Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause

BACKGROUND: Estrogen receptor (ER) and progesterone receptor (PgR) status at the time of breast carcinoma surgery is used as a marker of both prognosis and hormone dependency to guide adjuvant therapy. The authors studied the influence of hormonal milieu at the time of surgery on ER and PgR levels. METHODS: A population of 2020 patients with breast carcinoma, including 575 premenopausal women, was analyzed. ER and PgR levels were determined by radioligand binding assays (cutoff values, 10 fmol/mg). Serum estradiol (E2), progesterone (Pg), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels obtained on the day of surgery were used to define the menstrual cycle phase in premenopause. RESULTS: In premenopause, there was a higher proportion of ER positive (ER+) tumors in the follicular phase (62%, n = 316) than in the ovulatory phase (51%, n = 59) and the luteal phase (53%, n = 200, P = 0.03). The mean ER level was also higher in the follicular phase (30 fmol/mg) than in the ovulatory phase (20 fmol/ mg) and the luteal phase (25 fmol/mg, P < 0.001). The percentage of PgR positive (PgR+) tumors tended to be higher in the ovulatory phase (85%) than in the follicular (78%) and luteal (72%) phases (P = 0.11). The mean PgR was also higher in the ovulatory phase (177 fmol/mg) than in the follicular and luteal phases (134 and 92 fmol/mg, respectively; P < 0.001). The percentage of ER+ tumors was higher among menopausal women than among premenopausal women (67% vs. 59%, respectively; P < 0.001). Conversely, the percentage of PgR+ tumors was lower among menopausal women than among premenopausal women (65% vs. 78%, respectively; P < 0.001). In premenopause, there was a weak negative correlation between ER and E2 levels. No correlations were found between levels of ER and Pg and levels of FSH and LH or among levels of PgR and E2, Pg, and FSH and LH in premenopausal and menopausal women. CONCLUSIONS: Changes in ER and PgR levels in breast carcinoma during the menstrual cycle and menopause suggest that interpretations of hormone dependency on the basis of steroid receptor values should take into account hormonal status at the time of surgery.     

Hormone-dependent changes in A and B forms of progesterone receptor

The influence of different estrogen and/or progesterone treatments on concentrations of A and B forms of progesterone receptor (PR-A and PR-B) in the different cell types of chick oviduct was studied. A semiquantitative immunohistochemical assay for cellular PR concentrations was developed using a computer-assisted image analysis system. The staining intensity of nuclear PR in the basal layer of epithelial cells, glandular, smooth muscle and mesothelial cells was analysed separately using two monoclonal antibodies, PR6 and PR22. The measured concentrations of PR varied between different cell types and from cell to cell. A significant decrease in PR concentration, as noted by a decrease in staining intensity, was observed in all cell types studied 2 or 6 h after a single injection of progesterone with or without simultaneous estrogen administration. The decrease was also verified with immunoblotting and an immunoenzymometric assay (IEMA) for chicken PR. After down-regulation the concentration of PR recovered to the control level within 48 h after progesterone or estrogen administration. Estrogen administration alone was observed to cause changes in the concentration of PR-A only, having little or no effect on PR-B concentration depending on the cell type studied. These findings indicate that estrogen and progesterone cause cell-specific changes not only to the total concentration of PR but also to the cellular ratio of PR-A and PR-B.     

Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle

Nine periods in seven women with partial epilepsy have been invetigated with respect to frequency of fits, and estrogen-progesterone levels in blood plasma. Six cycles with ovulation showed a positive correlation between the number of secondary generalized seizures and the mean estrogen/progesterone (E/P) ratios and a negative correlation to plasma progesterone levels. Three periods without ovulation showed an increase in the number of fits during days of high estrogen. The number of fits seemed not to be correlated to changes in body weight.     

Endometrial glandular proliferation and estrogen receptor content during the normal menstrual cycle

The 5' untranslated region of an RNA molecule is thought to play an important role in the regulation of translation. Following a recent report that a single nucleotide is sufficient to act in this role in the unicellular organism Giardia, we show that this is also the case for a mammalian in vitro system. These results also demonstrate that an RNA can initiate translation from a start codon where an ideal translational consensus sequence is impossible.     

