The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis

Gene amplification and/or overexpression of the c-erbB-2/HER2/neu tyrosine kinase are linked with poor prognosis in breast cancer. This is manifest in shorter disease-free intervals, increased risk of metastasis, and resistance to many types of therapy. The molecular mechanisms and signaling circuitry underlying these phenomena are now being elucidated. c-erbB-2, although having no known soluble ligand, is transactivated by heterodimerization with other family members (EGFR, c-erbB-3, c-erbB-4). Receptor activation potentiates tumor cell motility, protease secretion and invasion, and also modulates cell cycle checkpoint function, DNA repair, and apoptotic responses. Since it is expressed at low levels in normal adult tissues, c-erbB-2 is an ideal target for therapy. There is reason for optimism that agents targeting c-erbB-2 signaling will have profound and selective effects in breast cancer, either as single agents or more likely in combination with other therapeutic agents, to enhance their potency.     

Immunohistochemical overexpression of C-erbB-2 in the prognosis of breast cancer

Immunohistochemical c-erbB-2 protein overexpression was detected in 34 of 124 (27.4%) paraffin-embedded breast cancer specimens. Although no difference was seen between the c-erbB-2 positive and negative groups in 5-year disease-free survival, 5-year overall survival was significantly less favorable in the c-erbB-2 positive group. Furthermore, patients graded as having positive c-erbB-2 staining and aneuploid DNA showed significantly poorer survival than those in other categories. The significant prognostic factors, determined by a multivariate analysis, were nodal status and c-erbB-2 overexpression. Our findings therefore suggest that c-erbB-2 expression is a prognostic factor in breast cancer and that it could be useful in the determination of postoperative adjuvant therapy.     

Effectiveness of an adriamycin immunoconjugate that recognizes the c-erbB-2 product on breast cancer cell lines

Adriamycin (ADM) was chemically conjugated to a murine monoclonal antibody, A0011, which recognizes the c-erbB-2 product, via a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolane (2-IT). The molar ratio of ADM to the monoclonal antibody ranged from 15:1 to 25:1 and enzyme-linked immunosorbent assay (ELISA) showed that the binding activity of the conjugate was almost retained. We compared the efficacy of A0011 alone, ADM alone, the A0011-ADM conjugate, and a nonspecific murine IgM-ADM conjugate, against the human breast cancer cell lines SK-BR-3, MDA-MB-361, MCF-7, and BT-20. The A0011-ADM conjugate was observed to be ten times more cytotoxic to the cell lines overexpressing the c-erbB-2 product, namely, SK-BR-3 and MDA-MB-361, than free ADM, but it showed weak cytotoxicity against the cell lines with a low level of c-erbB-2 product expression, namely, MCF-7 and BT-20. However, free A0011 and nonspecific murine IgM-ADM conjugate showed no cytotoxicity toward any of the four cell lines, while the addition of a tenfold molar excess of A0011 inhibited conjugate cytotoxicity. These data suggest that conjugate cytotoxicity is antibody-mediated. Moreover, conjugate cytotoxicity at 10^–6M was correlated with antigen volume, and the data were fitted to the regression equation y=–11.63logX+116.38 where the correlation coefficient =0.950. Our results indicate that targeting therapy aiming at the c-erbB-2 product may be useful in the treatment of breast cancers overexpressing the c-erbB-2 product.     

Characterization of cell surface antigens expressed in the HMA-1 breast cancer cell line

This report describes the characterization of an estrogen receptor-positive breast cancer cell line, HMA-1, established from a breast cancer patient, based on the expression of tumor-associated antigens (TAAs), the HLA-DR antigen, and the c-erbB-2 proto-oncogene product. In flow cytometric and immunohistochemical analyses, HMA-1 was found to express increased levels of several TAAs including MUC1, TAG-72 (sialyl Tn), Tn, T, sialyl Le^a, Le^x, and Le^y, HMA-1 also expressed enhanced levels of the HLA-DR antigen and c-erbB-2 protein. These results indicate that HMA-1 is a unique cell line with abundant TAAs which may serve as an appropriate breast cancer cell line for application in the multidisciplinary research of breast cancer.     

