Epidemiologic evidence on biological and environmental male factors in embryonic loss.
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Abortion, Spontaneous↗
Biomedical subjects
A Giwercman
Publications and source records attributed to A Giwercman.
No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions.
The functional role of the GGN repeat in the human androgen receptor gene is unknown, although mutations in this region have been found in patients with inter-sex conditions. We have investigated the prevalence of GGN mutations in the androgen receptor in the Swedish population and their relation to male reproductive function. A physical examination and semen analysis was carried out in 223 men under medical examination before military service and in 94 men referred due to infertility and having sperm concentrations <5 x 10(6)/ml. The GGN and CAG repeats in the androgen receptor gene were directly sequenced. Both populations contained two predominant alleles of 23 and 24 GGN repeats, 83.8 and 90.5% respectively. Four mutations, three in the conscripts and one among the infertile men, were found, resulting in three GGC to GGT substitutions and one GGT to GGC substitution. None of the men presented with genital abnormalities, but two conscripts had low ejaculate volumes (0.3 and 0.9 ml). All men carrying a mutation also had GGN lengths >or=24. Three subjects with GGN >24, with no mutations and with normal seminal volumes, were also found. Our findings indicate that point mutations in the GGN repeat are frequently found in the general male population (1.3%; 95% CI: 0.3-3.9%), but are usually not associated with profound changes in the male phenotype.
Humans↗
The impact of epididymal and accessory sex gland function on sperm motility.
BACKGROUND: Little is known about the regulation of sperm motility, which is an important predictor of male fertility. However, both testicular and post-testicular factors may be involved, although the impact of the latter has been relatively poorly investigated. METHODS: In semen samples from 301 young men from the general Swedish population (mean +/- SD age 18.2 +/- 0.4 years), we assessed sperm motility by use of a manual method as well as computer-assisted sperm analysis (CASA) and correlated these values to seminal levels of neutral alpha-glucosidase (NAG), prostate-specific antigen (PSA), zinc and fructose. RESULTS: There were significant positive correlations between seminal levels of NAG, and PSA and CASA percentage motile sperm (r = 0.158, P = 0.009; r = 0.155, P = 0.01 respectively), and significant negative correlations with CASA percentage immotile sperm (r = -0.206, P = 0.001; r = -0.157, P = 0.009 respectively). In a multiple regression analysis it was found that, apart from sperm concentration, the level of PSA was the most significant and independent parameter in predicting percentage motile sperm (beta = 0.220, P = 0.037). CONCLUSION: Our study demonstrated the regulatory effect of post-testicular glands on the motility of sperm. This is to our knowledge the first study showing a direct correlation between the seminal PSA levels and sperm motility in a group of men representing the general population. In future investigations and searches for specific treatment modalities in male infertility, more attention should be paid to the epididymis and accessory sex gland function.
Adolescent↗
The impact of testicular and accessory sex gland function on sperm chromatin integrity as assessed by the sperm chromatin structure assay (SCSA).
BACKGROUND: The sperm chromatin structure assay (SCSA) provides an objective assessment of sperm chromatin integrity, which is essential for normal sperm function. SCSA is valuable as a fertility marker in epidemiological studies and in the clinical situation. Little is known about the impact of testicular and post-testicular function on SCSA parameters. METHODS: Ejaculates from 278 military conscripts of median age 18.1 (range 18-21) years were included. Levels of reproductive hormones, the length of the CAG repeat of the androgen receptor gene, sperm concentration, abstinence period and biochemical parameters of epididymal and accessory sex gland secretions were correlated to the SCSA parameters, DNA fragmentation index (DFI) and highly DNA stainable (HDS) cells. RESULTS: Negative correlations were found between sperm concentration and DFI (r = -0.119, P = 0.049) and HDS (r = -0.513, P < 0.0001). DFI was negatively correlated with levels of estradiol (r = -0.19, P = 0.002) and free testosterone (r = -0.13, P = 0.03). DFI also correlated positively with abstinence time (r = 0.17, P = 0.005), and with seminal concentrations of fructose (r = 0.18, P = 0.004) and zinc (r = 0.12, P = 0.04). CONCLUSIONS: Sex steroid production, spermatogenic function, abstinence time and seminal vesicle function appear to impact on sperm chromatin integrity and thereby on sperm fertilizing capacity. These findings may improve present understanding of the pathophysiology of male infertility.
Adolescent↗
Higher sperm counts in Southern Sweden compared with Denmark.
