Baseline E2 Research Articles

Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins

Cancer patients produce similar numbers of oocytes after ovarian hyperstimulation compared with age-matched infertile controls, suggesting that malignancy does not adversely affect ovarian response.

Effect of follicle stimulating hormone and clomiphehne citrate on heart rate and QT intervals in women undergoing ovulation induction

OBJECTIVE: This study was designed to evaluate the effect of rising estradiol concentration on QT interval in women undergoing ovulation induction. DESIGN: 87 cycles received FSH alone, 59 cycles FSH plus clomiphene citrate (FSH/CC), and 49 cycles CC alone. MATERIALS AND METHODS: In patients receiving FSH, an EKG and E2 value were obtained at the onset of menses. FSH was begun on day 2. At follicular maturation a follow-up EKG and E2 were obtained. In the CC group an EKG was obtained at the onset of menses. Clomiphene was begun on day 3 for five days. At follicular maturity a follow-up EKG was obtained. Patients receiving FSH/CC had a baseline EKG and E2 level. CC was administered days 3-7 with FSH days 8, 9, 10. A follow-up EKG and E2 determined at follicular maturity. RR and QT intervals were measured and QTc was calculated using Bazett's formula QTc= QT/(R-R)1/2. RESULTS: In the FSH group the RR interval shortened after treatment (836+/−87 vs 791+/−87; p=.01). No change in heart rate was found in the other two groups. In the FSH group, a small but significant increase in the QTc was noted after treatment (pre-treatment 402+/−18 vs post-treatment 409+/−15; p=.002). No significant change was seen in the other two treatment groups. No significant change in the QT interval was seen in any of the three groups. There was no difference in age or maximum E2 concentration achieved between the FSH group and the FSH/CC group. However, the amount of FSH administered per patient was significantly greater in the FSH group compared to the FSH/CC group (1718 units vs. 741 units). In addition, the number of days exposed to FSH was greater in the FSH group compared to the FSH/CC group (9.2 days vs. 5.7 days). In the FSH group, no correlation was found between the change in QTc and the maximum E2 achieved. Similarly, no correlation was found between the change in QTc and the dose of FSH administered nor in days exposed to FSH. CONCLUSIONS: This study demonstrated a mild increase in heart rate, a minimal increase in QTc interval, and no change in QT interval in women treated with FSH. This effect was not seen in either group of patients treated with CC. Inhibition of estrogen receptors by CC prior to administration of FSH may explain the absence of the heart rate effect in the group who received both CC and FSH. These findings suggest that estrogen causes a mild increase in heart rate resulting in an increase in the QTc without affecting the QT interval.

The decline of serum testosterone levels in community-dwelling men over 70 years of age: descriptive data and predictors of longitudinal changes

This study was designed to assess longitudinal changes in serum testosterone levels, explore relationships with aging, genetic-, health-, and lifestyle-related factors, and investigate predictors of changes in healthy elderly men. Population-based, longitudinal, 4-year observational study in 221 community-dwelling men aged 71-86 years at baseline. Hormone levels assessed by immunoassay, anthropometry, questionnaires on general health, and genetic polymorphisms. Predictors of changes in testosterone levels explored using linear mixed-effects modeling for longitudinal analyses. Total testosterone (TT), free testosterone, and bioavailable testosterone (BioT) levels decreased with aging, decreases in BioT being most marked. No changes in sex hormone-binding globulin (SHBG) or estradiol (E(2)), while LH and FSH levels increased during follow-up. Subjects who gained weight displayed a greater decline in TT levels, mainly due to decreasing SHBG levels. However, baseline body composition was not predictive of subsequent changes in testosterone levels. Baseline E(2) (P=0.023 to 0.004), LH (P=0.046 to 0.005), and FSH (P<0.002) levels were independently positively associated with a faster decline in testosterone fractions, although only FSH remained significant when adjusting for baseline testosterone (P=0.041-0.035). Carriers of a 'TA' haplotype of the estrogen receptor alpha gene (ER alpha) PvuII and XbaI polymorphisms displayed a slower decline of TT and BioT (P=0.041-0.007). In elderly men with already low serum testosterone levels, a further decline was observed, independent of baseline age. The identification of FSH levels as a predictor of this decline appears to reflect the testicular mechanisms of aging-related changes in testosterone production, whereas associations with E(2) and ER alpha polymorphisms are suggestive of estrogen-related processes, possibly related to changes in the neuroendocrine regulation of testosterone production.

