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Treatment of male idiopathic infertility with recombinant human follicle-stimulating hormone: a prospective, controlled, randomized clinical study.

OBJECTIVE: To evaluate the effects of treatment with FSH on seminal parameters and spontaneous pregnancy in male infertility. DESIGN: Prospective, controlled, randomized clinical study. SETTING: Infertility center at a university hospital. PATIENT(S): One hundred twelve men affected by idiopathic oligozoospermia. INTERVENTION(S): Patients were randomized into two groups: 62 subjects were treated with 100 IU of recombinant human FSH on alternate days for 3 months, and 50 patients did not receive any treatment. Semen analysis was performed in all subjects at the end of this period of treatment and after the following 3 months. Subjects who had not reached spontaneous pregnancy underwent assisted reproductive techniques. MAIN OUTCOME MEASURE(S): Seminal parameters, testicular cytologic analysis, FSH, LH, T, and inhibin B concentrations. RESULT(S): The treatment group considered as a whole did not show modifications in sperm parameters. However, a subgroup of these (30, 48.4%) had a significant increase of sperm count (responder group). In the period including 3 months after the withdrawal of FSH therapy, we observed a significantly higher spontaneous pregnancy rate in the responder group (5 of 30 [16.7%]) with respect to nonresponder and nontreated groups (1 of 32 [3.1%] and 2 of 50 [4.0%], respectively). Furthermore, the improvement of seminal parameters in the responder group allowed these patients to undergo less frequent IVF-ET/intracytoplasmic sperm injection. CONCLUSION(S): Results from this controlled, randomized clinical trial show that FSH therapy does not improve sperm concentration or pregnancy rate when infertile male patients are chosen solely by the clinical criteria of idiopathic oligospermia and normal FSH concentration. Subgroup analysis, however, does indicate that patients without maturation arrest in addition to the clinical scenario do benefit from medical therapy.

Adult↗

A neonatal form of Steinert's myotonic dystrophy in twins after in vitro fertilization.

OBJECTIVE: To report a case of nonidentical twins affected with a congenital form of Steinert's myotonic dystrophy (DM1), conceived by IVF owing to parental sterility, in which the mother presented a paucisymptomatic form of DM1 which was diagnosed as a result of the condition inherited by the twins. DESIGN: Case report. SETTING: Neonatal intensive care unit of a tertiary hospital. PATIENT(S): Newborn twins affected with the congenital form of DM1 and a 35-year-old nulliparous mother. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): Molecular study of the CTG triplet expansion related with DM1. RESULT(S): Molecular study evidenced a pathologic expansion in both twins as well as in their mother. CONCLUSION(S): This case should serve as a reminder to practitioners that assisted reproductive techniques have opened the possibility that asymptomatic or paucisymptomatic carriers of a genetic syndrome can inadvertently conceive fetuses affected with more serious forms of the illness.

Adult↗

Complications after fertility-preserving radical trachelectomy.

OBJECTIVE: We report a case of cervical cancer treated by radical trachelectomy complicated by pelvic inflammatory disease, tubo-ovarian complex, and infertility. DESIGN: Case report. SETTING: Tertiary referral university hospital. PATIENT(S): A 35-year-old with stage IB1 cervical cancer underwent an uneventful radical vaginal trachelectomy. Three years later she presented with pelvic pain and fever after a new partner. Cervical chlamydia was positive, and sonography showed bilateral complex adnexal masses. Her symptoms resolved with prolonged IV, followed by oral, antibiotics. Temperature, cultures, and blood tests have all normalized but her sonogram demonstrates persistent bilateral hydrosalpinx. She has not conceived and underwent laparoscopic salpingectomy prior to IVF. She remains cancer free. INTERVENTION(S): Radical vaginal trachelectomy, salpingectomy and assisted reproductive techniques. MAIN OUTCOME MEASURE(S): Cancer disease status and fertility preservation. RESULT(S): Three years later, the patient remains cancer free but has been unable to conceive or carry a pregnancy. CONCLUSION(S): Fertility-preserving cancer treatments are relatively new. Complications may be encountered that must be reported, collected, and analyzed to maximize cancer cure and fertility preservation.

Abscess↗

Laparoscopic excision of recurrent endometriomas: long-term outcome and comparison with primary surgery.