BACKGROUND: A common aetiology behind time-related deterioration of male reproductive function, including decline of sperm concentration and rising incidence of testicular cancer and cryptorchidism, has been suggested. Accordingly, a high incidence of testicular cancer and low sperm counts have been observed in Denmark, while in Finland opposite figures were found. This may be due to genetic factors. The incidence of testicular cancer is 50% lower in Sweden than in Denmark. Data on sperm counts in a population of Danish military conscripts have been published and we wished therefore to compare them with semen parameters in a corresponding cohort from Southern Sweden, geographically and genetically very closely related to Denmark. METHODS: A total of 305 military conscripts was recruited and investigated in an identical way as those in the Danish study including a questionnaire, physical examination and semen analysis. RESULTS: Men born and raised in Sweden had a 23% higher mean sperm concentration, a 31% higher mean total sperm count and a 14% higher seminal volume compared with their Danish counterparts. CONCLUSIONS: The differences in reproductive parameters between the two genetically very similar populations could not be explained by possible confounders and may be due to unknown environmental or lifestyle-related factors.
Adult↗
Sperm count and chromatin structure in men exposed to inorganic lead: lowest adverse effect levels.
OBJECTIVES: To obtain knowledge on male reproductive toxicity of inorganic lead at current European exposure levels and to establish lowest adverse effect levels, if any. METHODS: A cross sectional survey of the semen of 503 men employed by 10 companies was conducted in the United Kingdom, Italy, and Belgium. The mean blood lead concentration was 31.0 microg/dl (range 4.6-64.5) in 362 workers exposed to lead and 4.4 microg/dl (range below the detection limit of 19.8) in 141 reference workers. Semen volume and sperm concentration were determined in a fresh semen sample according to an agreed protocol subject to quality assurance. The sperm chromatin structure assay (SCSA) was performed at a centralised laboratory. Extraneous determinants including centre, period of sexual abstinence, and age were taken into account in the statistical analysis. If appropriate, possible thresholds were examined by iterative threshold slope linear regression. RESULTS: The median sperm concentration was reduced by 49% in men with blood lead concentration above 50 microg/dl. There was no indication of a linear trend of lower sperm concentration with increasing blood lead values, but threshold slope least square regression identified a blood lead concentration of 44 microg/dl (beta=-0.037, F=4.35, p=0.038) as a likely threshold. Abnormal sperm chromatin structure was not related to blood lead concentration, but some indications of deterioration of sperm chromatin was found in men with the highest concentrations of lead within spermatozoa. Biological monitoring data did not indicate long term effects of lead on semen quantity or sperm chromatin. CONCLUSION: Adverse effects of lead on sperm concentration and susceptibility to acid induced denaturation of sperm chromatin are unlikely at blood lead concentrations below 45 microg/dl. Effects of low level exposure to lead on other measures of testicular function cannot be ruled out.
Adult↗
Inter-observer variation in the results of the clinical andrological examination including estimation of testicular size.
Inter-observer variation in andrological examination by 10 clinical investigators from five Nordic and Baltic countries was investigated. In addition, information on intra-observer variation was obtained for six of the 10 investigators. Testicular size was measured using Prader's orchidometer and one of the investigators also performed an ultrasound estimate of testicular size. A highly significant difference (p < 0.001) between observers was found with an inter-observer error of 16% in estimating testicular size in 23 young men. The difference in the estimate tended to increase with increasing testicular size. There was no significant intra-observer difference in two measurements performed on consecutive days. Only differences in median testis size, which were greater than 31% between measurements by two investigators, were found to be significant at the 5% level. The ultrasound estimate of testicular size was significantly lower than the orchidometer estimate, with a mean difference of 3.6 mL for the left testis and 4.3 mL for the right testis. Tanner staging of genitalia and diagnosis of a varicocele was subject to great inter-observer variation, and for the diagnosis of varicocele only one-third of the investigators was able to reproduce their results on a second examination. In conclusion, it was found that the clinical andrological examination of young men is subject to great inter-observer variation. This should be kept in mind when results from different studies are compared as well as in daily clinical practice.
Adult↗
Cancer and male infertility.
An increasing proportion of boys and young men with cancer will survive their disease and desire fertility. Unfortunately, the cancer treatment, and in some cases the malignant disease itself, may have a negative and permanent impact on the individual's fertility potential. This effect is highly dependent on the type and dose of therapy as well as the age at which it has been given. Basic knowledge in this field is necessary to enable oncologists and fertility specialists to counsel these patients about their fertility prospects and, if appropriate, advise them to take precautions (e.g. the cryopreservation of semen) to safeguard their fertility. Another aspect of the relationship between cancer and infertility is the possibility that men with testicular dysfunction may have an increased risk of testicular cancer. Screening for early testicular malignancy may therefore be advisable in some groups of men with poor semen quality.
