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1.  The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve reproductive outcome. A randomised controlled trial 
BMC Women's Health  2010;10:22.
In the Netherlands, 30% of subfertile women are overweight or obese, and at present there is no agreement on fertility care for them. Data from observational and small intervention studies suggest that reduction of weight will increase the chances of conception, decrease pregnancy complications and improve perinatal outcome, but this has not been confirmed in randomised controlled trials. This study will assess the cost and effects of a six-months structured lifestyle program aiming at weight reduction followed by conventional fertility care (intervention group) as compared to conventional fertility care only (control group) in overweight and obese subfertile women. We hypothesize that the intervention will decrease the need for fertility treatment, diminish overweight-related pregnancy complications, and will improve perinatal outcome.
Multicenter randomised controlled trial in subfertile women (age 18-39 year) with a body mass index between 29 and 40 kg/m2. Exclusion criteria are azoospermia, use of donor semen, severe endometriosis, premature ovarian failure, endocrinopathies or pre-existent hypertensive disorders.
In the intervention group the aim is a weight loss of at least 5% to10% in a six-month period, to be achieved by the combination of a diet, increase of physical activity and behavioural modification. After six months, in case no conception has been achieved, these patients will start fertility treatment according to the Dutch fertility guidelines. In the control group treatment will be started according to Dutch fertility guidelines, independently of the patient's weight.
Outcome measures and analysis
The primary outcome measure is a healthy singleton born after at least 37 weeks of gestation after vaginal delivery. Secondary outcome parameters including pregnancy outcome and complications, percentage of women needing fertility treatment, clinical and ongoing pregnancy rates, body weight, quality of life and costs.
Data will be analysed according to the intention to treat principle, and cost-effectiveness analysis will be performed to compare the costs and health effects in the intervention and control group.
The trial will provide evidence for costs and effects of a lifestyle intervention aiming at weight reduction in overweight and obese subfertile women and will offer guidance to clinicians for the treatment of these patients.
Trial registration
Dutch Trial Register NTR1530
PMCID: PMC2907305  PMID: 20579357
2.  The Association Risk of Male Subfertility and Testicular Cancer: A Systematic Review 
PLoS ONE  2009;4(5):e5591.
An association between male subfertility and an increased risk of testicular cancer has been proposed, but conflicting results of research on this topic have rendered this theory equivocal. To more precisely assess the association between subfertility and the risk of testicular cancer, we performed a systematic review of international epidemiologic evidence.
Principal Findings
We searched the Medline database for records from January 1966 to March 2008 complemented with manual searches of the literature and then identified studies that met our inclusion criteria. Study design, sample size, exposure to subfertility and risk estimates of testicular cancer incidence were abstracted. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the DerSimonian and Laird model. All statistical tests were two-sided. We identified seven case-control studies and two cohort studies published between 1987 and 2005. Analysis of the seven case-control studies that included 4,954 participants revealed an overall statistically significant association between subfertility and increased risk of testicular cancer (summary RR = 1.68, 95% CI: 1.22 to 2.31), without heterogeneity between studies (Q = 8.46, P heterogeneity = 0.21, I2 statistics = 0.29). The association between subfertility and testicular cancer was somewhat stronger in the United States (summary RR = 1.75, 95% CI: 1.01 to 3.02) than it was in Europe (summary RR = 1.53, 95% CI: 1.22 to 1.92). The source of the control subjects had a statistically significant effect on the magnitude of the association (population-based summary—RR = 2.15, 95% CI: 1.11 to 4.17; hospital-based summary—RR = 1.56, 95% CI: 0.93 to 2.61). After excluding possible cryptorchidism, an important confounding factor, we also found a positive association between subfertility and increased risk of testicular cancer (summary RR = 1.59, 95% CI: 1.28 to 1.98). These results were consistent between studies conducted in the United States and in Europe (Q = 0.20, P heterogeneity = 0.66). Of the two cohort studies that reported standardized incidence ratios, both reported a statistically significant positive association between subfertility and increased risk of testicular cancer.
Our findings support a relationship between subfertility and increased risk of testicular cancer and apply to the management of men with subfertility, and prevention and diagnosis of testicular cancer.
PMCID: PMC2680046  PMID: 19440348
3.  Case-control study of whether subfertility in men is familial. 
BMJ : British Medical Journal  1994;309(6954):570-573.
OBJECTIVE--To test the hypothesis that subfertility in men is familial and to examine the distribution of subfertility within families for consistency with a genetic cause. DESIGN--Case-control study and segregation analysis. SETTING--Two teaching hospitals in Leeds. SUBJECTS--Cases (probands) were men with an abnormal sperm count who attended a subfertility clinic and whose partners had no major factor contravening fertility. Controls were fathers of two or more children recruited through vasectomy clinics or a maternity department. MAIN OUTCOME MEASURES--The incidence of involuntary childlessness among brothers with partners and among sisters and second and third degree male relatives. When possible clinical and laboratory details were obtained from involuntarily childless brothers. RESULTS--Seventeen of the 148 (11.5%) brothers of probands but none of the 169 brothers of controls had sought medical advice for childlessness (P < 0.0005). Four probands had more than one involuntarily childless brother. There were six further brothers whose childlessness was thought to be involuntary bringing the total prevalence of subfertility among brothers of probands to 16%. Segregation analysis was consistent with an autosomal recessive mode of inheritance accounting for 60% of subfertility in men. Seventeen of the 346 (4.9%) uncles of probands and 10 of 420 (2.8%) uncles of controls were reported to be involuntarily childless (P = 0.09), but there was no difference in childlessness among sisters. In three families sperm counts from "affected" brothers confirmed the diagnosis and showed considerable similarities within but not between families. CONCLUSION--Subfertility in men has a familial component, and the observations are consistent with an autosomal recessive mode of inheritance in over half the cases. Several different genes are probably involved.
