Baseline Hormone Levels Research Articles

A rapid effect of handling on counts of white blood cells in a wintering passerine bird: a more practical measure of stress?

Measuring circulating glucocorticoids is a widely used method to assess stress in animals. However, hormones must be sampled within the first few minutes of capture, which makes it difficult to discriminate between hormone baseline levels and the levels caused by capture and handling stress. The use of white blood cell (WBC) counts made from blood smears represents an alternate method for measuring physiological stress. Since the increase in glucocorticoid hormones causes characteristic long-lasting changes in the leukocyte numbers, we tested whether stress-related handling of male Great Tits (Parus major) may cause rapid changes in their leukocyte profile. We found that handling stress significantly increased heterophil counts between 30 and 60 min after capture, while lymphocyte and eosinophil counts significantly declined between 60 and 120 min after capture. The increase in heterophil counts and reduction in lymphocyte counts caused an increase of the heterophil and lymphocyte ratio (H/L) between 60 and 120 min after capture. Overall, these results indicate that leukocyte profiles in wintering male Great Tits may change more rapidly than previously thought, reflecting acute stress of individual birds.

Genes regulating estradiol and estrone-conjugate levels in postmenopausal women with resected early-stage breast cancer detected by a genome-wide association study (GWAS).

1001 Background: There is large inter-individual variation in baseline estrone (E1), estradiol (E2), E1-conjugate (E1-C), androstenedione (A), and testosterone (T) levels in postmenopausal women with resected early stage breast cancer (Ingle et al., Ca Res 70:3278−86, 2010). We hypothesized that genetic variation can explain some of this variation in baseline (before anastrozole) hormone levels and performed a GWAS. Methods: Baseline plasma was obtained for E1, E2, E1-C, A, and T assays by GC-MS-MS. Genotypes were determined with the Illumina Human610-Quad BeadChip. Eigenstrat analyses were performed to control for population stratification (PS). Analysis of each baseline hormone level was assessed with each genotype using a quasi-likelihood model because of the skewness in baseline hormone levels, with adjustment for PS as well as body mass index, age and any additional clinical variables associated with baseline hormone levels (p<0.01). SNPs were imputed within 200 Kb on either side of regions containing SNPs with p < 3E-05 using HapMap. Results: 563,945 SNPs were used in the analyses. SNP genotypes were modeled in terms of the number of minor alleles (0, 1 or 2), with SNPs achieving genome-wide significance after Bonferroni correction (p<5E-08) identified for both E2 and E1-C. For E2 (n=757 patients), the genotyped SNP (rs1864729) with the lowest p-value (p=1.13E-08) was on chromosome (chr) 8 and had a multiplicative effect (ME: estimated fold change per minor allele) of 1.62 (95% CI: 1.38, 1.91), with the closest gene being TSPYL5 (Testis-specific Y-encoded-like protein 5), which we showed to be regulated by E2. There were 8 imputed SNPs near rs1864729 with lower p-values (1.03E-08-3.85E-09). For E1-C (n=752 patients), one nonsynonymous SNP (rs4149056) on chr 12 in the SLCO1B1 gene (which encodes an E1-C transporter) was significant (p=5E-08) with ME 1.41 (95% CI: 1.25, 1.60). Conclusions: This GWAS revealed novel loci associated with the baseline levels of E2 and E1-C in postmenopausal women that may be of importance for understanding the estrogen physiology of postmenopausal women and their response to aromatase inhibitor therapy.

Clinical significance of anaemia associated with prolactin-secreting pituitary tumours in men