OBJECTIVE: To compare the laparoscopic excision of primary versus recurrent ovarian endometriomas. DESIGN: Descriptive study. SETTING: Tertiary referral center for the treatment of endometriosis. PATIENT(S): Between 1993 and 2002, 359 consecutive patients: 305 primary surgeries (group A) and 54 reoperations for a recurrent endometrioma in the same ovary of the primary cyst (group B). INTERVENTION(S): Laparoscopic stripping of the cyst wall. Follow-up evaluations every 6 months, including clinical and ultrasonographic evaluations and a questionnaire for pain symptoms (mean follow-up time, +/- standard deviation: 35.4 +/- 27.6 months). MAIN OUTCOME MEASURE(S): Recurrence of pain symptoms, sonographic recurrence of endometriomas, need for a new medical or surgical treatment, and reproductive outcome. RESULT(S): In groups A and B, respectively, the 5-year cumulative rates were not statistically significantly different: pain recurrence 20.5% versus 17.4%; ultrasonographic recurrence 18.9% versus 15.1%; retreatment requirement 19.4% versus 17.3%; and pregnancy 40.8% versus 32.4%. Although the difference was not statistically significant, compared with patients of group A, the women of group B underwent assisted reproduction techniques more frequently (50% vs. 32.2%) and had more irregular menstrual cycles associated with follicle-stimulating hormone levels > or = 14 IU/mL in the early follicular phase (5.5% vs. 1.3%). CONCLUSION(S): After laparoscopic excision of recurrent ovarian endometriomas, the recurrence of pain and the reproductive outcome are comparable with those found after primary surgery.

Adult↗

Conjoined twins in a trichorionic quadruplet pregnancy after intracytoplasmic sperm injection and quarter laser-assisted zona thinning.

OBJECTIVE: To describe the occurrence and management of conjoined twins (CTs) in a trichorionic quadruplet pregnancy after the transfer of three embryos obtained by intracytoplasmic sperm injection (ICSI) that had undergone assisted zona hatching (AZH) using a noncontact laser. DESIGN: Case report. SETTING: Private and public IVF centers. PATIENT(S): A 38-year-old nulliparous woman. INTERVENTION(S): IVF, diagnosis by two-dimensional, three-dimensional, and four-dimensional ultrasound, selective termination at 12 weeks gestation. MAIN OUTCOME MEASURE(S): Clinical follow-up and delivery. RESULT(S): After diagnosis, counselling, and selective termination, the subsequent prenatal course was uneventful, and two healthy boys were delivered by elective cesarean section at 38 weeks gestation. CONCLUSION(S): Monozygotic twinning (MZT) and CTs could complicate multifetal pregnancies obtained by assisted reproduction techniques. The relationship between CTs, IVF, and AZH should be better studied to fully understand the mechanisms that lead to MZT (with the possible role of AZH) and CTs in MZT, in particular. Three-dimensional and four-dimensional ultrasound improve prenatal assessment of the condition. Selective embryo reduction is a safe procedure for the management of these pregnancies.

Adult↗

[A simple, low-cost and non-invasive method for screening Y microdeletions in infertile men].

OBJECTIVES: Recent investigations showed a high prevalence of Y chromosome microdeletions in men with severely impaired spermatogenesis. Screening for these men is recommended prior to assisted reproduction techniques. The aim of this study was to set up a simple method to detect Y deletion in infertile men. First, we tested the feasibility of cytobrush to collect oral cells as source of DNA. Second, we compared a classic PCR corresponding to European recommendations to the Promega kit. PATIENTS AND METHODS: Seventeen infertile male patients with previously characterized deletions were included in the present study, after fully informed written consent. Both oral cells and blood were used for DNA extraction. A specific DNA extraction protocol was carried out on the buccal cells. The DNAs were tested for Y deletion screening by two different methods. RESULTS: We retrieved between 4 and 10 microg of DNA per brush from buccal cells, allowing several multiplex PCR. The Promega kit detected all the deletions but one: an AZFa deletion was not detected by the two markers of the kit covering this region. In addition, sY130, sY133 and SY153, included in the kit, are not reliable. DISCUSSION AND CONCLUSIONS: Buccal cells represent a convenient substitute for blood in testing for Y microdeletions. Both false negative and false positive results were obtained with Promega Kit. On the opposite, PCR according to the European recommendations allow the accurate detection of Y microdeletion in our 17 cases, at a lower cost.

Chromosomes, Human, Y↗

[Conservative treatment of endometrial cancer and atypical hyperplasia].

Endometrial carcinoma is the most frequent pelvic cancer encountered in women. The discovery of an endometrial carcinoma in a woman seeking pregnancy cannot be considered as exceptional. The medical alternative to the classic radical surgical treatment is studied in a review. Treatment with progestins might be considered and discussed with the couple in special indications. The oncologic risk to which this treatment exposes is limited. However, the application and the surveillance of this therapeutic protocol must obey strict rules, in order to recognize without delay any resistance to treatment. The spontaneous fertility of such patients seems weak, most probably because of their age, but assisted reproductive techniques (ART) could be considered in particular cases. Secondary hysterectomy is controversial, but a recent tendency is to widen this practice is becoming apparent.

