Association of ovarian malignancy with expression of platelet-derived endothelial cell growth factor.

BACKGROUND: At the present time, the pathogenesis of ovarian cancer remains poorly understood, with invasive diagnosis and ineffective treatment for women with the disease. Despite scientific and medical advances in oncology, the overall 5-year survival rate of 30% for ovarian cancer patients has not changed in 20 years. An understanding of the angiogenic process as it occurs in ovarian cancer would not only increase our knowledge of the pathogenesis of this cancer but also might offer novel opportunities for therapeutic intervention. PURPOSE: Our aim was to study the expression of messenger RNA (mRNA) coding for four putative angiogenic factors in normal ovaries and benign and malignant ovarian tumors: platelet-derived endothelial cell growth factor (thymidine phosphorylase), vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta 1. METHODS: Four normal ovaries and 25 tumors (seven benign, one of borderline malignancy, and 17 malignant) were collected from 29 patients during elective oophorectomy. The site of sampling (areas of high-velocity blood flow) was directed by transvaginal color Doppler imaging performed within 24 hours of the surgery. Increased blood flow within the tissues was demonstrated by the presence of color (i.e., the velocity was > 7 cm/s) and, together with a pulsatile index of less than 1.0, constituted a positive scanning result. In scan-positive tissues, the area of maximum blood flow was chosen. In scan-negative tissues, a solid area was chosen in complex lesions, or the cyst wall was chosen in simple lesions. Ovarian RNA was subsequently extracted from areas of high-velocity flow (i.e., tissues with a positive scanning result) or from solid areas or septa in tissues with a negative scanning result. A ribonuclease protection assay was used to assess the expression of mRNA coding for the four angiogenic factors. RESULTS: Two normal ovaries (containing a corpus luteum) and one benign and 17 malignant tumors (plus the borderline) gave a positive scanning result. There was a significant difference between the expression of mRNA for platelet-derived endothelial cell growth factor between scan-positive and scan-negative tissues (P < .001) and between benign and malignant tumors (P < .001). CONCLUSIONS: Areas of high blood velocity in ovarian tumors are associated with increased expression of platelet-derived endothelial cell growth factor. IMPLICATIONS: Drugs that affect the angiogenic activity of platelet-derived endothelial cell growth factor offer a potential route for therapeutic intervention.

The measurement of steroid glucuronides in urine from mice to monitor gonadal function. I. Pregnanediol-3 alpha-glucuronide as an index of progestogen output.

An attempt has been made to assess the output of progesterone in mice by measuring the concentration of pregnanediol-3 alpha-glucuronide (PdGl in serial samples of unextracted urine. Longitudinal studies with 95 animals have shown that sufficient urine (greater than 40 microliter) can be obtained from individual animals (80% success rate) without stress every day or at intervals of 2 h. The sc administration of 50 microgram progesterone in lauric acid ethyl ester resulted in a 9-fold increase in the concentration of urinary PdGl (within 4 h) and a significantly elevated output for the next 26 h. During the induction of superovulation with PMS and hCG, the values of PdGl increased significantly (P less than 0.0005; by Student's t test) from 2.08 +/- 0.97 to 3.99 +/- 2.55 ng/ml (mean +/- SD) at the time of corpus luteum formation. There was a good correlation (r = 0.84; n = 154) between the values expressed as nanograms per ml urine and nanograms per mg creatinine. The results demonstrate that the concentration of PdGl in serial samples of urine may be used as an index of gonadal function in female mice.

LH effect on the pattern of steroidogenesis in cultured Graafian follicles of the rat: dependence on macromolecular synthesis.