Antineoplastic Agents↗
Computer-assisted semen analysis parameters as predictors for fertility of men from the general population. The Danish First Pregnancy Planner Study Team.
The predictive value of sperm motility parameters obtained by computer-assisted semen analysis (CASA) was evaluated for the fertility of men from general population. In a prospective study with couples stopping use of contraception in order to try to conceive, CASA was performed on semen samples from 358 men. A recently developed CASA system, Copenhagen Rigshospitalet Image house sperm Motility Analysis System (CRISMAS) was used for assessment of motility parameters. This system has an editing function which allows correction of tracks made by the computer. Probably due to this function, the concentration assessment made by CRISMAS was very close to that made by the technician (median difference <5%) in all concentration ranges. Correlation between CASA parameters and fertility of normal couples (measured as probability of achieving pregnancy) was examined by the Cox regression model. In univariate models ln(sperm concentration) [beta = 0.331, risk ratio (RR) = 1.392, P = 0.0001], ln(total sperm count) (beta = 0.252, RR = 1.286, P = 0.0007) and percentage motile spermatozoa (beta = 0.014, RR = 1.014, P = 0.0004) were most significant predictors for fertility. In a multivariate analysis ln(sperm concentration) (beta = 0.268, RR = 1.307, P = 0.0016) and percentage motile spermatozoa (beta = 0.010, RR = 1.010, P = 0.011) but even more significantly the combined parameter, ln(concentration of motile spermatozoa) (beta = 0.329, RR = 1.389, P = 0.0001), were the only parameters of predictive value for fertility of men in the general population. In conclusion, these parameters obtained by CASA measurements can be used for prediction of fertility potential in normal men. This appears to be the first study showing the value of CASA in prediction of fertility in the general male population.
Adult↗
Spontaneous abortion and physical strain around implantation: a follow-up study of first-pregnancy planners.
Existing studies of physical strain and spontaneous abortion are mainly retrospective or based only on pregnancies that have survived the first trimester. Furthermore, almost all studies have relied on averaged measures of physical strain, which tend to blur an effect if peak values during short time periods are the relevant measure. We followed a cohort of first pregnancy planners from termination of birth control until pregnancy for a maximum of six menstrual cycles. The analyses include 181 pregnancies, of which 32 were subclinical pregnancies detected by hCG analysis only. During early pregnancy the women recorded physical strain prospectively in a structured diary. Physical strain around the time of implantation was associated with later spontaneous abortion. The adjusted risk ratio for women who reported physical strain higher than average at day 6 to 9 after the estimated date of ovulation was 2.5 (95% CI = 1.3-4.6).
Abortion, Spontaneous↗
Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene.
Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility. Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C-->A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed that their grandfathers, on their mothers' side, were brothers; and the Gln824Lys mutation was also found in the one of them who was still alive. Binding studies with the mutant receptor in transfected COS-7 cells, with mibolerone as ligand, exhibited equal Kd (0.7 vs. 1.0 nmol/ L), IC50 (0.8 vs. 1.1 nmol/L), and maximum binding (7.1 vs. 8.9 fmol/ 10(6) cells), as compared with the wild-type (WT) receptor. In a chloramphenicol acetyl transferase trans-activation assay, the activity of the mutant receptor was identical to that of the WT, when the synthetic androgen R1881 was'used as a ligand; but with dihydrotestosterone, in concentrations up to 10 nmol/L, the activity of Gln824Lys mutated receptor was 10-62% of the WT variant. Thus, Gln824Lys mutation was found, both in vivo and in vitro, to cause slight impairment of receptor function but was compatible with preservation of male fertility. The patients inherited the mutation from their grandfathers through their mothers, and one of the young men possessing the mutation has fathered a daughter.
Adult↗
Male-mediated spontaneous abortion among spouses of stainless steel welders.