Letrozole Suppresses Plasma Estradiol and Estrone Sulphate More Completely Than Anastrozole in Postmenopausal Women With Breast Cancer

To compare the effects of anastrozole and letrozole on plasma estradiol (E2) and estrone sulfate (E1S) levels. Fifty-four postmenopausal women with estrogen receptor-positive breast cancer receiving aromatase inhibitors (AIs) as part of their adjuvant therapy were randomly assigned to receive either 3 months of anastrozole (1 mg) followed by 3 months of letrozole (2.5 mg), both given orally once daily, or 3 months of the opposite sequence. Blood was taken at the same time and the same day of the week from each patient, before and after 3 months of each drug, and plasma levels of E2 and E1S were determined using highly sensitive radioimmunoassays. There were 27 patients in each group. The mean age of the patients was 63 years (range, 49 to 83 years). Baseline E2 levels ranged from 3 pmol/L to 91 pmol/L with a mean of 25.7 pmol/L. Only one of 54 (2%) patients had an E2 value >or= 3 pmol/L after receiving letrozole, versus 20 of 54 (37%) patients after receiving anastrozole (P < .001). Extrapolation revealed a mean E2 level after anastrozole treatment of 2.71 pmol/L (range, 2.38 to 3.08 pmol/L). Following letrozole, it was 1.56 pmol/L (range, 1.37 to 1.78 pmol/L). Mean residual E2 was 10.1% for anastrozole and 5.9% for letrozole. Residual E1S levels were 4.6% for anastrozole and 2.0% for letrozole (P = .001). Letrozole reduces plasma E2 and E1S levels to a significantly greater extent than anastrozole in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor-positive breast cancer.

P-515: Expression of scavenger receptor class B, type I mRNA and StAR in the granulosa cells of women undergoing controlled ovarian hyperstimulation

Scavenger receptor class B, type I (SR-BI) is a lipoprotein receptor that is highly expressed in steroidogenic tissues. It participates in the selective uptake of cholesterol esters, which serve as a substrate for steroid synthesis. We have previously shown that low expression of SR-BI in granulosa cells isolated during oocyte retrievals in subfertile women was associated with lower baseline and stimulated estradiol (E2) levels and lower number of retrieved and fertilized oocytes. The purpose of this study was to examine whether other important enzymes in estradiol production such as steroidogenic acute regulatory protein (StAR), aromatase, and 3β-hydroxysteroid dehydrogenase (3β-HSD) were correlated with SR-BI expression. Prospective cohort analysis. RNA was isolated from the granulosa cells of 68 women undergoing controlled ovarian hyperstimulation (COH) for IVF or ICSI at The Johns Hopkins Fertility Center. Real-time PCR was performed to quantify SR-BI expression. High and low expressers of SR-BI were defined as subjects with a ΔCt above the 75th or below the 25th percentile, respectively. Expression of StAR, aromatase and 3β-HSD RNA was measured in the high and low SR-BI expressers. We then examined the correlation of StAR (n=13 matched pairs), aromatase (n=16) and 3β-HSD (n=15) with SR-BI expression, baseline and peak E2 levels, and the number of retrieved and fertilized oocytes. The strength of the associations was examined using Pearson’s correlations. P values less than 0.05 were considered statistically significant. StAR RNA expression was positively correlated with expression of SR-BI (r2=0.38, p<0.023) and with baseline E2 levels (p<0.001). StAR was not correlated with peak E2 levels or with the number of retrieved or fertilized oocytes. Neither aromatase nor 3β-HSD was correlated with SR-BI expression, baseline and peak E2 levels or with the number of retrieved or fertilized oocytes. In subfertile women, SR-BI and StAR may interact to influence E2 levels. Oocyte maturation and fertilization, which were previously shown to correlate with SR-BI levels, do not appear to be influenced by StAR, aromatase, or 3β-HSD.

O-49: Baseline serum FSH levels in poor prognostic IVF patients: Do abnormal levels predict fetal aneuploidy?