Graafian follicles explanted from proestrous rats before the preovulatory gonadotropin surge secreted predominantly 17beta-estradiol, and only small amounts of progestins and androgens, during 12 h of culture in hormone-free medium. Addition of ovine luteinizing hormone (NIH-LH-S18; 0.1-1.0 mug/ml) to the medium stimulated within 1-2 h the rate of accumulation of these steroids. However, accumulation of androstenedione and estradiol ceased after 4-6 h in the LH-treated cultures, whereas progesterone continued to accumulate and became the major secretory product at 6-12 h. Incubation of the follicles with LH for only 5 min resulted in significant stimulation of the accumulation of progesterone, androstenedione and estradiol during a subsequent 6-h culture period in hormone-free medium containing antibodies to LH; 30 min exposure to the hormone sufficed to elicit a maximal steroidogenic response and to induce ovum maturation in 95% of the follicles. Addition of actinomycin D (act D; 8 mug/ml) within the first hour after exposure of follicles to LH suppressed the LH-effect on progesterone but augmented the LH effect on estradiol accumulation; when addition of this inhibitor was delayed until 2 h, progesterone accumulation continued unabated for a further 10 h. By contrast, puromycin (80 mug/ml) inhibited progesterone accumulation when added to the medium at any time (1, 2 or 3 h) after the hormone. It is suggested that (i) a short-lived protein is essential for the stimulatory effect of LH on follicular steroidogenesis; (ii) the act D-sensitive product (mRNA?) required for the production of this protein is synthesized in adequate amount during the first 2 h of LH action, and is stable for at least 10 h; and (iii) LH may stimulate the production of an additional act D-sensitive regulatory protein that inhibits enzymes engaged in the cleavage of the 17-side-chain of progesterone, or cells equipped with these enzymes.

The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin.

The effect of hCG and pregnancy on the circulating levels of relaxin was investigated in 48 women undergoing in vitro fertilization and embryo transfer (ET) for the treatment of infertility. Subjects were allocated randomly to receive hCG (Profasi; 2000 IU, im) or placebo on the day of ET (day 0) and on day 3 after ET (day 3). Samples of peripheral blood were taken on days -4, 6, and 10. An additional sample was taken on day 22 from women who became pregnant. The subjects were allocated retrospectively to 1 of 4 groups: no pregnancy, no hCG (NP); pregnancy, no hCG (P); no pregnancy, hCG (NPH); and pregnancy, hCG (PH). Two patients with blighted ova and one with a tubal pregnancy were excluded from the analysis. The concentrations of relaxin were similar and rose significantly in all groups at each time point (P less than 0.05). On day 6 there was no significant difference in the increment between the groups, but by day 10, circulating levels in the P compared to the NP and those in the PH compared to the NPH group were significantly greater (P less than 0.05). By day 22 the difference between the PH and the P groups was significant (P less than 0.05). Relaxin levels correlated with progesterone levels on day 10 in the NP and P groups (r = 0.633; P less than 0.05 and r = 0.697; P less than 0.05, respectively) and with estradiol levels in the P group only on days 6 and 22 (r = 0.659; P less than 0.05 and r = 0.783; P less than 0.05, respectively). These data demonstrate that in women undergoing in vitro fertilization, relaxin levels increase during the luteal phase, and in those women who establish a pregnancy, the values are significantly greater by day 10. The administration of hCG in the early luteal phase, before implantation, to women who subsequently become pregnant significantly increased the level of circulating relaxin on day 22. The positive correlation between relaxin levels and ovarian steroid levels in the groups not receiving exogenous hCG suggests that a common factor may control the release of both.

Distribution of prostaglandins E2 and F2 alpha within the foetoplacental unit throughout human pregnancy.