Higher expression of oncoproteins c-myc,c-erbB-2/neu,PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors

Background: Expression of individual oncogenes may predict outcome in patients with metastatic colorectal cancer (CRC). We studied the oncogene profile in the tumors of patients with CRC and assessed their value as predictors of liver metastases. Methods: The oncoproteins c-myc, c-erbB-2/neu (c-neu), PCNA and p53, were measured by immunohistochemistry in sections of metastasizing human CRC (n=34) and their liver secondaries as well as in sections of nonmetastasizing CRC (n=25). Results: The metastasizing primary CRC expressed proliferating-cell nuclear antigen (PCNA), c-neu, and c-myc at significantly higher levels than the nonmetastasizing primary cancer. p53 was also overexpressed in the metastatic group compared with the nonmetastasizing CRC, but this difference was not significant. The frequency of expression of all these markers was similar in the metastasizing primary CRC and the liver secondaries from the same patients. There was no correlation between the expression of the individual markers and histological grade, DNA ploidy, and subsequent local recurrence and lung metastasis and survival. However, when both groups were assessed together, positive expression of c-myc was more likely to occur in poorly differentiated tumors, whereas PCNA expression increased with more advanced Dukes stages. Conclusion: These results suggest that the overexpression of c-myc, c-neu, PCNA, and p53 may occur in CRC that are likely to metastasise to the liver.     

An immunohistological demonstration of c-erbB-2 oncoprotein expression in primary urothelial bladder cancer

Summary Sections of formalin-fixed, paraffin-blocked tissue from 116 primary transitional cell carcinomas were stained immunohistochemically using a polyclonal antibody against the c-erbB-2 oncoprotein. Positive staining of cell membranes, known to correlate with gene amplification, was seen in 22 (19%) of the 116, with variable staining from tumour to tumour and within tumours themselves. Consistent with its mooted value as a prognosticator in bladder cancer, the c-erbB-2 oncoprotein was detected in 13 (of 40) grade III and 9 of the 26 muscle-invasive tumours examined compared to 1 (of 25) grade I and 6 (of 66) mucosa only (pTa) lesions. These results support further examination of c-erbB-2 expression in bladder cancer.     

Proper timing of breast reduction during the menstrual cycle

Breasts are known to show cyclic changes in accordance with the menstrual cycle, and speculations have been made regarding the ideal timing of breast surgery in this extent, but the clinical evidence to support global acceptance and application is lacking. This study was designed to establish the relationship of intraoperative bleeding and postoperative drainage with the menstrual period of 35 reduction mammaplasty patients. The results indicate that both perioperative blood loss and postoperative drainage were significantly reduced when breast reduction is performed during the periovulatory phase compared with the perimenstrual phase. The authors strongly recommend the interval between days 8 and 20 of the menstrual cycle as a more convenient period to perform breast reduction. Drains may be avoided during this period, but they are preferred if the surgery is done during the perimenstrual phase.     

Relation between phase of the menstrual cycle and asthma presentations in the emergency department

BACKGROUND: The phase of the menstrual cycle is thought to influence the course of asthma in women. One recent study reported a large increase in exacerbations during the perimenstrual phase, while another found a preovulatory increase. A study was undertaken to determine the relation between phase of the menstrual cycle and acute asthma in patients presenting to the emergency department (ED). METHODS: All women aged 18-54 years presenting with a diagnosis of acute asthma exacerbation were considered for enrollment in the study. Women who were pregnant, postmenopausal, following hysterectomy, with a >28 day menstrual cycle or incomplete reproductive history were excluded. The 792 eligible women were classified by menstrual phase based on both date of symptom onset and date of ED visit. RESULTS: When classified by date of symptom onset, 28% were preovulatory (days 5 to 11), 25% were periovulatory (days 12 to 18), 21% were postovulatory (days 19 to 25), and 27% were perimenstrual (days 26 to 4; p = 0.03). When classified by date of ED visit, 28% were preovulatory, 22% were periovulatory, 22% were postovulatory, and 27% were perimenstrual (p = 0.004). Using either approach, there were no significant differences in demographic factors or in asthma severity of women in the various menstrual phase groups. CONCLUSION: Acute asthma exacerbations do not markedly increase during the perimenstrual phase. The results support the suggestion that both preovulatory and perimenstrual phases are actual triggers of asthma exacerbation in some women, or that these two phases serve as "co-factors" that worsen other recognised triggers of acute asthma.     

