It has been suggested that estrogens can pass through the placenta because of their low molecular weight. This is supported by the demonstration of estriol in the urine of newborn male infants (1). However, there is no direct evidence to support the statment, nor is there information as to the nature of the estrogens that can or cannot be transferred. Estrogens, in common with other steroids, are rapidly conjugated in vivo with glucuronic acid. This converts them into water-soluble materials, in which form they are excreted in the urine. The unconjugated estrogens appear in the urine in only trace amounts. Wehave used C14 labeled estradiol and estriol in pregnant guinea pigs, and studied the relative permeability of the placenta to the unconjugated estrogens, as well as their conjugated forms, particularly the glucuronides. In the course of the investigation, it became obvious that the customary approach to the study of placental permeability may be misleading particularly when dealing with rapidly metabolized materials, unless the effects of fetal and maternal metabolism and of placental permeability are carefully differentiated. By using a technique which excludes fetal metabolism, clearly definable results were obtained. This was accomplished at hysterotomy by clamping the umbilical cord close to the fetus and perfusing the fetal side of the placenta.

The association between serum levels of endogenous estrogens in postmenopausal women and the subsequent risk of coronary heart disease (CHD) was examined in a prospective case–control study nested within the New York University Women's Health Study (NYUWHS). The NYUWHS is a prospective cohort study of 14,274 healthy women enrolled between 1985 and 1991. A total of 99 women who were postmenopausal and free of cardiovascular disease at enrollment and who subsequently experienced CHD, defined as non-fatal myocardial infarction (MI), fatal CHD, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG), were matched 1:2 by baseline age, blood sampling date, and postmenopausal status to controls who remained free of CHD as of the date of diagnosis of the matching case. Biochemical analyses for total estradiol, estrone, percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), and SHBG were performed on pre-diagnostic stored serum samples. Participants had not used any hormone medications in the 6 months prior to blood collection. In the model adjusting only for matching factors, the risk of CHD in the top tertile of calculated bioavailable estradiol was elevated compared with the bottom tertile (OR=2.10; 95% CI=1.13–3.90, P for trend=0.03), and the risk in the top tertile of SHBG was reduced (OR=0.50, 95% CI=0.28–0.92, P for trend<0.01). However, these associations disappeared after adjusting for baseline hypertension status, body mass index, and serum cholesterol levels. These findings suggest that circulating estradiol and SHBG are not associated with CHD risk in postmenopausal women beyond what can be explained by the variation in hypertension status, BMI, and cholesterol.

In this case-control study of euthyroid first-cycle IVF patients ≥ 38 years old with singleton baby, miscarriage, biochemical pregnancy, and no pregnancy outcomes from 2005-2008, we assayed frozen serum for autoimmune thyroid disease (AITD) and thyroid function at cycle start, trigger, and 4 and 5 weeks' gestation. AITD prevalence in older infertile women was similar across clinical outcomes, and although AITD was associated with a higher baseline TSH, TSH remained within acceptable ranges, suggesting that T(4) supplementation may not affect maternal outcomes in older euthyroid AITD patients through 5 weeks gestation.

Observational epidemiologic studies and randomized trials have reported a protective effect of oral hormonal replacement therapy on risk of colorectal cancer. Only one previous prospective study, the Women's Health Initiative Observational Study, has reported on the relationship between endogenous hormones and incident colorectal cancer. Contrary to expectation, the investigators found that women with higher circulating estradiol levels were at increased risk of developing colorectal cancer. We conducted a case-control study nested within the New York University Women's Health Study prospective cohort to evaluate the association between endogenous levels of estrone, estradiol, and sex hormone-binding globulin (SHBG) with risk of colorectal cancer. We measured hormones and SHBG in serum samples collected at enrollment from a total of 148 women who subsequently developed colorectal cancer and 293 matched controls. Circulating estrone levels were positively associated with risk of colorectal cancer: The odds ratio for the highest versus lowest quartile of estrone was 1.8 (95% confidence interval, 1.0-3.3). We found a nonsignificant inverse association between SHBG and colorectal cancer, which disappeared after adjusting for body mass index. We did not find an association between estradiol and colorectal cancer risk, but we cannot rule out a potential association because of substantial laboratory error in the measurement. Our results suggest that endogenous estrone is associated with increased risk of colorectal cancer in postmenopausal women.

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [alpha-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of alpha-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk.