Previous studies have suggested that abnormal day 3 hormone levels are associated with fetal aneuploidy. (F&S 1999) In this previous work, day 3 levels were assessed at a time prior to the patient achieving a pregnancy. Not all work has agreed with this hypothesis. (HR 2004) Therefore, we wanted to determine whether there is a correlation between baseline (day 3) serum FSH and E2 levels at the initiation of COH for poor-prognostic IVF patients and fetal aneuploidy conceived in the cycle of interest.

Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer

552 Background: Letrozole (L) is a more potent aromatase inhibitor in vitro than anastrozole (A). One study in 12 patients showed that in patients L provides more complete inhibition of whole body aromatase and suppression of estrone sulphate levels than A but L did not significantly suppress E2 levels more than A possibly because of the small size of the study and the difficulty of measuring E2 in postmenopausal women (Geisler et al, JCO, 20, 751, 2002). The current aim was to conduct a much larger study to determine whether 2.5mg L suppresses E2 significantly more than 1mg A and if so in what proportion of patients this is the case. Methods: 54 postmenopausal women with invasive estrogen receptor positive breast cancer were randomised as part of their adjuvant hormone therapy to receive either: 12 weeks of L followed by 12 weeks of A (L→A) or 12 weeks of A followed by 12 weeks of L (A→L). Blood for hormones were taken at the same time of the day before and after 12 weeks of each drug. E2 was measured by a highly sensitive radioimmunoassay (Dowsett et al, Cancer Res 1987;47:1957–61) with a formal detection limit of 3pmol/l. In this study we also quantified values by extrapolation below this limit. Results: 27 patients had L→A and 27 A→L. Baseline E2 levels varied from 3 to 91 pmol/l with a median of 26 pmol/l. Only 1of 54 (2%) patients had an E2 value ≥ 3pmol/l after L compared with 20 of 54 (37%) after A(p &lt;0.000005). After extrapolation, mean E2 level after A was 2.91 (SEM 0.18) pmol/l with a median of 2.70 pmol/l and after L was 1.76 (SEM 0.10) pmol/l with a median of 1.70 pmol/l (p&lt;0.0001). Mean residual estradiol was 9.2% of baseline with A and 5.6% with L. Conclusions: This study has demonstrated unequivocally that the more complete inhibition of aromatase achieved by 2.5mg of letrozole than 1mg of anastrozole results in a greater degree of suppression of E2, the most bioactive oestrogen. [Table: see text]

Comparison of Clinical, Ultrasonographic, and Biochemical Differences at the Beginning of Puberty in Healthy Girls Born Either Small for Gestational Age or Appropriate for Gestational Age: Preliminary Results

There are limited and controversial data concerning puberty characteristics in girls born small for gestational age (SGA). The objective of the study was to document clinical, ultrasonographic, and biochemical characteristics at the beginning of puberty in matched healthy girls born either SGA or appropriate for gestational age (AGA) recruited from the community. Inclusion criteria were breast Tanner stage II and a body mass index between the 10th and 95th percentiles. Recruited subjects underwent a complete physical exam, bone age, and ultrasound measurements of the internal genitalia. Hormonal assessment included fasting early morning dehydroepiandrosterone sulfate, androstenedione, SHBG, inhibin-B, FSH, LH, estradiol (E2), 17-hydroxyprogesterone (17OH Prog), and testosterone. Thereafter, a GnRH agonist test (leuprolide 500 microg, sc) was performed with FSH and LH at time 3 and 24 h for E2, 17OH Prog, and testosterone. Sixty-five girls (35 AGA, 30 SGA) with a mean age of 9.9 +/- 1.03 (7.8-12.5) yr, similar bone age/chronological age (1.02 +/- 0.8 in AGA and 1 +/- 0.76 in SGA), median height of 1.35 +/- 0.06 cm, and similar waist to hip ratio were included. No differences in the presence of pubic hair, axillary hair, apocrine odor, or ultrasound measurements were found. SGA girls had increased baseline E2 as well as stimulated E2 and 17OH Prog. In a preliminary sample of lean, healthy girls recruited from the community born either SGA or AGA, we observed slight hormonal differences at the beginning of puberty. Longitudinal follow-up of this cohort will allow us to understand whether these differences are maintained and have a clinical impact in their pubertal development.