An association between prolactin-secreting pituitary adenomas and anaemia in male patients has been recently reported. Our aim has been to evaluate the prevalence of anaemia in men with prolactinomas and to assess the relationships between haemoglobin concentrations and pituitary function at diagnosis in these patients. In a retrospective analysis, 26 male patients with prolactinomas (22 macroprolactinomas and 4 microprolactinomas) were studied. Blood haemoglobin concentration, haematocrit value and baseline hormonal levels were collected at the time of prolactinoma diagnosis. The presence or absence of partial or total hypopituitarism was also evaluated at diagnosis. Logistic regression analysis was used to assess the presence of anaemia as a function of serum hormone concentrations and pituitary dysfunction. Patient bearing macroprolactinomas showed significant lower haemoglobin concentrations than those found in patients with microprolactinomas (13.5 ± 1.2 g/dl vs. 15.1 ± 0.9 g/dl, p < 0.05). Anaemia (haemoglobin < 13 g/dl) was present in nine (34.6%) patients, all of them with macroprolactinomas. The degree of anaemia was mild (haemoglobin > 11 g/dl) in all patients. No correlation between haemoglobin and serum prolactin was found. Haemoglobin concentration was significantly lower in men with hypogonadism (n = 14) than in eugonadal men. Haemoglobin value was also significantly lower in patients with total hypopituitarism in comparison with patients with partial hypopituitarism (12.4 ± 1.0 g/dl, n = 7 vs. 14.0 ± 1.2 g/dl, n = 13, p = 0.007). The number of affected pituitary axes was found to be related with the presence of anaemia. Logistic regression analysis showed that anaemia was related with FT4 (OR 0.23; 95% CI 0.06-0.81, p = 0.02), cortisol (OR 0.81; 95% CI 0.68-0.96, p= 0.02) and the presence of hypopituitarism (OR 20.0; 95% CI 1.68-238.63, p = 0.02). Anaemia was found in about a third of men with prolactinomas. Our results also suggest that the presence of anaemia in these patients seems to be associated with panhypopituitarism.

A microsphere-based duplex competitive immunoassay for the simultaneous measurements of aldosterone and testosterone in small sample volumes: Validation in human and mouse plasma

Background The small blood volumes available in rodent studies often limit adequate quantification of all hormones of interest. We report here the development of two new assays combining an extraction step with multiplex immunoassay (MIA) technology for the simultaneous determination of aldosterone and testosterone in 50 μl sample volume. Methods Following solvent extraction, aldosterone and testosterone competitive immunoassays are performed incorporating biotinylated tracers and antibody-coated beads each having a unique fluorescence. Quantification is via addition of streptavidin–R–phycoerythrin (SA–PE). The assays were validated and compared to established methods. Baseline hormone levels in mice from four different strains, and changes after ACTH and HCG stimulation in CD-1 mice are shown. Results The assays are sensitive (aldosterone 15 pg/ml, testosterone 12 pg/ml), reproducible (intra-/inter-assay imprecision aldosterone 5.1–15.6%/9.9–15.8% and testosterone 9.7–10.9%/7.7–11.4%) and correlate significantly to established assays ( r = 0.94–0.95). Baseline aldosterone levels varied between strains, but not between the genders. Testosterone was significantly higher in male of all strains except in C57BL/6× NMRI mice. After ACTH injection, aldosterone (median, interquartile range) rose from 354 (261–396) pg/ml to 2008 (875–2467) in male and from 260 (210–576) to 1120 (734–1528) in female CD-1 mice. HCG injection in the same strain increased testosterone in male mice only (3.5 (0.4–8.3) ng/ml to 31.8 (30.4–33.9) ng/ml, P < 0.01). Conclusions We describe a MIA for the simultaneous measurement of aldosterone and testosterone in small volumes after extraction. In addition to presenting a new tool for steroid research in rodent models, our data show strain-dependent differences in steroid hormone metabolism in rodents.

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer––The Rotterdam Study

Purpose To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality. Methods 3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student's t-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox’ proportional hazard models were used to study prostate cancer incidence and mortality among genotypes. Results Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate ( p = 0.005) and higher levels of estradiol ( p = 0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate ( p = 0.02). CYP3A7 G-allele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate ( p = 0.05), androstenedione ( p = 0.006), estrone ( p = 0.0001) and estrone sulphate ( p = 0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers. Conclusion Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence.