PMCID: PMC2541440  PMID: 8086942
4.  Electroacupuncture enhances spermatogenesis in rats after scrotal heat treatment 
Spermatogenesis  2012;2(1):53-62.
Spermatogenesis is regulated by a cascade of steroid regulated genes in the testis. Recent studies suggested that acupuncture may improve fertility in men with abnormal semen parameters. Yet, the underlying mechanisms in which acupuncture enhances spermatogenesis remain largely unknown. Here we used a scrotal heat-treated rat model to study the effect of electroacupuncture (EA) on recovery of spermatogenesis. In this model, spermatogenesis was disrupted by 30 min scrotal heat treatment at 43°C. Ten sessions of EA were given at Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Sanyinjiao (SP6) from day 9 to day 36 post-treatment. Sperm motility and production, morphology of the germinal epithelium by Johnsen’s scoring, germ cell apoptosis by TUNEL staining, proliferation by proliferating cell nuclear antigen (PCNA) staining, as well as serum testosterone and inhibin B levels by immunoassays were evaluated on day 0, 1, 9, 25, 37, 46, 56 and 79. When compared with the heat-treated (H) group, the heat-treated plus EA (H+EA) group showed a significant increase (p < 0.05) in PCNA-positive cells and inhibin B levels on days 37 and 46, and a higher Johnsen’s score till day 56. On day 79, motile spermatozoa could be found in the vas deferens of H+EA group only. Consistently, there was a trend of improved motility and increased number of motile epididymal spermatozoa in the H+EA group than the H group; while apoptosis of germ cells and serum testosterone levels were similar between the two groups. Taken together, EA enhanced germ cell proliferation through improvement of Sertoli cell functions. This may facilitate the recovery of spermatogenesis and may restore normal semen parameters in subfertile patients.
PMCID: PMC3341246  PMID: 22553490
Apoptosis; electroacupuncture; proliferation; spermatogenesis; spermatozoa
5.  Mammalian E-type Cyclins Control Chromosome Pairing, Telomere Stability and CDK2 Localization in Male Meiosis 
PLoS Genetics  2014;10(2):e1004165.
Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.
Author Summary
Understanding the control of meiosis is fundamental to deciphering the origin of male infertility. Although the mechanisms controlling meiosis are poorly understood, key regulators of mitosis, such as cyclins, appear to be critical. In this regard, male mice deficient for cyclin E2 exhibit subfertility and defects in spermatogenesis; however, neither the stages of germ cell differentiation affected nor the responsible mechanisms are known. We investigated how E-type cyclins control male meiosis by examining their expression in spermatogenesis and the consequences that multiple deletions of Ccne1 and Ccne2 alleles produce. Loss of Ccne2 expression increases cyclin E1 levels as a compensatory effect, but there are still meiotic defects and subfertility. Further, loss of one Ccne1 allele in the absence of cyclin E2 results in infertility as does loss of the remaining Ccne1 allele, but with even more severe meiotic abnormalities. We further found that cyclin E1 is involved in sex chromosome synapsis while E2 is involved with homologous pairing and chromosome and telomere integrity. These processes and structures were severely disrupted in absence of both cyclin E1 and E2, uncovering new roles for the E-type cyclins in regulating male meiosis.
PMCID: PMC3937215  PMID: 24586195
6.  Association of body mass index with some fertility markers among male partners of infertile couples 
The available evidence on the role of obesity and body mass index (BMI) on male infertility has been controversial or inconclusive to some extent.
The aim of this study was to investigate the role of BMI on some male-fertility laboratory indicators both among infertile and fertile men in an Iranian population.
Methods and materials
A total of 159 male patients who had lived as a partner in an infertile couple for at least 1 year, after regular reproductive activity in their married life, and who sought infertility consultation, were investigated. BMI was assessed, and a morning blood sample was taken assessing serum levels of testosterone, sex hormone-binding globulin, prolactin, luteinizing hormone (LH), follicle-stimulating hormone, and estradiol. Semen-analysis parameters were also measured.
In this study, it was found that the likelihood of oligospermia was increased at higher BMI values. Obese men were found to be 3.5 times more likely to have oligospermia than those with normal BMI. BMI was not found to be associated with mean numeric values of the semen-analysis parameters, including sperm count, sperm morphology, and sperm motility. BMI was not significantly correlated with some hormone levels, such as LH, prolactin, and LH/follicle-stimulating hormone ratio. However, a statistically significant association was observed between BMI and estradiol (P < 0.01), sex hormone-binding globulin (P < 0.001), and also the testosterone/estradiol ratio (P < 0.001). A different pattern of associations in this study was observed when the associations between BMI and sexual hormone levels were compared between fertile and subfertile/infertile men.
The association explored between BMI and some sexual hormones and semen characteristics, as well as different patterns of this association between fertile and subfertile/infertile men, will be of help to broaden our understanding of the effect of obesity on some male reproductive physiologic characteristics among fertile and infertile men.
PMCID: PMC3682849  PMID: 23785240
male infertility; body mass index; sperm analysis; sexual hormones
7.  An Extract of Pomegranate Fruit and Galangal Rhizome Increases the Numbers of Motile Sperm: A Prospective, Randomised, Controlled, Double-Blinded Trial 
PLoS ONE  2014;9(10):e108532.
