Steven R. Lindheim

Behavioral stress responses in premenopausal and postmenopausal women and the effects of estrogen

OBJECTIVEnOur purpose was to determine the pattern of reactivity to stress in premenopausal and postmenopausal women and to assess the effects of estrogen.nnnSTUDY DESIGNnA behavioral stress test was given to premenopausal (n = 13) and postmenopausal women (n = 36). Biophysical and neuroendocrine responses were measured during and on completion of the stress test. The postmenopausal women were then randomized to placebo or transdermal estradiol treatment for 6 weeks, at which time another behavioral stress test was given.nnnRESULTSnStress reactivity to math and speech tasks elicited significantly greater systolic blood pressure responses in postmenopausal women compared with premenopausal women (p < 0.05). On retesting, significant biophysical responses that were present during the initial stress testing were still present (p < 0.05) in the placebo group but were blunted with estrogen treatment. Plasma corticotropin, cortisol, androstenedione, and norepinephrine increased during testing to a similar degree in premenopausal and postmenopausal women; this response was maintained after placebo treatment. Postmenopausal women treated with estrogen had blunted responses.nnnCONCLUSIONnSignificant differences in responses to psychologic stress exist in premenopausal and postmenopausal women. The lack of adaptation may account in part for the increased risk of cardiovascular disease in postmenopausal women. Estrogen appears to blunt the stress-induced response.

Mechanism for human papillomavirus transmission at birth

We attempted to investigate mechanisms, in addition to sexual contact, by which human papillomaviruses associated with anogenital tract lesions could be transmitted. Samples of exfoliated cervical cells were obtained from 45 pregnant women and were assayed by Southern blot hybridization analysis for the presence of human papillomavirus nucleic acids. Twenty-five of the 45 women had cells positive for human papillomavirus deoxyribonucleic acid. A neonatal nasopharyngeal aspirate was obtained at term and analyzed for the presence of human papillomavirus deoxyribonucleic acid. We documented the presence of human papillomavirus deoxyribonucleic acid in the oral pharyngeal cavity of the neonates in 15 of 45 nasopharyngeal samples analyzed. Amniotic fluid was obtained from 13 patients when their membranes were artificially ruptured. These samples were assayed for the presence of human papillomavirus deoxyribonucleic acid; two of the 13 amniotic fluid samples contained human papillomavirus deoxyribonucleic acid. The detection of human papillomavirus deoxyribonucleic acid in the oral cavity of neonates is indicative of a perinatal mechanism of viral transmission. The detection of human papillomavirus deoxyribonucleic acid in the amniotic fluid may suggest an in utero mechanism of transmission. However, problems encountered in collecting the amniotic fluid samples preclude us from definitive interpretation of these data.

Original ArticlesComparison of Estimates of Insulin Sensitivity in Pre- and Postmenopausal Women Using the Insulin Tolerance Test and the Frequently Sampled Intravenous Glucose Tolerance Test

OBJECTIVE: We assessed insulin sensitivity in women comparing the insulin tolerance test (ITT) with the intravenous glucose tolerance test with frequent sampling and computer modeling (FSIVGTT) and evaluated the effects ofhormonal therapy in postmenopausal women using both methods. METHODS: This prospective study tested 18 premenopausal women and ten postmenopausal women randomized to receive either estrogen alone or estrogen with a sequential progestin for 6 months at a menopause research clinic. All subjects received an ITT and an FSIVGTT within 48-72 hours of each other in random sequence. Postmenopausal women were then randomized to receive either 0.625 mg conjugated equine estrogen for 6 months or 0.625 mg conjugated equine estrogen with medroxyprogesterone acetate, 10 mg, for 10 days each month for 6 months. Both the ITT and the FSIVGTT were repeated following hormonal therapy at 2 and 6 months. Plasma insulin and glucose were measured; insulin sensitivity was calculated after the ITT (Kitt) and the FSIVGTT (Si) at each visit in each group. RESULTS: A close correlation was found between Kitt and Si values at initial testing in both pre- and postmenopausal women and following both types of hormonal therapy (r = 0.76 for all tests, P < .001). A reduction in insulin sensitivity was observed in postmenopausal compared to premenopausal women; this occurred in five of ten postmenopausal women using the Kitt mea surement and in four often women using Si. Estrogen replacement had a beneficial effect on insulin sensitivity. While Kitt increased by 24.2 ± 9.6% (P < .05), the increase in Si (6.7 ± 18%) was not significant because of the variability with this measurement. An attenuation in insulin sensi tivity was seen with added progestin. Kitt values decreased by 17.7 ± 7.7% and Si values by 31.9 ± 12%. Similar findings were noted at 2 and 6 months. CONCLUSIONS: The ITT and FSIVG TT provide quantitatively similar information regard ing insulin sensitivity in healthy women. A mild degree of insulin resistance appears to be present in some healthy postmenopausal women. Estrogen appears to improve insulin sensitivity, while added progestin may attenuate this beneficial effect. (J Soc Gynecol Invest 1994;1:150-4)

