M. Yusoff Dawood

Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis

OBJECTIVE(S) To determine [1] vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) levels in peritoneal fluid from women with endometriosis and compare them with those from oral contraceptive (OC) users and normal cycling women and [2] any correlation between VEGF and IL-6 concentrations. DESIGN Controlled clinical study. SETTING University medical center. PATIENT(S) Patients undergoing laparoscopy for infertility or other benign gynecologic conditions. INTERVENTION(S) Peritoneal fluid samples were collected. MAIN OUTCOME MEASURE(S) Levels of VEGF and IL-6 in peritoneal fluid were determined. RESULT(S) Compared with normal controls or women with less severe endometriosis (implant scores of 5 or less), women with more advanced endometriosis (implant scores of 6 or more) have elevated VEGF and IL-6 levels in peritoneal fluid. Compared with normal controls, markedly suppressed IL-6 but similar VEGF levels were found in peritoneal fluid from OC users. Neither VEGF nor IL-6 varied cyclically in normal women or those with endometriosis. There was no correlation between levels of VEGF and IL-6 in peritoneal fluid. There was no correlation between implant scores and VEGF or IL-6 levels. CONCLUSION The inflammation associated with endometriosis, through increased levels of peritoneal fluid VEGF, may promote angiogenesis for the progressive growth of endometriosis. Effective treatment of endometriosis by combination estrogen-progestin pills may involve the suppression of such inflammatory responses.

Depot leuprolide acetate versus danazol for treatment of pelvic endometriosis: changes in vertebral bone mass and serum estradiol and calcitonin *

OBJECTIVE To determine changes in trabecular vertebral bone mass, serum E2, and serum calcitonin during and after therapy of pelvic endometriosis with depot leuprolide acetate (LA) or danazol. DESIGN Prospective, randomized, double-blind study. SETTING Academic university hospital and department of obstetrics and gynecology. PATIENTS Twelve women with symptomatic pelvic endometriosis diagnosed and staged by laparoscopy. INTERVENTIONS All patients received blinded treatment with either 3.75 mg JM depot LA given every month and daily placebo tablets (n = 6) or 800 mg oral danazol daily with a monthly placebo injection (n = 6) for 24 weeks. MAIN OUTCOME MEASURES Quantitated computerized tomography of bone density of thoracic 12 to lumbar 4 vertebral bodies were determined before, at the end of 24 weeks of treatment, and 6 and 12 months after completing treatment. Gain or loss of bone mass was based against pretreatment levels. Serial serum levels of E2 and calcitonin before, throughout, and after therapy were compared with changes in bone mass. RESULTS Bone loss with LA was 14.0% +/- 0.5% (mean +/- SEM), recovering to a deficit of 4.2% +/- 3.8% and 3.3%, 6 and 12 months after stopping therapy. Danazol increased bone by 5.4% +/- 2.2%, with a further gain to 8.2% +/- 3.5% and 7.5%, 6 and 12 months after stopping treatment. Serum E2 levels usually were < 25 pg/mL (conversion factor to SI unit, 3.671) with LA but > 47.3 pg/mL with danazol. Calcitonin levels did not change significantly with either treatment. CONCLUSION Depot LA produced marked sustained hypoestrogenemia and significant bone loss with incomplete recovery 1 year after stopping treatment. Danazol maintained normoestrogenemia and increased bone mass with the gain maintained even 1 year after stopping therapy.

Fluorescence spectroscopy for cervical precancer detection: Is there variance across the menstrual cycle?

This study assesses one possible cause of inter-patient variation in fluorescence spectroscopy of the cervix: the menstrual cycle. Ten patients with no history of an abnormal Pap smear were seen daily throughout 30 consecutive days of their cycle. Fluorescence excitation-emission matrices were measured from three cervical sites on each patient. Principal component analysis was used to determine which spectral regions varied with the day of the cycle. Classification was performed to assess the influence of menstrual cycle on precancer diagnosis. Variations in the principal component scores and the redox ratio values show that the fluorescence emission spectra at 340-380 nm excitation appear to correlate with the cell metabolism of the cervical epithelium throughout the menstrual cycle; these changes do not affect diagnostic classification. The menstrual cycle affects intra-patient variation but does not appear to cause a significant level of inter-patient variation. It does not need to be controlled for in optical detection strategies based on fluorescence spectroscopy.

Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles

OBJECTIVE To determine the histologic development of midluteal corpus luteum (CL) and endometrium in normal fertile women after induction of ovulation with clomiphene citrate (CC). DESIGN, PATIENTS, INTERVENTIONS: Twelve normally cycling women planning to undergo an elective tubal ligation were treated with 50 to 150 mg of CC daily on days 5 through 9 of the cycle. Luteectomy and endometrial biopsy were performed simultaneously 7 days after the urinary luteinizing hormone surge. RESULTS Because polyovulation occurred in 10 of the 12 women, 22 CL and 12 endometrial biopsies were studied. Ten women had luteal and endometrial histology that were within 2 days of the ovulation to biopsy interval. The 2 remaining women had endometrial histology that lagged 3 days behind the chronological postovulatory date. In these women, out-of-phase endometrium occurred despite polyovulatory cycles in which two and three histologically normal CL lutea were present and associated with elevated progesterone concentrations. CONCLUSIONS In CC-induced ovulatory cycles: (1) midluteal CL histology is normal and (2) apparently out-of-phase preimplantation endometrium occurs in midluteal phase.