Polymorphism Pro12Ala of PPARG in Prepubertal Children with Premature Adrenarche and Its Association with Growth in Healthy Children

Background: The peroxisome proliferator-activated receptor-γ2 (PPARγ2) participates in the regulation of insulin sensitivity, and has connections to the GH-IGF system and ACTH-adrenal androgen axis. We hypothesized that PPARG Pro12Ala polymorphism leading to decreased receptor activity could contribute to the premature onset of adrenarche (PA). Methods: We performed a cross-sectional association study in 73 prepubertal children with PA and 97 age- and sex-matched healthy control children. Growth data, baseline hormone levels, and the values of oral glucose tolerance test (OGTT) were compared with PPARG genotypes. Results: We found no difference in the genotype distribution of PPARG between the PA and control children. The minor Ala12 variant was associated with lower current height SD scores (SDS) in the controls, but no similar association was seen in the PA children. Birth measures and current weight for height were equal between the genotype groups in both control and PA children. The Ala12 variant was associated with trends for a lower serum IGF-I level and lower serum insulin concentration at the 120-min time point of OGTT in control children. Conclusions: The Pro12Ala genotype of PPARG was not associated with PA. The minor Ala12 variant was associated with lower height SDS in healthy prepubertal children indicating its possible effects on growth.

Natural history of benign prostatic enlargement: long‐term longitudinal population‐based study of prostate volume doubling times

To measure prostate volume doubling times (PVDTs) for a large sample of community men followed serially by transrectal ultrasonography (TRUS), and to determine whether specific characteristics are associated with a rapid PVDT. A subsample of 446 subjects from a larger cohort of American white men aged 40-79 years were evaluated biennially for a median (range) follow-up of 10 (3-14) years. Mixed-effects regression models were used to estimate prostate growth rates and PVDT for subjects with three or more or with five or more serial biennial TRUS PV measurements. The median (25-75th percentile) PVDT was 32.6 (24.6-44.0) years. The average annual increase in PV was 2.2%. The PVDT distribution was constant in men of all age groups studied (r < 0.001, P = 0.99). The factor most strongly associated with PVDT was baseline transition zone volume (r = -0.55, P < 0.001). Baseline total prostate-specific antigen (PSA) level, free PSA and total PV were also significantly inversely associated with PVDT (r = -0.30, -0.44 and -0.32, respectively, all P < 0.001). Age, baseline anthropomorphic measurements, hormone levels and specific lifestyle characteristics were not significantly correlated with PVDT. These data indicate that PVDT might be a useful future measure of benign prostatic growth. They provide a basis to forecast PV at 10, 20, or 30 years later, after one baseline TRUS measurement of prostate volume, and can be presented in a simple nomogram.

LH Dynamics in Overweight Girls with Premature Adrenarche and Slowly Progressive Sexual Precocity

Background. Excess adiposity and premature adrenarche (PA) are risk factors for the development of polycystic ovary syndrome (PCOS). Methods. Girls with slowly progressive precocious breast development, who were overweight and had PA (SPPOPA, 6.2–8.2 years, n = 5), overweight PA (6.6–10.8 years, n = 7), and overweight premenarcheal controls (OW-PUB, 10.6–12.8 years, n = 8) underwent hormonal sleep testing and GnRH agonist (GnRHag) and ACTH tests. Results. Despite an insignificant sleep-related increase in LH and prepubertal baseline hormone levels, SPPOPA peak LH and estradiol responses to GnRHag were intermediate between those of PA and OW-PUB, the LH being significantly different from both. Conclusions. GnRHag tests indicate that SPPOPA is a slowly progressive form of true puberty with blunted LH dynamics. These results argue against the prepubertal hyperandrogenism of excess adiposity or PA enhancing LH secretion or causing ovarian hyperandrogenism prior to menarche. Excess adiposity may contribute to both the early onset and slow progression of puberty.