Pomegranate fruit (Punica granatum) and galangal (Alpinia galanga) have separately been shown to stimulate spermatogenesis and to increase sperm counts and motility in rodents. Within traditional medicine, pomegranate fruit has long been used to increase fertility, however studies on the effect on spermatogenesis in humans have never been published. With this study we investigated whether oral intake of tablets containing standardised amounts of extract of pomegranate fruit and powder of greater galangal rhizome (Punalpin) would increase the total number of motile spermatozoa. The study was designed as a prospective, randomized, controlled, double-blinded trial. Enrolment was based on the mean total number of motile spermatozoa of two ejaculates. The participants delivered an ejaculate after 4–8 days of tablet intake and two ejaculates just before they stopped taking the tablets. Seventy adult men with a semen quality not meeting the standards for commercial application at Nordic Cryobank, but without azoospermia, were included in the study. Participants were randomized to take tablets containing extract of pomegranate fruit (standardised with respect to punicalagin A+B, punicalin and ellagic acid) and freeze-dried rhizome of greater galangal (standardised with respect to 1′S-1′-acetoxychavicol acetate) or placebo on a daily basis for three months. Sixty-six participants completed the intervention (active treatment: n = 34; placebo: n = 32). After the intervention the total number of motile spermatozoa was increased in participants treated with plant extracts compared with the placebo group (p = 0.026). After three months of active treatment, the average total number of motile sperm increased by 62% (from 23.4 to 37.8 millions), while for the placebo group, the number of motile sperm increased by 20%. Sperm morphology was not affected by the treatment. Our findings may help subfertile men to gain an improved amount of motile ejaculated sperm by taking tablets containing preparations of pomegranate fruit extract and rhizome of greater galangal.
Trial Registration NCT01357044
PMCID: PMC4190413  PMID: 25275520
8.  Total fertilization failure and idiopathic subfertility 
To gain more insight in whether failure of intrauterine insemination (IUI) treatment in patients with idiopathic subfertility could be related to diminished fertilization, the aim of this study is to compare the fertilization of an initial IVF procedure after six cycles of IUI and the fertilization of an initial IVF procedure without preceding IUI cycles in couples with idiopathic subfertility.
We performed a complimentary analysis of a randomized controlled trial, in which the number of total fertilization failure (TFF) in the first IVF procedure after unsuccessful IUI was compared to those of IVF without preceding IUI in patients with idiopathic subfertility. These patients participated in a previous study that assessed the cost effectiveness of IUI versus IVF in idiopathic subfertility and were randomized to either IUI or IVF treatment.
45 patients underwent IVF after 6 cycles of unsuccessful IUI and 58 patients underwent IVF immediately without preceding IUI. In 7 patients the IVF treatment was cancelled before ovum pick. In the IVF after unsuccessful IUI group TFF was seen in 2 of the 39 patients (5%) versus 7 of the 56 patients (13%) in the immediate IVF group. After correction for confounding factors the TFF rate was not significantly different between the two groups (p = 0.08, OR 7.4; 95% CI: 0.5–14.9).
Our data showed that TFF and the fertilization rate in the first IVF treatment were not significantly different between couples with idiopathic subfertility undergoing IVF after failure of IUI versus those couples undergoing IVF immediately without prior IUI treatment. Apparently, impaired fertilization does not play a significant role in the success rate of IUI in patients with idiopathic subfertility.
PMCID: PMC2632644  PMID: 19138415
9.  Ascorbic Acid in Human Seminal Plasma: Determination and Its Relationship to Sperm Quality 
The objective of the present study was to assess the ascorbic acid (AA) levels in seminal plasma of the fertile and infertile men and to investigate its relationship with sperm count, motility and normal morphology. Semen samples were provided by fertile [smoker (n = 25), nonsmoker (n = 21)] and infertile men [smoker (n = 23), nonsmoker (n = 32)]. A simplified method of reverse phase high performance liquid chromatography (RP-HPLC) procedure using UV detection was applied for the determination of seminal AA. Fertile subjects, smoker or not, demonstrated significantly higher seminal AA levels than any infertile group (p<0.01). Nonsmokers had high, but no significant, mean AA levels in their seminal plasma compared with smokers. Seminal AA in fertile and infertile (smokers or nonsmokers) males correlated significantly with the percentage of spermatozoa with normal morphology (p<0.01). Seminal AA decreased significantly in infertile men. Decrease of seminal plasma AA is a risk factor for low normal morphology of spermatozoa and idiopathic male infertility. Measurement of seminal AA in the seminal plasma of males with a history of subfertility or idiopathic infertility is necessary and can be helpful in fertility assessment.