Spontaneous contractility and the response of the human uterine cervix to prostaglandins F2alpha and E2 during the menstrual cycle

The effect of prostaglandins E2 and F2alpha on the contractility of the uterine cervix was investigated in nonpregnant women throughout the menstrual cycle. PGF2alpha was found stimulatory to the cervix at all phases of the menstrual cycle, whereas PGE2 was inhibitory. The relaxing effect of PGE2 was most marked during midcycle.     

The timing of breast cancer surgery during the menstrual cycle

A number of recent studies have suggested that survival among premenopausal women after primary treatment of breast cancer may be affected by the estimated hormonal milieu at the time of surgery, especially in those with axillary lymph node metastases. The concept has created considerable controversy and has resulted in the publication of many negative reports. However, several biological mechanisms have been suggested for the observed survival advantage. These include cyclical patterns of immune function, as well as cell division and cell death, that correlate with hormonal fluctuations of the menstrual cycle. Comparisons among studies of timing have been complicated by differences in menstrual cycle divisions, variability in the sources of study populations, limited availability of menstrual history data, and changes over the past 2 decades in primary and adjuvant breast cancer therapy. Several recent publications have been enhanced by the availability of serum collected at the time of surgery that enables accurate measurement of the hormonal milieu. In these studies, the likelihood of misclassification by menstrual cycle phase is reduced, and dependence on recalled menstrual history is eliminated. High progesterone levels have been associated with improved survival. These findings have encouraged some to suggest that perioperative administration of progesterone or tamoxifen (Nolvadex) may provide a preventive avenue comparable to scheduling surgery during the luteal phase. Further multidisciplinary studies are needed, however, to clarify the influence of the naturally occurring or medically induced hormonal milieu at the time of breast cancer surgery on survival in premenopausal women.     

Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression

In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At -30 min the patients self-injected their usual morning insulin and at -15 min they injected the study drug (either placebo or 30, 60 or 90 microg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99mTc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with (111)In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal.     

Sex hormones affect spatial abilities during the menstrual cycle.

The aim of this study was (a) to show that different measures of spatial cognition are modulated by the menstrual cycle and (b) to analyze which steroid is responsible for these cognitive alterations. The authors collected blood samples in 3-day intervals over 6 weeks from 12 young women with a regular menstrual cycle to analyze concentrations of estradiol, progesterone, testosterone, luteinizing hormone, and follicle-stimulating hormone. The performance on 3 spatial tests was measured during the menstrual and the midluteal phases. A significant cycle difference in spatial ability as tested by the Mental Rotation Test was found, with high scores during the menstrual phase and low scores during the midluteal phase. Testosterone had a strong and positive influence on mental rotation performance, whereas estradiol had a negative one. These results clearly indicate that testosterone and estradiol are able to modulate spatial cognition during the menstrual cycle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Endometrial Th2 cytokine expression throughout the menstrual cycle and early pregnancy

Embryonic implantation and maintenance of pregnancy is influenced by the maternal immunological response. Type 2 T-helper (Th2) cells secrete interleukins 4, 5, 6 and 10 and are associated with suppression of cell-mediated immunity. Temporal changes in the expression of these cytokines were detectable by immunohistochemistry throughout the menstrual cycle. In pregnancy, 10-fold or greater increases in interleukin 6 and 10 secretion were detectable by enzyme-linked immunoassay compared with the non-pregnant state. The pattern of expression of Th2 cytokines suggests that progesterone may influence endometrial cytokine secretion. During pregnancy, Th2 expression paralleled that of vimentin, a stromal cell marker, suggesting that these cells may be a principal source of Th2 cytokines may be a mechanism of suppressing cell-mediated immunity in the endometrium, which may in turn enhance embryonic implantation and maintenance of pregnancy.     