The concentrations of prostaglandin E2 and F2 alpha have been measured by radioimmunoassay in portions of cord, placenta, amnion, chorion, decidua and myometrium. The samples were obtained at defined periods of pregnancy, and the results have been compared with those obtained from the analyses of endometrial and myometrial tissue removed from women during the secretory phase of a menstrual cycle. The results showed that during pregnancy the mean concentration of prostaglandin E2 was higher (27-518%) than the corresponding value for prostaglandin F2 alpha in all tissues. At term the concentration of prostaglandin E2 (ng/100 mg wet weight of tissue, mean +/- S.D.) was higher in the umbilical cord (5-54 +/- 0-88), decidua (4-02 +/- 1-78) and myometrium (4-19 +/- 1-06), than in the amnion (2-25 +/- 1-27), chorion (1-64 "/- 0-63) or placenta (1-04 +/- 0-25). During labour there was a significant rise (P less than 0.0005, Student's 't' test) in the concentration in decidua (10-76 +/- 4-45), and to a lesser extent (P less than 0-05) in the myometrium (5-84 +/- 2-65) and amnion (4-77 +/- 2-51). The overall concentration in decidua during the first trimester (3-09 +/- 1-02) was significantly lower (P less than 0-005) than in endometrial tissue(16-82 +/- 10-13). The concentration was lower in myometrial tissue from non-pregnant subjects (2-90 +/- 2-21), than in the corresponding tissue removed at term (4-19 +/- 1-06) or during labour 5-84 +/- 2-65). The results for prostaglandin F2 alpha showed a similar pattern, but the values were significantly lower in the umbilical cord, and the percentage changes in concentration in the decidua and myometrium were of a higher magnitude.

Potent inhibitory effects of steroids in an in vitro model of angiogenesis.

The regulation of angiogenesis in the ovarian follicle and corpus luteum is unclear. Steroids are produced at very high concentrations in these tissues and we therefore examined the effect of steroids on angiogenesis in vitro. Explants of rat aorta were embedded in collagen gel and cultured in serum-free medium. Capillary-like microvessels were produced from the explants and microvessel number and length were measured in the presence and absence of steroids. At a concentration of 10 micrograms/ml, cortisol, progesterone, 17 alpha-hydroxyprogesterone and medroxyprogesterone acetate produced degeneration of microvessels after 7 days of steroid treatment (P < 0.01). Androstenedione and tetrahydro-S-(11-deoxytetrahydrocortisol) (tetrahydro S) produced degeneration at a slower rate: androstenedione inhibited microvessel growth after 11 days (P < 0.01) and tetrahydro S after 14 days (P < 0.05). Oestriol had no effect on microvessels; oestrone had a slow degenerative effect with significant inhibition seen after 14 days (P < 0.01). Oestradiol-17 beta at a concentration of 10 micrograms/ml completely inhibited microvessel growth from the explant cultures (P < 0.01) while at 1 microgram/ml it caused degenerative effects on growing microvessels. The effects of oestradiol and cortisol were reversible on removal of steroid-containing medium and replacement with 10% serum. We conclude that oestradiol may modulate angiogenesis in tissues in which the steroid concentration is high.

Pattern of excretion of urinary steroid metabolites during the ovarian cycle and pregnancy in the marmoset monkey.

Non-invasive methods for monitoring reproductive status based on the measurement of urinary steroid conjugates were examined. Levels of urinary oestrone-3-glucuronide, oestrone-3-sulphate, oestradiol glucuronide, oestradiol sulphate and pregnanediol-3 alpha-glucuronide were determined during the ovarian cycle and pregnancy. Sequential hydrolysis showed oestradiol conjugates to be more abundant than oestrone conjugates. The levels of sulphates and glucuronides were similar in the follicular phase whereas sulphates predominated during the luteal phase and pregnancy. Although levels of oestrone-3-sulphate were two- to fourfold lower than those of oestradiol sulphate, measured after hydrolysis, the profiles throughout the cycle and pregnancy were similar. Levels of oestrone-3-sulphate, measured by direct assay, were below 1 mumol/mmol creatinine during the follicular phase, rising 3-4 days after ovulation to reach maximum values (2-8 mumol/mmol creatinine) in the mid-luteal phase. There was no consistent increase before ovulation. Levels during pregnancy rose gradually until days 70-90, after which there was no further increase (gestation length = 144 days). The pattern of pregnanediol-3 alpha-glucuronide was similar to that of oestrone-3-sulphate during the ovarian cycle but levels did not increase during pregnancy. The patterns of excretion of oestrogen and progesterone metabolites were similar to the pattern of the circulating hormones during the ovarian cycle. Circulating and urinary hormone patterns were similar for oestrogens throughout pregnancy but pregnanediol-3 alpha-glucuronide did not reflect progesterone secretion beyond day 70 of gestation.