PMCID: PMC2735625  PMID: 19794921
ascorbic acid; sperm quality; seminal plasma; male infertility; RP-HPLC
10.  Testicular obstruction: clinicopathological studies. 
Genital tract reconstruction has been attempted in subfertile men with obstructive azoospermia (370 patients) or unilateral testicular obstruction (80 patients), and in vasectomised men undergoing reversal for the first (130 patients) or subsequent (32 patients) time. Histopathological changes in the obstructed testes and epididymes, and immunological responses to the sequestered spermatozoa have been studied to gain insight into possible causes of failure of surgical treatment. The results of surgery have been assessed by follow-up sperm counts and occurrence of pregnancies in the female partners. The best results were obtained with vasectomy reversal (patency 90%, pregnancy 45%), even after failed previous attempts (patency 87%, pregnancy 37%). Epididymovasostomy gave good results with postinfective caudal blocks (patency 52%, pregnancy 38%), while postinfective vasal blocks were better corrected by total anatomical reconstruction (patency 73%, pregnancy 27%) than by transvasovasostomy (patency 9%, no pregnancies). Poor results were obtained with capital blocks (patency 12%, pregnancy 3%), in which substantial lipid accumulation was demonstrated in the ductuli efferentes; three-quarters of these patients had sinusitis, bronchitis or bronchiectasis (Young's syndrome). There is circumstantial evidence to suggest that this syndrome may be a late complication of mercury intoxication in childhood. After successful reconstruction, fertility was relatively reduced in those men who had antibodies to spermatozoa, particularly amongst the postinfective cases. Similarly, impaired fertility was found in men with unilateral testicular obstruction and antibodies to spermatozoa. Mononuclear cell infiltration of seminiferous tubules and rete testis was noted occasionally, supporting a diagnosis of autoimmune orchitis; although rare, this was an important observation as the sperm output became normal with adjuvant prednisolone therapy.
PMCID: PMC2499292  PMID: 2241062
11.  Relationship between seminal plasma zinc concentration and spermatozoa–zona pellucida binding and the ZP-induced acrosome reaction in subfertile men 
Asian Journal of Andrology  2009;11(4):499-507.
The aim of this study was to determine the relationship between seminal zinc concentration and spermatozoa–zona pellucida (ZP) binding and the ZP-induced acrosome reaction (ZPIAR) in subfertile men. Semen analyses and seminal zinc concentration assessments were carried out according to the World Health Organization manual for 458 subfertile men. A spermatozoa–ZP interaction test was carried out by incubating 2 × 106 motile spermatozoa with a group of four unfertilized oocytes obtained from a clinical in vitro fertilization programme. After 2 h of incubation, the number of spermatozoa bound per ZP and the ZPIAR of ZP-bound spermatozoa were examined. The effect of adding 0.5 mmol L−1 zinc to the media on the ZPIAR of spermatozoa from normozoospermic men was also tested in vitro. Seminal zinc concentration positively correlated with sperm count and duration of abstinence, but negatively correlated with semen volume. On analysis of data from all participants, both spermatozoa–ZP binding and the ZPIAR were significantly correlated with sperm motility and normal morphology, but not with seminal zinc concentration. However, in men with normozoospermic semen, the seminal zinc concentration was significantly higher in men with defective ZPIAR (< 16%) than in those with normal ZPIAR (≥ 16%) (P < 0.01). The addition of 0.5 mmol L−1 zinc to the culture media had no effect on spermatozoa–ZP binding, but significantly reduced the ZPIAR in vitro (P < 0.001). In conclusion, seminal zinc concentration is correlated with sperm count and the duration of abstinence in subfertile men. In men with normozoospermic semen, high seminal zinc concentration may have an adverse effect on the ZPIAR.
PMCID: PMC3735308  PMID: 19434054
semen analysis; seminal zinc; spermatozoa–zona pellucida interaction; subfertile men
12.  Male subfertility: communication, care, coping. An explorative study 
Facts, Views & Vision in ObGyn  2010;2(4):253-265.
Aim of the study: With this study, we wanted to examine the needs of men with fertility problems in terms of communication, care and coping with the diagnosis.
Methodology: data gathered prospectively by means of a written questionnaire (quantitative data), and semi-structured interviews (qualitative data).
Sample: 78 subfertile men who consulted for subfertility at the department for reproductive medicine at the University Hospital of Ghent, Belgium were included in the assessment; of these, 23 were interviewed for qualitative evaluation.
Results and conclusions: More than one fifth of the participants was dissatisfied with the way they had been informed about their fertility status. There was no significant difference in satisfaction with the care received immediately after diagnosis whether it was given by a general practitioner or by a specialist. A significant influence of nationality was noted on the satisfaction about being informed, Dutch men being much less satisfied than Flemish men.
Some men suggested to have a consult with the doctor on a structural basis about a week after the diagnosis.
The internet seemed to be a good medium for obtaining medical information
It could be useful to create an extra function: a ‘coach’ supporting the couple throughout the entire process., adding another argument to the need for professional psychological support of patients attending clinics for human reproduction.
The subfertile men often felt that they were watching from the sideline, and wanted to be more actively involved in the treatment.
PMCID: PMC4086010  PMID: 25009713
Care; communication; coping; male subfertility; questionnaire
13.  Endometriosis 
BMJ : British Medical Journal  2000;320(7247):1449-1452.