Association of lower plasma estradiol levels and low expression of scavenger receptor class B, type I in infertile women

To determine the expression of the scavenger receptor, class B, type I (SR-BI) in human granulosa cells. Prospective cohort analysis. Tertiary academic university hospital. Women undergoing IVF treatment. Granulosa cells were isolated from oocyte retrievals. Total RNA and cell lysates were isolated from the granulosa cells, and SR-BI RNA and protein expression were quantified by real-time polymerase chain reaction and western blotting, respectively. Baseline and peak E2 levels were drawn before IVF treatment and before hCG stimulation. The expression of SR-BI RNA and protein were positively correlated. The prevalence of low SR-BI RNA expression (defined as below 25th percentile) was 26%, whereas the prevalence of high SR-BI expression (defined as above 75th percentile) was 24%. Expression of SR-BI RNA was not correlated with body mass index, age, race or ethnicity, primary diagnosis of infertility, or pregnancy outcomes. However, baseline and peak E2 levels were significantly lower in subjects with low SR-BI RNA expression as compared with subjects with high SR-BI expression (P<.04). There was a positive correlation between the number of retrieved (P<.02) and fertilized oocytes (P<.002) and SR-BI RNA levels. Scavenger receptor-BI is expressed in human granulosa cells. Subjects with low SR-BI expression had lower baseline and peak E2 levels and lower number of retrieved and fertilized oocytes.

Elevated serum müllerian-inhibiting substance may be a marker for ovarian hyperstimulation syndrome in normal women undergoing in vitro fertilization

We identified patients who experienced ovarian hyperstimulation syndrome (OHSS) (n = 16) and compared their baseline pretreatment levels of müllerian-inhibiting substance (MIS) to age- and weight-matched patients with normal responses to gonadotropins (n = 14). Baseline serum MIS in patients with OHSS were sixfold higher than those seen in normal controls (3.62 +/- 0.87 vs. 0.63 +/- 0.09 ng/mL; P=.0036), indicating that MIS could potentially serve as a useful marker for identifying patients at risk for OHSS.

The hormonal effects of long-term DDT exposure on malaria vector-control workers in Limpopo Province, South Africa

DDT [1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane] compounds, used in many developing countries, including South Africa, for the control of malaria vectors, have been shown to be endocrine disruptors in vitro and in vivo. The study hypothesis was that male malaria vector-control workers highly exposed to DDT in the past should demonstrate clinically significant exposure-related anti-androgenic and/or estrogenic effects that should be reflected in abnormalities in reproductive hormone levels. A cross-sectional study of 50 workers from three camps situated near the Malaria Control Center (MCC) in Tzaneen was performed. Tests included blood sampling before and after a gonadotropin-releasing hormone (GnRH) challenge (100 μg). Serum o′ p′ and p′ p′ isomers of DDE, DDT, and DDD and basal and post-GnRH challenge hormone levels, including luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone-binding globulin, estradiol (E2), and inhibin, were measured. The mean number of years worked at the MCC was 15.8±7.8 years and the mean serum DDT was 94.3±57.1 μg/g of lipid. Mean baseline E2 levels (62.4±29.9 pg/mL) exceeded the laboratory reference range. Associations between DDT exposure measures (years worked at the MCC and DDT compounds) and hormonal outcomes were weak and inconsistent. The most important finding was a positive relationship of baseline E2 and baseline testosterone with DDT compounds, especially with p′ p′-DDT and -DDD. The strongest association found, adjusted for age and SHBG, was between baseline estradiol and p′ p′-DDT ( β ̂ =1.14±0.33 pg/mL/μg/g lipid , P=0.001, R 2=0.31, n=46). An overall anti-androgenic mechanism best explains the results, but with a number of inconsistencies. Associations might be due to chance, as multiple comparisons were made. The results therefore do not suggest an overt anti-androgenic or estrogenic effect of long-term DDT exposure on hormone levels, but correlations do exist in a manner that is not understood.

