltration. The increased TPA concentration in the breast cystic fluid and the occurrence of pathological CA 15-3 level in the above percentage of the cases suggest that GCBD represents not only a high risk group but possibly a precancerous state, too.     

Treatment of cystic ovarian follicles in dairy cows with chorionic gonadotropin

Thirty dairy cows exhibiting both nymphomania and cystic ovaries - 15 unilateral and 15 bilateral - were injected intravenously with human chorionic gonadotropin (hCG) over a twentyfold dose range, varying from 1.1 to 22.0 IU/kg (0.5 to 10.0 IU/1b) body weight to determine its efficacy of inducing ovulation and subsequent fertilization. Ovulation of cystic and/or noncystic follicles was induced in 28 cows (93.3%), with a higher rate among those with unilateral than bilateral cysts whether based on total (32 vs 22) or mean (2.1 vs 1.5) number of ovulations. While ovulations per cow varied from zero to three, no correlation between dose level of hCG and number of ovulations was evident. Time of ovulation following hCG injection did not differ significantly between unilaterally and bilaterally cystic cows nor between cystic and noncystic follicles, ranging from 23 to 31 +/- 1 hr and averaging 27.3 +/- 1 hr postinjection. A significant difference was found between unilaterally and bilaterally cystic cows in the occurrence of fertilized (11:1), unfertilized (11:6), degenerate (2:2), and unrecovered (8:11) ova.     

Structures and concentrations of fifteen different steroid sulfates in human breast cyst fluids

By applying capillary gas chromatography (GC) and gas chromatography mass spectrometry (GC-MS), a simultaneous quantitation of all important steroid sulfates present in a number of breast cyst fluids, has been obtained. The fact that prevailing androgen sulfate structures in the cyst fluids are different from those in blood suggests at least intracystic metabolism of blood-born precursors. Particularly greater amounts of 5 alpha-reduced steroids are found in breast cysts. 5 alpha-Androstane-3 alpha,17 beta-diol is a major androgen sulfate of breast cyst fluids, its concentration being some 2000-fold that of blood. After prolonged topical application of progesterone on the breast, an accumulation of the sulfates of several pregnanediol isomers could be observed.     

The effects of oral micronized progesterone on smoked cocaine self-administration in women

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.     

Effects of a systematic application of human chorionic gonadotropin, gonadotropin-releasing hormone analog and bovine anterior pituitary gonadotropin in cows with cystic ovarian disease

Fourty-one cows with ovarian follicular cysts (cysts) diagnosed by rectal palpation and observation of estrus behavior were injected intramuscularly (i.m.) with 20,000 IU of human chorionic gonadotropin (HCG). Ten days after this treatment all the cows were examined per rectum for changes in the ovaries with special regard to luteinization of cysts. Cows not responding to HCG were administered 500(10)mug of an analog of gonadotropin-releasing hormone (Gn-RH), Des-Gly-LH-RH-ethylamide, i.m.. If the cysts remained unchanged 10 days subsequent to the second treatment, a third treatment, 400 KE of bovine anterior pituitary gonadotropin (APG), was given i.m. HCG was clinically effective in only 8 cows (20 %). All of the 8 cows conceived. Of 33 cows not responding to HCG, 18 cows (55 %) responded to Gn-RH analog and 12 cows (36 %) conceived. Eleven (73 %) of 15 cows failing to respond to Gn-RH analog were successfully treated with APG and 6 cows (40 %) conceived. In 37 cases, treatment effects were also evaluated by determining serum levels of progesterone prior to and 10 days subsequent to each treatment. When effects of treatment were judged by 1.0 ng/ml or more increase of serum progesterone levels 10 days after treatment, HCG was effective in 13 of 37 cows (35 %), retreatment with Gn-RH analog was successful in 8 of 16 cows (50 %) and APG was ineffective in 3 cows not responding to both HCG and Gn-RH analog. It may be concluded that the therapeutic effect of HCG is disappointing and about half of the cases not responding to HCG were successfully treated with Gn-RH analog. If the cows did not respond to both HCG and Gn-RH analog, they may not respond to APG either.     