Endometrial Hyperplasia↗

[Pharmacoeconomic advantages of recombinant FSH vs urinary derived FSH].

Nowadays, the use of urinary FSH is essentially justified by a lower acquisition price compared to modern products generated by Biotechnology (recombinant FSH). However, the public price of a product is only one element of the total cost of a therapeutic regimen that must be taken into account in medical decision-making. This is the role of pharmacoeconomic studies including cost-effectiveness models, which allow proceeding to complex situational comparisons such as several attempts of Assisted Reproduction Techniques. Different models have been carried out and published in several countries and present consistently that recombinant FSH is more cost-effective that urinary derived FSH.

Cost-Benefit Analysis↗

[Aging and spermatogenesis: an histologic, cytogenetic and apoptosis study].

OBJECTIVE: The increase of frequency of Assisted Reproductive Techniques (ART) for elder men raises the question of the genetic risk for the offspring. Our aim was to evaluate the influence of ageing on the testicular histology, the aneuploidy rate in testis postmeiotic cells and the DNA fragmentation in sperm. PATIENTS AND METHODS: We performed a histomorphometric study of 36 men aged from 61 to 102 years and 10 young men from 29 to 40 years. The aneuploidy rate was evaluated by fluorescent in situ hybridation (FISH X, Y, 18) and DNA fragmentation in spermatozoa was evaluated by TUNEL. RESULTS: Histomorphometry showed various alterations of testicular histology with age including thickening of the basal membrane when spermatogenesis was arrested. The number of germinal cells and Sertoli cells decreased with age with important individual variations. Nevertheless spermatogenesis could be possible until 95 years. The rate of aneuploidy was not influenced by age when spermatogenesis was complete. However, we observed an increased aneuploidy rate in postmeiotic cells when spermiogenesis was arrested. On the other hand apoptosis was not increased with age. DISCUSSION AND CONCLUSION: Our study confirms that spermatogenesis is possible until a very advanced age (95 years) without any specific chromosome risk. The question of mutagenesis remains to be solved.

Adult↗

[Elective single embryo transfer: a justified policy for selected patients].

OBJECTIVE: Prevention of twin pregnancies using elective Single Embryo Transfer (e-SET) is now considered by many Assisted Reproductive Techniques teams as a necessity. The aim of this study was to assess the efficacy of e-SET in a prospective manner in a selective population of patients using Take Home Baby Rate per couple as principal parameter. PATIENTS AND METHODS: This prospective study was conducted from January 2003 to December 2004. Elective Single Embryo was proposed to women above 37 years in their first IVF or ICSI attempt. It was then performed only in cases when at least one embryo with high implantation potential (score-4 embryo in our embryo scoring) was obtained for transfer and one more (score-3 or score-4 embryo) was available for freezing. RESULTS: e-SET was proposed and accepted in 225 couples (25% of eligible couples and 7.8% of total population) and was possible in 96 of these). Two embryos were transferred in all other eligible patients (Double Embryo Transfer group=DET). Cumulative delivery rate after fresh embryo transfers and, if necessary, after frozen-thawed embryo transfers were 39.5% per couple e-SET group and 41.7% in DET group (NS). On the other hand, the percentage of twin pregnancies was significantly different between the two groups (2.6% vs 26.6% respectively; P<0.01). DISCUSSION AND CONCLUSION: In women younger than 37 years in their first IVF/ICSI attempt, the elective transfer of only one embryo with high implantation potential strongly allowed to avoid twin pregnancies without any significant delivery rate decrease. This transfer policy is particularly efficient in laboratories displaying good results in their embryo freezing program.

Cryopreservation↗

[Late paternity: spermatogenetic aspects].

The effect of maternal age on the risk of meiotic abnormality is well documented. In contrast little is known about the effect of the paternal age. The question of the risk related to paternal age is raised because of the increased demand of Assisted Reproduction Techniques for older men. This review focuses on the alterations of male semen parameters, testis histology and genetic risks related to age. The motility, vitality and morphology of spermatozoa and semen volume are found decreasing with age. Histomorphometric studies reveal various alterations including a thickening of the basal membrane when spermatogenesis is arrested. The number of germinal and Sertoli cells decreases with increased age. Up to 95 years old, we could find subjects with complete spermatogenesis. Chromosomal analyses in different studies have provided controversial results. Our investigation on subjects aged from 29 to 102 showed that the rate of aneuploidy in the group of aged subjects with preserved spermatogenesis was not statistically different from the young control group. However the incidence of postmeiotic aneuploidy was increased when spermiogenesis had stopped. On the other hand from epidemiological studies, autosomal dominant diseases are known to be associated with paternal age. However, in the case of achondroplasia and Apert syndrome, direct DNA sperm analysis did not reveal significant increase in the mutation frequency with paternal age.

