Gonadal protection and fecundity rates in cyclophosphamide-treated rats.

Premature ovarian failure and reduced fecundity are well-documented consequences of cytotoxic chemotherapy used to treat patients with malignant diseases. To investigate the ability of different hormonal agents to block the effects of cyclophosphamide (CTX) on reproductive function, sexually mature female Long-Evans rats were studied. Model development demonstrated that CTX, 6 mg/kg/day, 5 days/week for 3 weeks, was successful at inducing acyclicity and significantly reducing fertility and fecundity, with acceptable mortality, when compared to higher/lower dosages. Utilizing this model, animals were treated with CTX in combination with an inert vehicle, Lupron, 80 micrograms/kg every 24 h, Lupron, 40 micrograms/kg every 12 h, or s.c. progesterone capsules obtaining serum progesterone levels of 20-30 ng/ml. We concluded that progesterone was able to protect the gonad from the negative effects of CTX, maintaining fertility and fecundity rates not significantly different from those of untreated control animals. Lupron given every 12 h had a similar effect on fertility, but failed to protect fecundity (P less than 0.001).

In vivo effects of delta 1-testololactone on peripheral aromatization.

To evaluate the in vivo effect of delta 1-testololactone on peripheral aromatization, studies were performed on seven postmenopausal women with metastatic breast cancer. Analysis of variance indicated that there were significant increases of circulating androstenedione (p less than 0.05) and estradiol (p less than 0.001) during administration of different doses of testololactone. Androstenedione levels were increased with all doses of testololactone tested (50, 100, 250, and 500 mg every 6 hr for 14 days each), while estradiol rose with only the 250- and 500-mg dosages. With administration, there was a significant decrease of estrone (p less than 0.001) with the mean level falling from 26 +/- 3 (S.E.) to 11 +/- 2 pg/ml. The addition of adrenal suppression (dexamethasone, 1 mg nightly at 11 p.m.) significantly lowered androstenedione (p less than 0.05) but had no effect on estrone or estradiol levels. Long-term therapy (up to 6 months) with the 250-mg dosage showed continual suppression of estrone with no escape being observed. Studies to determine the reason for the increase of estradiol with testololactone suggested cross-reactivity of the antibody with in vivo metabolites of the drug. However, these possible metabolites did not bind to uterine cytosol estrogen receptors. The decrease in estrone with testololactone administration presumably explains its antitumor properties.

The effect of membrane permeability and binding by human serum proteins on sex steroid influx into the uterus.

To determine the effect of such factors as capillary membrane permeability, plasma protein binding, and capillary transit time on the availability of sex steroids to the uterus, the unidirectional influxes of 3H-labeled steroids from the circulation into the uterus were measured in vivo in anesthetized rats using a tissue-sampling, single injection technique. When dihydrotestosterone (DHT), estradiol (E2), and progesterone (P) were injected with Ringer's solution, the tissue extraction was in excess of 80%; hence, membrane permeability did not play a limiting role. With the more polar steroids, corticosterone and cortisol, uterine extraction was less than 40%. Significant inhibition of tissue extraction of DHT and E2, but not P, occurred with the addition of 4% albumin to the injection solution. Human sera containing increasing concentrations of sex hormone-binding globulin demonstrated inhibition of extraction of DHT and E2. Human sera also inhibited P extraction, presumably secondary to the presence of cortisol-binding globulin and orosomucoid. Large concentrations of unlabeled DHT, E2, and P in the injection solutions did not result in competitive inhibition of labeled steroid extraction. Thus, there is no evidence for a carrier mechanism mediating steroid transport into the uterus. When tissue extraction of E2 from Ringer's solution was compared in liver, brain, and uterus, no difference of tissue permeability could be found. Liver consistently had higher tissue E2 extraction than brain or uterus in the presence of human sera. The results are compatible with the influx of albumin-bound E2 into all three tissues and the influx of sex hormone-binding globulin-bound E2 into the liver.

Free estradiol in postmenopausal women with and without endometrial cancer.

To assess the role of biologically active estradiol in the development of endometrial cancer, 25 patients with endometrial tumors and a similar number of control subjects matched for age and body size were studied. No differences between the 2 groups were found for levels of total estradiol, sex hormone-binding globulin (SHBG), non-SHBG-bound estradiol, and absolute free estradiol. Body size correlated positively with levels of total, non-SHBG-bound, and absolute estradiol and negatively with SHBG levels. The obese postmenopausal women had higher total circulating levels and proportionally greater concentrations of free estradiol than nonobese subjects, suggesting a dual risk for the cellular action of circulating estradiol. These factors could contribute to the association of obesity and the occurrence of this tumor in susceptible women.

