Molecular Determinants of Uterine Receptivity: Comparison of Successful Implantation, Recurrent Miscarriage, and Recurrent Implantation Failure.

Embryo implantation is one of the most remarkable phenomena in human reproduction and is not yet fully understood. Proper endometrial function as well as a dynamic interaction between the endometrium itself and the blastocyst-the so-called embryo-maternal dialog-are necessary for successful implantation. Several physiological and molecular processes are involved in the success of implantation. This review describes estrogen, progesterone and their receptors, as well as the role of the cytokines interleukin (IL)-6, IL-8, leukemia inhibitory factor (LIF), IL-11, IL-1, and the glycoprotein glycodelin in successful implantation, in cases of recurrent implantation failure (RIF) and in cases of recurrent pregnancy loss (RPL). Are there differences at the molecular level underlying RIF or RPL? Since implantation has already taken place in the case of RPL, it is conceivable that different molecular biological baseline situations underlie the respective problems.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022).

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols. Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out. Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

Impact of Adenomyosis on Infertile Patients-Therapy Options and Reproductive Outcomes.

Adenomyosis is associated with a negative impact on reproductive outcomes. Although adenomyosis is detected more frequently in women of late reproductive age, its impact on pregnancy rates is important because, in today's world, family planning has shifted towards the late reproductive phase of life for many women. Although the diagnostic indications for imaging studies are well-known, we lack strict diagnostic criteria and classification systems concerning the extent of the disease. Selecting the optimal evidence-based treatment option for adenomyosis is difficult because of the paucity of evidence concerning the association between fertility and the degree and composition of adenomyosis. Furthermore, the treatment of infertility might interfere with the treatment of adenomyosis due to the presence of pain. The aim of this review is to analyze the association between adenomyosis and infertility, and describe treatment options to enhance reproductive outcomes. The following aspects will be addressed in detail: (a) prevalence and causes of adenomyosis, (b) diagnostic tools with imaging techniques, (c) clinical symptoms, (d) proposed pathomechanism of adenomyosis and infertility, and (e) different treatment approaches (pharmacological, surgical, others) and their impact on reproductive outcomes.

Vaginal Microbiome in Reproductive Medicine.

The human microbiome has been given increasing importance in recent years. The establishment of sequencing-based technology has made it possible to identify a large number of bacterial species that were previously beyond the scope of culture-based technologies. Just as microbiome diagnostics has emerged as a major point of focus in science, reproductive medicine has developed into a subject of avid interest, particularly with regard to causal research and treatment options for implantation failure. Thus, the vaginal microbiome is discussed as a factor influencing infertility and a promising target for treatment options. The present review provides an overview of current research concerning the impact of the vaginal microbiome on the outcome of reproductive measures. A non-Lactobacillus-dominated microbiome was shown to be associated with dysbiosis, possibly even bacterial vaginosis. This imbalance has a negative impact on implantation rates in assisted reproductive technologies and may also be responsible for habitual abortions. Screening of the microbiome in conjunction with antibiotic and/or probiotic treatment appears to be one way of improving pregnancy outcomes.

Live Birth Rates after Active Immunization with Partner Lymphocytes.

Although many potential causes have been established for recurrent implantation failure (RIF) and recurrent miscarriage (RM), about 50% of these remain idiopathic. Scientific research is focused on immunological risk factors. In the present study, we aim to evaluate live birth rates after immunization with paternal lymphocytes (lymphocyte immunotherapy (LIT)). This retrospective study consisted of 148 couples with a history of RM and/or RIF. The women underwent immunization with lymphocytes of their respective partners from November 2017 to August 2019. Fifty-five patients (43%) had live births. Stratified by indication (RM, RIF, combined), live birth rates in the RM and the combined group were significantly higher than that in the RIF group (53%, 59% and 33%, respectively, p = 0.02). The difference was especially noticeable during the first 90 days after immunization (conception rate leading to live births: 31%, 23% and 8% for RM, the combined group and RIF, respectively; p = 0.005), while there was no difference between groups during the later follow-up. LIT was associated with high live birth rates, especially in women with recurrent miscarriage. In view of the limited data from randomized studies, LIT cannot be recommended as routine therapy. However, it may be considered in individual cases.