Effect of the menstrual cycle on intraoperative bleeding in rhinoplasty patients

This study aimed to evaluate the effect of menstrual cycle phase on intraoperative bleeding in rhinoplasty patients. One hundred seven female patients grouped as G1 (perimenstrual) and G2 (periovulatory) according to menstrual cycle were included in this study. Intraoperative blood loss was compared using the t test. Fifty-two of the patients were in G1 and 49 were in G2 group. Operative surgeons, presence of additional interventions, and operation duration did not differ among the groups. Mean intraoperative blood loss was 69.0 ± 24.6 ml in G1 and 80.4 ± 27.7 ml in G2. The blood loss difference between the two groups was statistically significant. This study demonstrated that perioperative blood loss is higher in patients operated on during the periovulatory phase. This increase does not seem to create difficulty during the operation or to have an impact on the outcome. Nevertheless, this might be reflected in more pronounced ecchymosis in the early postoperative phase.     

HER-2/neu Gene Amplification in Esophageal Adenocarcinoma and Its Influence on Survival

Background

HER-2/neu (c-erbB-2, HER2) gene amplification and protein overexpression have been associated with poor prognosis in several solid tumors, including breast and gastric cancer. Its incidence and significance in esophageal adenocarcinoma is unknown.

Materials and Methods

Tissue microarrays were successfully constructed from 89 paraffin-embedded archival specimens of esophageal adenocarcinomas for HER2 gene amplification by silver-enhanced in situ hybridization (SISH). No patients had undergone neoadjuvant therapy. Protein overexpression was tested with immunohistochemistry (IHC) using automated immunostaining (Ventana Benchmark). Incidence of HER2 positivity, correlation to clinicopathological variables in esophageal cancer patients, and concordance between SISH and IHC were determined.

Results

True HER2 gene amplification was detected in 14 esophageal cancer specimens (16%), and 92% of those with high-level HER2 amplification showed positive HER2 protein overexpression. No significant associations were found among gene amplification and clinicopathological factors. The 5-year survival rates were 57% for esophageal cancer patients with HER2 amplification compared with 32% without, but the difference in overall survival was not significant (P = .37). The correlation between SISH and IHC was statistically significant (P < .0001).

Conclusion

While molecular targeting may be possible for approximately 16% of esophageal adenocarcinoma patients, HER2 oncogene amplification did not influence survival in this study.

     

Effects of the menstrual cycle on injection pain due to rocuronium

Study ObjectiveTo investigate the effect of the menstrual cycle on rocuronium injection pain.DesignProspective, randomized, double-blinded study.SettingAcademic medical center.Patients80 ASA physical status 1 and 2 women scheduled for elective surgery with general anesthesia.MeasurementsPatients were divided into two groups according to their time in the menstrual cycle. Forty patients at days 8 to 12 of the menstrual cycle were considered to be at the follicular phase (Group F), and 40 patients at days 20 to 24 of the menstrual cycle were considered to be at the luteal phase (Group L).Withdrawal movements were recorded.Main ResultsOverall frequency of withdrawal movements was significantly higher in Group L than Group F (P < 0.001). The mean withdrawal movement score was 1.77 ± 0.76 in Group L and 0.52 ± 0.67 in Group F.ConclusionMenstrual cycle phases affect the severity of rocuronium injection pain. Women exhibit greater pain sensitivity from rocuronium injection in the luteal phase than the follicular phase.     