Demographic and historic variables in women with idiopathic chronic pelvic pain.

A comprehensive historic, demographic, and medical questionnaire was administered to 106 women referred to a multidisciplinary clinic for evaluation of idiopathic chronic pelvic pain and to 92 age-matched, pain-free control patients presenting for routine annual examination. Although racial distribution, mean gravidity and parity, and rates of elective abortion were similar in both groups of respondents, spontaneous abortion was reported significantly more frequently among women with pelvic pain. Patients in the study group were also more likely to be on active military duty, to have undergone previous nongynecologic surgery, and to have sought treatment for unrelated somatic complaints. Finally, although the mean ages at first intercourse were similar, women with idiopathic pelvic pain reported a higher total number of sexual partners and were significantly more likely to have experienced previous significant psychosexual trauma. These findings confirm that predisposing psychosocial variables are important in the pathogenesis of idiopathic pelvic pain and emphasize the significance of multidisciplinary evaluation and management.

Appropriateness of hysterectomies performed for multiple preoperative indications.

OBJECTIVE: To correlate the listing of multiple preoperative indications for hysterectomy with the risk of non-confirmation of the preoperative diagnosis. METHODS: Records of 171 women undergoing consecutive hysterectomies for all indications at a large teaching hospital were reviewed for preoperative indication(s), compliance with published preoperative validation criteria for cases in which tissue pathology was not expected, and histologic verification of the preoperative diagnosis for cases in which tissue pathology was expected. Rates of confirmation (histologic verification plus successful compliance with validation criteria) of the preoperative diagnosis were compared between subgroups of cases in which single indications were listed (N = 124) or multiple indications were listed (N = 47) preoperatively. RESULTS: The rate of confirmation of single indications (115 of 124 cases, 93%) was significantly higher than the rate of confirmation of even one indication in cases in which multiple indications were listed (28 of 47 cases, 60%, P < .0001; relative risk for non-confirmation of multiple indications = 1.55). Multiple indications were more likely to be listed when tissue pathology was not expected, representing 49% of validatable indications as compared with only 18% of histologically verifiable indications (P < .0001). Overall, the rate of compliance with validation criteria (70%) was significantly lower than the rate of histologic verification (90%) (P < .01). CONCLUSION: These data suggest that listing of multiple preoperative indications for hysterectomy is associated with both decreased appropriateness, as reflected in decreased compliance with generally accepted preoperative validation criteria, and decreased diagnostic accuracy, as reflected in lower rates of histologic verification.

Consumer advocacy, elective surgery, and the "golden era of medicine".

The process of medical quality assurance evolved logically from the consumer advocacy movement of the past decades. This process has fundamentally altered the personal and legal relationship between patients and physicians. The need for development and adoption of a medically, ethically, and fiscally sound standard of elective surgical practice is clear and immediate. A system that may be used to evaluate the appropriateness of elective surgical procedures is proposed.

Quality assurance indicators and short-term outcome of hysterectomy.

Fifteen gynecologic quality assurance indicators recently published by The American College of Obstetricians and Gynecologists were applied to a previously reported hysterectomy data base. Chart reviews were performed for the most recent 257 cases in the data base, representing an 18-month interval. The indicators were divided into two groups: those intended to identify morbidity and mortality and those intended to screen for appropriateness of care. Rates of actual morbidity and cases that failed to meet published criteria sets for hysterectomy were determined by chart review regardless of the presence of a quality assurance indicator. A total of 135 indicators were identified in 114 (44%) of the 257 cases, including 64 patients (25%) with morbidity indicators and 50 (19%) with appropriateness indicators. Actual morbidity was correctly identified in all 64 cases in which morbidity indicators were present. Three cases with significant morbidity were identified by chart review but not identified by the indicators, yielding positive and negative predictive values of 100 and 98%, respectively, and an overall accuracy of 99% for morbidity indicators. By contrast, 14 of the 50 cases in which appropriateness indicators were present actually failed to meet published criteria sets. An additional seven cases failing to meet criteria sets were identified by chart review and not identified by the indicators, yielding a positive predictive value of 28%, a negative predictive value of 97%, and an overall accuracy of 83% for appropriateness indicators.

Routine hysterectomy for large asymptomatic uterine leiomyomata: a reappraisal.