Adult↗

[Do hysteroscopic metroplasties really improve really reproductive outcome?].

The aim of metroplasties is to restore a normal uterine anatomy to improve obstetrical outcomes in some uterine malformations. The hysteroscopic septoplasty cures the septate uterus. It is an effective procedure in the case of recurrent abortion losses. It probably improves the rate of live birth in women without obstetrical antecedent. For some authors, it could be considered at the time of the diagnosis, because of the simplicity of the gesture and the low complication rate. The enlarging hysteroscopic metroplasty has certainly a positive impact on the obstetrical outcome in patients presenting a uterine hypotrophy or dysmorphy, in particular in women exposed in utero to DES. However, the proofs are poor to propose this procedure as first-line treatment, apart from specific cases such as old null gravid patient or before inclusion in an Assisted Reproductive Techniques (ART) program.

Diethylstilbestrol↗

[Molecular anomalies of the Y chromosome: Consequences on male fertility].

Molecular anomalies of the Y chromosome leading to male infertility are mainly microdeletions of the long arm of the Y chromosome. Three recurrently deleted portions of the long arm are the AZFa, AZFb and AZFc (AZF: Azoospermia Factor) regions. Complete deletions of the AZFc region are found in 10% of cases of severe male infertility. In addition to the AZF deletions, certain classes of Y chromosome (haplogroups) may also predispose to male infertility and could be transmitted to future male descents by various Assisted Reproductive Techniques (ART). Since the first discovery of microdeletions, the sequence of the Y chromosome has become available, revealing the mechanisms underlying deletion formation and also resulting in a coherent screening strategy. Recently, partial deletions of the AZF regions have been described. The significance of these deletions in the clinical context remains to be defined.

Biological Evolution↗

Paternity in men with cystic fibrosis: a retrospective survey in France.

BACKGROUND: Because more patients reach adulthood, new questions as "what about having a child and/or paternity responsibility?" arose. METHOD: We performed a retrospective investigation based on the French CF registry. The context of the paternity and the health status of fathers were recorded. A comparison with clinical status of non-father patients and a compilation of follow-up data to evaluate its impact were done. RESULTS: Forty-eight men had 69 children. One fourth was said to be natural conceptions, 69% needed assisted reproduction techniques. No child had CF. Clinical status of men was satisfactory: mean BMI was 20.9 kg/m(2) and mean FEV(1) and FVC were 50.5% and 69.2% of predicted, respectively. When matched to CF non-fathers, few significant differences appeared. More non-fathers were F508del/F508del (p=0.03). Fathers' sputum cultures were positive for non-Pseudomonas aeruginosa strain (p=0.05), including Staphylococcus aureus (p=0.01). Mean age at diagnosis was higher, and based on minor evidence of sterility as first symptom leading to the diagnosis of CF (p=0.01) or aspergillosis (p=0.03). The 3-year follow-up showed no degradation of the clinical status. CONCLUSION: Men having paternity responsibility over children did not differ from the CF male population and neither did it seem to have an impact on the disease course.

Adult↗

Actions of gonadotropin-releasing hormone analogues in pituitary gonadotrophs and their modulation by ovarian steroids.

