Evaluation of decision rules for referring women for bone densitometry by  dual-energy x-ray absorptiometry

Abstract:
Context: Identification of women with low bone mineral density (BMD) is an important strategy in reducing the incidence of osteoporotic fractures. However, screening all women is not recommended.

Objectives: To assess the diagnostic properties of 4 decision rules--Simple Calculated Osteoporosis Risk Estimation (SCORE), Osteoporosis Risk Assessment Instrument (ORAI), Age, Body Size, No Estrogen (ABONE), and body weight less than 70 kg (weight criterion)--for selecting women for dual-energy x-ray absorptiometry (DXA) testing and to compare results with recommendations made in the National Osteoporosis Foundation (NOF) practice guidelines. DESIGN AND Setting: Analysis of data from the Canadian Multicentre Osteoporosis Study, a population-based community sample, collected from 9 study centers across Canada between February 1996 and September 1997.

Participants: Postmenopausal women aged 45 years or older (N = 2365) without bone disease who had DXA data for the femoral neck, data to apply selection criteria, and who were not currently taking estrogens or who had been taking hormone replacement therapy for 5 or more years.

Main Outcome Measures: Sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve of each of the 4 decision rules and the NOF guidelines for identifying women with a BMD T score of less than -1.0 SD, less than -2.0 SD, and no more than -2.5 SD at the femoral neck, and percentages of women recommended for testing, stratified by BMD level and age.

Results: The percent of women with a BMD T score less than -1, less than -2, and no more than -2.5 were 68.3%, 25.4%, and 10.0%, respectively. The AUROC curves were greatest using SCORE and ORAI. The sensitivity for identifying women with a BMD T score of less than -2.0 was 93.7% (95% confidence interval [CI], 91.8%-95.6%) using the NOF guidelines and was 97.5% (95% CI, 96.3%-98.8%), 94.2% (95% CI, 92.3%-96.1%), 79.1% (95% CI, 75.9%-82.3%), and 79.6% (95% CI, 76.4%-82.8%), respectively, using the SCORE, ORAI, ABONE, and weight criterion. However, the NOF guidelines also resulted in 74.4% (95% CI, 71.3%-77.6%) of women with a normal BMD (T score of -1.0 or higher) being tested compared with 69.2% (95% CI, 65.9%-72.5%), 56.3% (95% CI, 52.7%-59.8%), 35.8% (95% CI, 32.4%-39.2%), and 38.1% (95% CI, 34.6%-41.6%), respectively, using the 4 decision rules. Assessments suggest that ABONE and weight criterion are not useful case-finding approaches.

Conclusion: The SCORE and ORAI decision rules are better than the NOF guidelines at targeting BMD testing in high-risk patients. The acceptability of these rules in clinical practice merits further investigation given their potential effect on the use of densitometry services.


Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study

Abstract:
BACKGROUND: The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol.

METHOD: Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS).

RESULTS: At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients.

CONCLUSION: This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.


Influence of parity and lactation on hip fracture risk

Abstract: Several studies indicate that parity and lactation are associated with modest, short-term bone loss, but the long-term effect on osteoporotic fracture risk is uncertain. The authors therefore analyzed data from a population-based case-control study among Swedish postmenopausal women aged 50-81 years between October 1993 and February 1995. Mailed questionnaires and telephone interviews were used to collect data on 1,328 incident cases with hip fracture and 3,312 randomly selected controls. In age-adjusted analyses, the risk of hip fracture among all women was reduced by 10% per child (95% confidence interval (CI): 5, 14). After multivariate adjustment including body mass index as a covariate, the risk reduction was 5% per child (95% CI: 0, 10). Oral contraceptive use modified the association of parity with hip fracture risk. Among never users of oral contraceptives, the risk of hip fracture was reduced by 8% per child (95% CI: 2, 13), whereas among ever users of oral contraceptives, the risk was in the opposite direction, with an increase in risk by 19% per child (95% CI: 0, 41). After parity was considered, there was no association of duration of lactation period with fracture risk. The authors conclude that parity is modestly associated with a reduced hip fracture risk among women who had not used oral contraceptives previously.


A proposed role for hCG in clinical obstetrics

James Kurtzman

University of California, Irvine Medical Center

Abstract: The role of human chorionic gonadatropin (hCG) in the maintenance of early pregnancy is well known. Recent data suggests that hCG may play a role in the maintenance of the later stages of pregnancy as well, by directly and indirectly promoting uterine quiescence. If hCG acts as an endogenous tocolytic in normal pregnancy, then it may be an ideal candidate for therapy of preterm labor as well. We present compelling in vitro as well as in vivo data, which support the role of hCG in the maintenance of normal uterine quiescence. Additionally, we will present in vivo and in vitro data that confirms the ability of hCG to directly promote relaxation of uterine contractions. This review provides a basis for future study of the use of hCG in clinical obstetrics. Given the limited effectiveness of tocolytic therapies available at the time, hCG may provide a promising pharmacological approach to the pervasive problem of preterm labor in human pregnancy. While further work is needed, initial data strongly support this novel use of hCG in clinical obstetrics.


Pharmacokinetics of progesterone administered by the oral and parenteral routes

Abstract: Progestogens, which include the natural hormone, progesterone, and synthetic steroid derivatives, are used to treat a variety of reproductive disorders. Since synthetic progestogens are often associated with undesirable side effects, improved formulations and modes of administration of progesterone have been sought. In order to find an optimal therapeutic agent, different progesterone formulations and routes of administration have been studied. This paper explains several methods of measuring progesterone levels and summarizes clinical data on the pharmacokinetic profiles of natural progesterone administered by the oral, intramuscular, vaginal, intranasal, percutaneous, sublingual and rectal routes.


On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation

Abstract: Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.


Human chorionic gonadotropin: does it affect human endometrial morphology in vivo?

Dominique De Ziegler

Université de Versailles Saint-Quentin-en-Yvelines

Abstract: Human chorionic gonadotropin (hCG) is widely used as a surrogate to luteinizing hormone (LH) to trigger ovulation in controlled ovarian hyperstimulation (COH). Yet this molecule may exert direct effects on the endometrium. These effects, not mediated by ovarian hormones, are probably a consequence of stimulation of endometrial hCG/LH receptors. Because the half-life of hCG differs markedly from that of LH, possible pharmacological effects of hCG on the endometrium could alter endometrial receptivity in COH. Arguments supporting a clinical action of gonadotropins, and hCG in particular, on the endometrium abound. Notably, evidence has been reported of decidualization of stromal cells of the human endometrium in vitro as a result of exposure to gonadotropins, including hCG. The present article discusses, from a clinical standpoint, the main basis supporting the hypothesis that hCG administration as commonly used in infertility treatments may exert direct effects in vivo on endometrial histology and partake in endometrial transformations of the luteal phase. Preliminary results suggest that endometrial effects of hCG exist in vivo and should be taken into account when assessing the endometrial effects of hormones.


Use of progesterone in assisted reproduction

Abstract: Progesterone, supplied in a variety of formulations, is commonly used in assisted reproduction. However, even the commonly accepted uses of progesterone in fertility care are believed to be largely empirical, as are the current available treatment options. While a critical balance of estrogen and progesterone is necessary for successful embryo implantation, achieving that balance is subject to differences in prescribing practice. In evaluating recommendations for the use of progesterone, discussion of its role in assisted-reproduction procedures must distinguish between known therapeutic benefits and empirical benefits.


Indomethacin tocolysis and intraventricular hemorrhage

Abstract:
OBJECTIVE: To determine the association between indomethacin tocolysis and neonatal intraventricular hemorrhage.

METHODS: Fifty-six preterm neonates with intraventricular hemorrhage were matched by gestational age with neonates (n = 224) without this morbidity. Maternal and neonatal charts were reviewed to ascertain the type of tocolytic exposure experienced by the neonate. Other maternal and neonatal demographic and outcome data were also abstracted. Results were analyzed using the Student t test, chi(2) analysis, and multivariable logistic regression. The number of studied subjects provided 80% power to determine if antenatal exposure to indomethacin was twice as likely among infants with intraventricular hemorrhage.