Endometriosis is characterised by ectopic endometrial tissue, which can cause dysmenorrhoea, dyspareunia, non-cyclical pelvic pain, and subfertility. Diagnosis is made by laparoscopy. Most endometrial deposits are found in the pelvis (ovaries, peritoneum, uterosacral ligaments, pouch of Douglas, and rectovaginal septum). Extrapelvic deposits, including those in the umbilicus and diaphragm, are rare. Endometriomas are cysts of endometriosis within the ovary. InterventionsIn women with pain attributed to endometriosisBeneficial:Hormonal treatments (danazol, medroxyprogesterone, gestrinone, gonadotrophin releasing hormone analogues)Combined ablation of endometrial deposits and uterine nervePostoperative hormonal treatmentCystectomy for ovarian endometrioma (better than drainage)Likely to be beneficial:Oral contraceptive pillUnknown effectiveness:DydrogesteroneLaparoscopic uterine nerve ablation (LUNA)Laparoscopic ablation of endometrial depositsPreoperative hormonal treatmentIn women with subfertility attributed to endometriosisBeneficial:Laparoscopic ablation or excision of endometrial depositsCystectomy for ovarian endometrioma (better than drainage)Unlikely to be beneficial:Hormonal treatmentPostoperative hormonal treatment
In asymptomatic women, the prevalence ranges from 2% to 22%, depending on the diagnostic criteria used and the populations studied.1–4 In women with dysmenorrhoea, the incidence of endometriosis ranges from 40% to 60%, and in women with subfertility it ranges from 20% to 30%.256 The severity of symptoms and the probability of diagnosis increase with age.7 Incidence peaks at about age 40.8 Symptoms and laparoscopic appearance do not always correlate.9
The cause is unknown. Risk factors include early menarche and late menopause. Embryonic cells may give rise to deposits in the umbilicus, while retrograde menstruation may deposit endometrial cells in the diaphragm.10 11 Oral contraceptives reduce the risk of endometriosis, and this protective effect persists for up to a year after their discontinuation.9
We found one small randomised controlled trial (RCT) in which repeat laparoscopy was performed in the women treated with placebo. Over 12 months, endometrial deposits resolved spontaneously in a quarter, deteriorated in nearly half, and were unchanged in the remainder.12
To relieve pain (dysmenorrhoea, dyspareunia, and other pelvic pain) and to improve fertility, with minimal adverse effects.
American Fertility Society scores for size and number of deposits; recurrence rates; time between stopping treatment and recurrence; rate of adverse effects of treatment. In women with pain: relief of pain, assessed by visual analogue scale and subjective improvement. In women with subfertility: cumulative pregnancy rate, live birth rate. In women undergoing surgery: ease of surgical intervention (rated as easy, average, difficult, or very difficult).13
PMCID: PMC1127642  PMID: 10827052
14.  Fertile offspring derived from mouse spermatogonial stem cells cryopreserved for more than 14 years 
Human Reproduction (Oxford, England)  2012;27(5):1249-1259.
Approximately 80% of childhood cancers can now be cured but a side effect of treatment results in about one-third of the surviving boys being infertile or severely subfertile when they reach reproductive age. Currently, more than 1 in 5000 men of reproductive age who are childhood cancer survivors suffer from this serious quality of life problem. It is possible to obtain a testicular biopsy before treatment to preserve the spermatogonial stem cells (SSCs) of the male by cryopreservation, but the results of long-term storage of SSCs on their subsequent functional ability to generate normal offspring has not been examined in any mammalian species. Moreover, it will be necessary to increase the number of these cryopreserved SSCs to remove any contaminating malignant cells and assure regeneration of spermatogenesis.
In this report, we demonstrate that long-term cryopreservation (>14 years) of testis cells from mouse, rat, rabbit and baboon safeguards SSC viability, and that these cells can colonize the seminiferous tubules of recipient testes. Moreover, mouse and rat SSCs can be cultured and re-establish complete spermatogenesis, and fertile mouse progeny without apparent genetic or epigenetic errors were generated by the sperm produced.
These findings provide a platform for fertility preservation in prepubertal boys undergoing gonadotoxic treatments.
PMCID: PMC3329194  PMID: 22416011
cryopreservation; germ cells; spermatogenesis; spermatogonial stem cells; male infertility
15.  Relationship Between Creatine Kinase Levels and Clinical Diagnosis of Infertility 
Purpose:The creatine kinase level indicates sperm maturity and correlates with the spermatozoal fertilizing potential. The relationship between creatine kinase levels in subfertile men and their clinical diagnosis was examined.
Methods:Patients with unexplained infertility (n = 34), varicocele (n = 20), postvasectomy reversal (n = 7), or cancer (n = 22) were included in this prospective clinical study. The control group consisted of healthy normal donors (n = 15).
Results:The median and interquartile range values of creatine kinase for each group were as follows: normal donors, 0.061 U/108sperm (0.056 to 0.076 U/108sperm); idiopathic malefactor, 0.119 U/108sperm (0.061 to 0.190 U/108sperm); varicocele, 0.392 U/108sperm (0.209 to 1.494 U/108sperm); postvasectomy reversal, 0.589 U/108sperm (0.425 to 4.043 U/108sperm); and cancer, 0.068 U/108sperm (0.047 to 0.168 U/108sperm). Sperm creatine kinase levels were significantly higher in patients with varicocele compared to normal donors (P = 0.0001), cancer patients (P = 0.0002), and men with idiopathic infertility (P = 0.0009). Sperm concentration and creatine kinase level were inversely correlated in patients (r = −0.7,P < 0.001) but not in normal donors.
Conclusions:Semen quality is poorer in subfertile patients with clinical varicocele and postvasectomy reversal than in cancer patients and patients with idiopathic male infertility. That the creatine kinase levels in cancer patients were similar to those of normal donors suggests that the final phase of spermatogenesis may not be altered in men with cancer; thus semen from these patients should be banked to ensure fertility after cancer treatment.
PMCID: PMC3454933  PMID: 9565847
cancer patients; postvasectomy reversal; idiopathic infertility; sperm creatine kinase; varicocele
16.  Live Offspring from Mice Lacking the Y Chromosome Long Arm Gene Complement1 
Biology of Reproduction  2009;81(2):353-361.