The shortness of Pygmies is associated with severe under-expression of the growth hormone receptor

The stature is a highly heritable trait controlled by genetic and environmental factors. The African Pygmies represent a paradigmatic example of non-disease-related idiopathic short stature (ISS), showing a similar endocrine profile of Caucasian individuals with ISS. Pygmy children show normal anthropometric and endocrine parameters until puberty, while adult Pygmies show normal baseline and post-stimulation serum growth hormone (GH) levels but low values of baseline serum GH-binding protein (GHBP) and insulin-like growth factor-I (IGF-I). This discrepancy suggests a defective response to GH occurring in adulthood since Pygmies lack both the pubertal serum IGF-I surge and the growth spurt. However, sequencing of the key genes of the GH–IGF-I axis failed to identify Pygmy specific variants or haplotypes. We therefore aimed at assessing whether the quantitative gene expression profile of two key genes of the GH–IGF-I axis, GH and GHR, was also similar in low-stature and normal stature populations. We showed that the GH gene expression is 1.8-fold reduced and the GH receptor ( GHR) gene expression is 8-fold reduced in adult Pygmies in comparison with sympatric adult Bantu, and that this reduction is not associated with sequence variants of the GHR gene. The marked decrease of the GHR expression in Pygmies is associated with reduced serum levels of the IGF-I and GHBP. Our results, documenting a markedly reduced GHR gene expression in adult Pygmies, could contribute to elucidate the mechanisms involved in ISS in Caucasoid subjects.

Distinct, Time-Dependent Effects of Voluntary Exercise on Circadian and Ultradian Rhythms and Stress Responses of Free Corticosterone in the Rat Hippocampus

Previous work has shown that allowing rats to voluntarily exercise in a running wheel for 4 wk modifies the hypothalamic-pituitary-adrenal axis and behavioral coping responses to stress. To investigate whether long-term voluntary exercise would also affect the free, biologically active fraction of corticosterone in the brain, we conducted an in vivo microdialysis study in the hippocampus of rats. We monitored both the baseline circadian and ultradian patterns of corticosterone in hippocampus dialysates over the diurnal cycle and the responses to forced swim and novelty stress at different stages of exercise. Exercise for 1 d, 2 d, or 1 wk did not affect baseline circadian and ultradian pulse parameters or stress-induced hippocampal free corticosterone concentrations suggesting that acute or short-term periods of exercise do not affect baseline and stress-induced hormone levels. Baseline hormone parameters in 4 wk exercised rats, however, showed significantly increased pulse amplitudes (+108%) and mean free corticosterone levels (+42%) between 1500 and 2100 h but not between 0900 and 1500 h. Surprisingly, although our previous work showed substantial changes in stress-evoked plasma (total) corticosterone responses in long-term exercised animals, no differences in stress-induced hippocampal free hormone responses could be observed between exercised and sedentary animals. This lack of differences was not caused by compensatory changes in plasma corticosteroid-binding-globulin binding levels in exercising rats. Thus, long-term exercising rats show anticipatory increases in glucocorticoid output before the start of the active phase. These rats also reveal the putative existence of a containment mechanism preventing overexposure of the brain to glucocorticoid hormones.

Reference change values and determinants of variability of NT-proANP and GDF15 in stable chronic heart failure

Biovariability, reference change values (RCV), and index of individuality (IOI) have not been previously described for NT-proANP or GDF15. Also, the relation of changes of these markers to other clinical variables or biomarkers is unknown. In 41 patients with stable chronic systolic dysfunction, NT-proANP and GDF15 were measured alongside with clinical variables/markers comprising NT-proBNP, hsTnT, and hsCRP at four sampling intervals (2 weeks, 1-, 2-, 3-month intervals). At 2 weeks, 1-, 2-, and 3-month-follow-up, individual NT-proANP variations were 27.1, 22.5, 28.9, 15.6%, respectively, corresponding to RCVs of 53.2, 62.4, 80.2, and 43.2%, respectively. For GDF15, the respective individual variations were 6.8, 4.1, 5.5, 6.8%, corresponding to RCVs of 18.8, 11.5, 15.3 and 18.8%. Neither changes of NT-proANP or GDF15 correlated with changes in any of the clinical variables or biomarkers examined except for GDF15 with renal function. Baseline hormonal levels and clinical variables did not consistently influence the extent of change. The IOI was 0.19-0.35 according to interval for NT-proANP and 0.06-0.09 for GDF 15. In patients with CHF preselected for clinical stability changes of NT-proANP at intermediate follow-up do not correlate with changes in other variables; changes of GDF15 inversely correlate with renal function. The extent of change in both markers is not related to baseline hormonal levels or other baseline variables. RCVs are high for NT-proANP and low for GDF15, while inter-individual variation is high in GDF15 and intermediate in NT-proANP.