RESULTS: Univariate analysis revealed that there were no significant differences between the study and control groups with respect to maternal age, parity, or betamethasone exposure. Infants with intraventricular hemorrhage were significantly more likely to be born at an earlier gestational age, a lower birth weight, after maternal chorioamnionitis, after vaginal delivery, and after exposure to either indomethacin alone or a combination of indomethacin and magnesium. Additionally, their neonatal course was significantly more likely to be complicated by sepsis and respiratory distress syndrome. In a multivariable logistic model, only gestational age, chorioamnionitis, vaginal delivery, and respiratory distress syndrome continued to be significantly associated with intraventricular hemorrhage. Indomethacin exposure, either as single-agent (adjusted odds ratio 1.3, 95% confidence interval 0.5, 3.3) or combination tocolytic therapy (adjusted odds ratio 2.0, 95% confidence interval 0.8, 4.8), was not significantly associated with intraventricular hemorrhage.

CONCLUSION: Indomethacin tocolysis is not associated with an increased risk of intraventricular hemorrhage.


Psychopathology, personality, and marital relationship in patients undergoing in vitro fertilization procedures

Abstract:
OBJECTIVE: To compare the psychopathology, personality features, and marital relationships of women undergoing in vitro fertilization (IVF) with those of control patients, and to compare IVF inductees with program veterans.

DESIGN: Cross-sectional clinical study.

SETTING: A university hospital.

PATIENT(S): One hundred and one women undergoing IVF treatment.

INTERVENTION(S): Psychometric tests were administered at first visit (baseline) of index treatment cycle.

MAIN OUTCOME MEASURE(S): Achievement of pregnancy.

RESULT(S): Women undergoing IVF show higher levels of anxiety and emotional tension than do controls. Although the infertile women showed no abnormal personality dimensions, the IVF group did have a particular psychological profile and a different marital relationship pattern when compared with the control participants. Between IVF veterans and inductees, there are significant differences with respect to psychopathology, psychological dimensions, and couple dynamics. The achievement of pregnancy is not associated with any special psychopathological, personality, or marital characteristics among the IVF women.

CONCLUSION(S): The most crucial period in IVF procedures may immediately follow the end of the first cycle because of the high risk of patients dropping out of the program. To determine the most effective supporting therapies for women undergoing fertilization procedures it could be useful to consider the psychological and relational differences between veterans and inductees.


Effects of vaginal progesterone administration on uterine contractility at the time of embryo transfer

Abstract:
OBJECTIVE: To investigate whether uterine contractility at the time of embryo transfer (ET) can be reduced by early onset of luteal support with progesterone administered vaginally.

DESIGN: Prospective analysis.

SETTING: Assisted reproduction unit.

PATIENT(S): Eighty-four women undergoing 84 GnRH-a and FSH/hCG cycles for IVF-ET were studied.

INTERVENTION(S): Vaginal progesterone was randomly started on the day of oocyte retrieval (group A, n = 43) or on the evening of ET (group B, n = 41). On the day of hCG administration and just before ET, 2-minute sagittal uterine scans were obtained by ultrasound and digitized with an image analysis system for assessing uterine contraction frequency.

MAIN OUTCOME MEASURE(S): Uterine contraction frequency.

RESULT(S): Whereas uterine contraction frequency was similar in both groups on the day of hCG (4.6 +/- 0.3 and 4.5 +/- 0.3 contractions per minute, respectively), only women in group A showed decreased uterine contraction frequency on the day of ET (2.8 +/- 0.2 vs. 4.2 +/- 0.3 contractions per minute).

CONCLUSION(S): Vaginal progesterone administration starting on the day of oocyte retrieval induced a decrease in uterine contraction frequency on the day of ET as compared with preovulatory values. Uterine relaxation before ET is likely to improve IVF-ET outcome by avoiding the displacement of embryos from the uterine cavity.


Nurse-midwives' knowledge and promotion of lactational amenorrhea and other natural family-planning methods for child spacing

Abstract: The purpose of this study was to describe and assess certified nurse-midwives' (CNMs) knowledge and promotion of two modalities for child spacing, natural family-planning (NFP) and the lactational amenorrhea method (LAM). One thousand two hundred CNMs were randomly selected from a national membership list and mailed a 24-item questionnaire on NFP and LAM. Of the 514 respondents (42.8% return rate), 450 (87.5%) were currently practicing as CNMs. Respondents had an average age of 46 years, with an average of 10 years of practice. CNMs ranked NFP as the ninth most used and the eighth most effective family-planning method in their practice, with an average perceived method-effectiveness of 88% and use-effectiveness of 70%. Although most respondents felt somewhat prepared during their education program to provide NFP, only 22% would offer NFP as a family-planning option for child spacing.


[Clinical discussion of the relationship between endometriosis and epithelial ovarian cancer]

Hefeng Huang

International Peace Maternity & Child Health Hospital

Abstract:
OBJECTIVE: To analyse the relationship between endometriosis and epithelial ovarian cancer.

METHODS: We analyzed retrospectively the 20 cases associated with endometriosis in 371 cases of epithelial ovarian cancer, and these 20 cases were also compared with the left 351 cases not associated with endometriosis(including endomtriod carcinoma 38 cases and clear cell carcinoma 39 cases).

RESULTS: Among 20 cases, endomtriod carcinoma and clear cell carcinoma were most frequently associated with endometriosis, with 11 cases and 7 cases respectively, there was also 1 case of gland carcinoma and 1 case of serous papillary carcinoma. Cases of carcinomas associated with endometriosis had higher pathological grade and 5-year survival probability (Kaplan-Meier method) than those cases not associated with endometriosis.

CONCLUSIONS: There is a close relationship between endometriosis and ovarian endomtriod carcinoma and clear cell carcinoma, the malignant transformation of endometriosis foci may be an important origin of them. Drug therapy is recommended for endomtriosis after the operation. In the treatment of endomtriod carcinoma and clear cell carcinoma, progestin can be used as an accessory method.


Risk for birth defects among premature infants: a population-based study

Sonja A Rasmussen

Center for Surveillance, Epidemiology, and Laboratory Services

C A Moore

National Center on Birth Defects and Developmental Disabilities

L J Paulozzi

Centers for Disease Control and Prevention

Abstract:
OBJECTIVE: To investigate the relationship between prematurity and birth defects.

STUDY DESIGN: In a population-based cohort study, infants with birth defects were ascertained through the Metropolitan Atlanta Congenital Defects Program, a surveillance system with active methods of ascertainment. Gestational age data were obtained from birth certificates of liveborn, singleton infants with and without birth defects born in the 5-county metropolitan Atlanta area.

RESULTS: Among 264,392 infants with known gestational ages born between 1989 and 1995, 7738 were identified as having birth defects (2.93%). Premature infants (<37 weeks' gestation) were more than two times as likely to have birth defects than term infants (37-41 weeks) (risk ratio = 2.43; 95% CI 2.30-2.56). This relationship was evident for several categories of birth defects. The rate of birth defects varied by gestational age categories, with the highest risk in the 29- to 32-week gestational age category (risk ratio = 3.37).

CONCLUSIONS: The risk for birth defects is increased in premature infants. Awareness of this relationship is important for clinicians caring for premature infants. The morbidity and mortality associated with a particular defect may be significantly altered by the presence of prematurity. Further study of this association may provide insight into the etiology of these relatively common problems.


Eating attitudes and habitual calcium intake in peripubertal girls are associated  with initial bone mineral content and its change over 2 years

Susan I Barr

Vancouver Hospital and Health Sciences Centre

Abstract: This 2-year prospective study examined associations among bone mineral acquisition and physical, maturational, and lifestyle variables during the pubertal transition in healthy girls. Forty-five girls, initially 10.5+/-0.6 years, participated. Body composition and bone mineral content (BMC) at the spine and total body (TB) were assessed at baseline and annually thereafter using dual-energy X-ray absorptiometry (DXA). Nutrient intakes were assessed using 3-day diet records and a calcium food frequency questionnaire (FFQ), physical activity by questionnaire, sexual maturation using Tanner's stages of breast and pubic hair maturation, growth by height and weight, and eating attitudes using the children's Eating Attitudes Test (Children's EAT). Mean children's EAT subscale scores (dieting, oral control [OC], and bulimia) were stable over time. Median split of OC subscale scores was used to form high and low OC groups. Groups had similar body composition, dietary intake, activity, and Tanner stage at baseline and 2 years. Using height, weight, and Tanner breast stage as covariates, girls with low OC scores had greater TB BMC at baseline (1452+/-221 g vs. 1387+/-197 g; p = 0.030) and 2 years (2003+/-323 g vs. 1909+/-299 g; p = 0.049) and greater lumbar spine (LS) BMC at 2 years (45.2+/-8.8 g vs. 41.2+/-9.6 g; p = 0.042). In multiple regression analysis, OC score predicted baseline, 2 years, and 2-year change in TB and spinal BMC, contributing 0.9-7.6% to explained variance. Calcium intake predicted baseline, 2 years, and 2-year change in TB BMC, explaining 1.6-5.3% of variance. We conclude that both OC and habitual calcium intake may influence bone mineral acquisition.