Comparison of transvaginal color Doppler imaging and color Doppler energy for assessment of intraovarian blood flow.

OBJECTIVE: To investigate any systematic differences in the analysis of blood flow velocity waveforms derived by color Doppler imaging and color Doppler energy examination of corpora lutea and adnexal tumors, to test whether the accuracy for diagnosing ovarian malignancy differs between end points derived by color Doppler imaging and color Doppler energy, and to compare the reproducibility of flow velocity waveform analysis obtained by both methods. METHODS: Fifty-six asymptomatic women with presumed corpora lutea and 67 women with known adnexal masses were included in the study. They all were examined using transvaginal sonography with color Doppler imaging and color Doppler energy. Pulsed Doppler sonography was used to obtain flow velocity waveforms to determine the pulsatility index (PI), resistance index (RI), peak systolic velocity, and time-averaged maximum velocity. The tumors were classified retrospectively according to histologic criteria. RESULTS: There were 52 women with benign, three with borderline, and 12 with malignant ovarian tumors. Repeated-measures analysis of variance revealed no systematic differences in the values of all four measurements performed under color Doppler imaging and color Doppler energy for all cases of corpora lutea and adnexal tumors (PI: P=.153, RI: P=.197, peak systolic velocity: P=.355, time-averaged maximum velocity: P=.159). All cases of borderline and malignant tumors had detectable pulsatile blood flow with color Doppler imaging and color Doppler energy. Forty-two (80.8%) of the benign tumors had flow detectable with color Doppler imaging, compared with 40 (76.9%) with color Doppler energy (P=.480). Analysis of receiver operating characteristic curves showed a marginal but nonsignificant improvement in diagnostic performance with color Doppler energy compared with color Doppler imaging for all four measurements (PI: P=.182, RI: P=.178, peak systolic velocity: P=.254, time-averaged maximum velocity: P=.238). The intraclass correlation coefficients for all four measurements were superior with color Doppler imaging compared with color Doppler energy. CONCLUSION: Flow velocity waveform analysis and diagnostic accuracy for ovarian malignancy are not significantly different between color Doppler imaging and color Doppler energy. Examinations with color Doppler imaging appear to be more reproducible than those with color Doppler energy.

An estrogen test to determine the times of potential fertility in women.

Defined changes in the concentration of estrone glucuronide in daily samples of early morning urine have been used to locate the limits of the fertile period and the time of maximum conception probability during 118 cycles (106 menstrual, 12 conceptional) in 73 women. The peak day of urinary luteinizing hormone was used as an index of ovulation. Follicular growth was monitored daily by ultrasonography throughout 38 cycles, and the time of maximum follicular diameter was used as an alternative reference point to define the times of potential fertility according to the life spans of the gametes. With optimized algorithms and the best index of ovulation, the estrogen test delineated the limits of the fertile period in 89% of the tests (mean length, 10.8 days; range, 5 to 17 days) and the time of maximum conception probability in 82% of the cycles, with a mean time to the maximum follicular diameter of 0.42 days (range, -4 to +4 days).

Prediction of oocyte recovery rate by transvaginal ultrasonography and color Doppler imaging before human chorionic gonadotropin administration in in vitro fertilization cycles.