OBJECTIVES: Male-mediated spontaneous abortion has never been documented for humans. The welding of stainless steel is associated with the pulmonary absorption of hexavalent chromium, which has genotoxic effects on germ cells in rodents. Clinical and early subclinical spontaneous abortions were examined among spouses of stainless-steel welders. METHODS: A cohort of first-pregnancy planners was recruited from members of the union of metal workers and 3 other trade unions. The cohort was followed for 6 menstrual cycles from the cessation of contraceptive use. Altogether, 280 pregnancies were conceived, of which 35 were detected by human chorionic gonadotrophic hormone analysis and did not survive to a clinically recognized pregnancy. Information on exposure was collected prospectively in relation to the outcome and was available for all cycles resulting in a pregnancy. Information on pregnancy outcome was collected for all 245 clinically recognized pregnancies. RESULTS: Increased risk of spontaneous abortion was found for pregnancies with exposure to paternal stainless-steel welding (adjusted relative risk 3.5, 95% confidence interval 1.3-9.1). The results were consistent in analyses of both biochemically and clinically recognized abortions. There was no increased risk for spontaneous abortion in pregnancies with paternal exposure to the welding of metals other than stainless steel. CONCLUSIONS: Male welding of stainless steel was associated with an increased risk of spontaneous abortion in spouses. A mutagenic effect of hexavalent chromium has been found previously in both somatic and germ cells, and the findings could be due to mutations in the male genome.
Abortion, Spontaneous↗
Initiation of sperm production after bilateral orchiopexy: clinical and biological implications.
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Adult↗
Human semen quality in relation to dietary pesticide exposure and organic diet.
The objective of the study was to corroborate or refute the hypothesis that farmers having a high intake of organic grown commodities have a high semen quality due to their expected lower level of dietary pesticides intake. Food frequency data and semen were collected from 256 farmers (171 traditional farmers and 85 organic farmers, overall participation rate: 32%) who were selected from central registers. Each farmer delivered one semen sample before the spraying season started. The farmers were divided into three groups where the commodities from organic production contributed no (N, 0%), medium (M, 1-49%), or a high (H, 50-100%) proportion of the fruit and vegetables consumed. Farmers having a high relative intake of organically grown fruit and vegetables also had a high relative consumption of organically produced meat, milk, and bread, and differences were observed comparing the actual mean intake of single commodities, such as rice, potato, and pork meat. The current individual dietary intake of 40 pesticides was estimated using food frequencies and generalized serving size data in combination with data on pesticide concentrations in food commodities as obtained from the National Danish Food Monitoring Program. The estimated pesticide intake was significantly lower among farmers of group H, but for all three groups of farmers the average dietary intake of 40 pesticides was at or below 1% of the acceptable daily intake (ADI) except for the dithiocarbamates (max = 0.21 microg/kg day = 2.2% ADI), methidathion, (max = 0.01 microg/kg day = 1.4% ADI), and 2-phenylphenol (max = 0.21 microg/kg day = 1.1% ADI). The median sperm concentration for the three groups of farmers was not significantly different (p = 0.40, median sperm concentration was N = 62, M = 44, and H = 75 million/ml). The group of men without organic food intake had a significant lower proportion of morphologically normal spermatozoa, but in relation to 14 other semen parameters no significant differences were found between the groups. Intake of 40 individual pesticides was correlated with four semen parameters (concentration, percentage dead spermatozoa, percentage normal sperm heads, and motility [VCL]). Five significant correlations (p value 0.01) were found among the 160 comparisons in relation to percentage dead spermatozoa: azinphos-methyl, carbaryl, chlorfenson, fenitrothion, and tetradifon. For all of them a lower percentage of dead spermatozoa were found in the groups with a high dietary intake of the specific pesticide. In contrast, for all pesticides evaluated only minor differences were found between the groups when considering spermatozoa concentration, morphology, and motility. In conclusion, the estimated dietary intake of 40 pesticides did not entail a risk of impaired semen quality, but precautions should be taken when generalizing this negative result to populations with a higher dietary exposure level or an intake of other groups of pesticides.
Adult↗
Menstrual cycle pattern and fertility: a prospective follow-up study of pregnancy and early embryonal loss in 295 couples who were planning their first pregnancy.
OBJECTIVE: To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. DESIGN: Prospective follow-up study. SETTING: Healthy couples recruited throughout Denmark. PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity. CONCLUSION(S): The mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.
Abortion, Spontaneous↗
Distress and reduced fertility: a follow-up study of first-pregnancy planners.