Journal of Bone and Mineral Research : the Official Journal of the American  Society for Bone and Mineral Research


A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction

Abstract:
OBJECTIVE: To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility.

DESIGN: Prospective randomized trial.

SETTING: Infertility clinic in a university teaching hospital.

PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction.

INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9.

MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities.

RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group.

CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.


Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

Patricia A Straneva

Department of Psychology, University of North Carolina at Chapel Hill, 27599-7175, USA. susan_girdler@med.unc.edu

Abstract:
BACKGROUND: This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels.

METHODS: Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed.

RESULTS: During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls.

CONCLUSIONS: These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.


One-year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit?

P.-M. Schumm-Draeger

Medical Clinic I, Endocrinology, Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.

Abstract: Studies in animal models of spontaneous Hashimoto's autoimmune thyroiditis (HT) show that prophylactic treatment with levothyroxine (LT4) can reduce incidence and degree of lymphocytic infiltration in HT. The aim of the present study was to clarify whether there is a benefit of prophylactic treatment with LT4 in patients with euthyroid HT with respect to the progression of the autoimmune process. Twenty-one patients with euthyroid HT were checked for thyroid function (thyrotropin [TSH], free triiodothyronine [FT3], free thyroxine [FT4]), thyroid volume, antibodies (thyroglobulin [Tg-Ab], thyroid peroxidase [TPO-Ab]), and lymphocyte subsets. Peripheral (PBL) and thyroid-derived lymphocytes (TL) were analyzed by triple color flow cytometry. One-half of the patients with euthyroid HT were treated with LT4 for 1 year (n = 10). The other half (n = 11) were never treated with LT4. TL were obtained by fine-needle aspiration biopsy (FNAB). Thirteen healthy subjects (C) without medical history of thyroid disease served as controls concerning PBL, and patients with non-toxic nodular goiter (NG; n = 10) served as controls concerning TL. Thyroid-derived T-helper cells were found more frequently in euthyroid patients with HT compared to patients with NG (p < 0.01). After 1 year of therapy with LT4, TPO-Abs and B lymphocytes decreased significantly only in the treated group of euthyroid patients with HT (p < 0.05). In contrast, TPO-Abs levels did not change or even increased in untreated euthyroid patients with HT. Thyroid volume did not differ before and after therapy. Prophylactic treatment of euthyroid patients with HT reduced both serological and cellular markers of autoimmune thyroiditis. Therefore, prophylactic LT4 treatment might be useful to stop the progression or even manifestation of the disease. However, the long-term clinical benefit of prophylactic LT4 therapy in euthyroid patients with HT is yet to be established.

Thyroid : Official Journal of the American Thyroid Association


Maternal serum tumor necrosis factor-alpha in patients with preterm labor

Abstract:
OBJECTIVE: To evaluate maternal serum tumor necrosis factor-alpha (TNF alpha) levels in patients with preterm labor without clinical signs of chorioamnionitis and to compare these with levels in nonlaboring controls.

STUDY DESIGN: The study group consisted of 44 patients with a singleton pregnancy admitted to our department with the diagnosis of preterm labor between 26 and 36 weeks' gestation. The control group consisted of 25 healthy consecutive patients with a singleton pregnancy without preterm contractions who were seen for routine antenatal visits. Maternal serum TNF alpha was measured using a solid-phase, two-site chemiluminescent enzyme immunometric assay method, and levels were compared in patients with preterm labor and nonlaboring controls.

RESULTS: The median maternal serum TNF alpha level for patients with preterm labor was 29.4 pg/mL (range, 12.3-173) as compared with 23 pg/mL (range, 11.9-62.7) in the control group (P = .031). Among 44 patients with preterm labor, 14 (32%) delivered within one week of admission. The median maternal serum TNF alpha level was significantly higher in patients who delivered within one week than in those who delivered after one week and controls (71.3 pg/mL [range, 28-173]) versus 22 pg/mL (range, 12.3-86) versus 23 pg/mL (range, 11.9-62.7) (P < .0001).

CONCLUSION: TNF alpha was elevated in patients with preterm labor, suggesting a role for maternal serum TNF alpha in its initiation.


Neuromodulation in polycystic ovary syndrome

B N Kalro

Departments of Obstetrics, Gynecology, and Reproductive Services, Magee-Womens Hospital, University of Pittsburgh School of Medicine, USA.

Abstract: Although central and peripheral factors have been implicated in the neuromodulation of GnRH in PCOS, there are no definitive or conclusive data to establish a primary causal role for any one factor. Because increased GnRH pulse frequency is at least a contributor to the secretion of excess LH and insufficient FSH that are the proximate cause of chronic anovulation in PCOS, strategies to slow the GnRH pulse generator are likely to promote ovulation in women with PCOS. Several pharmacologic agents, such as dopamine agonists and antagonists, have been tried, but the lack of consistent effects in women with PCOS limits their clinical utility. Current treatment strategies include the use of the combined oral contraceptive pills, antiandrogens or androgen receptor blockers, and insulin sensitizers. Oral contraceptive preparations are effective in suppressing ovarian hyperandrogenemia, regulating menstrual cycles, and reducing the risk of endometrial hyperplasia. Androgen blockade and antiandrogens provide symptomatic relief from androgen-induced acne and hirsutism and have been reported to restore ovulation in women with PCOS. Whether this effect is mediated peripherally or centrally remains to be clarified. The most recent class of pharmacologic agents to gain popularity are the "insulin modifiers." With increasing evidence that insulin resistance constitutes a key metabolic element, it seems logical that improving insulin sensitivity and glucose disposal might wholly, or partially, reverse certain features of PCOS, including anovulation. To date, insulin modifiers have proved most promising in improving the clinical features and promoting fertility, but whether this effect is centrally mediated is yet to be elucidated.

Obstetrics and Gynecology Clinics of North America


Serum human chorionic gonadotropin levels are correlated with body mass index rather than route of administration in women undergoing in vitro fertilization--embryo transfer using human menopausal gonadotropin and intracytoplasmic sperm injection

K E Elkind-Hirsch

Center for Reproduction at Gramercy, MacGregor Medical Association, Texas, Houston, USA. res-keh@womans.com

Abstract:
OBJECTIVE: To compare subcutaneous (SC) and intramuscular (IM) hCG administration and their association with body mass index (BMI) in women undergoing IVF-ET using hMG and ICSI.

DESIGN: Prospective, randomized controlled trial.

SETTING: Private infertility clinic.

PATIENT(S): Twenty-one ovulatory women, 29-39 years, were enrolled. Treatment of one patient who failed to respond to hMG was canceled.

INTERVENTION(S): A standard IVF-ET treatment plan using an initial dose of 300 U of hMG was followed. Patients were randomly assigned to receive 10,000 IU hCG, either IM in the gluteal region or SC in the lower abdomen. Exactly 12 hours later, serum for hCG determination was obtained. All oocytes were fertilized using ICSI technology.

MAIN OUTCOME MEASURE(S): Human chorionic gonadotropin levels 12 hours after injection, BMI, and oocyte maturity.

RESULT(S): No significant differences in hCG levels were found, with mean levels of 225 +/- 24 mIU/mL for SC injection versus 213 +/- 26 mIU/mL for IM injection. No differences were observed in the percentage of mature oocytes. A significant negative correlation was found between BMI and hCG levels in all patients, regardless of route of administration.

CONCLUSION(S): The highest levels of hCG were measured in women with the lowest BMI. Patients' body size, rather than route of hCG delivery, appears to determine circulating levels of hCG.


Acceptability of home monitoring as an aid to conception

LJ Severy

Department of Psychology, University of Florida, Gainesville, Florida, USA

Abstract: This paper considers the concept of consumer acceptance of medical products and its importance to successful healthcare provision. The critical dimensions ('domains') of acceptance for a product designed to assist family planning, and the importance of using high-quality psychometric scales to assess these domains, are discussed. Qualitative and quantitative data from acceptance studies with a personal contraceptive monitor, PERSONA, are presented. These data indicate that the monitor is user-friendly and acceptable to couples, and underline the importance of user acceptability for home monitors designed to assist family planning--including those used for conception purposes.