Non-surgical management of leiomyoma: impact on fertility

Purpose of review This review is designed to discuss the literature, published from December 2002 to January 2004, on the non-surgical treatment of fibroid. All established and new modalities are reviewed, and all new developments in the field are discussed. The resulting impact on the treatment of infertility will also be evaluated. Recent findings In the past year important advances occurred in the medical treatment of uterine fibroids. It was found, in a large randomized trial, that preoperative treatment with gonadotropin-releasing hormone analogue did not improve surgical results or decrease blood loss. However, important strides were made in understanding the molecular biology of the effect of the hormone analogue on fibroids. Other medical therapies investigated include danazol, raloxifene, mifepristone, aromatase inhibitors, and the levonorgestrel-containing intrauterine device. Most promising in terms of long-term usage for reduction of size and symptoms appears to be the combination of gonadotropin-releasing hormone analogue and raloxifene, although selective progesterone receptor modulators may also achieve this aim. However, none avoid producing an anovulatory state that inhibits fertility, and none have been shown to enhance fertility following discontinuation. Uterine artery embolization is another non-surgical technique under intense investigation. The years literature suggests that while results are comparable with hysterectomy in terms of complication rate and patient satisfaction, there may be important issues for women who wish to undergo the procedure and retain future fertility. Specifically, there is a significant rate of premature ovarian failure, as well as occasional damage to the endometrial vasculature with resulting atrophy and adhesion formation. Improvements in technique, in particular the use of larger and more spherical microspheres for embolization, may reduce these unwanted effects. However, few data exist regarding the course of pregnancy and outcome following embolization. Summary A number of non-surgical treatments exist for uterine fibroids, but none has been shown to be of value in the patient desiring future fertility. Myomectomy remains the standard of care for such women, and all other therapies should be designated experimental and limited to appropriate investigational studies.

Circulating leptin levels during ovulation induction : relation to adiposity and ovarian morphology

