Douglas C. Daly

Prolactin production during in vitro decidualization of proliferative endometrium

Decidua obtained in the late luteal phase of the human menstrual cycle has been shown to produce immunoreactive prolactin (PRL). The amount of PRL produced is a function of the extent of decidual differentiation. Further, the maintenance of decidualization and PRL production in specimens of late luteal phase in explant culture is dependent on the presence of progesterone (P). To further examine Ps effect on decidualization, PRL production was monitored during P-induced decidualization of proliferative endometrium in vitro. Samples of proliferative endometrium obtained from six hysterectomy specimens were cultured in Dulbeccos modified Eagle medium in the presence of no hormones, 200 pg/ml estradiol (E2) 20 ng/ml P, and 20 ng/ml P with 200 pg/ml E2. It was found that P alone or with E2 caused PRL production and histologic decidualization. However, E2 slowed the histologic progression of P-induced decidualization on days 2 and 4 and decreased the rate of PRL production (p less than 0.01) on days 6, 8, and 10 of culture. These data indicate that P alone is capable of inducing decidualization and initiating PRL production. Further, E2 can modify the rate and/or extent of this P-mediated phenomenon.

Cadmium, Lead, and Other Metals in Relation to Semen Quality: Human Evidence for Molybdenum as a Male Reproductive Toxicant

Background Evidence on human semen quality as it relates to exposure to various metals, both essential (e.g., zinc, copper) and nonessential (e.g., cadmium, lead), is inconsistent. Most studies to date used small sample sizes and were unable to account for important covariates. Objectives Our goal in this study was to assess relationships between exposure to multiple metals at environmental levels and human semen-quality parameters. Methods We measured semen quality and metals in blood (arsenic, Cd, chromium, Cu, Pb, manganese, mercury, molybdenum, selenium, and Zn) among 219 men recruited through two infertility clinics. We used multiple statistical approaches to assess relationships between metals and semen quality while accounting for important covariates and various metals. Results Among a number of notable findings, the associations involving Mo were the most consistent over the various statistical approaches. We found dose-dependent trends between Mo and declined sperm concentration and normal morphology, even when considering potential confounders and other metals. For example, adjusted odds ratios (ORs) for below-reference semen-quality parameters in the low, medium, and high Mo groups were 1.0 (reference), 1.4 [95% confidence interval (CI), 0.5–3.7], and 3.5 (95% CI, 1.1–11) for sperm concentration and 1.0 (reference), 0.8 (95% CI, 0.3–1.9), and 2.6 (95% CI, 1.0–7.0) for morphology. We also found preliminary evidence for interactions between Mo and low Cu or Zn. In stratified analyses, the adjusted ORs in the high Mo/low Cu group were 14.4 (1.6, 132) and 13.7 (1.6, 114) for below-reference sperm concentration and morphology, respectively. Conclusions Our findings represent the first human evidence for an inverse association between Mo and semen quality. These relationships are consistent with animal data, but additional human and mechanistic studies are needed.

A randomized study of dexamethasone in ovulation induction with clomiphene citrate

Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).

Environmental exposure to metals and male reproductive hormones: circulating testosterone is inversely associated with blood molybdenum

OBJECTIVE To explore associations between exposure to metals and male reproductive hormone levels. DESIGN Cross-sectional epidemiology study with adjustment for potential confounders. SETTING University Medical Center. PATIENT(S) Men recruited through two infertility clinics in Michigan. INTERVENTION(S) Metal concentrations and reproductive hormone levels were measured in blood samples collected from 219 men. MAIN OUTCOME MEASURE(S) Serum FSH, LH, inhibin B, T, and sex hormone-binding globulin levels. RESULT(S) Cadmium, copper, and lead were all significantly or suggestively positively associated with T when modeled individually, findings that are consistent with limited previous human and animal studies. Conversely, molybdenum was associated with reduced T. A significant inverse trend between molybdenum and T remained when additionally considering other metals in the model, and a positive association between T and zinc was also found. Finally, in exploratory analysis there was evidence for an interaction between molybdenum and zinc, whereby high molybdenum was associated with a 37% reduction in T (relative to the population median level) among men with low zinc. CONCLUSION(S) Although reductions in T and reproductive toxicity after molybdenum exposure have been previously demonstrated in animal studies, more research is needed to determine whether molybdenum poses a risk to human reproductive health.