OBJECTIVE: To detect and quantify follicular vascularity before hCG administration in women undergoing IVF-ET. To correlate follicular vascularity with the oocyte recovery rate after direct follicle aspiration. DESIGN: A prospective, longitudinal study of consecutive women undergoing IVF-ET at the assisted conception unit of King's College Hospital, London and having at least 20 follicles between the two ovaries on the day of hCG administration. INTERVENTIONS: An Acuson 128XP1O computed sonography system (Acuson Ltd., Uxbridge, United Kingdom) was used to measure follicular diameters, indices of blood flow impedance (pulsatility index), peak systolic velocities (Vmax), and the proportion of follicles demonstrating pulsatile vascularity, i.e., follicular vascularity index. For the purpose of analysis, each woman was classified into one of four groups (I to IV) based on their oocyte recovery rate. RESULTS: The mean age, duration of infertility, Dmax, pulsatility index, and Vmax were similar in the four groups, but the follicular vascularity index was higher in the groups with the highest oocyte recovery rates. Furthermore, there was a positive correlation between the follicular vascularity index and the oocyte recovery rate. CONCLUSION: The follicular vascularity index correlates positively with oocyte recovery rates. Detection and quantification of follicular vascularity with color Doppler imaging can therefore be used to predict oocyte recovery rate and hence may be useful in determining the most appropriate time to administer hCG to optimize oocyte recovery rates.

Intrafollicular hemodynamics before the administration of human chorionic gonadotropin in women at risk of the ovarian hyperstimulation syndrome.

OBJECTIVE: To test the hypothesis that alteration of intrafollicular hemodynamics precedes the ovarian hyperstimulation syndrome (OHSS). DESIGN: A prospective study. SETTING: The IVF unit and the Doppler imaging laboratory of King's College Hospital, London. PATIENTS: Twenty-four women undergoing IVF and considered to have an exaggerated response to ovarian stimulation and hence at risk of OHSS. INTERVENTIONS: Transvaginal Doppler imaging of the intrafollicular blood flow was performed before hCG administration to determine the indexes of intrafollicular hemodynamics. MAIN OUTCOME MEASURES: Moderate or severe OHSS. RESULTS: There was no statistically significant difference in mean age (32.63 +/- 1.77 versus 31.48 +/- 3.87), duration of infertility (6.00 +/- 2.19 versus 5.29 +/- 2.73), maximum peak systolic velocity (0.25 +/- 0.16 versus 0.26 +/- 0.21 m/s), mean of six maximal peak systolic velocity (0.15 +/- 0.04 versus 0.21 +/- 0.10), minimum pulsatility index (0.76 +/- 0.26 versus 0.59 +/- 0.23), mean of six minimal pulsatility indexes (0.89 +/- 0.30 versus 0.79 +/- 0.14), minimum resistance index (0.47 +/- 0.06 versus 0.41 +/- 0.10), and mean of six minimal resistance indexes (0.56 +/- 0.05 versus 0.53 +/- 0.06) of intrafollicular blood flow between the women who developed moderate or severe OHSS and matched controls. CONCLUSION: Measurement of intrafollicular hemodynamics before hCG administration does not predict the development of the OHSS.

The temporal effect of progestogen on uterine artery pulsatility index in postmenopausal women receiving sequential hormone replacement therapy.

OBJECTIVE: To determine the time relationship between the ingestion of progestogen during sequential hormone replacement therapy (HRT) and impedance to blood flow in the uterine arteries. DESIGN: Nine postmenopausal women who had already received HRT for at least 6 months were treated with either transdermal 17 beta-E2, 0.1 mg/d, or conjugated equine estrogens (Es), 1.25 mg/d, to which norethindrone, 0.7 mg/d, was added for 12 days in a single 28-day cycle of therapy. Transvaginal ultrasonography with color flow imaging was used to measure the pulsatility index (PI) in the uterine arteries every 3 to 5 days over one 28-day treatment cycle. RESULTS: The ingestion of norethindrone increased the mean uterine artery PI by 30% (SE 16.4%). The PI fell significantly within 4 days of ceasing norethindrone. CONCLUSION: Progestogen addition in sequential HRT causes changes in the uterine arterial tone, but the effect subsides within 4 days of progestogen withdrawal.

Hormone excretion during early pregnancy following spontaneous and clomiphene citrate-induced ovulation.