Endometrial "Scratching" An update and overview of current research.

About one in every six couples is affected by sterility. Assisted reproduction procedures are currently the treatment of choice for a number of patients who desire children. Many causes of sterility can be overcome with the aid of in vitro fertilization, but successful implantation of the embryos is the major limiting factor. Failure of implantation may occur repetitively. In the treatment of sterility, many approaches have been used to overcome the barrier of implantation failure and improve the chances of successful nidation. Scratching the endometrium prior to embryo transfer has been suggested as one means of enhancing the likelihood of implantation. The current literature was examined to investigate if there was any possible benefit from endometrial scratching. The studies were divided according to whether the women suffered from recurrent implantation failure or not. In summary, it was found that unselected subfertile women generally benefit less from endometrial scratching, but scratching appears to be successful in women who have experienced repeated implantation failure. Although the heterogeneous body of data on the subject deserves further clarification. The latest data presented at "European Society of Human Reproduction and Embryology" 2018 in Barcelona suggested that the method should be abandoned.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050).

PURPOSE: Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (ÖGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members. METHODS: Based on the current literature, the committee members developed the statements and recommendations of this guideline in a formalized process which included DELPHI rounds and a formal consensus meeting. RECOMMENDATIONS: Recommendations for the diagnosis and treatment of patients with RM were compiled based on the international literature. Specific established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders were taken into consideration.

Active Immunisation with Partner Lymphocytes in Female Patients Who Want to Become Pregnant - Current Status.

Around 1 - 3% of all couples who try to have a child are affected by recurrent miscarriage. According to the WHO, recurrent miscarriage is defined as the occurrence of three or more consecutive miscarriages up to the 20th week of pregnancy. There are various causes of recurrent miscarriage; in many cases, the causes remain unclear, with the result that immunological factors are one of the possible causes discussed. For the mother's immune system, the embryo represents a semi-allogeneic transplant, as half of the embryo's genes are of paternal origin. In place of a conventional immune response, the embryo induces a secondary protection mechanism, which contributes to the successful implantation. When performing immunisation with partner lymphocytes, the patient receives an intradermal injection of her partner's prepared lymphocytes into the volar side of the forearm in order to induce immunomodulation with a consequently increased rate of pregnancy and live birth. A prerequisite for this procedure is that all other possible causes of sterility have been ruled out in advance. Due to the highly heterogeneous nature of the data, a significant benefit as a result of the immunisation cannot yet be clearly proven. However, there are signs that the therapy may be effective when using lymphocytes that have been extracted as short a time beforehand as possible. Overall, the treatment represents a safe, low-risk procedure. Following a detailed informative discussion with the couple regarding the chances of success and following a detailed review of the indication and contraindications, immunisation with partner lymphocytes can be discussed with the couple on a case-by-case basis - provided that all other possible causes of sterility have been ruled out in advance.

Two-year outcome after recurrent first trimester miscarriages: prognostic value of the past obstetric history.

PURPOSE: Recurrent miscarriage (RM) is a stressful condition which gives rise to extensive diagnostic evaluation and is seen as a potentially curable maternal disease. Nevertheless, epidemiological data have shown that outcome is related to fertility. In addition to maternal age and number of preceding miscarriages, further markers derived from the past history may support counselling. METHODS: Observational trial comprising 228 couples who were referred between 1996 and 2003 for immunological evaluation at maternal ages 20-39 years after three or more spontaneously conceived primary first trimester miscarriages. They were interviewed in 2005, ongoing pregnancies were followed up until birth in 2006. Past obstetric history was correlated with 2 year cumulative pregnancy and delivery rates (CPR, CDR). RESULTS: CPR and CDR were 206/228 (90.4 %) and 174/228 (76.4 %). Duration of infertility was associated with lower CPR (up to 3/>3 years, p < 0.01), whereas age and number of preceding losses inversely correlated with CDR (<35 years/35-39 years, p < 0.002; 3/>3 miscarriages, p < 0.002). Detection of an embryonic heart beat in 2-3 of the first three miscarriages resulted in favourable outcome (CPR: p < 0.02, CDR: p < 0.002). Prognosis was excellent in younger fertile women after three miscarriages where vital signs had been detected; under less favourable conditions not only risks for further miscarriage, but also for secondary infertility were elevated. CONCLUSION: Secondary infertility is a feature of RM. Embryonic vital signs in preceding pregnancies are prognostic markers and should be regarded as a strong confounding factor in trials on therapeutic interventions. Prevention may be more appropriate than treatment.