No effect of timing of biopsy in the menstrual cycle on incidence of bone marrow micrometastasis in patients with breast cancer

Background: The timing of breast cancer excision relative to the menstrual cycle has been debated to be of significant prognostic value. The differences in survival relative to the timing in the menstrual cycle have been attributed to the incidence of micrometastasis. Methods: All patients underwent bone marrow aspiration after the diagnostic surgical biopsy, immediately before definitive surgery. The timing of the diagnostic surgical biopsy in the menstrual cycle was calculated according to Senie. Monoclonal antibodies to epithelium-specific antigens were used to detect bone marrow micrometastasis (BMM). Results: This study reports on the effect of the phase of the menstrual cycle on incidence of BMM after surgical biopsy. Ninety-two patients with regular cycles underwent bone marrow aspiration an average of 12 days (range 0–32 days) after biopsy. Thirty-nine patients had undergone biopsy during the follicular phase and 53 patients during the luteal phase. BMM were detected in 31% of patients (29 of 92). We observed BMM in 33% of patients (13 of 39) in the follicular phase and in 30% of patients (16 of 53) in the luteal phase. This difference is not significant (p>0.70). The mean number of cells detected and the presence of clumps of cells is similar in the two groups. Conclusions: The incidence and characteristics of bone marrow micrometastases are independent of the timing of diagnostic excision biopsy in the menstrual cycle. Dr. Singhal is now with the Department of Surgery, University of Wales College of Medicine, Cardiff, CF4 4XN United Kingdom.     

Loss of c-met protooncogene in primary and metastatic sites of breast cancer

Background: It has been proposed that clones of tumor cells acquire higher metastatic potential as a result of specific genetic alterations. This study was designed to determine the role of the c-met protooncogene in systemic spread by comparing the loss of the c-met protooncogene between primary and metastatic breast carcinomas. Methods: Only patients who had not received chemotherapy or radiotherapy in the preceding 6 months were included in this study. Histologically proven malignant tissue was obtained from the primary tumor, involved nodes, and distant metastatic and recurrent tumors of patients with breast carcinomas. Allelic loss of the c-met protooncogene in tumor tissue was determined by Southern blotting using a polymerase chain reaction-generated 347-bp human met-H probe. Restriction digestion was performed usingTaq I andMsp I, with the patient's lymphocyte DNA as controls. Results: Of 52 patients, lymphocyte DNA from 36 patients was heterozygous for the c-met protooncogene (69% informative). Forty-six tumors from these 36 patients were analyzed. Four of 30 primary tumors (13%) showed allelic loss of c-met. Of the nine nodal metastases examined, three (33%) showed allelic loss of the c-met protooncogene. Of seven distant metastatic breast tumors or recurrent disease, two (29%) showed allelic loss (both in patients with skin metastasis in the chest wall). Conclusions: Allelic loss of the c-met protooncogene was detected in both primary (13%) and metastatic sites (31%) of breast cancer. Although a higher proportion of allelic loss of c-met was noted in nodal and distant/recurrent disease, the difference when compared with the primary tumor was not statistically significant. These findings indicate a limited role of the c-met protooncogene in breast cancer metastases.     

Influence of the menstrual cycle on the incidence of nausea and vomiting after laparoscopic gynecological surgery: a pilot study