The Journal of International Medical Research


Neonatal outcome of spontaneous and assisted twin pregnancies

Abstract:
OBJECTIVES: Over the last 10 years, diffusion of assisted reproduction techniques (ovarian stimulation, IVF, GIFT) has led to an increased incidence of multiple pregnancies and consequently, of the related obstetric-neonatal problems. In this study, multiple births have been studied, with particular reference to the twin births occurring in the Gemelli hospital, Rome. The hospital is also a reference centre for obstetric pathologies and infertility treatment. In particular, attention has been focused on neonatal outcome, comparing twins born from spontaneous and assisted pregnancies.

STUDY DESIGN: 228 neonates from spontaneous twin pregnancies and 32 from assisted twin pregnancies were taken into consideration with regard to: premature birth, low birth-weight, intrauterine growth retardation, weight discordance, Apgar score, major neonatal diseases, and mortality.

RESULTS: Results showed a significant higher incidence of prematurity and low birth-weight, as well as a significant lower gestational age, occurring more frequently in twins resulting from assisted pregnancies than in twins from spontaneous pregnancies. Furthermore, the incidence of severe depression at birth and respiratory disease was significantly higher in twins from assisted pregnancies than in those from spontaneous pregnancies, despite similar gestational age and birth-weight.

European Journal of Obstetrics, Gynecology, and Reproductive Biology


Polycystic ovary syndrome: new perspective on an old problem

Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. New treatment approaches resulting from a refined understanding of the pathophysiology are evolving. The literature shows that PCOS is an endocrinopathy resulting from insulin resistance and the compensatory hyperinsulinemia. This results in adverse effects on multiple organ systems and may result in alteration in serum lipids, anovulation, abnormal uterine bleeding, and infertility. In addition, PCOS may place the patient at long-term risk for the development of type 2 diabetes, hypertension, endometrial cancer, and cardiovascular disease. Oral contraceptives, progestins, antiandrogens, and ovulation induction agents remain standard therapies. However, insulin-sensitizing agents are now being shown to be useful alone or combined with standard therapies. Early identification of patients at risk and prompt initiation of therapies, followed by long-term surveillance and management, may promote the patient's long-term health.


Physiologic effects of lowering caloric intake in nonhuman primates and nonobese humans

S B Roberts

Jean Mayer Human Nutrition Research Center on Aging

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Sue A. Shapses

Rutgers, The State University of New Jersey

Abstract: Caloric restriction (CR) reduces the rate of aging and increases life span in all small animal species studied to date, but the effects of CR in humans remain uncertain. This review summarizes current knowledge of the effects of CR in nonhuman primates and humans. The results suggest that CR has a range of beneficial effects in nonhuman primates studied under laboratory conditions, and short-term markers of CR seen in animal models appear to occur in humans subject to CR also. However, the overall benefit of CR in human populations remains to be established, and studies in human populations are needed.


Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review

Abstract:
OBJECTIVE: To examine the effectiveness of oral hormone replacement therapy (HRT) with regard to hot flushes and night sweats, which are vasomotor symptoms commonly experienced by menopausal women.

METHODS: Double-blind, randomized, placebo-controlled trials of oral HRT for at least 3 months' duration and reporting vasomotor outcomes were identified using a search strategy developed by the Menstrual Disorders Group and Subfertility Group of the Cochrane Collaboration. Twenty-one trials meeting the selection criteria were included in the review. Study participants totalled 2511. Trial duration ranged from 3 months to 3 years.

RESULTS: There was a significant reduction in the weekly hot flush frequency for HRT compared with placebo (weighted mean difference -17.46, 95% confidence interval (CI) -24.72 to -10.21). This was equivalent to a 77% reduction in frequency (95% CI 58.2-87.5) for HRT relative to placebo. Symptom severity was also significantly reduced compared with placebo (odds ratio (OR) 0.13, 95% CI 0.08-0.22). Withdrawal for lack of efficacy occurred significantly more often with placebo therapy (OR 17.25, 95% CI 8.23-36.15). Withdrawal for adverse events, commonly breast tenderness, edema, joint pain and psychological symptoms, was not significantly increased for HRT (OR 1.38, 95% CI 0.87-2.21). In women who were randomized to placebo treatment, a 50.8% (95% CI 41.7-58.5) reduction in hot flushes was observed between baseline and the end of the study.

CONCLUSIONS: Oral HRT is highly effective in alleviating hot flushes and night sweats. Owing to the marked effect seen with placebo treatment, it is important to compare therapies purported to alleviate vasomotor symptoms with a placebo or an established therapy.

Climacteric : the journal of the International Menopause Society


Prevalence of depressive symptoms in late pregnancy and postpartum

Abstract:
BACKGROUND: Postnatal depression refers to a non-psychotic depressive episode that begins in or extends into the postpartum period. The aims of this study were to examine the prevalence of depressive symptoms in a pregnant and later postnatal population, to determine the natural course of these symptoms and whether there is an association between antenatal and postnatal depressive symptomatology.

METHODS: A longitudinal study with a total population of 1,558 consecutively registered pregnant women in the southeast region of Sweden. Presence of depressive symptoms was measured with the Edinburgh Postnatal Depression Scale on four occasions namely in gestational week 35-36, in the maternity ward, 6-8 weeks and 6 months postpartum.

RESULTS: The prevalence of depressive symptoms during late pregnancy was 17%; in the maternity ward 18%; 6-8 weeks postnatally 13%; and 6 months postnatally, 13%. A correlation between antenatal and postnatal depressive symptoms was found (r=0.50, p<0.0001).

CONCLUSION: Detection of women at risk for developing postnatal depressive symptoms can be done during late pregnancy. Antenatal care clinics constitute a natural and useful environment for recognition of women with depressive symptoms.

Acta Obstetricia Et Gynecologica Scandinavica


Estimation of the prevalence of low bone density in Canadian women and men using  a population-specific DXA reference standard: the Canadian Multicentre  Osteoporosis Study (CaMos)

CaMos Research Group.Canadian Multicentre Osteoporosis Study

Abstract: The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will measure the incidence and prevalence of osteoporosis and fractures, and the effect of putative risk factors, in a random sample of 10,061 women and men aged > or = 25 years recruited in approximately equal numbers in nine centers across Canada. In this paper we report the results of studies to establish peak bone mass (PBM) which would be appropriate reference data for use in Canada. These reference data are used to estimate the prevalence of osteoporosis and osteopenia in Canadian women and men aged > or = 50 years. Participants were recruited via randomly selected household telephone listings. Bone mineral density (BMD) of the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry using Hologic QDR 1000 or 2000 or Lunar DPX densitometers. BMD results for lumbar spine and femoral neck were converted to a Hologic base. BMD of the lumbar spine in 578 women and 467 men was constant to age 39 years giving a PBM of 1.042 +/- 0.121 g/cm2 for women and 1.058 +/- 0.127 g/cm2 for men. BMD at the femoral neck declined from age 29 years. The mean femoral neck BMD between 25 and 29 years was taken as PBM and was found to be 0.857 +/- 0.125 g/cm2 for women and 0.910 +/- 0.125 g/cm2 for men. Prevalence of osteoporosis, as defined by WHO criteria, in Canadian women aged > or = 50 years was 12.1% at the lumbar spine and 7.9% at the femoral neck with a combined prevalence of 15.8%. In men it was 2.9% at the lumbar spine and 4.8% at the femoral neck with a combined prevalence of 6.6%.

Osteoporosis International : a Journal Established As Result of Cooperation  Between the European Foundation for Osteoporosis and the National Osteoporosis  Foundation of the USA


Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate

Mohamed F Mitwally

Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lununfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

Abstract:
OBJECTIVE: To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful.

DESIGN: Prospective trial in infertility patients treated with CC.

SETTING: Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto.

PATIENT(S): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of < or =0.5 cm).

INTERVENTION(S): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses.

MAIN OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and pregnancy rates.

RESULT(S): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of < or =0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%).

CONCLUSION(S): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.


Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone

S W Kauma

Virginia Commonwealth University Medical Center

D T Vandermolen

Department of Obstetrics and Gynecology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.

Abstract:
OBJECTIVE: To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone.

DESIGN: Randomized, double-blind, placebo-controlled trial.

SETTING: Multicenter environment.

PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC.

INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC.

MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates.

RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant.

CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.