REPRODUCTIVE HEALTH EFFECTS OF LONG TERM DDT EXPOSURE ON MALARIA CONTROL WORKERS IN SOUTH AFRICA

Metabolites of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane), used in many developing countries including South Africa for the control of malaria vectors, have been shown to be endocrine disruptors in vitro and in vivo. The study hypothesis was that male vector control workers highly exposed to DDT in the past should demonstrate clinically significant exposure-related anti-androgenic and/or estrogenic effects reflected in abnormalities in hormone levels, semen, sexual function and fertility. A cross-sectional study of 60 workers from 3 camps situated near the Malaria Control Center (MCC) in Tzaneen was performed. Tests included a questionnaire, a physical examination, semen analysis (produced via coitus interruptus or masturbation) and blood sampling before and after a gonadotropin releasing hormone (GnRH) challenge (100 μg). Semen count, density and motility using the World Health Organisation's criteria, and morphology using the Tygerberg criteria, were determined. Serum DDT metabolites and basal and post GnRH challenge hormone levels were measured. Forty-eight (81.0%) out of 60 participants produced a semen sample, and 31 (51.8%) completed all tests in full. The mean age of partcipants was 45.3 ± 9.1 years; mean years of education was 6.9 ± 2.7 years. The mean number of years worked at the MCC was 15.8 ± 7.8 years & mean serum DDT, 94.3 ± 57.1 μg/g of lipid. Mean baseline E2 (mean = 62.4 ± 29.9 pg/ml) levels exceeded the normal reference range. The mean sperm count was 93.8 ± 130.3 million, density 74.6 ± 85.1 million/ml, normal morphology 2.5 ± 1.8 percent, using strict Tygerberg criteria Associations between DDT exposure measures (years worked at MCC and DDT metabolites) and reproductive outcomes were weak and inconsistent. The most important finding was a positive relationship of baseline E2 and testosterone with DDT metabolites, especially with p'p' DDT and DDD. The strongest association was a linear regression relationship between baseline estradiol and p'p' DDT (= 1.14 ± 0.33 pg/ml/mg/g lipid, p = 0.001, R2 = 0.31, n = 46; adjusted for age and SHBG). An overall anti-androgenic mechanism best explains the results, but with a number of inconsistencies. Associations might be due to chance as multiple comparisons were made (n = 175). The results therefore suggest that DDT exposure experienced by male malaria vector control workers does not result in clinically or subclinically meaningful adverse reproductive effects.

Effect of ovarian cysts detected on the beginning day of ovulation induction to the success rates in ART cycles.

In the present study, we examined the outcome of assisted reproductive technology cycles in patients with or without baseline ovarian cysts following gonadotrophin-releasing hormone analogs administration. Three-hundred and fifty-six patients who had undergone assisted reproductive technology treatment were enrolled in the study. The patients, all of who had undergone cyst aspiration prior to ovarian stimulation, were grouped into two groups according to the absence or presence of ovarian cysts. These two groups were compared on the basis of the clinical pregnancy rates, the baseline E2 levels, the total follicle stimulating hormone ampules used, the total number of days of induction, the maximum E2 levels, the number of oocytes retrieved, the fertilization rates and the number of embryos available for transfer per controlled ovarian hyperstimulation cycle. The number of ampules used for induction was significantly higher in the cyst group 37.2 +/- 13.0, 32.1 +/- 11.7, respectively, (P = 0.001). The number of total induction days was also longer in the cyst group 9.7 +/- 2.2, 8.9 +/- 1.6, respectively, (P = 0.001). There was no difference between the mean E2 levels measured on the human chorionic gonadotropin administration days (P = 0.339). There was also no difference in terms of the number of oocyte retrieved (P = 0.846). The number of embryos transferred did not differ statistically between the groups (P = 0.233). Finally, there was no significant difference between the groups according to the clinical pregnancy rates 25.3%, 30.7%, respectively, (P = 0.218). Baseline ovarian cysts have a negative impact on the quality of ovarian hyperstimulation procedure; however, they have no negative effect on the pregnancy rates in IVF cycles.