Study ObjectiveTo investigate whether the phase of menstrual cycle influences the incidence of postoperative nausea and vomiting (PONV) in women undergoing general anesthesia for elective laparoscopic gynecological surgery.DesignProspective, observational, blinded study.SettingGeneral hospital, Postanesthesia Care Unit, and gynecologic floor room.Patients111 ASA physical status 1 and 2 women, aged 18 to 53 years.InterventionsPatients were classified into three groups according to the phase of menstrual cycle at the time of anesthesia: Group F1: follicular phase (menstrual days 1-8; n = 34); Group O2: ovulatory phase (days 9-15; n = 40); and Group L3: luteal phase (days 16 to end of cycle; n = 37). Anesthetic, postoperative pain management, and antiemetic regimens were standardized.MeasurementsFrequency of nausea, vomiting, or both were assessed for early (0-2 hrs). Late PONV (2-24 hrs) along with the use of rescue antiemetic, severity of nausea, and pain.Main ResultsIn the follicular (n = 34), ovulatory (n = 40) and luteal phase (n = 37) groups, the frequencies of PONV over 24 hours were 35%, 38%, and 14% (P = 0.04), respectively. This was due to differences in the early postoperative period where the frequencies were 21%, 25%, and 3% (P = 0.02), respectively, as frequencies were similar in the late period (15%, 20% and 14%, P = 0.71), respectively. Nausea scores, rescue antiemetic usage, pain scores, and opioid consumption were similar in the groups.ConclusionPatients in the luteal phase of their menstrual cycle may have a decreased risk of PONV after laparoscopic gynecological surgery in the early postoperative period.     

Menstrual cycle affects bladder pain sensation in subjects with interstitial cystitis

PURPOSE: Using psychophysical methods we compared the effect of the menstrual cycle on bladder sensation in subjects with the diagnosis of interstitial cystitis (IC) and in controls. MATERIALS AND METHODS: Female participants with normal menstrual cycles, including 7 with IC and 8 healthy controls, were recruited into this study. They completed daily diaries related to bladder pain and other body pain, and tracked daily micturition frequency. In a subset formal psychophysical testing of thermal and ischemic pain was performed at 2 times of the menstrual cycle, corresponding to the luteal and follicular phases. Cystometrograms were performed at the same time. RESULTS: Subjects with IC had higher pain scores and frequency than controls throughout the entire menstrual cycle. Pain scores were highest in the perimenstrual period in subjects with IC and controls. Micturition frequency was highest in the perimenstrual period in subjects with IC. Cystometric evaluation of a first need to void and the evocation of bladder pain demonstrated that lower intravesical volume and pressure were necessary to evoke bladder pain during the follicular period than during the luteal period in subjects with IC, although there was no effect on the first need to void. CONCLUSIONS: These findings are consistent with clinical lore that suggests a perimenstrual flare in pain in subjects with IC. To our knowledge it also demonstrates for the first time a menstrual cycle effect on bladder sensory function in subjects with IC. This suggests a potential role of gonadal hormones on bladder sensory processing and, therefore, a potential role for hormonal modulation as a therapeutic modality in this patient population.     

pS2 expression induced by American ginseng in MCF-7 breast cancer cells

Background: Alternative medicines are frequently used by patients with breast cancer for general health benefits. American ginseng, an herbal remedy, purportedly alleviates treatment-induced postmenopausal symptoms. Methods: Estrogenic potential of American ginseng root extract to induce the expression of pS2, an estrogen-regulated gene, was evaluated in breast cancer cell lines MCF-7, T-47D, and BT-20 by Northern and Western blot analysis. Competitive studies were performed with ginseng in combination with tamoxifen. Cell proliferation assays were performed using the tetrazolium dye procedure and direct cell count. Results: Ginseng and estradiol induce the expression of pS2 RNA and protein in MCF-7 cells, whereas tamoxifen suppresses expression. Neither ginseng nor estradiol induced increased pS2 expression in T-47D or BT-20 cell lines. Although estradiol exhibited a proliferative effect and tamoxifen had an inhibitory effect, ginseng demonstrated no significant effect on cell proliferation. Conclusions: The results of this study suggest that ginseng may exhibit estrogenlike effects on estrogen receptor-positive breast cancer cells by inducing pS2 expression and that the effect of ginseng may be mediated in part through the estrogen receptor. Because ginseng does not exhibit a proliferative effect, it may play a protective role against breast cancer rather than serve as a mitogen.Presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Does the menstrual cycle influence cystometry?