Endocrine changes during early pregnancy have been studied in 12 patients between days 35 and 91 from the last menstrual period. Ovulation had occurred spontaneously in five patients and was induced with clomiphene citrate (CC) in the remaining seven women. All the patients collected daily samples of early morning urine throughout the period of study; on each sample, human chorionic gonadotropin (hCG), pregnanediol-3-alpha-glucuronide (PGDG) and estrone-3-glucuronide (E1G) were measured by chemiluminescence immunoassay. No significant difference was observed between the two groups of patients with respect to the concentrations of hCG and PGDG. The excretion of E1G, however, was significantly higher in patients treated with CC. These data suggest that the induction of ovulation with CC may affect estrogen production in early pregnancy.

Transvaginal color Doppler study of blood flow in ectopic pregnancies.

OBJECTIVE: To compare Doppler indices of blood flow in the uterine and spiral arteries and the corpus luteum (CL), in ectopic and intrauterine pregnancies (IUPs). DESIGN: A prospective study of women with an ectopic or singleton IUP at the corresponding stage of gestation. SETTING: The Gynaecological Ultrasound Clinic, King's College Hospital. PATIENTS: Fifty-two women, 19 with an ectopic pregnancy (EP) and 33 with an IUP. INTERVENTIONS: All women were examined by transvaginal ultrasonography with color Doppler immediately before surgery. MAIN OUTCOME MEASURES: The resistance index from the left and right uterine arteries, the spiral arteries, and the CL. The peak blood velocity (cm/sec) from the uterine arteries. The length of gestation. RESULTS: Fetal heart activity was observed in all cases of IUP at 5 weeks' gestation. Three women had an EP with a live embryo, 5 had an embryo with no heart activity, 5 contained only a yolk sac, and 2 had an empty sac. A hematocele was seen in 3 women, and 1 had tubal thickening. The mean uterine and spiral arterial resistance index decreased with the gestational age of IUPs but remained constant during EPs. Peak blood velocity in the uterine arteries increased with the gestational age of IUPs, and the values were significantly higher than in EPs. A CL was seen in 88% of women with an IUP and in 100% of women with an EP. The resistance index was similar in CL associated with both types of pregnancy, and the values did not change with gestational age. CONCLUSION: These data show that: (1) blood flow impedance in the uterine and spiral arteries, and CL, is similar in IUPs and EPs and (2) peak flow velocity in the uterine arteries reflects a decreased blood supply to EPs.

Transvaginal color blood flow imaging of the periovulatory follicle.

OBJECTIVE: To assess intrafollicular blood flow in relation to ovarian morphology and function during the periovulatory period. DESIGN: A prospective, longitudinal study of random, natural ovarian cycles. SETTING: The Ovarian Screening Clinic and Endocrine Laboratory of the Department of Obstetrics and Gynaecology, King's College Hospital, London, United Kingdom. PATIENTS: Women with apparently normal ovarian function awaiting treatment for infertility by IVF-ET during subsequent natural cycles. INTERVENTIONS: All women were examined by transvaginal ultrasonography with color flow imaging and had a sample of peripheral venous blood taken at each scan for hormone analysis. MAIN OUTCOME MEASURES: The minimum pulsatility index (PI) and maximum peak systolic velocity from vessels within the dominant follicle; the maximum follicular diameters (and hence volume); serum FSH, E2, LH, and P. RESULTS: The dominant follicle ruptured in 10 of 11 women. The median interval between the two scans that delineated the time of follicular rupture was 9.5 hours (range, 0.0 to 24.5 hours). These cycles appeared to be morphologically and endocrinologically normal. There was an apparent increase in intrafollicular blood flow over the periovulatory period with an insignificant trend toward lower values for the mean PI and a significant increase in the peak systolic velocity. These changes appeared to follow the rise in circulating LH. CONCLUSION: Indexes of blood flow at a given site within the leading follicle can be monitored by transvaginal ultrasonography with color Doppler imaging over the periovulatory period. The increase in the peak systolic velocity and the relatively constant PI suggest a marked increase in blood flow at this time during the ovarian cycle.

The use of transvaginal color flow imaging after in vitro fertilization to identify optimum uterine conditions before embryo transfer.