The mouse Y chromosome long arm (Yq) comprises ∼70 Mb of repetitive, male-specific DNA together with a short (0.7-Mb) pseudoautosomal region (PAR). The repetitive non-PAR region (NPYq) encodes genes whose deficiency leads to subfertility and infertility, resulting from impaired spermiogenesis. In XSxraY*X mice, the only Y-specific material is provided by the Y chromosome short arm-derived sex reversal factor Sxra, which is attached to the X chromosome PAR; these males (NPYq- males) produce sperm with severely malformed heads and are infertile. In the present study, we investigated sperm function in these mice in the context of intracytoplasmic sperm injection (ICSI). Of 261 oocytes injected, 103 reached the 2-cell stage, and 46 developed to liveborn offspring. Using Xist RT-PCR genotyping as well as gamete and somatic cell karyotyping, all six predicted genotypes were identified among ICSI-derived progeny. The sex chromosome constitution of NPYq- males does not allow production of offspring with the same genotype, but one of the expected offspring genotypes is XY*XSxra (NPYq-2), which has the same Y gene complement as NPYq-. Analysis of NPYq-2 males revealed they had normal-sized testes with ongoing spermatogenesis. Like NPYq- males, these males were infertile, and their sperm had malformed heads that nevertheless fertilized eggs via ICSI. In vitro fertilization (IVF), however, was unsuccessful. Overall, we demonstrated that a lack of NPYq-encoded genes does not interfere with the ability of sperm to fertilize oocytes via ICSI but does prevent fertilization via IVF. Thus, NPYq-encoded gene functions are not required after the sperm have entered the oocyte. The present work also led to development of a new mouse model lacking NPYq gene complement that will facilitate future studies of Y-encoded gene function.
The sperm from infertile males lacking the Y chromosome long arm are able to fertilize oocytes via ICSI and to transmit all expected sperm genotypes to the offspring.
PMCID: PMC2849819  PMID: 19420387
assisted reproductive technology; ICSI; intracytoplasmic sperm injection; IVF; in vitro fertilization; sperm; Y chromosome deletions
17.  Risk of testicular cancer in subfertile men: case-control study 
BMJ : British Medical Journal  1999;318(7183):559-562.
To evaluate the association between subfertility in men and the subsequent risk of testicular cancer.
Population based case-control study.
The Danish population.
Cases were identified in the Danish Cancer Registry; controls were randomly selected from the Danish population with the computerised Danish Central Population Register. Men were interviewed by telephone; 514 men with cancer and 720 controls participated.
Outcome measure
Occurrence of testicular cancer.
A reduced risk of testicular cancer was associated with paternity (relative risk 0.63; 95% confidence interval 0.47 to 0.85). In men who before the diagnosis of testicular cancer had a lower number of children than expected on the basis of their age, the relative risk was 1.98 (1.43 to 2.75). There was no corresponding protective effect associated with a higher number of children than expected. The associations were similar for seminoma and non-seminoma and were not influenced by adjustment for potential confounding factors.
These data are consistent with the hypothesis that male subfertility and testicular cancer share important aetiological factors.
Key messagesThe incidence of testicular cancer has increased in the past 50 years, and there is some evidence to suggest that sperm quality has decreased in the same periodIt has been hypothesised that common aetiological factors may exist for testicular cancer and for male subfertilityThe association between male subfertility and subsequent risk of testicular cancer is strong and consistent with the hypothesis of a common aetiologyThe association is similar for seminoma and non-seminoma, and it persists when several potentially confounding factors are taken into account
PMCID: PMC27753  PMID: 10037628
18.  Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia 
Developmental biology  2009;330(1):167-174.
In eukaryotes, mRNA is actively transported from nucleus to cytoplasm by a family of nuclear RNA export factors (NXF). While yeast harbors only one such factor (Mex67p), higher eukaryotes encode multiple NXFs. In mouse, four Nxf genes have been identified: Nxf1, Nxf2, Nxf3, and Nxf7. To date, the function of mouse Nxf genes has not been studied by targeted gene deletion in vivo. Here we report the generation of Nxf2 null mutant mice by homologous recombination in embryonic stem cells. Nxf2-deficient male mice exhibit fertility defects that differ between mouse strains. One third of Nxf2-deficient males on a mixed (C57BL/6 × 129) genetic background exhibit meiotic arrest and thus are sterile, whereas the remaining males are fertile. Disruption of Nxf2 in inbred (C57BL/6J) males impairs spermatogenesis, resulting in male subfertility, but causes no meiotic arrest. Testis weight and sperm output in C57BL/6J Nxf2-/Y mice are sharply reduced. Mutant epididymal sperm exhibit diminished motility. Importantly, proliferation of spermatogonia in Nxf2-/Y mice is significantly decreased. As a result, inactivation of Nxf2 causes depletion of germ cells in a substantial fraction of seminiferous tubules in aged mice. These studies demonstrate that Nxf2 plays a dual function in spermatogenesis: regulation of meiosis and maintenance of spermatogonial stem cells.
PMCID: PMC2702087  PMID: 19345203
NXF2; spermatogenesis; spermatogonia; stem cell; meiosis; mouse
19.  Protective Effects of Antioxidants on Sperm Parameters and Seminiferous Tubules Epithelium in High Fat-fed Rats 
Prescription of antioxidants might increase the quality of sperm parameters and improve the rate of pregnancy in obese people who suffer from infertility. Therefore, the present study investigated protective effects of vitamin A, E and astaxanthin on sperm parameters and seminiferous tubules epithelium in high-fat diet model.