A Pilot Study Associating Urinary Concentrations of Phthalate Metabolites and Semen Quality

Phthalates are ubiquitous industrial chemicals that are reported to adversely affect human reproductive outcomes. Divergent effects on semen quality have been reported in a limited number of studies. To assess the possible contribution of regional differences in phthalate exposure to these results, we wished to determine if ambient phthalate exposure of men from the Great Lakes region was associated with human sperm parameters. Male partners (N=45) of subfertile couples presenting to a Michigan infertility clinic were recruited. Urinary concentrations of several phthalate metabolites were measured in these men. Semen parameters, measured according to the World Health Organization [WHO 1999] protocols, were divided into those at or above WHO cutoffs for motility (50% motile), concentration (20thinsp;million/mL) and morphology (4% normal) and those below. Phthalate metabolite concentrations were divided into those concentrations above the median and those at or below the median. Specific gravity was used as a covariate in the regression models to adjust for urine dilution. Low sperm concentration was significantly associated with above median concentrations of monoethyl phthalate (MEP) (OR=6.5, 95% CI: 1.0–43.6) and low morphology with above median concentrations of mono-3-carboxypropyl phthalate (OR=7.6, 95% CI: 1.7–33.3). Increased odds for low concentration and above median concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP) (OR=5.4, 95% CI: 0.9–30.8) and low morphology and above median concentrations of MEP (OR=3.4, 95% CI: 0.9–13.8) were also found. A significant trend was observed for tertiles of MEP and low sperm concentration (p=0.05). Results suggest that ambient phthalate metabolite concentrations may adversely affect human semen quality.

Endometrial biopsy during treatment of luteal phase defects is predictive of therapeutic outcome

Luteal phase deficiency (LPD), as diagnosed by endometrial biopsy, is not a single disorder but rather a spectrum of dysfunction that reflects both endometrial cycle and ovarian cycle abnormalities. Forty-three patients were diagnosed as having LPD by two consecutive abnormal cycles. Seven patients (16%) with hyperprolactinemia received bromocriptine, and one hypothyroid patient received thyroid replacement. The remaining patients were treated sequentially with progesterone suppositories, clomiphene, the combination, and follicle-stimulating hormone and luteinizing hormone. If no conception occurred in 6 months on a given type of therapy, treatment was advanced. Patients were rebiopsied on each medication. In all, 33 of 41 (81%) compliant patients conceived. No viable pregnancies occurred without normal endometrial maturation, regardless of the treatment modality employed. When compared with time-life table projections, pregnancies occurred at rates comparable to those of a normal population once normal endometrial maturation was obtained with therapy. The endometrial biopsy accurately reflects the functional state of both the ovarian cycle and the endometrial cycle and can be used to determine adequacy of therapy, thereby improving conception rates in patients with LPD and eliminating the need for therapeutic trials.

Hysteroscopic metroplasty: surgical technique and obstetric outcome

Congenital Müllerian abnormalities, particularly the septate uterus, may result in recurrent abortion or premature labor. Twenty-five patients found to have a septate uterus during evaluation for infertility or recurrent abortion were treated by hysteroscopic metroplasty with laparoscopic visualization. Surgical outcome was excellent, intraoperative and postoperative morbidity was negligible, and the postoperative course was similar to that following laparoscopy alone. Preoperative fetal wastage in 17 previously fertile patients was 90%. Of 11 patients, 6 or more months postoperatively, 10 had conceived: 5 delivered vaginally at term, 2 delivered by cesarean section, and 2 pregnancies are in progress. One pregnancy miscarried at 21 weeks secondary to an incompetent cervix. With hysteroscopic metroplasty, septa can be incised successfully with lower morbidity and as good a surgical outcome as with abdominal procedures. If further studies confirm the pregnancy outcome reported, then hysteroscopic metroplasty should become the treatment of choice for the septate uterus.

Prolactin production by luteal phase defect endometrium

The production of prolactin (PRL) by explants of late secretory endometrium obtained during normal cycles (n = 61) and that by similar explants obtained during luteal phase deficient (n = 17) cycles was compared. The amount of prolactin produced in vitro correlated with the degree of histologic decidualization in both normal and luteal phase defect endometria. However, samples of luteal phase defect endometrium produced significantly less prolactin (p less than 0.01) than did control tissues of the same ideal menstrual dates. These data indicate that the amount of prolactin produced by late secretory endometrium in explant culture can be used as an additional criterion for the diagnosis of luteal phase defects and may also provide a method for evaluating the response of the endometrium to progesterone.

Multiple metals predict prolactin and thyrotropin (TSH) levels in men.

Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated with arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.

Ambient manganese exposure is negatively associated with human sperm motility and concentration.

Background: Occupational and experimental animal studies indicate that exposure to high levels of manganese impairs male fertility, but the effects of ambient manganese in humans are not known. Methods: We measured blood levels of manganese and selenium in 200 infertility clinic clients in a cross-sectional study. Correlations between metals and semen variables were determined, adjusting for other risk factors. Outcomes were low motility (<50% motile), low concentration (<20 million/mL), or low morphology (<4% normal). We also investigated dose–response relationships between quartiles of manganese exposure and sperm parameters. Results: High manganese level was associated with increased risk of low sperm motility (odds ratio = 5.4; 95% confidence interval = 1.6–17.6) and low sperm concentration (2.4; 1.2–4.9). We saw a U-shaped dose–response pattern between quartiles of manganese exposure and all 3 sperm parameters. Conclusion: Ambient exposure to manganese levels is associated with a reduction in sperm motility and concentration. No adverse effects were seen for high selenium.