As part of an ongoing quality improvement process, the records of 104 consecutive patients undergoing hysterectomy for uterine leiomyomata were reviewed. The diagnosis was confirmed histologically in 93 cases (89%) and in eight of the remaining 11, other disease such as adenomyosis or an ovarian neoplasm was discovered. The 93 consecutive patients with a confirmed diagnosis of uterine leiomyomata were then stratified according to preoperative estimate of uterine size and actual uterine weight. The physician's clinical estimate of uterine size correlated well with specimen weight (r = 0.65, P less than .001). Intraoperative estimated blood loss correlated less well with actual change in hematocrit (r = 0.31, P = .03). Women with a uterine size estimate larger than 12 weeks' gestation were no more likely to suffer perioperative complications than were those with smaller uteri. Furthermore, there was no significant increase in mean estimated blood loss or blood transfusion in women with larger uteri compared with those with smaller uteri. We conclude that there is no increase in adverse short-term outcomes associated with hysterectomy for leiomyomata in women with uteri greater than 12 weeks' size. Therefore, hysterectomy need not be routinely recommended to asymptomatic women with larger uteri as prophylaxis against increased operative morbidity associated with future growth.

Effect of epidural analgesia for labor on the cesarean delivery rate.

OBJECTIVE: To use meta-analysis to evaluate the effect of epidural analgesia on the cesarean delivery rate. DATA SOURCES: The MEDLINE data base was searched for articles published in English between January 1981 and April 1992. We also interviewed experts and conducted a bibliographic follow-up and manual review of recent journals published from April to July 1992. METHODS OF STUDY SELECTION: We excluded articles with irrelevant titles, and those case studies, book chapters, or articles that did not provide primary and relevant data. Two hundred thirty articles were read, including articles that reported on women of standard obstetric risk and on cesarean delivery rates for an epidural group and for a concurrent no-epidural group. These criteria yielded six studies for a primary analysis and two others for a secondary analysis. DATA EXTRACTION AND SYNTHESIS: The sample size of the epidural and no-epidural groups and the number of cesareans within each group were extracted. Tests of homogeneity were conducted. The pooled cesarean delivery risk difference as a result of epidural analgesia was estimated. The cesarean rate for women undergoing epidural analgesia was ten percentage points greater than for no-epidural women (P < .05). More than a nine percentage point increase was shown for cesarean deliveries for dystocia (P < .05), when pooling either all studies or only randomized studies. CONCLUSIONS: The results of this meta-analysis strongly support an increase in cesarean delivery associated with epidural analgesia. Further research should evaluate the balance between analgesia associated with the use of epidurals, and postpartum morbidity and costs associated with cesarean deliveries.

Validation of hysterectomy indications and the quality assurance process.

Hysterectomy is one of the most commonly performed major operations in the United States. Despite efforts to explain its high incidence, the perception remains that a significant number of hysterectomies are unjustified. More indications are listed for hysterectomy than for any other major operation. A quality assurance process is presented that requires the surgeon to select preoperatively one designated indication for each hysterectomy performed. The pathology report is expected to verify the surgical indication in 66% of the cases. The other 34% of hysterectomy specimens are not expected to show tissue pathology based on the listed indication. For these cases, predetermined validation criteria must be satisfied in the surgeon's preoperative note. Applying the process in this series of 584 consecutive hysterectomies, 93% (N = 396) of the "pathology expected" indications were verified by the pathology report and 98% (N = 188) of the "no pathology expected" indications were validated by the surgeon's preoperative note. The process of using a single designated indication and reviewing only two documents (the pathology report and the surgeon's preoperative note) has greatly simplified the quality assurance process. This system enables a quality assurance committee to monitor easily the appropriateness of hysterectomy indications for their institution. Information obtained from this process can influence changes regarding the acceptability of certain indications. As a result of this study, adenomyosis, because of its low (38%) verification rate, is no longer considered a reliable preoperative indication for hysterectomy at San Diego Naval Hospital.

Rate-based calculation of failure to progress: a proposed quality improvement method.

The rate of "failure to progress" as the indication for primary cesarean delivery used by the Joint Commission on Accreditation of Health Care Organizations is based upon the total number of cesareans performed for this indication divided by the total number of primary cesareans. This denominator includes a large number of patients who are not at risk for the diagnosis of failure to progress, including cases of malpresentation or multiple gestation in which cesarean is performed without trial of labor. Each of these variables may vary dramatically between individual physicians and institutions. Inclusion of patients not at risk for failure to progress results in a misclassification bias, which renders this rate less meaningful for purposes of comparison and trend assessment. We describe a simple method that bases the rate of failure to progress upon the population at risk for this diagnosis; that is, the total number of vaginal deliveries plus primary cesareans for failure to progress minus vaginal births after cesarean. Such a method controls for multiple differences in local practice standards and allows more meaningful assessment of trends and intra-institutional and inter-regional comparisons.

Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age.

OBJECTIVES: To determine pregnancy and livebirth rates for women age 40 and older undergoing ovulation induction and to assess the impact of basal follicle-stimulating hormone (FSH) on outcome in these patients. DESIGN: Prospective, observational. SETTING: Fertility service of university medical center. PATIENTS: Infertile couples in whom the female partner was age 40 or older referred for ovulation induction therapy. INTERVENTION: Assessment of basal hormonal status; ovulation induction. MAIN OUTCOME MEASURES: Clinical pregnancy rate (PR), livebirth rate. RESULTS: Analysis of 402 cycles in 85 women age 40 and older demonstrated a clinical PR of 3.5% per cycle (95% confidence interval [CI] 1.7% to 5.3%). The livebirth rate was 1.2% per cycle (95% CI 0.1% to 2.3%). Women with a basal FSH < 25 IU/L and age < 44 years had a clinical PR of 5.2% per cycle (95% CI 2.5% to 7.9%) compared with 0.0% per cycle (95% CI 0.0% to 2.1%) in cases in which either basal FSH was > or = 25 IU/L or age was > or = 44 (P < 0.005). The prognostic importance of basal FSH and chronological age was confirmed by multivariate logistic regression analysis. The predictive value of the resulting regression equation was high (R2 = 0.94; P < 0.01). CONCLUSIONS: Pregnancy and livebirth rates are generally low during ovulation induction in women age 40 and older. In combination, basal FSH and chronological age are accurate predictors of PR, in these couples and can define a subset of patients with a more favorable prognosis. The spontaneous abortion rate in women who do conceive is high, substantially lowering the livebirth rate.

The effects of combining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis.

Treatment of endometriosis with gonadotropin-releasing hormone agonists (GnRH-a) is associated with side effects secondary to the induced hypoestrogenic state. In an effort to ameliorate these symptoms, 10 patients with symptomatic endometriosis self-administered the GnRH-a [D-His6(Imbzl)-Pro9-NET]-GnRH in combination with norethindrone daily for 24 weeks. Painful symptoms were significantly suppressed after therapy (P less than 0.005). Objective review of photographs taken at laparoscopy before and after therapy demonstrated significant reduction of visible implants (P less than 0.005). Vasomotor symptoms were minimized when compared with a group of 16 patients previously treated with GnRH-a alone. Bone mineral density of the distal radius assessed by single photon absorptiometry was not reduced during therapy, although lumbar spine bone density assessed by quantitative computerized tomography was minimally but reversibly reduced. No metabolic derangements were detected. The combination of norethindrone with GnRH-a is a well tolerated and effective means of treating symptomatic endometriosis.

Long-term effects of transdermal estradiol with and without medroxyprogesterone acetate.

OBJECTIVE: To study the long-term biological and metabolical effects of estradiol (E2) administered by transdermal therapeutic systems with and without the addition of medroxyprogesterone acetate (MPA). DESIGN: Open, randomized, comparative trial. SETTING: The reproductive endocrine unit of a tertiary care university-affiliated hospital. PATIENTS: Fifty-seven postmenopausal women were given E2 transdermally, whereas 28 were randomized to take MPA by mouth. Fifteen premenopausal women were studied for comparison. INTERVENTIONS: Estradiol, 0.1 mg, was administered by a transdermal therapeutic system for 24.5 of 28 days and was cycled for 96 weeks. Medroxyprogesterone acetate, 10 mg, was given for days 13 to 25 of each 28-day cycle (E+P group), whereas the remainder received E2 only. MAIN OUTCOME MEASURES: Serum E2, estrone (E1), luteinizing hormone, follicle-stimulating hormone, low-density, high-density, very low-density, and total cholesterol, triglycerides, blood pressure, renin substrate, plasma renin activity, and serum aldosterone levels were measured in all subjects at baseline and in the postmenopausal women every 24 weeks until the end of study. RESULTS: Mean +/- SE levels of E2 rose significantly from baseline at 24 weeks to 426 and 355 pmol/L for the E only and E+P groups, respectively. Smaller increases of estrone (E1) were observed to 263 and 244 pmol/L for the same respective groups. As expected, baseline levels of both gonadotropins were elevated, fell significantly with E2 administration, but remained increased in comparison with values observed in younger women. Decreases of total and low-density lipoprotein (LDL) cholesterol were observed in both groups that reached statistical significance at 48 weeks or later with the exception of LDL cholesterol in the E only group. No significant change of high-density lipoprotein or very low-density lipoprotein cholesterol or triglycerides was observed. There were reductions of mean systolic and diastolic blood pressures in both groups that reached significance at 72 weeks. Mean baseline plasma renin substrate, plasma renin activity, and serum aldosterone levels were within the ranges observed in younger, healthy women and did not change significantly with E2 administration in either group. CONCLUSION: These data support the long-term efficacy and safety of this form of replacement therapy, particularly in combination with MPA, in women with a uterus.