Thirty-six numbers of 3 months old albino Wistar rats were divided to control, high-fat diet and high-fat diet with antioxidants groups. After 12 weeks, levels of LDL-C and HDL-C were detected in the groups. Sperm was obtained from the tail of epididymis and its parameters (count, vitality, motility and morphology) were analyzed. Testes were fixed in 10% formalin and after tissue processing, stained with Hematoxylin and Eosine (H&E) for histological evaluation. Data were analyzed by a one-way ANOVA and p < 0.05 was considered significant.
Our results indicated that viability, motility and normal morphology of sperm in high-fat diet (HFD) decreased significantly compared to high-fat diet with antioxidant (HFD + A) and the control groups (p < 0.05). Also spermatogonium and the number of Sertoli cells increased significantly in HFD + A compared to the control (p < 0.05).
As it is shown in our study, application of antioxidants decreased serum triglyceride, cholesterol and HDL-C/LDL-C in high-fat diet model and improved the semen parameters. Therefore, it is suggested that the low quality of sperm can be improved in obese men through antioxidant prescription. Finally, it seems that the antioxidants in obese patients with subfertility or infertility is a new and efficient strategy with few side effects.
PMCID: PMC3955420  PMID: 24696792
Antioxidant; Astaxanthin; High-fat diet; Spermatogenesis; Testis; Vitamin A; Vitamin C
20.  Physiology: DAZLA: An Important Candidate Gene in Male Subfertility? 
Purpose: To study the role of the autosomal candidate gene DAZLA (Deleted in AZoospermia Like Autosome) in male subfertility.
Methods: We reviewed clinical data of subfertile men with oligozoospermia or azoospermia, mostly candidates for intracytoplasmic sperm injection (ICSI). Mutation detection was performed using polymerase chain reaction followed by single strand conformation polymorphism analysis. All shifted bands were analyzed by sequencing.
Results: We searched for mutations in 44 subfertile men. Nine subfertile men were included, because family history showed that their brothers also faced fertility problems. In these men a possible autosomal gene defect may contribute to their fertility problem. No mutations were found, except for two polymorphisms in intron 4 and 5.
Conclusion: At this moment it does not seem relevant to search for possible mutations in the DAZLA gene in clinical practice.
PMCID: PMC3455824  PMID: 11499325
DAZLA; genetics; ICSI; male subfertility
21.  Molecular and cytogenetic studies of 101 infertile men with microdeletions of Y chromosome in 1,306 infertile Korean men 
To determine the prevalence of Y chromosome microdeletions in infertile Korean men with abnormal sperm counts and to assess the clinical features and frequency of chromosomal abnormalities in Korean patients with microdeletions.
A total of 1,306 infertile men were screened for Y chromosome microdeletions, and 101 of them had microdeletions. These 101 men were then retrospectively studied for cytogenetic evaluation, testicular biopsy and outcomes of IVF and ICSI.
The overall prevalence of Y chromosome microdeletions in infertile men was 7.7 % (101/1,306). Most microdeletions were in the AZFc region (87.1 %), including deletions of AZFbc (24.7 %) and AZFabc (8.9 %). All patients with AZFa, AZFbc and AZFabc deletions had azoospermia, whereas patients with an AZFc deletion usually had low levels of sperm in the ejaculate or in the testis tissues. Chromosomal studies were performed in 99 men with microdeletions, 36 (36.4 %) of whom had chromosomal abnormalities. Among the infertile men with Y chromosome microdeletions in this study, the incidence of chromosomal abnormality was 48.6 % in the azoospermic group and 3.7 % in the oligozoospermic group. Among the 69 patients with microdeletions and available histological results, 100.0 % of the azoospermic group and 85.7 % of the oligozoospermic group had histological abnormalities. The frequency of both chromosomal abnormalities and histological abnormalities was higher in the azoospermic group compared to the oligozoospermic group. Thirty-four ICSI cycles with either testicular (n = 14) or ejaculated spermatozoa (n = 20) were performed in 23 couples with men with AZFc microdeletion. Thirteen clinical pregnancies (39.4 %) were obtained, leading to the birth of 13 babies.
The study results revealed a close relationship between microdeletions and spermatogenesis, although IVF outcome was not significantly affected by the presence of the AZFc microdeletion. Nevertheless, Y chromosome microdeletions have the potential risk of being transmitted from infertile fathers to their offspring by ICSI. Therefore, before using ICSI in infertile patients with severe spermatogenic defects, careful evaluations of chromosomal abnormalities and Y chromosome microdeletions screening should be performed and genetic counseling should be provided before IVF-ET.
PMCID: PMC3370041  PMID: 22456825
Y chromosome microdeletion; Chromosomal abnormality; Azoospermia factor (AZF); Intracytoplasmic sperm injection (ICSI)
22.  Preterm birth in twins after subfertility treatment: population based cohort study 
BMJ : British Medical Journal  2005;331(7526):1173.
Objectives To assess gestational length and prevalence of preterm birth among medically and naturally conceived twins; to establish the role of zygosity and chorionicity in assessing gestational length in twins born after subfertility treatment.
Design Population based cohort study.
Setting Collaborative network of 19 maternity facilities in East Flanders, Belgium (East Flanders prospective twin survey).
Participants 4368 twin pairs born between 1976 and 2002, including 2915 spontaneous twin pairs, 710 twin pairs born after ovarian stimulation, and 743 twin pairs born after in vitro fertilisation or intracytoplasmic sperm injection.
Main outcome measures Gestational length and prevalence of preterm birth.