Thermic effect of food during each phase of the menstrual cycle

The effect of the menstrual cycle on the thermic effect of food (TEF) was examined in eight healthy, normal-weight [mean +/- SD: 56.1 +/- 5.6 kg and body mass index (in kg/m2) 21.3 +/- 1.8] women aged 22-38 y. Their lean body mass and fat mass were 39.4 +/- 2.7 kg and 16.9 +/- 6.5 kg, respectively. TEF was measured on 4 separate days selected to match the four phases of a menstrual cycle: early follicular, follicular, luteal, and late luteal. The volunteers consumed a 3138-kJ liquid meal (54.5% carbohydrate, 14.0% protein, and 31.5% fat) on each test day. Resting metabolic rate was measured for 55 min before the meal and every 30 min after the start of the meal for 205 min. Although resting metabolic rate remained unchanged, there was a significant difference (P < 0.01 by ANOVA) in mean (+/- SEM) values for TEF among the four phases of the cycle: 0.94 +/- 0.05 kJ/min during the early follicular phase, 0.86 +/- 0.09 kJ/min during the follicular phase, 0.70 +/- 0.10 kJ/min during the luteal phase, and 0.76 +/- 0.07 kJ/min during the late luteal phase. TEF decreased significantly (P < 0.025 by paired t test) during postovulation (average of luteal and late luteal phases), when it was 0.73 +/- 0.07 kJ/min, compared with preovulation (average of early follicular and follicular phases), when it was 0.90 +/- 0.06 kJ/min. In conclusion, TEF decreased during the luteal phase of the menstrual cycle, possibly as a result of impairment of glucose uptake and slower transit of food through the upper gastrointestinal tract.     

Endometrial cytology during menstrual cycle, menopause and progestinic treatment

The AA. examined 72 cytological smears of the human normal endometrium. Twenty-three were taken during the proliferative phase, 17 during the secretory phase, 21 during menopause and 11 during estro-progestinic treatment. The study pointed out that the endometrial smear, which has been employed up to now almost exclusively in the cyto-oncological field, is also quite suitable for a dynamic cyto-functional evaluation of ovarian function, because of the series of interpretative elements, easily and readily identifiable at the microscope, which it furnishes.     

Sleep and the menstrual cycle.

To evaluate changes in sleep across the phases of the menstrual cycle, sleep-wake diaries were completed by 32 healthy women twice daily for 2 menstrual cycles. There was a significant increase in sleep onset latency and a significant decrease in sleep efficiency and sleep quality during the luteal phase. This increase in sleep disturbance was observed in the entire sample and was not related to the severity of other premenstrual symptoms. However, women having increased severity of other premenstrual symptoms reported greater luteal increase in daytime sleepiness. Thus, although menstruating women are likely to show increased sleep disturbance during the luteal phase, those with other, more severe premenstrual symptoms are more likely to experience a luteal increase in daytime sleepiness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serum levels of the pregnancy zone protein during the normal menstrual cycle

pregnancy zone protein (PZ), low polar estrogen, progesteorne, luteinizing hormone, and follicle stimulating hormone levels during normal menstrual cycles were studied. Serum samples were taken from 12 healthy women of different ages throughout their menstrual cycle. PZ levels showed no significant pattern and no statistically significant association was shown between PZ levels and any of the hormones. PZ levels were higher in older women and varied within each women's cycle. The study results indicate that peak estrogen levels during the menstrual cycle are not sufficient in duration or magnitude to cause increased serum levels of PZ.     

Endocrine regulation of the menstrual cycle

Physiological data concerning the serum concentrations and the pituitary content of varian steroids and gonadotropins, respectively, are reviewed. On the basis of these physiological data results from experimental studies are critically evaluated as far as their significance for the understanding of the physiology of the cycle is concerned. Data from the literatur and results from own studies are incorporated in a concept of the endocrine regulation of the human menstrual cycle.     

Ethnic differences in the length of the menstrual cycle during the postmenarcheal period

In 1989, 125 African-American and 123 European-American girls aged 12-14 years were enrolled in a 2-year study in which they maintained a menstrual calendar, recording the date and amount of menstrual bleeding. Weight, exercise, and stress during the previous week were recorded at the start of each menstrual cycle. Although only minor ethnic differences were observed in expected cycle length (29.3 vs. 28.8 days for European-American and African-American girls, respectively), more prominent differences were observed in the between-subjects standard deviation of cycle length (2.9 vs. 2.2 days, respectively) and in the odds of having a cycle longer than 45 days (odds ratio=1.86, 95% confidence interval 1.17-2.97) for European-American compared with African-American girls. Low weight for height and high levels of exercise increased the probability of having a cycle longer than 45 days and decreased expected cycle length of 13- to 45-day cycles. Additional investigation of potential ethnic differences in menstrual cycle characteristics is warranted.