Comparison of ectopic pregnancy rates between patients undergoing embryo transfer on day 3 vs. day 5

Objective: To compare the incidence of ectopic pregnancy between patients receiving embryos at cleavage stage (day 3) or at morula/blastocyst stage (day 5) and to examine factors that may contribute to the ectopic pregnancy rate. Design: Retrospective analysis of data collected from all IVF/ET cycles at a large University-based IVF center of all IVF/ET cycles from 1996 to 2002. Materials/Methods: The protocol for extending embryo culture to day 5 (D5) for blastocyt transfer was initiated in September 1999. Only those patients with an appropriate number of good quality embryos were considered to be candidates for blastocyst transfer (Group A); otherwise embryos were transferred on day 3 (D3, Group B). Variables examined included patient age and diagnosis, baseline and peak serum estradiol (E2) levels, number of eggs retrieved, number of embryos transferred, the type of catheter used for embryo transfer, the degree of difficulty of the transfer, and the physician and embryologist handling the embryos. Pregnancy was defined by the presence of a fetal heartbeat. Chi-square and t-tests were used for statistical analysis; p <0.05 was considered significant Results: The rate of clinical pregnancy rate per transfer and the ectopic pregnancy rate per clinical pregnancy remained unchanged for patients who had D3 embryo transfers prior to (44% and 1.2%) and following (41% and 1.4%) the adoption of blastocyst protocol. Although a significantly greater proportion of ectopic pregnancies occurred after D5 transfers (Group A: 11/ 719 transfers) compared to D3 transfers (Group B: 9/ 1570 transfers, p <0.05), the incidence of ectopic pregnancy as a function of clinical pregnancies observed did not differ (Group A:11/ 426 or 2.6%; Group B: 9/ 659 or 1.4%). There was no difference between groups A and B with respect to patient age (35 ± 3 vs. 37 ± 4 yrs), baseline E2 (31 ± 17 vs. 35 ± 11 pg/ml), peak E2 (2052 ± 878 vs. 1719 ± 1136 pg/ml), number of eggs retrieved (19 ± 9 vs. 12 ± 10) and the number of embryos transferred (3 ± 1 vs. 4 ± 1). Furthermore, there was no difference between Groups A and B with respect to the physician and embryologist handling the transfer, the frequency of various diagnoses as indication for IVF including the diagnosis of pelvic factor (pelvic adhesions, endometriosis and tubal disease), the degree of difficulty of the transfer and the type of catheter used for embryo transfer. Conclusions: Although a higher rate of ectopic pregnancy per transfer was experienced with D5 compared to the conventional D3 embryo transfers, this higher ectopic rate is most likely related to the higher implantation and pregnancy rates that result from the transfer of morulae or blastocysts. Previous studies by other investigators have linked ectopic pregnancy to an aberrant uterine contractility pattern; our data suggest that IVF patients are as likely to develop such anomalous patterns on D3 as on D5. Supported by: None.

Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors

The rationale for the hormonal treatment of breast cancer (BC) is based on depriving tumor cells of estrogenic stimulation. Aromatase inhibitors (Als) block the conversion of peripheral tissue androgens to estrogens with different levels of potency. In an attempt to investigate the relationship between tumor response and estrogen suppression, we reviewed the hormonal and clinical data of two previous studies with formestane (250 and 500 mg i.m. fortnightly) in advanced BC patients. Two hundred four BC patients were selected on the basis of the availability of records concerning their plasma estrone (El) and estradiol (E2) levels assessed at scheduled times. The degree of estrogen suppression and the best clinical response of each patient during the trials were considered. There was a positive and significant (P < 0.05) correlation between baseline and post-formestane E1 and E2 levels, with a decrease in the levels of both hormones irrespective of any antitumor response. In particular, the degree of plasma estrogen suppression was similar in the patients who experienced a complete remission and those with progressive disease (PD). The plasma estrogen suppression induced by aromatase inhibition is not the only mechanism accounting for its clinical activity. Many clinical trials have demonstrated that all AIs induce a similar antitumor response regardless of their potency, and further investigations are warranted in order to improve our understanding as to why the patients with PD also show a significant plasma estrogen suppression. It is possible that intratumoral aromatase activity may be a marker for selecting the BC patients most likely to respond to AI treatment.