Effect of human chorionic gonadotropin administered at specific times following breeding on milk progesterone and pregnancy in cows

Two trials were conducted to investigate the efficiency of human chorionic gonadotropin (hCG) following breeding to increase progesterone (P(4)) secretion and pregnancy rates in cows. In Trial 1, 79 lactating Holstein cows were randomly allocated to four groups to receive hCG either at breeding (Day 0, n=20), Day 7 (n=20) or Day 14 (n=20), or to receive no hCG treatment (control n=19). Whole milk samples were collected every other day from breeding until Day 21 and, thereafter, at weekly intervals until Day 42 or until the return to estrus for determination of P(4) concentrations. Similar treatments were employed in Trial 2, and 121 lactating Holstein cows were randomly assigned to treatment at Day 0 (n=29), Day 7 (n=32), or Day 14 (n=29), or to receive no treatment and serve as a control group (n=31). Milk samples were obtained at weekly intervals from breeding until Day 42, or the return to estrus for determination of P(4) concentrations. Pregnancy diagnosis was made by palpation per rectum at approximately 60 days post breeding. Significant increases in P(4) concentrations were observed in Day-7 and Day-14 treated cows from Days 18 to 42 after breeding compared with the Day 0 or the control cows. A slight decrease in P(4) concentration throughout the sampling period was observed in the Day-0 treated cows. Significant increases in pregnancy rates were observed in hCG-treated cows compared with that of the controls, with the highest rate observed in the Day-7 treated group. The overall pregnancy rates were 47, 62, 55 and 40% for the Day 0, 7 and 14 groups and for the control groups, respectively. In nonpregnant cows the mean (+/- SEM) numbers of days to basal P(4) concentrations were 21.6 +/- 1.3, 24.1 +/- 1.6, 24.6 +/- 1.3 and 23.2 +/- 1.3 for cows treated on Days 0, 7 and 14 and for the control group, respectively. It is concluded that the administration of hCG at Day 7 or Day 14 after insemination could be used as a management tool to improve pregnancy rates in postpartum cows.     

Effect of chorionic gonadotropin, triamcinolone, progesterone and estrogen on enzymes of placenta and liver in rats

The activity of several enzymes of regulatory importance for the pathways of glycolysis, gluconeogenesis and lipogenesis was investigated in the placenta and liver of pregnant rats and in the liver of non-pregnant female rats. The rats received daily hormonal treatments on Days 15 to 17 of pregnancy and enzyme activities were measured on Day 18. Chorionic gonadotropin induced minor changes in enzyme activity, apart from a decrease in the activity of hepatic enzymes of lipogenesis in non-pregnant rats. Triamcinolone induced a marked increase in enzymes of gluconeogenesis and a decrease in the activity of pyruvate k kinase in the liver of pregnant and non-pregnant rats; in contrast, inverse changes in activity, these enzymes were observed in the placenta. This response in the placenta was considered to arise not from direct hormone effect, but from the accompanying hyperglycemia and hyperinsulinemia. Triamcinolone also increased the activity of hepatic acetyl-CoA carboxylase in pregnant and non-pregnant rats, whereas it reduced the activity of this enzyme in the placent. Estrogen produced changes similar to those of triamcinolone in the liver and placenta, except that it depressed the activity of acetyl-CoA carboxylase in both tissues. Progesterone had little effect on placental and hepatic enzymes. In general, the changes induced by these hormones in the placenta affected fewer enzymes than in the liver, were less extensive in magnitude and not necessarily in the same direction as in the liver. This indicates that the regulatory placental enzymes are subject to specific control mechanisms not necessarily influenced by direct hormone action.     

Effect of human chorionic gonadotropin and prostaglandin F2a on progesterone production by human luteal cells

To determine and compare the direct effects of prostaglandin F2a (PGF2a) and human chorionic gonadotropin (hCG) on luteal cell progesterone production in vitro, 9 human corpora lutea obtained at tubal ligation were minced and treated with collagenase to disaggregate luteal cells. Dispersed luteal cells (80% viable) were incubated in air at 37 degrees C in a shaking water bath for 3 h and total progesterone in the media and cells was determined by radioimmunoassay. Optimum progesterone production was obtained using 25,000 or more cells per incubate and an incubation time of 2-4 h. hCG-stimulated progesterone production increased significantly with 0.01 IU to as high as 100 IU. In the early luteal phase (days 1-5 post ovulation or days 15-20 of the luteal phase), PGF2a (10-1000 ng) significantly inhibited progesterone production but significantly stimulated progesterone production in the mid-luteal phase (days 21-25). PGF2a had no effect on luteal cell progesterone production in the late luteal phase (days 26-30). This age-dependent direct effect of PGF2a on human luteal cell progesterone production in vitro indicates a role for PGF2a in the total intragonadal regulation of progesterone output, possibly through a paracrine or autocrine manner directed towards synchronizing luteal progesterone secretion and endometrial preparation for nidation.