OBJECTIVE: To assess the effect of psychological distress on time to first pregnancy. DESIGN: A follow-up study of time to pregnancy with prospective data on distress, with controlling for potential confounding variables. SETTING: Two university hospitals. PATIENT(S): Danish couples (n = 430) who were planning their first pregnancy and had no previous reproductive experience were followed for six menstrual cycles. Psychological distress was measured in each menstrual cycle by the General Health Questionnaire. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A clinically recognized pregnancy or a biochemical pregnancy detected in urine samples from each period of vaginal bleeding. RESULT(S): For cycles with the highest distress score (General Health Questionnaire score >80th percentile), the probability of conception per cycle was 12.8%, compared with 16.5% in other cycles (adjusted odds ratio [OR] 0.6; 95% confidence interval [CI] 0.4-1.0). The effect of distress was found almost exclusively among women with long menstrual cycles (OR 0.1; 95% CI 0.01-0.4 and OR 0.9; 95% CI 0.5-1.4 for women with cycles of > or =35 and <35 days, respectively). An increased incidence of early embryonal loss was also found among highly distressed women with long cycles, but was based on a small number of observations. CONCLUSION(S): Psychological distress may be a risk factor for reduced fertility in women with long menstrual cycles.
Abortion, Spontaneous↗
Secular and seasonal changes in semen quality among young Danish men: a statistical analysis of semen samples from 1927 donor candidates during 1977-1995.
The objective of this study was to investigate whether semen quality has changed during the years 1977-1995 in a group of unselected semen donor candidates, and to determine whether semen quality is subject to seasonal variation, by analysis of time- and season-related changes in semen quality using multiple regression and ANOVA. The study was based on analysis of the first semen sample delivered by 1927 semen donor candidates in Copenhagen during the period 1977-1995, with determination of semen volume, sperm concentration, total sperm count, percentage motile spermatozoa, and a semiquantitative sperm motility score. Multiple linear regression analysis with year, sexual abstinence and season as covariates showed a significant increase in mean sperm concentration from 53.0 x 10(6)/mL in 1977 to 72.7 x 10(6)/mL in 1995 (p < 0.0001) and in mean total sperm count from 166.0 x 10(6) to 227.6 x 10(6) (p < 0.0001). Mean semen volume and percentage motile spermatozoa did not change. Sperm motility deteriorated, as the spermatozoa in 74.2% of the samples were of excellent motility in 1977-1980 compared to only 41.9% in 1993-1995 (chi 2 = 130.0, p < 0.0001). Analysis of variance showed significant variation between seasons regarding sperm concentration (p < 0.0001) and total sperm count (p < 0.0001). Highest sperm counts were found in spring, with a mean concentration (95% C.I.) of 77.6 x 10(6)/mL (71.9-83.7), and lowest in summer, with a mean of 57.5 x 10(6)/mL (50.1-65.4). No other semen parameter varied with season. It is concluded that sperm counts increased, whereas sperm motility decreased, in a group of Danish semen donor candidates, from 1977 to 1995. Due to the retrospective design and the anonymity of the donors, we were unable to control for variation in donor age, and we cannot exclude the possibility that some donor candidates were selected by being accepted as donors by other semen donor services in Copenhagen. With these limitations in mind, we suggest our results should be interpreted cautiously and regarded as a contribution to the ongoing dispute on whether or not there is a continuous decrease in sperm quality. The seasonal variations found in sperm concentration and total sperm count were pronounced and were not attributable to seasonal differences in the length of sexual abstinence. Additionally, the same seasonal pattern was observed in five successive year-intervals. These findings strongly indicate that human testicular function is influenced by season, a phenomenon well known in many lower mammals.
Adult↗
Semen quality and sex hormones among organic and traditional Danish farmers. ASCLEPIOS Study Group.
OBJECTIVES: To confirm or refute the hypothesis that organic farmers have higher sperm concentrations than traditional farmers. METHODS: Traditional and organic farmers were selected randomly from central registers, and 171 traditional farmers and 85 organic farmers delivered one semen sample before the start of the spraying season. The participation rate was 28.8% among traditional farmers and 42.9% among organic farmers. RESULTS: The median sperm concentration for traditional and organic farmers was 58 million/ml and 64 million/ml, respectively. After adjustment for several confounders, sperm concentration, total count, proportion of non-vital spermatozoa, sperm chromatin structure, and motility variables did not differ significantly between the two groups. The traditional farmers had a significantly lower proportion of normal spermatozoa, but this result was not confirmed in a second sample. Organic farmers had slightly higher inhibin B concentration and testosterone/sex hormone binding globulin ratio. CONCLUSION: Despite slight differences in concentrations of reproductive hormones, no significant differences in conventional measures of semen quality were found between organic and traditional farmers.
Adult↗