OBJECTIVE: To assess the accuracy of vaginal fetal fibronectin sampling without use of a sterile speculum examination as a screening test for predicting spontaneous preterm birth.METHODS: A historical cohort of patients who were followed up with serial fetal fibronectin testing between 1998 and 2001 was identified. All patients were considered to be at high risk for preterm delivery and were screened with fetal fibronectin testing without using a speculum. at 2- to 3-week intervals from 22 weeks to 32 weeks of gestation. Charts were reviewed for fetal fibronectin results and pregnancy outcome data. Groups were compared using chi(2) analysis or Fisher exact test with significance defined as P < .05.RESULTS: A total of 1,396 fetal fibronectin tests from 416 pregnancies were performed via the "blind" sampling technique. Overall, 24.9% of pregnancies delivered spontaneously before 37 weeks; 9.1% delivered spontaneously before 34 weeks. For delivery before 34 weeks of gestation, the test had a sensitivity of 44.7%, a specificity of 88.4%, a positive predictive value of 27.9%, and a negative predictive value of 94.1%. For delivery within 14 and 21 days of a single fetal fibronectin assessment, the test had a sensitivity of 52% and 45.5%, a specificity of 94.5% and 94.9%, a positive predictive value of 14.6% and 22.5%, and a negative predictive value of 99.1% and 98.2%, respectively.CONCLUSION: "Blind" vaginal fetal fibronectin sampling has high negative predictive values and specificities in predicting spontaneous preterm birth.

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre‐diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76–9.72), p trend = 0.0008 for estradiol, 3.67 (1.71–7.88), p trend = 0.0007 for estrone, 2.15 (1.05–4.40), p trend = 0.04 for androstenedione, 1.74 (0.88–3.46), p trend = 0.06 for testosterone, 2.90 (1.42–5.90), p trend = 0.002 for DHEAS and 0.46 (0.20–1.05), p trend = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis. © 2003 Wiley‐Liss, Inc.

Objective: Characterize follicular fluid (FF) hormone profiles in women undergoing controlled ovarian hyperstimulation for IVF with GnRH antagonist or agonist treatment. Design: Prospective observational study. Materials and Methods: In IRB-approved protocol H6902, 11 patient pairs were matched for primary diagnosis (male factor, tubal disease, unexplained, etc.), body mass index (± 2 kg/m2) and age (± 2 years). Patients aged >37 years or with polycystic ovaries were excluded. Serum and FF samples were collected at retrieval. FF was collected from large mature follicles (>14 mm); hormone concentrations were measured by Immulite 2000 or Elisa kits. Data was analyzed by paired t-test. Results: Primary analysis revealed no differences in FF hormone levels between recombinant FSH only or/and urinary gonadotropin treatment. Moreover, when a GnRH agonist vs. antagonist comparison was made, only leptin concentrations varied significantly (Table 1). However, this difference was not seen for serum leptin concentrations at retrieval or on day 3 although there was a significant decline in serum leptin levels in both groups as the IVF treatment progressed.Table IFollicular fluid (FF) and serum (S) hormone concentrations at retrieval(mean+SEM) (mean+SEM) Conclusion: Selection of GnRH agonist or antagonist treatment during controlled ovarian hyperstimulation effects the intrafollicular leptin profile. This effect likely results from the modulation of local leptin production and this might affect intermediate or final treatment outcome(s). Supported by: A research grant from Serono.

Estriol has long been considered to be the end product of estrogen metabolism in man. After administering estriol triacetate to a human subject, Schiller and Pincus (2) found that by bioassay 57 per cent of the estriol could be recovered in the urine and that there was no increase in the excretion of estrone or estradiol. In more recent years, four new urinary estrogens substituted in the 16 position have been reported. These are 16-epiestriol I (3), l&-hydroxyestrone II (4), 16-ketoestrone III (5), and 16-ketoestradiol-178 IV (6).

We assessed the association of postmenopausal serum levels of oestrogens and sex hormone-binding globulin (SHBG) with endometrial cancer risk in a case–control study nested within the NYU Women’s Health Study cohort. Among 7054 women postmenopausal at enrolment, 57 cases of endometrial cancer were diagnosed a median of 5.5 years after blood donation. Each case was compared to 4 controls matched on age, menopausal status at enrolment, and serum storage duration. Endometrial cancer risk increased with higher levels of oestradiol (odds ratio = 2.4 in highest vs lowest tertile, P for trend = 0.02), percent free oestradiol (OR = 3.5, P< 0.001), and oestrone (OR = 3.9, P< 0.001). Risk decreased with higher levels of percent SHBG-bound oestradiol (OR = 0.43, P = 0.03) and SHBG (OR = 0.39, P = 0.01). Trends remained in the same directions after adjusting for height and body mass index. A positive association of body mass index with risk was substantially reduced after adjusting for oestrone level. Our results indicate that risk of endometrial cancer increases with increasing postmenopausal oestrogen levels but do not provide strong support for a role of body mass index independent of its effect on oestrogen levels. © 2001 Cancer Research Campaign

Fibrocystic disease of the breast manifesting palpable cysts express breast cyst fluids frequently containing estrogen sulfates at concentrations far exceeding those found in sera of the patient. The study explored the potential of the breast cyst to synthesize some of these estrogen sulfates. Deuterated estrone and estradiol were synthesized and either (estradiol, 4 cases or estrone, 2 cases) was injected into a cyst. The cyst was aspirated at approximately 0, 4 and 8 h, the target being 1 ml, 50% and complete aspiration respectively. Metabolites were purified sequentially by ether extraction, enzymatic hydrolysis of estrogen conjugates, chromatography on Sephadex LH 20 and identified by gas chromatography linked to mass spectrometry. The unconjugated fraction isolated from the ether extract was subjected to the same purification and detection scheme. Among the conjugates, deuterated estrone sulfate was the major metabolite of either precursor in all studies, while estradiol sulfate was not detected in any of the 6 experiments. The sulfate fractions also yielded traces of 16α-hydroxyestrone (2 studies), 4-hydroxyestrone (4 studies) and 2-hydroxyestrone (1 study). In the unconjugated fraction, one study with deuterated estradiol, 4- hydroxyestrone was obtained. In one study with deuterated estrone, traces of 2-hydroxyestrone and 16α- hydroxyestrone were obtained. These novel data are significant because patients with fibrocystic disease are at slightly elevated risk for developing breast cancer and 16α-hydroxyestrone and 4- hydroxyestrone are reported carcinogens.