Seasonal Variations and Maturity Stages in Relation to Differences in Serum Levels of Gonadal Steroids, Vitellogenin, and Thyroid Hormones in the Common Dentex (Dentex dentex)

Seasonal variations in serum concentrations of 17β-estradiol (E2), vitellogenin (Vg), testosterone (T), 11 ketotestosterone (11-KT), and thyroid hormones (T4, l-thyroxine; and T3, 3,5,3′-triiodo-l-thyronine) were investigated during the first, second, and third reproductive cycles in intensively reared populations of common dentex, Dentex dentex, and correlated with gonadal development and spawning. In females, there were baseline E2 values (<0.10 ng/ml) and negligible Vg concentrations during the postspawning and pregametogenesis period (June to December), and these increased thereafter to peak during the spawning period. Maximum T3 and T4 serum concentrations were found around spawning. There was a positive correlation during vitellogenesis and final maturation between Vg and T3 (r2=0.366). In addition, Vg and T3 concentrations were statistically higher in the stages of vitellogenesis and final maturation than at the other stages (P<0.001). Minimum T3 and T4 concentrations (October) coincided with the decrease in water temperature and the associated decrease in the daily feeding rate and the specific growth rate. In males, as in females, seasonal changes in serum levels of T and 11-KT were well correlated with gonadal development. The presence of males in the stage of completed spermiogenesis in December coincided with the surge in both androgens and this increase lasted until the end of the spawning period. There were no significant differences in serum T3 and T4 levels among the maturity stages. The observed seasonal changes in serum gonadal steroids and Vg reflected the pattern of oocyte development and the spawning behavior of common dentex and were typical of the patterns described in most multiple spawners studied to date. Thyroid hormones may enhance early ovarian development and stimulate vitellogenesis in female dentex.

Estrogen absorption and metabolism in postmenopausal women with end-stage renal disease.

Women with end-stage renal disease (ESRD) have a higher rate of death from heart disease than women with normal renal function. Because estrogen replacement therapy may significantly decrease the incidence of death due to cardiovascular disease in postmenopausal women with normal renal function, their use has been considered for women with ESRD. However, the pharmacokinetics of estrogen have not been studied in postmenopausal women with ESRD to determine the optimal estrogen dose. Six postmenopausal women with ESRD receiving maintenance hemodialysis and six controls matched for body mass index were admitted to the in-patient Clinical Research Center. A 1- or 2-mg oral estradiol (E2) pill was given while subjects fasted. Blood sampling was performed over the next 24 h for measurement of E2, estrone (E1), albumin, and sex hormone-binding globulin (SHBG). Three weeks later, the subjects were given the other E2 dose under identical conditions. At baseline, total and free E2 levels were higher in the subjects with ESRD than in controls (P = 0.0005 and 0.0035, respectively). After ingestion of 1 and 2 mg E2, total and free E2 levels remained significantly higher in the ESRD subjects from 2-8 h after treatment (P < or = 0.05). After 1 mg oral E2, total serum E2 peaked at 65 pg/mL at 4 h in ESRD subjects and at 27 pg/mL in control subjects at 8 h. After 2 mg oral E2 treatment, total serum E2 peaked at 8 h in both ESRD and control subjects, with levels of 99 and 37 pg/mL, respectively. E1 was higher in the subjects with ESRD than in the control subjects at baseline (P < 0.05). After ingestion of 1 mg E2, E1 concentrations were not significantly higher in ESRD than in control subjects, peaking at 180 and 121 pg/mL, respectively (P = 0.3). E1 concentrations were higher in ESRD than in control subjects after the ingestion of 2 mg E2, with peak levels of 376 and 201 pg/mL, respectively (P = 0.03). Total and free E2 levels are higher in patients with ESRD than in control subjects at baseline and after E2 ingestion, indicating that renal failure alters the pharmacokinetics of both endogenous and exogenous E2. Therefore, conventional E2 doses used in individuals with normal renal function may be excessive for patients with ESRD.

Age and follicular phase estradiol are better predictors of pregnancy outcome than luteinizing hormone in menotropin ovulation induction for anovulatory polycystic ovarian syndrome