Postlaparoscopic small bowel obstruction secondary to unrecognized nodular endometriosis of the terminal ileum

W P Dmowski

University of Arkansas for Medical Sciences

Abstract: Small bowel involvement by endometriosis occurs in about 0.5% of patients, but nodular endometriosis involving the entire wall of the terminal ileum is extremely rare. Endometriotic nodules protruding into the intestinal lumen may lead to chronic, partial, or acute complete small bowel obstruction and associated clinical changes. If obstruction is partial, preoperative diagnosis is difficult and seldom suspected, and no reliable diagnostic tests are available. At laparoscopic surgery, performed typically for associated pelvic endometriosis, bowel lesions may easily be overlooked, especially in women with abdominal adhesions from earlier surgery. Surgical injury, tension tears, or postoperative edema may contribute in such cases to the development of acute, complete small bowel obstruction, which may be difficult to differentiate from postoperative ileus. The patient may deteriorate rapidly and develop abdominal sepsis and multiple organ failure with high risk of mortality. Because of increased production of tumor necrosis factor-alpha by autologous monocytes, endometriosis may predispose to development of severe sepsis and septic shock. (J Am Assoc Gynecol Laparosc 8(1):161-166, 2001)

The Journal of the American Association of Gynecologic Laparoscopists


Multicenter study of the lactational amenorrhea method (LAM) III: effectiveness,  duration, and satisfaction with reduced client-provider contact

Abstract: The objective of this effort was to assess the use and efficacy of the Lactational Amenorrhea Method (LAM) with reduced numbers of client-provider contacts. A co-sponsored multicenter study of LAM was performed to test the efficacy and acceptability of the method under "post-marketing" conditions, with investigator-initiated contact occurring only twice: at the time of intake and then again at month 7 of postpartum. These data are assumed to provide an assessment of LAM's use, efficacy, and performance that more closely reflects the prevailing conditions of these populations during normal use. Three hundred and sixty-two subjects were recruited through centers that had participated in the previous, more contact-intensive studies. Using a cooperatively developed protocol, data were gathered prospectively on at least 10 and up to 50 LAM acceptors at nine sites, and entered and cleaned on site. Data were further cleaned and analyzed at the Georgetown University Institute for Reproductive Health (IRH) and the Department of Nutrition at the University of Connecticut. Using country-level and pooled data, descriptive statistics and life tables were produced. LAM efficacy in this sample is 100% because there were no pregnancies at any of the participating sites. Satisfaction with the method was high, and the rate of continuation on to another method after LAM was 66.7% at 7 months postpartum. Of the women who had never used family planning prior to LAM, 63.0% went on to use another method of family planning in a timely manner. LAM can be highly effective as an introductory postpartum family planning method when offered in a variety of cultures, health care settings, and industrial and developing country locales. Under conditions of limited client-provider contact, LAM remains effective and leads to acceptance of another method by about two-thirds of the acceptors. Women are able to use LAM effectively without extensive counseling or follow-up, with a high level of user satisfaction.


GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer

Abstract: It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer.


Current concepts in the polycystic ovary syndrome

Abstract: Over the past 20 years, it has been clearly documented that the polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and that insulin resistance plays an important role in the pathogenesis of the reproductive disturbances of the disorder. Family studies have indicated a genetic susceptibility to PCOS. Polycystic ovaries and hyperandrogenemia are present in approximately 50% of sisters of affected women. Increased androgen secretion and insulin resistance persist in cultured theca cells and skin fibroblasts, respectively, from women with PCOS; this finding suggests that these are intrinsic, presumably genetic, defects. Insulin resistance and elevated low-density lipoprotein (LDL) levels also cluster in the sisters of women with PCOS, consistent with genetic traits. Moreover, the brothers of women with PCOS have insulin resistance and elevated dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis for these findings. Family-based studies of linkage and association have implicated several genes in the pathogenesis of PCOS. The strongest evidence to date points to a gene in the region of the insulin receptor. Insulin-sensitizing therapy mitigates the reproductive disturbances of PCOS.


Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study

Abstract:
OBJECTIVES: To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome.

DESIGN: Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles.

SETTING: General medicine community clinics.

PARTICIPANTS: 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days.

INTERVENTIONS: Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles.

MAIN OUTCOME MEASURES: Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms).

RESULTS: Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment.

CONCLUSIONS: Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.


Assisted reproductive interventions and multiple birth

Abstract:
OBJECTIVE: To investigate the contributions of ovulation-inducing drugs and assisted reproductive technologies to multiple birth.

METHODS: This historic prospective study was conducted in a cohort of 13,151 women who delivered after 20 weeks' gestation between October 1996 and December 1999. The study setting was a Colorado health maintenance organization. Cases were women who were pregnant as a result of exposure to treatment with either assisted reproductive technologies or ovulation induction in the absence of assisted reproductive technologies. The main outcome measure was multiple birth.

RESULTS: There was a significant association between assisted conception and multiple birth. Compared with women with naturally conceived pregnancies, there was a 25-fold likelihood (95% confidence interval 18, 35, P <.001) of multiple birth among women exposed to any of those treatments. In the total cohort the proportion of multiple births attributable to those treatments was 33%. After adjusting for the use of assisted conception and other covariates, we found no association between advanced maternal age and multiple birth.

CONCLUSION: In this cohort, assisted reproductive interventions were strongly associated with multiple birth. Although a higher proportion of older women sought assisted reproductive technologies, we did not find an independent relationship between advanced maternal age and multiple birth. The increasing number of multiple births attributable to assisted conception raises public health concerns regarding multiple gestation-related maternal and infant morbidities.


Multiple pregnancies: a call for action

Multiple pregnancies: a call for action


Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study

Abstract:
OBJECTIVE: To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS).

DESIGN: Prospective pilot study.

SETTING: Outpatient.

PATIENT(S): Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin.

INTERVENTION(S): Metformin, 1.5-2.55 g/day, throughout pregnancy.

MAIN OUTCOME MEASURE(S): Rates of first-trimester spontaneous abortion and teratogenicity.

RESULT(S): Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04).

CONCLUSION(S): Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.


Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS

Abstract:
OBJECTIVE: To determine the rate of clinically evident polycystic ovary syndrome (PCOS) among first-degree female relatives within families with a proband affected by PCOS.

DESIGN: Clinical and biochemical evaluation of the mothers and sisters of 93 patients with PCOS. The diagnosis of PCOS was established by: [1] a history of oligomenorrhea, [2] clinical evidence (i.e., hirsutism) or biochemical evidence (i.e., elevated total or free T) of hyperandrogenism, and [3] the exclusion of related disorders.

SETTING: Tertiary care university.

PATIENT(S): Patients with PCOS and their mothers and sisters.

INTERVENTION(S): Interview, physical examination, and hormonal testing on blood samples were performed for all subjects.

MAIN OUTCOME MEASURE(S): The presence of hirsutism and hyperandrogenemia was determined in the mothers and sisters of the patients with PCOS.

RESULT(S): Of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) and 16 (32%) were affected with PCOS, respectively. A higher rate of PCOS was observed when only premenopausal women not taking hormones (i.e., untreated) were considered (i.e., 35% of mothers and 40% of sisters), consistent with amelioration of symptoms with hormonal therapy or aging. These rates of PCOS are significantly higher than that observed in our general population (approximately 4%) and suggest the involvement of a major genetic component in the disorder.

CONCLUSION(S): The rates of PCOS in mothers and sisters of patients with PCOS were 24% and 32%, respectively, although the risk was higher when considering untreated premenopausal women only.


Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study


Reliability of ovulation tests in infertile women

Abstract:
OBJECTIVE: To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation.

METHODS: We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard.

RESULTS: Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects.

CONCLUSION: Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.


Serum allopregnanolone in women with postpartum "blues"

Rossella E Nappi

Department of Obstetrics and Gynecology, Institute for Clinical and Scientific Research (IRCCS) S. Matteo, University of Pavia, Pavia, Italy. renappi@tin.it

Abstract:
OBJECTIVE: To relate serum allopregnanolone and progesterone levels postpartum to maternity "blues."

METHODS: Forty primiparous, healthy, married women (24-39 years of age; at least 13 years of education) who delivered healthy neonates in the Department of Obstetrics at the University of Pavia entered the present study. Blood samples were drawn at 8:30 AM on postpartum day 3 for measurements of serum allopregnanolone, progesterone, cortisol, prolactin, and estradiol. On the same day, every woman was interviewed using the Hamilton Rating Scale for Depression for psychometric testing and completed a self-administered version of the Stein Questionnaire for symptoms of the "blues."