Induction of labor with pulsatile oxytocin

In a prospective, randomized study, 106 patients underwent induction of labor with either pulsed (every 8 minutes) (n = 50) or continuous (n = 56) intravenous infusion of oxytocin. Maternal characteristics, gestational age at induction, induction-delivery interval, analgesia for labor, cesarean section rates, and newborn characteristics were similar in both groups. The mean +/- SEM total oxytocin administered was significantly less in the pulsed group (3564 +/- 487 mU) than in the continuous group (7684 +/- 844 mU; p less than 0.0001); the average dose of oxytocin administered per minute was significantly lower in the pulsed group (3.9 +/- 0.3 mU/min) than in the continuous group (7.8 +/- 0.4 mU/min; p less than 0.0001); the peak or highest administered dose of oxytocin expressed per minute was also signficantly lower in the pulsed group (9.6 +/- 0.8 mU/min) than in the continuous group (14.1 +/- 0.7 mU/min; p less than 0.0001). These significant differences persisted even when controlled for parity, Bishops score of the cervix, and number of days induction of labor was carried out. Uterine hyperstimulation occurred infrequently in both groups (3.6% to 4.0%). The pulsed group required a significantly smaller infusion volume (25 +/- 14 ml) than the continuous group (780 +/- 84 ml; p less than 0.0001). Thus pulsatile administration uses significantly less oxytocin and infusion fluid but is as effective and safe as continuous infusion.

Cyclic perimenstrual pain and discomfort: the scientific basis for practice.

OBJECTIVE To review and organize the science related to cyclic perimenstrual pain and discomfort for the fifth research-based practice project of the Association of Womens Health, Obstetric and Neonatal Nurses. DATA SOURCES Computerized searches in CINAHL, MEDLINE, and the Cochrane Library, as well as hand searches of cited references. Keywords included cyclic pelvic pain, comfort, pain guidelines, and dysmenorrhea. DATA EXTRACTION All relevant articles prior to 1999 were considered. Thirty-three research-based articles (1992-1999) were reviewed for relevance by the science team as part of the fifth research-based practice project of the Association of Womens Health, Obstetric and Neonatal Nurses. DATA SYNTHESIS The literature review and synthesis resulted in a cogent description of cyclic perimenstrual pain and discomfort and the development of three nursing diagnoses: perimenstrual cyclic pelvic pain, perimenstrual discomfort, and perimenstrual negative affect. Cyclic pelvic pain is a new concept, developed by the science team during the project. Perimenstrual cyclic pelvic pain is an acute, subjective experience defined by pelvic pain that presents in a repeating time frame associated with the menstrual cycle. It is usually clustered with other discomforts and appreciably affects a womans quality of life. Because the science about interventions is complex and extensive, data synthesis led to organization of the interventions within seven categories. CONCLUSIONS Translation of research into practice is essential. Cyclic perimenstrual pain and discomfort is an important clinical issue, yet the science had not previously been comprehensively reviewed with the mission to translate it for nursing practice. Translation of this complex literature was accomplished though an innovative clinical practice guideline and subsequently evaluated in nursing practice through the research-based practice project.

Luteal insufficiency: Correlation between endometrial dating and integrated progesterone output in clomiphene citrate-induced cycles

Midluteal phase endometrium was histologically dated with midcycle luteinizing hormone surge time in 29 cycles from 10 parous women during untreated cycles (control) and treatment with clomiphene citrate 50 mg and 150 mg daily on days 5 through 9. Integrated progesterone output for 7 days after luteinizing hormone surge calculated from the daily plasma progesterone levels was 66.6 +/- 9.8 ng/ml in the control group compared with 117.5 +/- 18.6 ng/ml for clomiphene citrate 50 mg treatment and 152.1 +/- 11 ng/ml for clomiphene citrate 150 mg treatment (p less than or equal to 0.05). Only one cycle (clomiphene citrate 150 mg) had an out-of-phase endometrium and a significantly reduced integrated progesterone output of 28 ng/ml. All other cycles showed synchronous endometrial maturation. We conclude that luteal insufficiency as a result of clomiphene citrate treatment in ovulatory women is infrequent and is more likely to be a result of functional outcome of a relative lack of luteal phase progesterone output.