OBJECTIVE: To assess whether a measure of uterine blood flow impedance (the pulsatility index, PI) as determined by transvaginal ultrasonography with color blood flow imaging, may be used to assess endometrial receptivity immediately before the time of embryo transfer (ET) after assisted conception. DESIGN: A prospective study of infertile women who had undergone treatment to induce multiple follicular development followed by ultrasound-guided oocyte retrieval. The oocytes were fertilized in vitro. SETTING: The Hallam Medical Centre. PATIENTS: Eight-two women (22 to 44 years of age) who all had three or four good quality embryos available for transfer to the uterus. INTERVENTIONS: All women were examined by transvaginal ultrasonography, with color flow imaging and blood flow analysis, immediately before ET. MAIN OUTCOME MEASURES: The mean PI of the left and right uterine arteries, the pregnancy rate (PR) (%), the embryo implantation rate (%), and the multiple PR (%). RESULTS: The patients were grouped according to whether the PI was low (1.00 to 1.99), medium (2.00 to 2.99), or high (3+). There were 27 women in the low PI group, 36 in the medium, and 19 in the high. The PR (%), embryo implantation rate (%), and multiple PR (%) were 41%, 15.3%, and 27.3% for the low PI group and 47%, 22.2%, and 47.1% for the medium PI group. There were no pregnancies in the high PI group. Thus 35% (19/54) of women who failed to become pregnant had a PI value greater than 3.0. CONCLUSIONS: These data suggest that the PI value on the day of ET could be used to: (1) increase the implantation rate by showing which embryos should be cryopreserved until the uterus is more receptive and (2) reduce the multiple PR by indicating that the number of embryos transferred should be limited when the uterus is most receptive.

Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women.

OBJECTIVE: To investigate the relationship between estradiol (E2), progestogen, and impedance to blood flow in the uterine artery. SUBJECTS: Twelve postmenopausal women treated for two cycles with transdermal E2, 0.05 mg/d, with either norethindrone acetate, 0.7 mg, or medroxyprogesterone acetate, 10 mg added sequentially. MEASUREMENTS: Transvaginal ultrasonography and color flow imaging were used to measure the pulsatility index in the uterine arteries before and during the E2-only and combined E2/progestogen phases. RESULTS: The mean pulsatility index fell to 53% of its pretreatment value within 12 days E2 administration (P < or = 0.0001) and was 66% of its pretreatment value in the combined phase (P < 0.005). Similar changes were seen in cycle 2. Time since menopause was correlated with the pretreatment pulsatility index (r = 0.674, P < 0.05) and change in pulsatility index on treatment (r = 0.856, P < 0.001). CONCLUSION: Gonadal hormones have a profound effect on arterial tone in postmenopausal women; this action may help explain some of the beneficial effects of estrogen on arterial disease risk.

Preovulatory changes of blood flow in different regions of the human follicle.