RESULTS: Eighteen of 40 women (45%) experienced maternity "blues" (12 who delivered vaginally and six who delivered by cesarean). Serum allopregnanolone levels were significantly lower in those women experiencing postpartum "blues" with respect to euthymic women (1.1 +/- 0.4 versus 2.3 +/- 1.0 nmol/L; P <.001), whereas progesterone levels did not differ significantly (11.6 +/- 5.6 versus 19.1 +/- 15.6 nmol/L; P >.058). Allopregnanolone and progesterone levels correlated significantly in euthymic women (r =.648; P =.001) but not in those with postpartum "blues" (r =.317; P =.199). There was a significant negative correlation between the Hamilton score and levels of serum allopregnanolone (r = -.62; P =.001) and progesterone (r = -.36; P =.024).

CONCLUSION: Serum allopregnanolone levels were detectable postpartum and were significantly decreased in women with maternity "blues."


Polycystic ovary disease and the risk of pregnancy-induced hypertension

Abstract:
OBJECTIVE: To compare the incidence of pregnancy-induced hypertension in patients with and without polycystic ovary disease (PCOD).

STUDY DESIGN: We conducted a retrospective, case-control analysis of patients who achieved singleton pregnancies with human menopausal gonadotropin (hMG) therapy. Twenty-two PCOD patients were compared to 27 infertility patients without PCOD who were pregnant after hMG therapy. Non-PCOD patients received hMG for superovulation as part of superovulation/intrauterine insemination or in vitro fertilization/embryo transfer. PCOD patients were receiving hMG for simple ovulation induction. Pregnancy-induced hypertension was defined as late pregnancy blood pressure > 140/90 mm Hg on two readings six hours apart and return to normal blood pressure by four to six weeks postpartum.

RESULTS: There were no differences between PCOD and non-PCOD patients with reference to age, body mass index, parity or other pregnancy-induced hypertension risk factors (i.e., chronic hypertension, diabetes or chronic renal disease). Pregnant PCOD patients had a much higher incidence of pregnancy-induced hypertension, 31.8% (7/22), versus non-PCOD patients, who only had a pregnancy-induced hypertension incidence of 3.7% (1/27) (P = .016, OR = 12.1, 95% CI = 1.3-566.8).

CONCLUSION: PCOD patients are at very high risk of pregnancy-induced hypertension when pregnant after ovulation induction.


Increased incidence of numerical chromosome abnormalities in spermatozoa injected into human oocytes by ICSI

Abstract: The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived


Preserved forearm endothelial responses with acute exposure to progesterone: A  randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta  estradiol with progesterone in healthy menopausal women

K J Mather

Indiana University – Purdue University Indianapolis

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Abstract: Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.

The Journal of Clinical Endocrinology and Metabolism


Natural Hormone Balance

Natural Hormone Balance


Ethics Expert Supports Sex Selection in IVF


Williams Obstetrics, 21st Edition

Williams Obstetrics, 21st Edition

F G Cunningham

The University of Texas Southwestern Medical Center


Estrogens and Progestins in Goodman and Gillman’s The Pharmacologic Basis of Therapeutics


Estrogens and Progestins. In: Hardman JG, Limbird LE, Gilman AG (Eds). Goodman and Gillman's The Pharmacologic Basis of Therapeutics


Integrative treatments for premenstrual syndrome

Alternative Therapies in Health and Medicine


DIR Jahrbuch 2000 (Deutsches IVF-Register Annual Report 2000)

Abstract: Annual report (Jahrbuch) of the Deutsches IVF-Register (DIR) for treatment year 2000. DIR is the German national IVF/ICSI registry, founded 1982 — the oldest continuously operating ART registry. Voluntary professional-society database with high de-facto coverage of German fertility centres. Reports cycles, transfers, pregnancies and clinical outcomes by treatment type (IVF, ICSI, frozen embryo transfer, donor). German-language registry document. Used as a Phase B historical-archive source for the ART Registry Comparison study (cross-registry classification by reporting completeness on 7 framework dimensions).


Improvement in Symptoms and Estrogen Metabolism in Women with Premenstrual Syndrome (PMS) Using a Newly Formulated Medical Food


FDA review practices and priorities for drugs used in cancer treatment

R J DeLap

United States Food and Drug Administration

Abstract: The Federal Food, Drug, and Cosmetic Act and related regulations (21 U.S.C. 301 et seq.) give FDA staff the legal authority and responsibility to review the safety and effectiveness of drugs and biological products (including products used in cancer treatment), from preclinical testing through all phases of clinical research and marketing. FDA review activities in the oncology arena can be divided into five major categories: (1) initial review of investigational new drug (IND) applications; (2) ongoing review of premarketing research (including new research protocols submitted to existing INDs and IND safety reports describing adverse events with the new drug); (3) discussions with commercial sponsors regarding their clinical development plans, including the design and conduct of key studies that are intended to support initial marketing approval for a new product or to support the addition of new indications to the prescribing information for currently marketed products; (4) review of submitted new drug applications (NDAs) or biological licensing applications (BLAs); and (5) continuing review of the safety and effectiveness of marketed products. Through these review activities, FDA staff work to ensure that products approved for marketing for cancer treatment are effective and adequately safe for their intended uses and to ensure that the quality, effectiveness, and safety of products on the market are preserved or enhanced, so patients and physicians may use these products with confidence and with adequate safety. Because these review activities generally fall into a chronologic sequence, the following discussion parallels the development course of a typical new drug.

Annals of the New York Academy of Sciences


Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine


Gonadotropins and the uterus: is there a gonad-independent pathway?

Abstract: In the gonads, LH and hCG act via the same receptor to stimulate the production of progesterone in the luteal phase of the menstrual cycle and in early pregnancy. There are numerous reports that these two hormones can have direct actions on the uterus in addition to their indirect actions via stimulation of ovarian steroid hormones. However, unlike the situation in the gonads, various uterine tissues have been shown to respond to the related hormones FSH and TSH or the alpha-subunit common to these hormones. These additional actions cannot be mediated by the gonadal LH/hCG receptor. There have also been a series of reports that the uterus contains LH/hCG receptors. Attempts to characterize the molecular structure of these receptors have been difficult; thus, the possibility of a variant receptor cannot be excluded. The possibility also exists of a nonhomologous receptor, which would explain the differences in ligand specificity in uterine tissues. I will review the evidence regarding gonadotropin action in nongonadal tissues, primarily the uterus. In addition, the data regarding receptors will be reviewed. Finally, the clinical areas informed by this information will be explored.

Journal of the Society for Gynecologic Investigation


Estrogens and Progestins in Goodman and Gilman's: The Pharmacologic Basis of Therapeutics, 10th Ed


Progesterone Injection, USP in Sesame Oil - Product Literature by Watson Pharma, Inc (2001)


PCOS: The Hidden Epidemic

PCOS: The Hidden Epidemic


Identifying and Addressing Data-Analytic Challenges in Studies of IVF and ART


The Picture Dictionary of the Creighton Model FertilityCare™ System

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.


Annual summary of vital statistics--2001

Abstract: The number of births, the crude birth rate (14.5 in 2001), and the fertility rate (67.2 in 2001) all declined slightly (by 1% or less) from 2000 to 2001. Fertility rates were highest for Hispanic women (107.4), followed by Native American (70.7), Asian or Pacific Islander (69.4), black (69.3), and non-Hispanic white women (58.0). During the early to mid 1990s, fertility declined for non-Hispanic white, black, and American Indian women. Rates for these population groups have changed relatively little since 1995; however, fertility has increased for Asian or Pacific Islander and Hispanic women. The birth rate for teen mothers continued to fall, dropping 5% from 2000 to 2001 to 45.9 births per 1000 females aged 15 to 19 years, another record low. The teen birth rate has fallen 26% since 1991; declines were more rapid (35%) for younger teens aged 15 to 17 years than for older teens aged 18 to 19 years (20%). The proportion of all births to unmarried women remained about the same at one-third. Smoking during pregnancy continued to decline; smoking rates were highest among teen mothers. The use of timely prenatal care increased slightly to 83.4% in 2001. From 1990 to 2001, the use of timely prenatal care increased by 6% (to 88.5%) for non-Hispanic white women, by 23% (to 74.5%) for black women, and by 26% (to 75.7%) for Hispanic women. The number and rate of twin births continued to rise, but the triplet/+ birth rate declined for the second year in a row. For the first year in almost a decade, the preterm birth rate declined (to 11.6%); however, the low birth weight rate was unchanged at 7.6%. The total cesarean delivery rate jumped 7% from 2000 to 2001 to 24.4% of all births, the highest level reported since these data became available on birth certificates (1989). The primary cesarean rate rose 5%, whereas the rate of vaginal birth after a previous cesarean delivery tumbled 20%. In 2001, the provisional infant mortality rate was 6.9 per 1000 live births, the same as in 2000. Racial differences in infant mortality remain a major public health concern, with the rate for infants of black mothers 2.5 times those for infants of non-Hispanic white or Hispanic mothers. In 2000, 66% of all infant deaths occurred among the 7.6% of infants born low birth weight. Among all states, Maine and Massachusetts had the lowest infant mortality rates. The United States continues to rank poorly in international comparisons of infant mortality. The provisional death rate in 2001 was 8.7 deaths per 1000 population, the same as the 2000 final rate. In 2000, unintentional injuries and homicide remained the leading and second-leading causes of death for children 1 to 19 years of age, although the death rate for homicide decreased by 10% from 1999 to 2000. Among unintentional injuries to children, two-thirds were motor vehicle-related; among homicides, two-thirds were firearm-related.