OBJECTIVEnTo assess serum leptin levels based on body habitus and ovarian morphology during controlled ovarian hyperstimulation.nnnDESIGNnProspective analysis.nnnSETTINGnUniversity IVF program.nnnPATIENT(S)nWomen undergoing IVF-ET were divided into two groups, obese ovulatory women (n = 6; mean (+/-SD) body mass index, 30.1 +/- 0.6 kg/m(2)) and lean ovulatory women (n = 20); mean (+/- SD) body mass index 22.0 +/- 0.2 kg/m(2)). Lean women were categorized further according to whether they had polycystic-appearing ovaries (n = 8) or normal-appearing ovaries (n = 12).nnnINTERVENTION(S)nControlled ovarian hyperstimulation and IVF.nnnMAIN OUTCOME MEASURE(S)nSerum estradiol, testosterone, and leptin.nnnRESULT(S)nMean (+/- SD) leptin levels were significantly higher before and after GnRH agonist down-regulation in obese women (41.7 +/- 5.2 pg/mL and 36.1 +/- 5.8 pg/mL, respectively) compared with lean women (8.4 +/- 1.0 pg/mL and 6.9 +/- 1.1 pg/mL, respectively). Mean (+/- SD) leptin levels increased significantly in both groups (54.5 +/- 5.1 pg/mL and 11.7 +/- 1.2 pg/mL, respectively), and the mean (+/-SD) percentage increase was similar (55% +/- 18% and 54.8% +/- 17%, respectively). Mean (+/-SD) leptin levels were similar in women with polycystic-appearing and normal-appearing ovaries before controlled ovarian hyperstimulation, but increased significantly in women with polycystic-appearing ovaries afterward (14.7 +/- 1.8 pg/mL and 9.3 +/- 1.0 pg/mL, respectively).nnnCONCLUSION(S)nSignificant increases in leptin levels occur during controlled ovarian hyperstimulation, suggesting that leptin plays a role in follicular growth and maturation. The exaggerated response in women with polycystic-appearing ovaries reflects either a greater number of recruited follicles or a predisposition of adipocytes to leptin production.

Ultrasound guided embryo transfer significantly improves pregnancy rates in women undergoing oocyte donation.

Objectives: Recent reports suggest ultrasound (US) guided embryo transfer (ET) improves pregnancy rates. Using the ovum donation model to eliminate confounding variables, we assessed the impact of US guided ET on pregnancy rates, implantation rates, and multiple gestation rates. Methods: All women who underwent IVF‐ET cycles using donated oocytes from November 1997 to September 1998 (n=137) were evaluated retrospectively. ET from November 1997 to April 1998 were performed without US, while all ET from May 1998 to September 1998 were performed using transvaginal or transabdominal US. ET was further categorized as easy or difficult. Difficult ET was defined as requiring at least two attempts and/or the presence of blood on the catheter and/or >5 min. Results: Pregnant patients (n=73) were similar with respect to the number and morphology of the embryos transferred compared to non‐pregnant patients (n=65). US guidance significantly improved implantation and pregnancy rates in cycles with easy transfers [28.8 vs. 18.4% and 63.1 vs. 36.1%, respectively (P<0.05)] without impacting multiple pregnancy rates. Conclusion: US guided ET is simple and reassuring and appears to significantly improve pregnancy outcomes in ovum donation cycles by optimizing the placement of embryos.

Insulin sensitivity is decreased in normal women by doses of ethinyl estradiol used in oral contraceptives.

OBJECTIVEnWe determined the independent effects of various doses of ethinyl estradiol used in oral contraceptives or norethindrone acetate, as well as their combination, on insulin sensitivity in normal women.nnnSTUDY DESIGNnThirty-three normal ovulatory female volunteers were recruited for this study. Insulin tolerance tests were performed after carbohydrate loading to determine the kinetic disappearance of glucose and insulin. After initial testing the women were randomized into four groups: ethinyl estradiol 20 micrograms, 35 micrograms, and 50 micrograms and norethindrone 1 mg. Insulin tolerance tests were repeated after 1 month of treatment and again after a second month, when all ethinyl estradiol groups received the addition of norethindrone 1 mg to their doses of ethinyl estradiol. Plasma glucose and insulin were measured, and insulin sensitivity (K(itt) glucose) and the disappearance of insulin (K(itt) insulin) were calculated.nnnRESULTSnAll groups were comparable at baseline, and no significant changes in fasting glucose and insulin were evident with treatment. After ingestion of 50 micrograms ethinyl estradiol the K(itt) glucose value decreased significantly (p < 0.03) and ingestion of 20 micrograms and 35 micrograms showed individual changes, but as groups the changes were not statistically significant. All ethinyl estradiol groups combined had a significant decrease in K(itt) glucose (p < 0.01). Norethindrone 1 mg alone did not change K(itt) glucose values, and after the addition of norethindrone to ethinyl estradiol, K(itt) glucose values normalized. K(itt) insulin values were also lower with treatment but were lower with ethinyl estradiol plus norethindrone compared with ethinyl estradiol alone (p < 0.04), suggesting an attenuation of insulin clearance with the progestin.nnnCONCLUSIONnEthinyl estradiol alone decreases insulin sensitivity, and this may occur at lower doses, but norethindrone 1 mg does not appear to do so. However, progestins may alter insulin clearance.