Objective: To compare the effects of three commonly prescribed estrogen replacement therapies—oral conjugated equine estrogens (CEE; n = 37), oral micronized estradiol (ME; n = 25), and transdermal estradiol (TE; n = 24)—on the binding characteristics of plasma estradiol as related to the concentrations of blood sex hormone‐binding globulin (SHBG), estradiol, and estrone. Design: Menopausal volunteers, opting for estrogen replacement therapy, gave blood at 0, 2, and 4 months. SHBG was assayed by automated immunoabsorbent technology. Estradiol and estrone were determined by quantitative gas chromatography/mass spectrometry. After tritiated estradiol was added to serum, the percentage of estradiol not bound to protein was determined by ultrafiltration and the percentage of estradiol bound to SHBG was measured by a method exploiting that this protein, even when bound to estradiol, binds avidly to Concanavalin A‐Agarose. Results: In each study, 2‐ and 4‐month data were similar. Increases in SHBG concentrations were 100% (p < 0.001), 45% (p < 0.001), and 12% (nonsignificant) for subjects who were receiving CEE, ME, and TE regimens, respectively. Decreases in the percentage of estradiol not bound to protein and increases in the percentage of estradiol bound to SHBG correlated with changes in the concentrations of this protein mediated by the therapies. The order for increases in estradiol was ME∽TE >> CEE, whereas for estrone, the order was ME > CEE >> TE, divergent from the SHBG responses. Conclusions: The diverse responses observed can be explained by differences in the estrogen load delivered to target tissues as controlled by the intermediary circulation and metabolism of the hormones introduced in these regimens. (Menopause 2000;7:243‐250. © 2000, The North American Menopause Society.)

Annals of the New York Academy of SciencesVolume 828, Issue 1 p. 358-365 Sex Hormone-binding Globulin in Estrogen-dependent Cancer and Estrogen Replacement Therapya M. LEVITZ, M. LEVITZ Department of Obstetrics and GynecologySearch for more papers by this authorS. BANERJEE, S. BANERJEE Department of Obstetrics and GynecologySearch for more papers by this authorU. RAJU, U. RAJU Department of Obstetrics and GynecologySearch for more papers by this authorP. G. TONIOLO, P. G. TONIOLO Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this authorR. E. SHORE, R. E. SHORE Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this authorL. E. NACHTIGALL, L. E. NACHTIGALL Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this author M. LEVITZ, M. LEVITZ Department of Obstetrics and GynecologySearch for more papers by this authorS. BANERJEE, S. BANERJEE Department of Obstetrics and GynecologySearch for more papers by this authorU. RAJU, U. RAJU Department of Obstetrics and GynecologySearch for more papers by this authorP. G. TONIOLO, P. G. TONIOLO Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this authorR. E. SHORE, R. E. SHORE Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this authorL. E. NACHTIGALL, L. E. NACHTIGALL Department of Environmental Medicine New York University School of Medicine New York, New York 10016Search for more papers by this author First published: 17 December 2006 https://doi.org/10.1111/j.1749-6632.1997.tb48557.xCitations: 6 a This work was supported by a grant from the National Cancer Institute (CA-34588) and a grant from Wyeth-Ayerst Laboratories. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Toniollo, P. G., M. Levitz, A. Zeleniuch-Jacquotte, S. Banerjee, K. L. 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Bile acid conjugates are found in human breast cyst fluid in average concentrations about 50-fold greater than those in blood. Because epidemiologic studies have linked colon and breast cancer and aberrant bile acid profiles are associated with colon cancer risk, we decided to study the influence of bile acid conjugates (glycochenodeoxycholic acid, glycodeoxycholic acid, glycocholic acid, and glycolithocholic acid) on thymidine incorporation into DNA in cancer (MCF-7) and noncancer (MCF-10A) human mammary cell lines. The two lines responded differently. In MCF-7, bile acids, except for glycolithocholic acid, stimulated thymidine incorporation. Estradiol caused even greater stimulation, an effect that was not influenced further by the addition of bile acids. Bile acids suppressed incorporation in MCF-10A cells. Estradiol at 1 nM had no effect, but 10 nM estradiol was stimulatory. In most cases bile acids appeared to diminish the incorporations observed with estradiol alone, but not significantly. The relevance of these studies to the possible impact of bile acids on the course of fibrocystic disease of the breast would require further investigation.