The effects of metformin on endogenous androgens and SHBG in women: a systematic review and meta‐analysis

Elevated circulating androgens are risk factors for several chronic, metabolic and reproductive disorders. Metformin is an insulin-sensitizing agent that may lower androgen levels. To evaluate the effects of metformin on endogenous androgens and SHBG levels in women, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing metformin with placebo or no treatment. We used OVID to search MEDLINE, EMBASE and CENTRAL until March 2007. Two reviewers independently extracted data on methodological quality, participants, interventions and outcomes of interest. Our a priori primary outcome was post-treatment measurements. In a secondary analysis, we evaluated the difference between the pre- and post-treatment levels. We computed the weighted mean difference (WMD) as a measure of effect for each outcome using the DerSimonian-Laird random effects method. We used the I2 statistic to assess heterogeneity and explored its causes in subgroup analyses of features related to participants' characteristics and study design. Based on a regression model, we conducted sensitivity analyses by investigating the use of placebo as a predictor of effect size. Twenty RCTs fulfilled the inclusion criteria. Pooled WMDs in post-treatment levels between the metformin and control group were -0.31 nmol/l (95% CI -0.65 to 0.03) for total testosterone (TT), 0.10 pmol/l (95% CI -0.89 to 1.10) for free testosterone (FT), 0.14 micromol/l (95% CI -0.34 to 0.62) for dehydroepiandrosteronesulfate (DHEAS), -0.60 nmol/l (95% CI -1.67 to 0.46) for androstenedione (AND) and 5.88 nmol/l (95% CI 2.01-9.75) for SHBG. Pooled WMDs of the pre- to post-treatment differences (i.e. with adjustment for baseline hormone levels) were -0.38 (95% CI -0.51 to -0.25) for TT, -2.71 (95% CI -10.35 to 4.93) for FT, -0.50 (95% CI -0.83 to -0.16) for DHEAS, -1.39 (95% CI -2.30 to -0.49) for AND and 6.63 (95% CI 2.32-10.94) for SHBG. In subgroup analyses, features related to the administered treatment (i.e. metformin as a single agent or as part of combined regimens) partly explained the heterogeneity. Sensitivity analyses of studies using placebo showed similar results to those not using placebo. Our systematic review and meta-analysis provides evidence of metformin-induced changes in circulating androgens and SHBG levels in women but the quality of evidence is not high. However, there are no data from RCTs regarding these effects in postmenopausal women or healthy premenopausal women. High-quality RCTs are required to evaluate whether metformin has effects on surrogate markers and patient-important outcomes in these patient groups.

Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women

Some postmenopausal women use over-the-counter dehydroepiandrosterone because of its purported beneficial effects. Although without major inherent androgenic activity, it is metabolized to potent androgens and estrogens. We investigated the pharmacokinetics of dehydroepiandrosterone and its relevant metabolites after prolonged treatment of postmenopausal women with 25 mg/d of dehydroepiandrosterone. Twenty healthy postmenopausal women were randomized to either 25 mg/d of dehydroepiandrosterone or placebo for 6 months. Frequent blood samples were obtained over 24 hours on day 1 and after 3 and 6 months. Mean baseline androgen levels at day 1 and month 3 in the treated group (seven evaluable women) were the following: dehydroepiandrosterone, 1.82 and 3.56 ng/mL; dehydroepiandrosterone sulfate, 0.96 and 3.37 microg/mL; 5-androstene-3beta,17beta-diol, 0.32 and 0.66 ng/mL; androstenedione, 0.50 and 0.86 ng/mL; testosterone, 17.9 and 28.7 ng/dL; dihydrotestosterone, 6.91 and 17.4 ng/dL; and 3alpha-androstanediol glucuronide, 2.66 and 10.7 ng/mL, respectively; these increases were significant. Small changes (-6% to 16%) were observed from month 3 to month 6. Nonsignificant increases were observed in baseline estrone and estradiol levels and in Cmax and AUC0-24h values for the androgens and estrogens from day 1 to months 3 and 6 of treatment. Sex hormone-binding globulin levels were unchanged, but free testosterone increased significantly from day 1 to month 3. Baseline hormone levels did not increase in the placebo group (six evaluable women). Changes in baseline values over time differed significantly between the groups for all hormones except estrone and estradiol. In postmenopausal women treated orally with a commonly available dose of dehydroepiandrosterone, the daily exposure (AUC) of dehydroepiandrosterone and its principal androgenic metabolites was found to be similar during 6 months of treatment despite increased serum baseline concentrations of these androgens.