Alterations in the hormonal milieu associated with the menstrual cycle appear to influence the dynamic interaction between the bladder and urethra as well as detrusor function, probably because of the common embryological origin of the lower genital and urinary tracts. In this retrospective study we investigated the effect of the menstrual cycle on cystometric diagnosis. A retrospective case note review of 687 consecutive patients attending the urogynecology unit of St Georges University Hospital, a tertiary referral center, was carried out. The study group comprised 57 women with regular menstrual periods. In both patients whose symptoms were adversely affected premenstrually and those whose symptoms were not influenced by the menstrual cycle, the majority of normal cystometric diagnoses were made in the luteal phase: 45.5% vs. 25% (P⩽0.002) and 38.5% vs. 4.8% (P⩽0.05), respectively. Diagnoses of genuine stress incontinence, detrusor instability and mixed genuine stress incontinence and detrusor instability were most frequently made in the follicular phase of the cycle. More normal cystometric diagnoses were made in the influenced group (36.8%) than in the uninfluenced group (21%) (P<0.02). The results of this preliminary study indicate that the timing of cystometric evaluation may influence the detection of a positive diagnosis. The luteal phase may not be the correct time to make an accurate diagnosis, especially in patients whose symptoms are influenced by their menstrual cycle. EDITORIAL COMMENT: It is not uncommon to hear from patients that their urinary symptoms of frequency, urgency and/or incontinence worsen prior to their menses. A study by Sorensen et al. performed complete urodynamic evaluation three times during the menstrual cycle in 10 healthy women without urologic symptoms, and found no difference in urologic parameters, suggesting that the timing of urodynamic evaluation during the menstrual cyle is unimportant. The present study looks retrospectively at patients who stated that their symptoms worsened premenstrually compared to patients who experienced no change in their urologic symptoms through their cycle. Interestingly, both groups had more normal (or possibly false negative) evaluations during the luteal phase than in the follicular phase of the menstrual cycle, in spite of the increased symptomatology reported in group 2. Unfortunately this study is limited by the small number of subjects and the fact that no patients in group 2 underwent urodynamic evaluation during their menses. To really determine whether the menstrual cycle influences urologic symptoms and diagnosis, repeated urodynamic evaluation of patients with premenstrual exacerbation of symptoms at different times of their cycle should be performed.     

Prognostic Value of Laurén Classification and c-erbB-2 Oncogene Overexpression in Adenocarcinoma of the Esophagus and Gastroesophageal Junction

Background: The prognostic value of the Laurén classification and of c-erbB-2 oncogene overexpression has been described for gastric cancer. The aim of this study was to investigate the clinical significance of these factors in adenocarcinoma of the esophagus and/or gastroesophageal junction (GEJ).Methods: Forty-one adenocarcinomas of the esophagus and/or GEJ were reviewed for tumor stage, lymph node status, Laurén classification, and c-erbB-2 overexpression, as assessed by immunohistochemical analysis.Results: According to the Laurén classification, tumors were classified as intestinal-, mixed-, or diffuse-type (54%, 32%, and 15%, respectively). Diffuse-type tumors were associated with a significantly worse prognosis than were intestinal-type tumors (P = .018; log-rank test). The prognostic value of the Laurén classification was independent of stage (P = .048; Cox regression model). Overexpression of c-erbB-2 was detected in 24% of the tumors and was present exclusively in intestinal-type tumors and in intestinal-type areas of mixed-type tumors. Ten of the 30 stage III/IV tumors (33%) were c-erbB-2-positive, whereas none of the 11 stage I/II tumors (0%) overexpressed the oncogene product (P = .04; Fisher exact test). The prognostic value of c-erbB-2 overexpression was not independent of stage (P = .7; Cox regression model).Conclusions: (1) The Laurén classification is an independent prognostic factor in adenocarcinoma of the esophagus and GEJ. (2) c-erbB-2 overexpression is limited to (areas of) intestinal-type tumors, indicating that intestinal- and diffuse-type tumors differ oncogenetically. (3) c-erbB-2 overexpression is associated with the stage of disease, indicating that it is a late event during tumor progression.WP, who was originally affiliated with the 2nd Department of General Surgery, Medical Academy (Lublin, Poland), is a fellow of the European Postgraduate Gastro-surgical School at the Academic Medical Center, University of Amsterdam (Amsterdam, The Netherlands).     