The role of natural progesterone in natural hormone replacement therapy

International Journal of Pharmaceutical Compounding


Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women

Carolyn Webb

Royal Brompton & Harefield NHS Foundation Trust

Dominique De Ziegler

Université de Versailles Saint-Quentin-en-Yvelines

G M Rosano

Department of Cardiology, Istituto H San Raffaele, Milan, Italy. rosanog@roma.hsr.it

Abstract:
OBJECTIVES: We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarction, or both.

BACKGROUND: Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women; however, women with an intact uterus also take progestin to protect against uterine malignancies. The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown.

METHODS: Eighteen postmenopausal women (mean +/- SD age 59+/-7 years) were given 17-beta-estradiol in single-blinded manner for four weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then continued, and the patients were randomized (double-blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. After another two weeks on estradiol alone, the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment. Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase.

RESULTS: Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two patients (11%) were withdrawn while taking estradiol/MPA owing to unstable angina.

CONCLUSIONS: Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.

Journal of the American College of Cardiology


Cognitive dietary restraint is associated with higher urinary cortisol excretion  in healthy premenopausal women

Susan I Barr

Vancouver Hospital and Health Sciences Centre

Abstract:
Background: Cognitive dietary restraint, assessed by the Three-Factor Eating Questionnaire restraint subscale, is associated with subclinical menstrual cycle disturbances. This association may be mediated by stress-activated cortisol release.

Objective: We assessed whether 24-h urinary cortisol excretion differs between women with high and low restraint scores.
Design: Participants (aged 21.6+/-2.5 y; n = 62) with normal-length menstrual cycles and high (n = 33) or low (n = 29) restraint scores completed a questionnaire describing weight history, dietary practices, and exercise. Cortisol, calcium, and creatinine were measured in urine collected over 24 h on a day when all food and beverages were provided and measured. Previously, 3-d food records and anthropometric measurements were obtained.

Results: Age, height, weight, body mass index, and length of menstrual cycle were similar between groups. The reported amount of exercise was higher (3.4+/-1.7 compared with 2.2+/-1.8 h/wk; P<0.05) and energy intakes (assessed from 3-d and 24-h food records) were lower in the highthan in the low-restraint group. Ratios of urinary cortisol (nmol) to creatinine (mmol) were higher in the high-restraint than in the low-restraint group (42.9+/-12.9 compared with 36.3+/-8.9; P<0.05), whereas ratios of urinary calcium (mmol) to creatinine were lower (0.3+/-0.1 compared with 0.4+/-0.2; P<0.05) in the high-restraint group. Urinary cortisol was not associated with exercise, nutrient intakes, or anthropometric measurements.

Conclusions: High dietary restraint scores are associated with urinary cortisol, a biological marker of stress, and high cortisol excretion may affect bone health. Our results suggest that further research is warranted to clarify these associations and to determine whether they persist over time.

The American Journal of Clinical Nutrition


Thyroid disease and female reproduction

Thyroid disease and female reproduction

Abstract:
OBJECTIVE: To review the menstrual function and fertility in thyroid disease, mainly in hyperthyroidism and hypothyroidism. Also to register the consequences of (131)I therapy, which is used widely in the treatment of Graves' disease and thyroid cancer, on subsequent pregnancies and on fertility in these patients.

DESIGN: A MEDLINE computer search was used to identify relevant studies. The type of menstrual disturbances and the status of fertility were recorded from all the studies found. Also, the fertility and genetic hazard of female patients with Graves' disease and thyroid cancer who were treated with (131)I were registered.

RESULT(S): Both hyperthyroidism and hypothyroidism may result in menstrual disturbances. Menstrual abnormalities are less common now than in previous series. In a recent study, we found that only 21.5% of 214 thyrotoxic patients had some type of menstrual disturbance, compared to 50 to 60% in some older series. The most common manifestations are hypomenorrhea and oligomenorrhea. According to the results of endometrial biopsies, most thyrotoxic women remain ovulatory. Moreover, the genetic hazard incident to radioiodine therapy in Graves' disease and thyroid carcinoma is very small; exposure to (131)I does not cause reduced fecundity, and the risk of loss of fertility is not a contraindication for its use in these patients. mIn hypothyroidism, the frequency of menstrual irregularities has very recently been reported to be 23.4% among 171 hypothyroid patients studied. This is much less than that reported in previous studies, which showed that 50 to 70% of hypothyroid female patients had menstrual abnormalities. The most common manifestation is oligomenorrhea. Severe hypothyroidism is commonly associated with failure of ovulation. Ovulation and conception can occur in mild hypothyroidism. These pregnancies are, however, often associated with abortions, stillbirths, or prematurity. The latter may be of greater clinical importance in infertile women with unexplained infertility.

CONCLUSION(S): These new data, mainly concerning menstrual abnormalities in hyperthyroidism and hypothyroidism, are inconsistent with what is generally believed and written in the classic thyroid textbooks and indicate that such opinions should be revised.


Prediction of ovulation by urinary hormone measurements with the home use ClearPlan Fertility Monitor: comparison with transvaginal ultrasound scans and serum hormone measurements

Abstract: The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception. Daily serum LH measurements or transvaginal ultrasonography are not practical to determine ovulation in consecutive cycles for an individual. A prospective study was initiated to test the home use performance of the ClearPlan Fertility Monitor (CPFM) in ovulation prediction compared with transvaginal ultrasonography and serum hormone measurements. A total of 53 women aged 18-39 years with a normal uterus and at least one ovary, cycle length between 21-42 days and not using medication which interferes with ovarian function contributed 150 cycles for analysis. One cycle was anovulatory and no LH surge, indicating peak fertility, was detected by the monitor. Of the remaining 149 cycles, 135 (90.6%) had a monitor LH surge and ultrasonographically confirmed ovulation. Ovulation was detected in 91.1% of cycles during the 2 days of CPFM peak fertility. Ovulation was observed in 51.1% of cycles 1 day and in 43.2% of cycles 2 days after the surge in serum LH. Ovulation never occurred before CPFM peak fertility or the serum LH surge day. CPFM can help women who desire pregnancy to time intercourse. It may also have potential as a diagnostic aid and for monitoring the treatment of infertility.


Common genetic changes between endometriosis and ovarian cancer

Abstract: We analyzed 81 ovarian cancers for loss of heterozygosity (LOH) on 10q23 and for mutations in PTEN. LOH was common among the endometrioid (43%) and serous (28%) cancers, but was infrequent among the other histological subtypes. Somatic PTEN mutations were detected in seven (21%) endometrioid cancers and the mutation in all informative cases was accompanied by loss of the wild-type allele. One mucinous cancer without 10q23 LOH was shown to harbor two somatic PTEN mutations. Frequent LOH was observed on chromosome 6q (60.0%) and chromosome 10q (40.0%) in ovarian atypical endometriosis, but no PTEN mutations were observed. These findings support the hypothesis that endometrioid and clear cell ovarian carcinomas may arise through malignant transformation of endometriotic lesions.