24-Hour Serum Levels of Growth Hormone, Prolactin, and Cortisol in Pre- and Postmenopausal Women: The Effect of Combined Estrogen and Progestin Treatment

Previous studies of the effects of hormone therapy (HT) on levels of growth hormone (GH), prolactin (PRL), and cortisol have yielded conflicting results. The present study analyzed 24-hour profiles of these hormones before and after estrogen/progestin treatment (EPT) in 17 healthy premenopausal women 45 to 51 years of age and 18 postmenopausal women 58 to 70 years of age. Using a randomized, placebo-controlled, double-blind design, hormone levels were sampled at 20-minute intervals for 24 hours, before and after 6 months of EPT. Premenopausal women received cyclic EPT with 2 mg of estradiol valerate for 16 days, followed by estradiol plus 1 mg of norethisterone acetate (NETA) for 12 days. Postmenopausal women received continuous EPT with 2 mg of estradiol valerate plus 0.7 mg of NETA. Some women in each of these groups received placebo. Mean 24-hour levels of both GH and PRL were lower in postmenopausal than in premenopausal women. Average serum concentrations were 1.0 versus 1.8 mU/L, respectively, for 24-hour GH, and 6.8 versus 10.0 ng/ml for PRL. No such difference was found for either GH or PRL following EPT, at which time baseline hormone levels were comparable in pre and postmenopausal women. Mean postmenopausal 24-hour levels of GH and PRL were higher during EPT than in control subjects, as were daytime GH levels and nighttime PRL concentrations. No differences in serum cortisol were observed. In premenopausal women, mean nighttime PRL and cortisol levels were higher during EPT than in placebo recipients. Postmenopausal PRL levels and premenopausal levels of GH and PRL were higher at night than during the day, whether or not subjects were receiving EPT.

Luteal Support for IVF/ICSI Cycles with Crinone 8% (90 mg) Twice Daily Results in Higher Pregnancy Rates Than with Intramuscular Progesterone

The use of progesterone for luteal support has been demonstrated to be beneficial in assisted reproductive cycles, yet the optimal route of progesterone administration has still not been established. This article is a retrospective study in a tertiary reproductive medical unit to compare luteal progesterone supplementation with vaginal gel or intramuscular progesterone. A total of 144 in vitro fertilization or intracytoplasmic sperm injection cycles were analyzed, 67 cycles using vaginal gel 90 mg twice daily and 77 cycles using intramuscular progesterone 50 mg daily as luteal support. Both groups had similar mean age, cause of infertility, baseline hormone levels, dosage of recombinant follicle-stimulating hormone, number of retrieved and fertilized oocytes, and number of transferred embryos. The vaginal gel group had significantly lower mid-luteal serum progesterone levels but higher implantation rate (32.5% vs. 18.5%, p = 0.001) and ongoing pregnancy rate (55.2% vs. 32.5%, p = 0.006). Within each group, mid-luteal serum progesterone levels between pregnant or non-pregnant patients were comparable. For patients with serum estradiol levels on day of human chorionic gonadotropin greater than 5,000 pg/mL, vaginal gel still resulted in better ongoing pregnancy and implantation rates. The use of vaginal progesterone gel twice daily for luteal support results in better pregnancy outcomes than intramuscular progesterone. A high local progesterone effect from vaginal gel might improve endometrial receptivity under extraordinarily high serum estradiol levels.