Recently, GnRH antagonists (GnRHant) like cetrorelix and ganirelix have been introduced in protocols of controlled ovarian hyperstimulation for assisted reproductive techniques to prevent premature luteinizing hormone (LH) surges. Here we tested, whether the actions of cetrorelix and the GnRH agonist (GnRHag) triptorelin in gonadotrophs are dependent on the steroid milieu. Furthermore, we characterized the actions of cetrorelix and triptorelin on LH secretion and the total LH pool. Female rat pituitary cells were treated either with 0.1 nM triptorelin for 1, 2, 4 and 6 days or for 1, 3, 5 and 6 h or with 1, 10 or 100 nM cetrorelix for 1, 2, 3 and 5 h or for 10 min. Cells were stimulated for 3h with different concentrations of GnRH (10 pM-1 microM). For analysis of the total LH pool, which is composed of stored and released LH, cells were lysed with 0.1% Triton X-100 at -80 degrees C overnight. To test, whether the steroid milieu affects the actions of cetrorelix and triptorelin, cells were incubated for 52 h with 1 nM estradiol (E) alone or with combinations of 100 nM progesterone (P) for 4 or 52 h, respectively. Cells were then treated with 0.1 nM triptorelin for 9 h or 1 nM cetrorelix for 3 h and stimulated for 3 h with different concentrations of GnRH (10 pM-1 microM). The suppressive effect of triptorelin on LH secretion was fully accomplished after 3 h of treatment, for cetrorelix only 10 min were sufficient. The concentration of cetrorelix must be at least equimolar to GnRH to block LH secretion. Cetrorelix shifted the EC50s of the GnRH dose-response curve to the right. Triptorelin suppressed total LH significantly (from 137 to 36 ng/ml) after 1 h in a time-dependent manner. In contrast, only high concentrations of cetrorelix increased total LH. In steroid treated cells the suppressive effects of triptorelin were more distinct. One nanomolar cetrorelix suppressed GnRH-stimulated LH secretion of cells not treated with steroids from 10.1 to 3.5 ng/ml. In cells, additionally treated with estradiol alone or estradiol and short-term progesterone, LH levels were higher (from 3.5 to 5.4 or 4.5 ng/ml, respectively). In cells co-treated with estradiol and progesterone for 52 h LH secretion was only suppressed from 10.1 to 9.5 ng/ml. Steroid treatments diminished the suppressive effect of cetrorelix on LH secretion. In conclusion, the depletion of the total LH pool contributes to the desensitizing effect of triptorelin. The actions of cetrorelix and triptorelin are dependent on the steroid milieu.

Animals↗

Epidemiology of myomas.

Fibroids are a prevalent disorder occurring in at least half of American reproductive-age women. In general, the incidence and size increases with age. Most women never attribute or report any symptoms from their fibroids, and because of this the actual contribution of disease to symptoms of pelvic pain,menstrual symptoms, and infertility is poorly understood. The presence of fibroids can lead to multiple and disabling difficulties. Fibroids may cause pain and menstrual bleeding to the point of anemia. Fibroids clearly reduce fertility,increase preterm labor and delivery, and markedly increase the risk for cesarean delivery. Because the incidence varies according to population of interest, fibroids may explain some health disparities in different populations. For example,African Americans have a relatively poor outcome with assisted reproductive techniques compared with whites. Controlling for fibroid disease may explain this disparity, at least in part. Fibroids represent a tremendous public health burden on women and economic cost on society. Strategies to prevent, limit growth, and treat nonsurgically are needed. Fundamental and significant questions remain about fibroid disease,such as whether different clinical disease phenotypes (multiple versus single leiomyomas) contribute equally to symptoms and possess an equal likelihood of disease progression. For epidemiologic assessment of disease, a scoring system is urgently needed. Well-designed, controlled, prospective studies are still needed to define the natural history and correlate the presence of disease with symptomatology in women.

Epidemiologic Studies↗

Genetic causes of male infertility.

Genetic causes account for 10-15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, while this protective mechanism may be overcome by assisted reproduction techniques. Consequently the identification of genetic factors has become good practice for appropriate management of the infertile couple. Furthermore, patients affected by some forms of genetic alterations produce a higher frequency of sperm with aneuploidies. Sperm aneuploidies are the direct result of the constitutional genetic abnormality or are caused by meiotic errors induced by the altered testicular environment that these men present. In this review we will report and discuss the genetic causes of male infertility known up to date and we will analyse genetic polymorphisms possibly associated with male infertility.

Chromosome Aberrations↗

Genetic complexity of FSH receptor function.

The interaction between follicle-stimulating hormone (FSH) and the FSH receptor (FSHR) is essential for normal oogenesis and spermatogenesis. Recently, single-nucleotide polymorphisms (SNPs) have been assigned to the FSHR gene. These give rise to different FSHR haplotypes that modify the action of FSH. In women, FSH sensitivities during the menstrual cycle and different cycle lengths are observed, depending on the FSHR haplotype. Thus, SNPs of the FSHR determine the ovarian response and should, therefore, be considered in controlled ovarian hyperstimulation during assisted-reproduction techniques in women with normal ovarian function. In men, the impact of the FSHR SNPs is unclear. The genetic complexity of FSHR should be considered when studying FSH action. These SNPs are one of the first examples in which genetic changes contribute to fine-tuning the endocrine regulation of reproduction. A rational pharmacogenetic approach that combines FSH dose according to the FSHR haplotype is envisaged.

Animals↗