To examine the relationship of baseline and preovulatory serum E2, P, and LH levels and age with pregnancy outcome in polycystic ovarian syndrome (PCOS) patients undergoing hMG ovulation induction. Retrospective analysis of all available data over 2 years. Tertiary referral ovulation induction clinic. Forty-four anovulatory PCOS patients with 25 ovulatory nonconception and 50 conception cycles after hMG ovulation induction. Ovulation (midluteal serum P > 25 nmol/L [7.86 ng/mL]); pregnancy (serum beta-hCG > 30 mIU/mL 16 days after ovulating injection); pregnancy outcome: pregnancy termination < 20 weeks' or > or = 20 weeks' amenorrhea. Of the endocrine parameters considered, none was significantly different in nonconceptive and conceptive ovulatory cycles. Miscarriage was associated with low basal serum E2: median value for pregnancies ending < 20 weeks, 105 pmol/L (28.6 pg/mL) and for > or = 20 weeks 150 pmol/L (40.9 pg/mL). It was also significantly associated with age. For patients > 29.5 years of age, (29.5 years, population mean age) a baseline E2 < or = 140 pmol/L (38.2 pg/mL) had sensitivity 92%, specificity 54%, positive predictive value 65%, and negative predictive value 87% for the prediction of miscarriage. The nature of the previous cycle, the day of the cycle on which therapy commenced, and a past history of miscarriage were not related either to pregnancy outcome or to basal serum E2.

The pattern of gonadotropin and estradiol secretion in exaggerated thelarche

To assess the dynamics of the pituitary-ovarian axis in exaggerated thelarche, defined as premature thelarche associated with signs of systemic estrogen effects (advanced bone age and/or growth acceleration) without progression to complete puberty. Seven girls (age < 2.5 years) with exaggerated thelarche, 6 girls with inactive pituitary-ovarian axis (premature adrenarche) and 21 girls with activated axis (central precocious puberty) had serum FSH, LH and E2 measured serially before and 1 to 24 h after gonadotropin-releasing hormone agonist (GnRHa) administration (leuprolide, 20 micrograms/kg sc), used as a test of combined pituitary-ovarian stimulation. Although girls in the exaggerated thelarche and adrenarche group had similar [mean (SEM)] baseline FSH [3.2 (0.9) vs 1.4 (0.3) IU/l], LH [0.36 (0.1) vs 0.27 (0.02) IU/l] and E2 [20 (1.2) vs 21 (2) pmol/l] concentrations, and similar peak post-GnRHa LH concentrations [5.5 (1.1) vs 2.4 (0.5) IU/l], girls with exaggerated thelarche achieved higher peak FSH [41 (9) vs 14 (3) IU/l, p < 0.01] and E2 [243 (40) vs 37 (6) pmol/l, p < 0.001] concentrations after GnRHa. In comparison to patients with exaggerated thelarche, girls with precocious puberty had higher (p < 0.01-0.001) baseline LH [3.6 (0.8) IU/l], baseline E2 [69(11) pmol/l], GnRHa-stimulated peak LH [68 (17) IU/l] and peak E2 [648 (58) pmol/l] concentrations, but similar FSH parameters. Girls with exaggerated thelarche exhibit substantial E2 secretory potential that can be demonstrated by GnRHa stimulation, is predominantly FSH-driven, and probably accounts for the manifestations of estrogen effect seen in these girls.

Ovarian sensitivity to follicle-stimulating hormone during the follicular phase of the human menstrual cycle and in patients with polycystic ovarian syndrome

To investigate the existence of a different sensitivity of ovaries to follicle-stimulating hormone (FSH) during the follicular phase of the human menstrual cycle and in patients with polycystic ovarian syndrome (PCOS). Thirty-four normal subjects and 13 patients with PCOS were treated intravenously by FSH (75 or 225 IU) or saline at different stages of follicular phase. Plasma levels of luteinizing hormone (LH), FSH, estradiol (E2), and testosterone (T) in samples collected for a period of 26 hours after the injection. In patients at the early stages of follicular phase (baseline E2 < 50 pg/mL), FSH increased in dose-dependent manner E2 and E2:T-stimulated area under curve (AUC) in respect to saline experiments. In PCOS subjects, saline E2, and E2:T-stimulated AUC were significantly lower than normal women. Follicle-stimulating hormone (75 IU) dramatically increased these values, and no difference was seen in respect to 75 and 225 IU FSH-treated controls. In patients with E2 baseline plasma levels > 50 pg/mL, FSH (75 or 225 IU) failed to increase both E2 and E2:T-stimulated AUC in comparison with saline studies. Early stages of follicular phase in normal and polycystic ovaries are the most responsive to the elevation of circulating FSH levels, whereas the ovarian sensitivity spontaneously decreases as follicular maturation enhances.