The Effect of Progestins on Behavioral Stress Responses in Postmenopausal Women

OBJECTIVE: We assessed the effects of progestin when added to estrogen on the adaptive patterns to provoked stress in postmenopausal women. METHODS: Fourteen postmenopausal women were randomized to receive either a transdermal estrogen patch (TE2) (n = 7) for 6 weeks or TE2 with added medroxyprogesterone acetate (10 mg) (TE2/MPA) (n = 7) for the last 10 days of the 6-week regimen. Behavioral stress tests were administered to each group, with measurements of biophysical and neuroendocrine responses. In a crossover fashion, after each group received the first treatment and testing, treatment was continued for another 6 weeks with the alternate regimen, at which time another stress test was administered. Responses to stress in the two treatment groups were compared to each other and to established placebo responses. RESULTS: Biophysical responses in the TE2 group were significantly blunted compared to both TE2/MPA and placebo responses (P < .05). Without MPA treatment, there were significantly blunted speech (P < .05) and cold pressor (P < .01) blood pressure responses. With added progestin, there was a greater systolic blood pressure response (P < .01) compared with estrogen alone. Both groups (TE2 and TE 2/MPA) had blunted and nonsignificant responses of ACTH and cortisol upon testing, whereas the placebo group showed a significant response (P < .01). Plasma norepinephrine responses, however, were significantly blunted after TE2, compared with the increased responses observed with both TE2/MPA and placebo (P < .01). CONCLUSION: Although estrogen significantly reduces behaviorally induced stress reactivity in postmenopausal women, certain doses of progestin administration may blunt this effect. (J Soc Gynecol Invest 1994;1:79-83)

Sonohysterography: a valuable tool in evaluating the female pelvis.

A number of medical conditions, including abnormal uterine bleeding, endometrial cancer, monitoring tamoxifen therapy, infertility, and recurrent abortion, warrant investigation of the female genital tract. Diagnostic studies including hysterosalpingogram, ultrasound, and sonohysterography have proved useful in the investigation of these gynecologic conditions. This article discusses each of these tests with particular emphasis on sonohysterography and their current and potential contributions in both diagnostic and therapeutic applications. The utility of each as well as their comparative value to each other and existing gold standards is reviewed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to outline the current screening methods for uterine cavity and pelvic abnormalities, to list the advantages of sonohysterography, and to describe the clinical situations where sonohysterography can be used.

Follicular and luteal phase endometrial thickness and echogenic pattern and pregnancy outcome in oocyte donation cycles.

PurposeTo study the effect of endometrial thickness (ET) and echogenic pattern (EP) in oocyte donation cycles upon pregnancy outcomes.MethodsSeventy-nine cycles resulting in blastocyst embryo transfer were evaluated. Donors underwent ovarian hyperstimulation using rFSH and GnRH-antagonist. Recipients were synchronized to donors using GnRH-agonist down-regulation followed by fixed dose of estrogen (E2) and progesterone (P4) following hCG. Transvaginal ultrasound (US) obtained ET and EP 10-11 days after initiation of E2 and on day of embryo transfer. Primary outcome was ET and EP in pregnant and non-pregnant cycles. Stimulation and embryology data was analyzed in donors to assess differences prior to transfer.ResultsFifty-nine cycles resulted in clinical pregnancy. No differences were observed in pregnant vs. non-pregnant cycles in proliferative or secretory ET and EP. Similar baseline and stimulation characteristics were found in pregnant and non-pregnant cycles. Regression analysis showed end thickness were not predictive of pregnancy outcomes.ConclusionsEndometrial characteristics in recipients prior to and following progesterone were not predictive of pregnancy outcomes.