OBJECTIVE: To assess regional changes in ultrasound-derived indices of blood flow in the dominant human follicle after the plasma LH surge. DESIGN: A cross-sectional, prospective study. SETTING: Reproductive medicine unit at a university. PATIENT(S): Women attending an assisted conception clinic to determine the appropriate time to transfer previously frozen embryos during a natural cycle. INTERVENTION(S): Transvaginal ultrasonography with color Doppler imaging and pulsed Doppler spectral analysis was used to obtain indices of blood flow and velocity from vessels in the base, lateral part, and apex of the dominant follicle on days 10-12 (from day 1 of menses) and after the LH surge, but before rupture. Immunoassays were used to measure the blood concentrations of LH twice daily (at 8-10 A.M. and 4-6 P.M.) from cycle day 10. MAIN OUTCOME MEASURE(S): The pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), and time-averaged maximum velocity (TAMXV) in the uterine arteries and three regions of the dominant follicle (apical, lateral, and basal parts); follicular volume; the day and time of the onset of the LH surge (defined as first concentration of LH > 22 U/L) and the times of each scan. RESULT(S): Twenty-two women (aged 28-39 years) were studied and seven were scanned on days 10-12. A retrospective examination of the data from the remainder showed that eight were scanned < 20 hours after onset of the LH surge and seven were scanned > 20 hours after the onset of the LH surge. There was a significant increase in follicular volume after the LH surge. The PI was similar in vessels from the base (0.86 +/- 0.11; mean +/- SEM), lateral part (0.72 +/- 0.51) and apex (0.67 +/- 0.09) at cycle days 10-12 and then gradually decreased in the apex. There were similar changes in the RI. The PSV (mean +/- SEM; cm/s) was similar in vessels from the base (10.1 +/- 1.64), lateral side (8.2 +/- 1.43), and apex (9.2 +/- 1.91) in follicles of days 10-12. Within 20 hours of the onset of the LH surge, the PSV had increased in basal vessels (23.4 +/- 4.10), remained similar in lateral vessels (11.64 +/- 3.18), and was undetectable in apex vessels from six of eight follicles. Twenty hours after the LH surge, there was no pulsatile blood flow observed in the apical part of the follicle, but there was a sustained high PSV in the base (15.73 +/- 3.42) and lateral side (9.02 +/- 1.5). There were corresponding changes in the TAMXV. CONCLUSION(S): During the ovulatory process there are prominent changes in the regional blood flow of the follicle with a marked increase of the flow to the base of the follicle and a concomitant decrease of blood flow to the apex. These changes may be essential for the release of a mature oocyte.

Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women.

OBJECTIVE: To assess the effect of indomethacin (taken at defined times) on follicular rupture, indexes of intrafollicular blood flow, and steroidogenesis. PARTICIPANTS: Six healthy volunteers awaiting treatment for infertility by IVF-ET during subsequent natural cycles. INTERVENTIONS: All women were examined (at least every 8 hours) by transvaginal ultrasonography with color Doppler imaging and had samples of blood taken for hormone analysis. A self-test for urinary LH was performed before each scan. Indomethacin was first taken (50 mg three times per day) according to the maximum follicular diameter (first four women) or when the LH dipstick gave a positive result; the drug was taken for > or = 3 days. RESULTS: Follicular rupture was delayed in five of six cases (by 2 to 12 days). There was a reduction in intrafollicular peak systolic velocity before and after the positive urinary LH test compared with historical controls. Three follicles (50% of women) with the highest peak systolic velocity had an hemorrhagic appearance and persisted longer. There was no significant effect on menstrual cycle length or the levels of circulating FSH, E2, LH, or P. CONCLUSION: Indomethacin administered at the time of a positive self-test for urinary LH can delay follicular rupture with an associated reduction in intrafollicular blood flow but with no apparent effects on hormonal or menstrual status.

Ultrasound studies of vascular and morphological changes in the human corpus luteum during the menstrual cycle.

OBJECTIVE: To determine changes in corpus luteum (CL) volume, echogenicity, vascularity, and P production relative to a positive test result for urinary LH and day 1 of next menses. SUBJECTS: Thirteen healthy volunteers (age 23 to 32 years). INTERVENTIONS: All women underwent transvaginal ultrasonography on cycle day 11 and a urinary LH self-test was used daily. The plan was to rescan all women immediately after a positive test result and then at least every 48 hours (until day 6 of the next cycle); samples of peripheral blood were taken for analysis. MAIN OUTCOME MEASURES: The times of follicular rupture, a positive urinary LH test, and the start of menses; CL volume and echogenicity, maximum peak systolic velocity and minimum impedance, the circulating levels of serum P, E2, LH, and FSH. RESULTS: Nine women fulfilled criteria for an ovulatory cycle. There was a good correlation between peak systolic velocity, CL volume, and the concentration of serum P from day 4 to 10 after a positive LH test. Peak systolic velocity reached a maximum value between days 7 and 9 relative to a positive urinary LH test and started to decline from day 1 of menses minus 3, 4 days. CONCLUSION: Changes in peak systolic velocity from the time of a positive urinary LH self-test might be a useful adjunct for monitoring CL function.