Changes in serum collagen markers,IGF‐I,and Knee joint laxity across the menstrual cycle

Variations in serum markers of collagen production (CICP) and degradation (ICTP), insulin‐like growth factor I (IGF‐I) and anterior knee laxity (AKL) were measured in 20 women [10 with spontaneous cycles (eumenorrheic), 10 using oral contraceptives] over 5 consecutive days at menses (M1–M5, 1st pill week), the initial estrogen rise near ovulation (O1–O5, 2nd pill week), the initial progesterone rise of the early luteal phase (EL1–EL5, 3rd pill week) and post‐progesterone peak of the late luteal phase (LL1–LL5, 4th pill week). ICTP was higher in oral contraceptive women (5.3 ± 1.7 vs. 3.7 ± 1.3 µg/L; p = 0.030), primarily during days near ovulation and the early luteal phase when concentrations decreased in eumenorrheic women (p = 0.04). IGF‐I concentrations increased during menses then decreased and remained lower during the early and late luteal phase in oral contraceptive women, resulting in lower concentrations compared to eumenorrheic women at EL2 and LL1 (p = 0.03). CICP decreased in early and late luteal days (p <0.01), and there was a trend toward lower concentrations in eumenorrheic versus oral contraceptive women (85.7 ± 35.7 ng/ml vs. 123.2 ± 49.8 ng/ml; p = 0.07). Lower CICP and greater IGF‐I concentrations predicted greater AKL across the 20 cycle days in both groups (R² = 0.310 and 0.400). Sex hormone concentration changes across the menstrual cycle are of sufficient magnitude to influence collagen metabolism, and may indirectly influence knee structure and function. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1405–1412, 2012     

The effects of hormonal status on upper airway patency in normal female subjects during propofol anesthesia

Study Objective

To determine the mechanical upper airway properties and compensatory neuromuscular responses to obstruction during propofol anesthesia in the follicular and luteal phases of the menstrual cycle.

Design

Prospective, randomized study.

Setting

University-affiliated hospital.

Subjects

12 premenopausal female volunteers for studies of upper airway collapse throughout their menstrual cycle during the follicular phase (6 -10 days) and mid-late luteal phase (20 - 24 days).

Measurements

The level of propofol anesthesia (1.5 - 2.0 μg/mL) required to suppress arousal responses was determined by Observer's Assessment of Alertness/Sedation scoring (level 2) and confirmed by bispectral index monitoring. Pressure-flow relationships were constructed to evaluate collapsibility (P_CRIT) and up-stream resistance (R_US) during acute [Passive; hypotonic electromyography (EMG)] and sustained (Active; elevated EMG) changes in nasal mask pressure. The difference between passive P_CRIT and active P_CRIT (ΔP_{CRIT A-P}) represented the magnitude of the compensatory response to obstruction.

Main Results

Passive P_CRIT was significantly higher in the mid-late luteal phase (-4.7 cm H₂O) than in the follicular phase (-6.2 cmH₂O; P < 0.05). Active P_CRIT significantly decreased compared with passive P_CRIT in the follicular phase (-10.1 cm H₂O) and in the mid-late luteal phase (-7.7 cm H₂O) and (P < 0.05). No significant difference was noted in ΔP_CRIT between the follicular (3.9 ± 2.9 cm H₂O) and mid-late luteal phases (3.0 ± 2.6 cm H₂O). No differences were seen in R_US between the menstrual phases for either the passive (P = 0.8) or active (P = 0.75) states.

Conclusions

Menstrual phase has an effect on anatomical alterations (mechanical properties) in the hypotonic upper airway during propofol anesthesia.