Evidence that endometriosis behaves in a malignant manner

Abstract: It is well known that certain aspects of endometriosis are similar to those of malignant disease. For example, like cancer, endometriosis can be both locally and distantly metastatic; it attaches to other tissues, invades, and damages them. Endometriosis is a common disease that does not create a cachectic or catabolic state, and is rarely fatal. There are, however, numerous reported cases of malignancy arising from endometriotic deposits and substantial histologic evidence that endometriosis is associated with endometrioid carcinoma and clear cell carcinoma of the ovary. A large review article by Mostoufizadeh and Scully investigated the association between endometriosis and endometrioid carcinoma, noting that women who had both diseases tended to be younger [1]. They found no association between endometriosis and serous or mucinous carcinoma of the ovary, and reported that malignant transformation of endometriosis was rare and associated with the use of exogenous estrogens. An epidemiological study of Swedish women reported a higher incidence of breast and ovarian cancer and non-Hodgkin's lymphoma in women with endometriosis compared with controls [2]. Vercellini and colleagues also reported a higher incidence of endometrioid and clear cell carcinoma in women with endometriosis compared with controls [3]. Mutations in genes associated with galactose metabolism have been identified as one possible mechanism for this association. These mutations are more common in ovarian cancer and have been reported to be more common in women with endometriosis. We compared 78 women with endometriosis with 248 controls and were unable to demonstrate an increased frequency of these mutations in any of these groups.


Prevalence of endometriosis in ovarian cancer

Abstract: Endometriosis may be the precursor of clear cell or endometrioid ovarian cancer. In this review, we focus on the prevalence of endometriosis in ovarian cancer and related clinical and epidemiological issues. According to 15 published reports, the rank order of the prevalence of endometriosis in each histologic type was clear cell (39.2%) > endometrioid (21.2%) > serous (3.3%) > mucinous type (3.0%). The high prevalence of endometriosis in clear cell and endometrioid types is a consistent finding in Japan and western countries. However, the incidence of the clear cell type is much higher (15-20% vs. 7-8%), and that of the endometrioid type is lower (7-16% vs. 18-26%), in Japan compared with western countries. This review is also concerned with the relationship between the presence of ovarian endometriosis and clinical features such as age, parity, menopausal status, clinical stage, and survival in ovarian cancer patients.


Malignant transformation of ovarian endometriosis

Abstract: One hundred forty-seven cases of ovarian endometriosis, encountered from 1976 to 1999 at Tsukuba University Hospital, were studied to clarify the incidence of malignant transformation. There were 18 cases (12.2%) of atypical endometriosis, among which we found a case (5.6%) of ovarian cancer arising from endometriosis not diagnosed before surgery. This is accounted for 0.7% of all ovarian endometriosis cases. Because the incidence was equal to that of the previous reports, it is most likely that the malignant change in ovarian endometriosis occurred in 0.7% of this disease.


The timing of the "fertile window" in the menstrual cycle: day specific estimates  from a prospective study

A J Wilcox

Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA

Abstract:
Objectives: To provide specific estimates of the likely occurrence of the six fertile days (the "fertile window") during the menstrual cycle.
Design: Prospective cohort study.

Participants: 221 healthy women who were planning a pregnancy.

Main Outcome Measures: The timing of ovulation in 696 menstrual cycles, estimated using urinary metabolites of oestrogen and progesterone.

Results: The fertile window occurred during a broad range of days in the menstrual cycle. On every day between days 6 and 21, women had at minimum a 10% probability of being in their fertile window. Women cannot predict a sporadic late ovulation; 4-6% of women whose cycles had not yet resumed were potentially fertile in the fifth week of their cycle.

Conclusions: In only about 30% of women is the fertile window entirely within the days of the menstrual cycle identified by clinical guidelines-that is, between days 10 and 17. Most women reach their fertile window earlier and others much later. Women should be advised that the timing of their fertile window can be highly unpredictable, even if their cycles are usually regular.


Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review

Abstract:
BACKGROUND: Selective serotonin-reuptake inhibitors (SSRIs) are increasingly being used as first-line therapy for severe premenstrual syndrome (PMS). We undertook a meta-analysis on the efficacy of SSRIs in this disorder.

METHODS: We searched medical and scientific databases, approached pharmaceutical companies, and reviewed citations of relevant articles to identify 29 studies of the use of SSRIs in PMS. 14 were excluded (no placebo group, preliminary report of included trial, or low quality). 15 randomised placebo-controlled trials were included. Information on study design, participants, drugs used and dosing regimens, outcome measures, side-effects, and sources of funding was extracted. Standardised mean differences between treatment and placebo groups were calculated to obtain an overall estimate of efficacy. The primary outcome measure was a reduction in overall PMS symptoms.

FINDINGS: The primary analysis included data on 904 women (570 assigned active treatment and 435 assigned placebo, including 101 in crossover trials). The overall standardised mean difference was -1.066 (95% CI -1.381 to -0.750), which corresponds to an odds ratio of 6.91 (3.90 to 12.2) in favour of SSRIs. SSRIs were effective in treating physical and behavioural symptoms. There was no significant difference in symptom reduction between continuous and intermittent dosing or between trials funded by pharmaceutical companies and those independently funded. Withdrawal due to side-effects was 2.5 times more likely in the active-treatment group than in the placebo group.

INTERPRETATION: SSRIs are an effective first-line therapy for severe PMS. The safety of these drugs has been demonstrated in trials of affective disorder, and the side-effects at low doses are generally acceptable.


Induction of Ovarian Follicle Development and Ovulation with Exogenous Gonadotropins: A Technical Bulletin by American Society for Reproductive Medicine

Abstract:
Purpose: A large part of infertility treatment involves the use of exogenous gonadotropins. The last decade has seen a progressive switch from human menopausal gonadotropin (hMG), the original gonadotropin product, to progressively more costly products, primarily or exclusively containing follicle-stimulating hormone (FSH). Though obviously at least in part driven by marketing efforts of pharmaceutical companies, this switch has received relatively little scrutiny despite its obvious cost implications. We therefore investigated whether a switch back to a generic or less costly hMG-driven ovulation induction protocol would affect patient outcome after ovulation induction and, by implications, with other assisted reproductive technologies.

Methods: We prospectively studied clinical pregnancy rates in a large number of consecutive ovulation induction cycles in a well-defined patient population (group 1) which, after October of 1997, had been switched from a predominantly FSH to an hMG-driven protocol, based on an institutional formulary change. Until a transition period (between July and September 1997), this patient population had been on a primarily FSH-driven protocol (between July 1996 and June 1997). In parallel, we evaluated a second patient population (group 2), which was managed by the same physicians outside of formulary requirements and remained almost exclusively on principally FSH-driven ovulation induction cycles.

Results: FSHand hMG-driven ovulation induction protocols did not differ in pregnancy outcome during the prospective study period. Group 1 patients, however, demonstrated a significant increase in pregnancy rates after the switch from FSH to hMG stimulation had taken place (P = 0.02), while group 2 patients demonstrated no change in pregnancy rate during the same time period.

Conclusions: Generic hMG products do not adversely affect pregnancy rates in comparison to more costly FSH products in routine ovulation induction cycles and should be considered an appropriate alternative to more expensive FSH products.

Journal of assisted reproduction and genetics


Randomized, Controlled Comparison of Transdermal Estradiol with Oral Conjugated Estrogens for the Relief of Hot Flashes


Serial salivary estriol to detect an increased risk of preterm birth

Abstract:
OBJECTIVE: To evaluate serial measurements of salivary estriol (E3) to detect increased risk of spontaneous preterm labor and preterm birth.

METHODS: A masked, prospective, multicenter trial of 956 women with singleton pregnancies was completed at eight United States medical centers. Saliva was collected weekly, beginning at the 22nd week of gestation until birth, and tested for unconjugated E3 by enzyme-linked immunosorbent assay. Women were separated into high-risk and low-risk groups using the Creasy scoring system.

RESULTS: A single, positive (at or above 2.1 ng/mL) salivary E3 test predicted an increased risk of spontaneous preterm labor and delivery in the total population (relative risk [RR] 4.0, P <.005), in the low-risk population (RR 4.0, P < or =.05), and in the high-risk population (RR 3.4, P =.05). Two consecutive positive tests significantly increased the RR in all study groups, with a dramatic improvement in test specificity and positive predictive value but only a modest decrease in sensitivity. In women who presented with symptomatic preterm labor, salivary E3 identified 61% of those who delivered within 2 weeks, using a threshold of 1.4 ng/mL.

CONCLUSION: Elevated salivary E3 is associated with increased risk of preterm birth in asymptomatic women and symptomatic women who present for evaluation of preterm labor.