Inhibition by indomethacin of increased estradiol extraction by the IUD-containing rat uterine horn.

The role of prostaglandins on the extraction of estradiol (E2) by the rat uterine horn in the presence of the intrauterine device (IUD) was evaluated. Increased extraction of E2 by the IUD horn compared to the contralateral control horn was consistently observed irrespective of the estrogen status of the animals. This increased extraction was abolished by indomethacin, an inhibitor of prostaglandin synthesis, suggesting a role of prostaglandin in this process.

Nongynecologic somatic pathology in women with chronic pelvic pain and negative laparoscopy.

One hundred eighty-three women with chronic pelvic pain were referred to a multidisciplinary chronic pelvic pain clinic after negative laparoscopy. One hundred twenty-two of them completed a thorough medical and psychologic evaluation and were followed for a minimum of six months after completion of therapy. Occult somatic pathology was diagnosed in 57 women (47%), including 19 in whom coexistent psychopathology was diagnosed. Myofascial pain was the most common somatic diagnosis, followed by atypical cyclic pain (dysmenorrhea or mittelschmerz); gastroenterologic, urologic and infectious diseases; and pelvic vascular congestion. No plausible somatic etiology was apparent in the remaining 65 (53%) of the 122 referrals. Nongynecologic somatic pathology accounted for 34 (29%) and gynecologic pathology for 23 (19%) of the referrals, only 6 (5%) of whom ultimately required hysterectomy. Women with a somatic diagnosis were found to be significantly older than the remainder of the referral population. Long-term symptomatic improvement or resolution of pain was obtained in 43 (75%) of the 57 patients with somatic diagnoses. Coexistent psychopathology was found to correlate with a poorer long-term prognosis. Our findings underscore the importance of a multidisciplinary approach to evaluating and treating chronic pelvic pain in women and confirm that hysterectomy is indicated in this setting only rarely.

Lifestyle and metabolic approaches to maximizing erectile and vascular health.

Oxidative stress and inflammation, which disrupt nitric oxide (NO) production directly or by causing resistance to insulin, are central determinants of vascular diseases including ED. Decreased vascular NO has been linked to abdominal obesity, smoking and high intakes of fat and sugar, which all cause oxidative stress. Men with ED have decreased vascular NO and circulating and cellular antioxidants. Oxidative stress and inflammatory markers are increased in men with ED, and all increase with age. Exercise increases vascular NO, and more frequent erections are correlated with decreased ED, both in part due to stimulation of endothelial NO production by shear stress. Exercise and weight loss increase insulin sensitivity and endothelial NO production. Potent antioxidants or high doses of weaker antioxidants increase vascular NO and improve vascular and erectile function. Antioxidants may be particularly important in men with ED who smoke, are obese or have diabetes. Omega-3 fatty acids reduce inflammatory markers, decrease cardiac death and increase endothelial NO production, and are therefore critical for men with ED who are under age 60 years, and/or have diabetes, hypertension or coronary artery disease, who are at increased risk of serious or even fatal cardiac events. Phosphodiesterase inhibitors have recently been shown to improve antioxidant status and NO production and allow more frequent and sustained penile exercise. Some angiotensin II receptor blockers decrease oxidative stress and improve vascular and erectile function and are therefore preferred choices for lowering blood pressure in men with ED. Lifestyle modifications, including physical and penile-specific exercise, weight loss, omega-3 and folic acid supplements, reduced intakes of fat and sugar, and improved antioxidant status through diet and/or supplements should be integrated into any comprehensive approach to maximizing erectile function, resulting in greater overall success and patient satisfaction, as well as improved vascular health and longevity.