Insulin-like growth factor I receptors in human corpora lutea

OBJECTIVE To determine the presence and binding characteristics of insulin-like growth factor (IGF) receptors in corpora lutea (CL) of spontaneous and clomiphene citrate (CC)-induced cycles and to identify any relationship between IGF receptors and cytosol progesterone (P) and 17 alpha-hydroxyprogesterone (17 alpha-OHP) levels. DESIGN Women undergoing bilateral tubal ligation were divided into two groups. One group received no medication (controls) and the other took 50 mg of CC. Midluteal phase CL were recovered at tubal ligation for hormone and receptor analysis. SETTING Patients were recruited from a university hospital setting. PATIENTS Eleven fertile women 26 to 37 years of age requesting bilateral tubal ligation were studied. INTERVENTIONS Four women were given 50 mg/d of CC from days 5 through 9 of study cycle. Seven women did not take any medication. Minilaparotomy bilateral tubal ligation and luteectomy were performed 7 to 9 days after midcycle urinary (LH) surge. MAIN OUTCOME MEASURES Insulin-like growth factor receptor concentrations and binding characteristics and cytosol P and 17 alpha-OHP levels in individual CL. RESULTS Optimal binding for 125I-IGF-I with membrane fractions of homogenized CL was obtained with incubation at 4 degrees C for 16 hours. Specific binding (mean +/- SEM) was significantly higher in CC-treated (53.6% +/- 4.8%) than in control cycles (25.9% +/- 5.5%, P less than 0.001). Receptor concentrations were also significantly higher in CL from CC-induced (145.6 +/- 21.8 pmol/mg protein) than from control cycles (74.8 +/- 15.2 pmol/mg protein, P less than 0.02). Insulin-like growth factor receptor levels correlated with neither serum nor cytosol P and 17 alpha-OHP in CL from either cycles. CONCLUSION Specific IGF-I receptors are present in human CL of the menstrual cycle with higher concentrations present in CC-induced cycles. Thus IGF may express its action on luteal function through its receptors in CL.

Plasma insulin-like growth factor-I, CA-125, estrogen, and progesterone in women with leiomyomas*

OBJECTIVE To determine plasma levels of insulin-like growth factor-I (IGF-I), CA-125, estrone (E1), E2, and P in women with uterine leiomyomas compared with normal women. DESIGN Women with leiomyomas were compared with normal women (control). SETTING University Department of Obstetrics and Gynecology. PATIENTS Fifty-one premenopausal women with uterine myomas > 14 weeks gestation and 30 normal fertile women (controls) were studied. Peripheral blood samples were obtained before myomectomy or hysterectomy and during the nonmenstruating phase in the controls. MAIN OUTCOME MEASURES Plasma levels of E1, E2, P, CA-125, and IGF-I were determined by specific and sensitive RIAs and immunoradiometric assays. RESULTS Plasma IGF-I levels were 2,006 +/- 185 mU/mL (mean +/- SEM, n = 35) and 2,335 +/- 287 mU/mL (n = 16) in women with leiomyomas during the follicular and luteal phases, respectively, whereas the corresponding values for normal women were 1,702 +/- 120 (n = 30) and 1,774 +/- 239 mU/mL (n = 30). Similarly, plasma CA-125 levels were unchanged in women with leiomyomas (myomas: 18.8 +/- 2.4, 21.5 +/- 3.7 U/mL; normal: 15.9 +/- 1.5, 15.8 +/- 1.3 U/mL during follicular and luteal phases, respectively). Women with leiomyomas had plasma E1, E2, and P levels during the follicular phase (91.9 +/- 11.5 pg/mL; conversion factor to SI unit, 3.699; 94.6 +/- 19.0 pg/mL; conversion factor to SI unit, 3.671; and 1.5 +/- 0.4 ng/mL; conversion factor to SI unit, 3.180, respectively) and the luteal phase (105.8 +/- 11.2 pg/mL; conversion factor to SI unit, 3.699; 128.7 +/- 24.8 pg/mL; conversion factor to SI unit, 3.671; and 9.6 +/- 1.6 ng/mL; conversion factor to SI unit, 3.180) similar to normal women. CONCLUSION Plasma levels of IGF-I, CA-125, E1, E2, and P are normal in women with leiomyomas.

Detecting the Signal of the Menstrual Cycle in Fluorescence Spectroscopy of the Cervix

Fluorescence spectroscopy of the cervix has been shown to be an effective noninvasive diagnostic tool for cervical intraepithelial neoplasia (precancer). To assess the effect of the menstrual cycle on fluorescence spectroscopy, daily measurements were made on ten subjects for the length of their cycle. These measurements were analyzed to determine if there was a statistically significant signal associated with the menstrual cycle. A signal was found for emission wavelengths between 425 and 445 nm inclusive—near the main hemoglobin absorption band, the Soret band, at 420 nm. We suspect that the slight displacement of the Soret band is due to the nearby dominant NAD(P)H peak, which increases the signal-to-noise ratio and affects statistical significance. The signal consists of a reduction in fluorescence intensity for the first few days of the cycle. This analysis indicates that hemoglobin absorption is the main menstrual-cycle effect on the use of fluorescence spectroscopy on the cervix. The effect is confined to a small set of excitation/emission wavelengths and to approximately the first 8 days of the cycle. This suggests that any problems from the menstrual cycle can be avoided with a simple requirement that the device not be used during the period of menstrual bleeding.