Embolization of Varicocles: Pretreatment Sperm Motility Predicts Later Pregnancy in Partners of Infertile Men

To identify predictors of future pregnancy in partners of infertile men undergoing embolization of varicoceles. This study was conducted within local institutional review board guidelines, and written informed consent was obtained. In 223 clinically infertile men (age range, 18-50 years) with varicoceles and associated oligoteratoasthenospermia, endovascular embolization of the spermatic veins was performed with distal coil embolization and sclerotherapy. Additional anti-inflammatory treatment was initiated if required. Baseline clinical examination, semen specimen, and hormone level findings were compared to follow-up data. Posttreatment pregnancy rate of their healthy female partners was assessed with a standardized questionnaire. Unconditioned logistic regression was used to identify factors among all available clinical and laboratory data predicting treatment success (sired pregnancy during follow-up). A total of 226 of 228 varicoceles in 223 patients were successfully treated. Resolution of varicoceles at clinical examination and ultrasonography (US) was observed in 206 patients (92.4%). Three-month follow-up semen analysis in these patients showed significant improvement in sperm motility (P < .001) and sperm count (P < .001); however, average values remained in the abnormal range (World Health Organization guidelines). In 173 patients, follow-up data were successfully obtained, with pregnancy reported in 45 (26%). Baseline sperm motility was identified as the only significant pretreatment factor (standardized regression coefficient beta = 3.285, t = 7.560, P = .006) predicting sired pregnancy. Hormone levels, clinical grading of varicoceles, Doppler US findings, and other semen parameters did not reach statistical significance. Sperm motility prior to varicocele treatment in infertile men is an important predictor of later pregnancy.

C.18.01 Use of adjunct therapy in the maintenance treatment of bipolar disorder

Hypothermic and hormonal responses to a challenge with a selective 5-HT1A receptor agonist ipsapirone are considered to provide an index of 5-HT1A receptor function in humans. To examine the effects of divalproex sodium (DVP) on 5-HT1A receptor function in humans, we measured the hypothermie, adrenocorticotropic hormone (ACTH) cortisol, and behavioral responses to ipsapirone in 10 healthy male volunteers. After obtaining a blood sample for baseline hormone levels and measuring body temperature, a single dose of 0.3 mg/kg of ipsapirone was given orally to all the subjects and further bloods and temperature reading were obtained at regular intervals for three hours. The ipsapirone challenge tests were repeated after the subjects had been treated with DVP (1000 mg/day) for one week. The results showed that the hypothermia induced by ipsapirone was significantly attenuated by the DVP treatment, whereas the ACTH/cortisol release and the behavioral responses following ipsapirone challenges were not altered. Our findings suggest that DVP may enhance 5-HT neurotransmission in humans via a subsensitization of 5-HT1A autoreceptors but does not appear to affect postsynaptic 5-HT1A receptors.

Disordered Mineral Metabolism in Hemodialysis Patients: An Analysis of Cumulative Effects in the Hemodialysis (HEMO) Study

Serum markers of disordered mineral metabolism have been associated with adverse outcomes in patients requiring long-term dialysis therapy. Although the values of these markers often evolve over time, no study has examined the accumulated effects of these abnormalities on important clinical end points. Retrospective cohort study. 1,846 prevalent hemodialysis patients randomly assigned in the Hemodialysis (HEMO) Study. Serum phosphorus, calcium, calcium-phosphorus (Ca x P) product, and intact parathyroid hormone, each analyzed at the time of randomization (baseline), as a standard time-dependent covariate and as a cumulative time-dependent covariate. All-cause mortality and the composite of all-cause mortality and first cardiac hospitalization. Cox proportional hazards models. In all analyses, serum phosphorus level greater than 6 mg/dL was associated with a heightened risk of mortality of approximately 25% compared with phosphorus values of 4.1 to 5 mg/dL. Serum calcium level greater than 11 mg/dL was associated with a 60% greater risk of death, but only when this parameter was analyzed as either a time-dependent or cumulative time-dependent variable. Ca x P product greater than 50 mg(2)/dL(2) was strongly associated with mortality, but only when assessed cumulatively. Similar relationships were observed when phosphorus, calcium, and Ca x P product values were related to the composite end point of all-cause mortality and first cardiac hospitalization. No relationships between baseline, time-dependent, and cumulative time-dependent intact parathyroid hormone levels and the outcomes of interest were observed. Residual confounding, lack of access to patient information before randomization in the HEMO Study, and concerns regarding generalizability given changes in practice patterns since the completion of the HEMO Study. Cumulative time-dependent analyses provide a different framework for analyzing the impact of factors that may mediate adverse events in hemodialysis patients. Our findings support maintaining serum phosphorus levels at less than 6 mg/dL, calcium levels at less than 11 mg/dL, and Ca x P product at less than 50 mg(2)/dL(2).