Results Compared with naturally conceived twins, twins resulting from subfertility treatment had on average a slightly decreased gestational age at birth (mean difference 4.0 days, 95% confidence interval 2.7 to 5.2), corresponding to an odds ratio of 1.6 (1.4 to 1.8) for preterm birth, albeit confined to mild preterm birth (34-36 weeks). The adjusted odds ratios of preterm birth after subfertility treatment were 1.3 (1.1 to 1.5) when controlled for birth year, maternal age, and parity and 1.6 (1.3 to 1.8) with additional control for fetal sex, caesarean section, zygosity, and chorionicity. Although an increased risk of preterm birth was therefore seen among twins resulting from subfertility treatment, the risk was largely caused by a first birth effect among subfertile couples; conversely, the risk of prematurity was substantially levelled off by the protective effect of dizygotic twinning.
Conclusions Twins resulting from subfertility treatment have an increased risk of preterm birth, but the risk is limited to mild preterm birth, primarily by virtue of dizygotic twinning.
PMCID: PMC1285094  PMID: 16249191
23.  Coordinated transcriptional regulation patterns associated with infertility phenotypes in men 
Journal of Medical Genetics  2007;44(8):498-508.
Microarray gene‐expression profiling is a powerful tool for global analysis of the transcriptional consequences of disease phenotypes. Understanding the genetic correlates of particular pathological states is important for more accurate diagnosis and screening of patients, and thus for suggesting appropriate avenues of treatment. As yet, there has been little research describing gene‐expression profiling of infertile and subfertile men, and thus the underlying transcriptional events involved in loss of spermatogenesis remain unclear. Here we present the results of an initial screen of 33 patients with differing spermatogenic phenotypes.
Oligonucleotide array expression profiling was performed on testis biopsies for 33 patients presenting for testicular sperm extraction. Significantly regulated genes were selected using a mixed model analysis of variance. Principle components analysis and hierarchical clustering were used to interpret the resulting dataset with reference to the patient history, clinical findings and histological composition of the biopsies.
Striking patterns of coordinated gene expression were found. The most significant contains multiple germ cell‐specific genes and corresponds to the degree of successful spermatogenesis in each patient, whereas a second pattern corresponds to inflammatory activity within the testis. Smaller‐scale patterns were also observed, relating to unique features of the individual biopsies.
PMCID: PMC2597934  PMID: 17496197
testis; infertility; microarray; spermatogenesis; germ cell
24.  Semen quality in men from subfertile couples from the region of Łódź (Poland) according to the new reference values recommended by WHO 2010 
The semen analysis is the main diagnostic tool for evaluating the male fertility potential. The standard semen analysis includes evaluation of the sperm concentration, motility, and their morphology. The most important question is whether the results from semen analysis may be accurate markers for male fertility. Therefore, we retrospectively studied sperm quality among men attending the infertility clinic due to reproductive problems consistent with the WHO manual from 1999, which were reassessed according to the manual from 2010. Semen results from 571 males from couples undergoing fertility investigation were analyzed. All subjects included in the study had no abnormalities during examination. In 64 samples (11.2%), a leukocyte count above 1 x 106/ml was found and their semen volume (median 3.2 ml) was significantly lower in comparison with the group without leukocytes (3.6 ml; p <0.001). Normal semen parameters were found in 290 subjects (50.8%) according to the 1999 manual and in 362 men (63.4%) according to the 2010 manual. The normozoospermia group, according to the 2010 manual, had a significantly lower percentage of sperm with progressive motility, motile sperm concentration, and total number of motile sperm in comparison with the normozoospermia group according to the manual from 1999. It seems that routine semen analysis is not sufficient to estimate male fertility potential and some men with normal semen parameters may be subfertile. Further investigations are needed.
PMCID: PMC3921700  PMID: 24578858
semen quality; subfertility; sperm concentration; sperm motility
25.  Histological and histochemical effects of Gly-phosate on testicular tissue and function 
Background: In this study we aimed to evaluate the impact of chronic exposure to the Gly-phosate (GP) on rat’s testicular tissue and sperm parameters.
Objective: Testicular tissue, morphology of sperms and testosterone level in serum of mature male rats were analyzed.
Materials and Methods: Animals were divided into two test and control-sham groups. The test group was subdivided into 4 groups (10, 20, 30 and 40 days GP administrated). Each test group (n=8) received the compound at dose of 125 mg/kg, once a day, orally for 40 days while control-sham group (n=16) received the corn oil (0.2 ml/day).
Results: Microscopic analyses revealed increased thickness of tunica albuginea, obvious edema in sub-capsular and interstitial connective tissue, atrophied seminiferous tubules, arrested spermatogenesis, negative tubular differentiation and repopulation indexes, decreased Leydig cells/mm2 of interstitial tissue, hypertrophy and cytoplasmic granulation of Leydig cells, elevated death, immature sperm and increased immotile and abnormal sperm percentage. The carbohydrate ratio was reduced in first three layers of the germinal epithelium (GE) cytoplasm. The upper layers of the GE series were manifested with low rate of lipid accumulation in cytoplasm, while the cells which were located in first layers were revealed with higher amount of lipid foci. Hematological investigations showed significant (p<0.05) decreasing of testosterone level in serum.
Conclusion: The current data provide inclusive histological feature of chronic exposure against GP with emphasizing on reproductive disorders including histological adverse effect on the testicular tissue, spermatogenesis, sperm viability and abnormality which potentially can cause infertility.
PMCID: PMC4165960  PMID: 25242992
Abnormal sperm; Carbohydrate accumulation; Gly-phosate; Lipid foci; Spermatogenesis; Testosterone; Testis

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