Ronald L. Young

Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Recent advances in prevention and management.

Aim: To summarize the most common etiologic factors and describe the pathophysiology in the formation of peritoneal adhesions, to outline their clinical significance and consequences, and to evaluate the pharmacologic, mechanical, and surgical adjuvant strategies to minimize peritoneal adhesion formation. Methods: We performed an extensive MEDLINE search of the internationally published English literature of all medical and epidemiological journal articles, textbooks, scientific reports, and scientific journals from 1940 to 1997. We also reviewed reference lists in all the articles retrieved in the search as well as those of major texts regarding intraperitoneal postsurgical adhesion formation. All sources identified were reviewed with particular attention to risk factors, pathophysiology, clinical manifestations, various methods, and innovative techniques for effectively and safely reducing the formation of postsurgical adhesions. Results: The formation of postoperative peritoneal adhesions is an important complication following gynecological and general abdominal surgery, leading to clinical and significant economical consequences. Adhesion occur in more than 90% of the patients following major abdominal surgery and in 55–100% of the women undergoing pelvic surgery. Small-bowel obstruction, infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery are the most common consequences of peritoneal adhesions. Despite elaborate efforts to develop effective strategies to reduce or prevent adhesions, their formation remains a frequent occurrence after abdominal surgery. Conclusions: Until additional information and findings from future clinical investigations exist, only a meticulous surgical technique can be advocated in order to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery.

Clomiphene protects against osteoporosis in the mature ovariectomized rat

SummaryClomiphene citrate, a mixed estrogen agonist-antagonist, protects mature ovariectomized breeder rats from changes in total body calcium and from deterioration of femur structure. Over 6 months, mature ovariectomized rats took up calcium at the rate of 0.7 ± 0.5 mg/day, while normal controls gained 2.5±0.7 mg/day (mean±SE) as measured by whole body neutron activation analysis. Injections of clomiphene (20 mg/kg/week) kept ovariectomized rats in positive calcium balance at 2.0±0.5 mg/day. Reductions in total femur calcium content, cortical thickness, and visible trabeculae of femurs in ovariectomized animals were prevented by chronic clomiphene administration. These results in animals suggest a possible new line of investigation of the use of antiestrogenic drugs as therapeutic agents for hormone-dependent osteoporosis in animals and humans.

Hormonal status affects the reactivity of the cerebral vasculature

OBJECTIVE We compared the blood velocity and vascular resistance in the central retinal and ophthalmic arteries in healthy nonpregnant, pregnant, and postmenopausal women (before and after estrogen replacement therapy). STUDY DESIGN Color flow Doppler ultrasonography was used to determine systolic, diastolic, and mean velocity, as well as the resistance index in the central retinal and ophthalmic arteries in 10 nonpregnant women, 10 third-trimester pregnant women, and 10 hypoestrogenic postmenopausal women. The postmenopausal patients were again studied 2 months after starting daily oral therapy with 2 mg of micronized 17 beta-estradiol. RESULTS Pregnant women had a significantly (p < 0.05) higher diastolic blood velocity (4.2 +/- 0.8 cm/sec) and a lower resistance index (0.56 +/- 0.05) in the central retinal artery, when compared with nonpregnant women (diastolic velocity 2.8 +/- 0.8 cm/sec, resistance index 0.68 +/- 0.1), and hypoestrogenic postmenopausal women (diastolic velocity 2.6 +/- 0.9 cm/sec, resistance index 0.73 +/- 0.08). Significant differences were not seen in the ophthalmic artery. In the postmenopausal patients estradiol therapy was associated with an increase in diastolic velocity (2.6 +/- 0.9 cm/sec vs 4.1 +/- 1.6 cm/sec) and a decrease in the resistance index (0.73 +/- 0.08 vs 0.66 +/- 0.1) in the central retinal artery but not in the ophthalmic artery. CONCLUSIONS The blood velocity and vascular resistance in the cerebral microcirculation appear to change according to the phases of a womans reproductive life. This may be related, in part, to estrogen levels, because estradiol vasodilates small-diameter cerebral vessels in hypoestrogenic postmenopausal women.

Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial

BACKGROUND Isoflavones are naturally occurring plant estrogens that are abundant in soy. Although purported to protect against bone loss, the efficacy of soy isoflavone supplementation in the prevention of osteoporosis in postmenopausal women remains controversial. OBJECTIVE Our aim was to test the effect of soy isoflavone supplementation on bone health. DESIGN A multicenter, randomized, double-blind, placebo-controlled 24-mo trial was conducted to assess the effects of daily supplementation with 80 or 120 mg of soy hypocotyl aglycone isoflavones plus calcium and vitamin D on bone changes in 403 postmenopausal women. Study subjects were tested annually and changes in whole-body and regional bone mineral density (BMD), bone mineral content (BMC), and T scores were assessed. Changes in serum biochemical markers of bone metabolism were also assessed. RESULTS After study site, soy intake, and pretreatment values were controlled for, subjects receiving a daily supplement with 120 mg soy isoflavones had a statistically significant smaller reduction in whole-body BMD than did the placebo group both at 1 y (P < 0.03) and at 2 y (P < 0.05) of treatment. Smaller decreases in whole-body BMD T score were observed among this group of women at 1 y (P < 0.03) but not at 2 y of treatment. When compared with the placebo, soy isoflavone supplementation had no effect on changes in regional BMD, BMC, T scores, or biochemical markers of bone metabolism. CONCLUSION Daily supplementation with 120 mg soy hypocotyl isoflavones reduces whole-body bone loss but does not slow bone loss at common fracture sites in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00665860.

The use of an amniotic membrane graft to prevent postoperative adhesions.

Grafts of trypsin-treated, gamma-irradiated human amniotic membranes were used to cover injured uterine horns of nulliparous female rabbits to prevent adhesions. In this study, the gradual integration of the membranes into the serosal layer of the uterus, together with marked neovascularization, was observed. By the 30th postoperative day, the grafts had been completely integrated, with little evidence of rejection and no evidence of infection at the graft sites. Of 30 uterine horns treated with membrane grafts, only 4 (13.4%) showed any adhesion formation at or among the graft sites. All of the 24 untreated controls showed adhesion formation at the site of injury. Furthermore, whatever adhesions were found in membrane-treated horns could be graded as thin and filmy, accounting for less than 10% of the surface area of the graft, whereas the controls showed dense, thick adhesions covering 50% to 100% of the injured areas. We conclude that these specially prepared amniotic membranes are safe and effective in dramatically reducing postoperative adhesion formation in this animal model.

Various Doses of Soy Isoflavones Do Not Modify Mammographic Density in Postmenopausal Women

Soy isoflavones have functional similarity to human estrogens and may protect against breast cancer as a result of their antiestrogenic activity or increase risk as a result of their estrogen-like properties. We examined the relation between isoflavone supplementation and mammographic density, a strong marker for breast cancer risk, among postmenopausal women. The Osteoporosis Prevention Using Soy (OPUS) study, a multi-site, randomized, double-blinded, and placebo-controlled trial assigned 406 postmenopausal women to 80 or 120 mg/d of isoflavones each or a placebo for 2 y. Percent densities were assessed in digitized mammograms using a computer-assisted method. The mammogram reader did not know the treatment status and the time of mammograms. We applied mixed models to compare breast density by treatment while considering the repeated measures. The mammographic density analysis included 358 women, 88.2% of the OPUS participants; 303 had a complete set of 3 mammograms, 49 had 2, and 6 had only 1 mammogram. At baseline, the groups were similar in age, BMI, and percent density, but mean breast density differed by study site (P = 0.02). A model with all mammograms did not show a treatment effect on any mammographic measure, but the change over time was significant; breast density decreased by 1.6%/y across groups (P < 0.001). Stratification by age and BMI did not reveal any effects in subgroups. In this randomized 2-y trial, isoflavone supplements did not modify breast density in postmenopausal women. These findings offer reassurance that isoflavones do not act like hormone replacement medication on breast density.

Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women

BACKGROUND Soy isoflavones are naturally occurring phytochemicals with weak estrogenic cellular effects. Despite numerous clinical trials of short-term isoflavone supplementation, there is a paucity of data regarding longer-term outcomes and safety. OBJECTIVE Our aim was to evaluate the clinical outcomes of soy hypocotyl isoflavone supplementation in healthy menopausal women as a secondary outcome of a trial on bone health. DESIGN A multicenter, randomized, double-blind, placebo-controlled 24-mo trial was conducted to assess the effects of daily supplementation with 80 or 120 mg aglycone equivalent soy hypocotyl isoflavones plus calcium and vitamin D on the health of 403 postmenopausal women. At baseline and after 1 and 2 y, clinical blood chemistry values were measured and a well-woman examination was conducted, which included a mammogram and a Papanicolaou test. A cohort also underwent transvaginal ultrasound measurements to assess endometrial thickness and fibroids. RESULTS The baseline characteristics of the groups were similar. After 2 y of daily isoflavone exposure, all clinical chemistry values remained within the normal range. The only variable that changed significantly was blood urea nitrogen, which increased significantly after 2 y (P = 0.048) but not after 1 y (P = 0.343) in the supplementation groups. Isoflavone supplementation did not affect blood lymphocyte or serum free thyroxine concentrations. No significant differences in endometrial thickness or fibroids were observed between the groups. Two serious adverse events were detected (one case of breast cancer and one case of estrogen receptor-negative endometrial cancer), which was less than the expected population rate for these cancers. CONCLUSION Daily supplementation for 2 y with 80-120 mg soy hypocotyl isoflavones has minimal risk in healthy menopausal women. This trial was registered at clinicaltrials.gov as NCT00665860.

A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development

OBJECTIVE This investigation tests the hypothesis that triphasic oral contraceptives are associated with the development of large, persistent ovarian cysts. STUDY DESIGN Weekly vaginal ultrasonography was used in a randomized, double-blind, placebo-controlled, parallel-group, single-center study that compared the incidence, risk, size, and time to resolution of ovarian follicles in healthy women who took Estrostep or Loestrin oral contraceptives (manufactured by Parke-Davis) or a placebo during three consecutive menstrual cycles. RESULTS Sixty-three percent of placebo-treated subjects developed follicles greater than 18 mm, compared with 39% and 23% in the Estrostep and Loestrin groups. The risks for each group of developing a large follicle during a single cycle were not different. No dominant follicle persisted for greater than 2 weeks for any subject. CONCLUSION These results demonstrate that follicular development continues during treatment with oral contraceptives. In addition, the findings fail to support the hypothesis that triphasic oral contraceptives result in persistent ovarian cysts.

Management of menopause when estrogen cannot be used

SummaryEstrogen deficiency, whether surgically induced or as a consequence of natural ovarian failure, has destructive effects on many organ systems. With current levels of life expectancy, untreated women may expect to spend a third of their lifetime in this state. Appropriate estrogen replacement therapy (ERT) can avert (if started promptly) or ameliorate these devastating consequences, some of which (osteoporotic fractures, increased cardiovascular morbidity) can be lethal. Nevertheless, from 10 to 20% of postmenopausal women may have significant contraindications to ERT. Treatment of symptoms and improving the quality of life is imperative, yet many physicians abjure intervention, for reasons which are not entirely clear. Recent studies of conventional intervention with sedatives or tranquillisers show results equivalent to placebo therapy. On the other hand, specific agents with demonstrated effectiveness are available for management of the major estrogen-deficiency effects, although none of them are truly adequate replacement for the effect of estrogen itself.

The endocrine effects of spironolactone used as an antiandrogen

Eight castrate, estrogen-replaced women were given 200 mg spironolactone daily for 4 weeks. The response of plasma dehydroepiandrosterone sulfate (DHEAS), testosterone (T), and androstenedione (delta 4A), all indicators of adrenal C19-steroid production, varied greatly among individuals. Sixteen women with idiopathic hirsutism were given night-time dexamethasone (DEX) and then superimposed spironolactone for 4 weeks, followed by DEX without spironolactone for an additional 4 weeks. As expected, DHEAS, T, and delta 4A declined on DEX treatment. On addition of spironolactone, there was little further change in DHEAS, while plasma T declined in 7 of 16 women, including all those whose T level had remained elevated despite DEX treatment; most values rebounded when spironolactone was discontinued. The authors conclude from intact DEX-suppressed women that ovarian T, especially when increased, is frequently lowered by spironolactone. Thus, both adrenal and ovarian androgen production (as measured by prevailing plasma levels) may be diminished by this agent. These highly variable effects on androgen production are unlikely to account for the consistent antiandrogenic effects reported clinically.