Effectiveness of antidepressant treatments in pre-menopausal versus post-menopausal women: A pilot study on differential effects of sex hormones on antidepressant effects

The incidence or recurrence of major depression is greatly increased in women during the transition to and after menopause and hormonal changes occurring during these periods are thought to play an important role in depressive recurrence. It has been also suggested that a chronic hypoestrogenic state may reduce the response to antidepressant drugs, but whether or not, and the extent to which hormonal changes related to menopause influence the response to antidepressant drugs, is yet to be determined. Thirty-nine female patients ( n = 17 in pre-menopause; n = 22 in post-menopause) with major depressive disorder (MDD) based on DSM-IV criteria, who were not on hormonal replacement therapy, participated in the study in order to prospectively evaluate the effect of menopausal status and its hormonal correlates on the effectiveness of antidepressant treatment for 6 weeks. The Hamilton Depression Rating Scale-17 item (HAMD), the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression Severity scale (CGI-S) were administered at baseline, week 1, week 3, and week 6. The CGI-I scale was also assessed at weeks 1, 3, and 6. After controlling for age, age at onset, baseline symptom severity, antidepressant dosage and hormonal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), post-menopausal women showed a poor response to antidepressants over 6 weeks of treatment, compared to the response of pre-menopausal women. Old age and high levels of FSH were also associated with the efficacy of antidepressants in post-menopausal women. In conclusion, sex hormones are known to interact with serotonergic, noradrenergic and dopaminergic systems. Despite methodological limitations, our study suggests that menopausal status and old age are predictors of a poor response to antidepressant treatment. Furthermore, the FSH may interfere with the mechanism of action of the antidepressant agents. Hence, larger, randomized and controlled trials are warranted to expand our understanding of this area.

Whites have a more robust hypothalamic–pituitary–adrenal axis response to a psychological stressor than blacks

Differences in the hypothalamic-pituitary-adrenal (HPA) axis response to stress may confer differences in susceptibility to a variety of diseases. We hypothesized that whites would differ from blacks in HPA axis response to a psychological stressor. Healthy subjects aged 18-30 were recruited from Baltimore, Maryland. At initial assessment, they completed psychometric tests measuring anxiety, mood, and personality. Subjects then participated in the Trier Social Stress Test (TSST), which consisted of 10 min of public speaking and mental arithmetic exercises. Subjective anxiety was measured immediately pre- and post-TSST. Race effects on cortisol, adrenocorticotrophin (ACTH), and prolactin responses to the TSST were analyzed by GEE longitudinal analysis methods. The analysis controlled for gender, baseline hormone levels, socioeconomic factors, anxiety, mood, and dimensions of personality. Ninety-eight subjects participated in the TSST. Whites had 36% greater relative mean cortisol response than blacks (95% CI: 10-67%, P=0.004). Whites had significantly higher mean ACTH compared to blacks at 25 min after the start of the TSST (35%, 95% CI: 16-58% greater, P<0.001). There was no difference in prolactin response. Of note, whites and blacks did not differ in subjective anxiety response to the TSST. In sum, we found that whites have a more robust HPA axis response to the TSST compared with blacks, even after controlling for several socioeconomic and psychological factors. In contrast, we observed no difference in prolactin response. There were no differences in subjective response to the TSST to explain the difference in HPA axis response. Further study is indicated to explain this finding and to test whether it can be extrapolated to other forms of stress.