Array-based DNA methylation profiling in male infertility reveals allele-specific DNA methylation in PIWIL1 and PIWIL2.

OBJECTIVE: To identify CpG sites differentially methylated in peripheral blood of men with idiopathic infertility due to impaired spermatogenesis as compared with fertile controls. DESIGN: DNA methylation profiling on peripheral blood samples using the HumanMethylation450 BeadChip (Illumina) in patients and controls, single-nucleotide polymorphism (SNP) typing by Sanger sequencing. SETTING: University institute in cooperation with genetic and infertility clinics. PATIENT(S): 30 infertile men with normal CFTR and AZF tests and karyotype, and 10 fertile male controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA methylation levels at CpG sites. RESULT(S): We identified 471 CpGs (287 genes) as differentially methylated between patients and controls. These were significantly enriched for the gene ontology functions MHC class II receptor activity and piwi-interacting (piRNA) binding. The latter was associated with two methylation-sensitive SNPs in the genes PIWIL1 and PIWIL2, respectively, which showed significant allele distribution skewing in the infertile cohort. We found that 445 (94.5%) of 471 differentially methylated CpGs were associated with SNPs, but 26 (15 genes) were not genomically templated, including the ENO1, MTA2, BRSK2, and LBX2 genes previously associated with fertility and spermatogenesis. CONCLUSION(S): Our study identifies surrogate DNA methylation markers for idiopathic infertility in peripheral blood and suggests that allele-specific DNA methylation differences at regulatory sites of genes involved in piRNA regulation are associated with disturbed spermatogenesis.

Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study.

The threat of severe ovarian hyperstimulation syndrome (OHSS) and the increase in discomfort for the patient has limited the feasibility of maximizing the oocyte yield per treatment cycle. A gonadotrophin-releasing hormone (GnRH) antagonist protocol with agonist triggering and vitrification of all 2PN oocytes can eliminate the risk of OHSS. This prospective, single-centre, cohort study in 30 good-responder IVF patients ≤ 36 years reports the feasibility of arbitrarily intensifying stimulation in a GnRH antagonist protocol in terms of tolerability, safety and efficacy. Ovarian stimulation was performed with 225-375IU FSH, induction of final oocyte maturation with 0.2mg GnRH agonist followed by vitrification of all 2 pronuclear (2PN) oocytes and repetitive vitrified-warmed embryo transfer cycles. Main outcomes were severe OHSS incidence, tolerability, assessed by a questionnaire, and cumulative live birth rate. On average, 17 oocytes were retrieved (range 4-42) and 8.4 oocytes at the 2PN stage were cryopreserved (range 3-22). No case of severe OHSS was observed (0%, 95 CI 0-11.4%). Tolerability was good. The cumulative live birth rate per patient undergoing at least one vitrified-warmed embryo transfer was 26.9% (7/26, 95% CI 13.7-46.1%). This approach can be explored in future larger-sized controlled studies.

Follicular fluid high-density lipoprotein-associated sphingosine 1-phosphate (S1P) promotes human granulosa lutein cell migration via S1P receptor type 3 and small G-protein RAC1.

Coordinated migration and progesterone production by granulosa cells is critical to the development of the corpus luteum, but the underlying mechanisms remain obscure. Sphingosine 1-phosphate (S1P), which is associated with follicular fluid high-density lipoprotein (FF-HDL), was previously shown to regulate ovarian angiogenesis. We herein examined the effects of S1P and FF-HDL on the function of granulosa lutein cells. Both FF-HDL and S1P induced migration of primary human granulosa lutein cells (hGCs) and the granulosa lutein cell line HGL5. In addition, FF-HDL but not S1P promoted progesterone synthesis, and neither of the two compounds stimulated proliferation of granulosa lutein cells. Polymerase chain reaction and Western blot experiments demonstrated the expression of S1P receptor type 1 (S1PR1), S1PR2, S1PR3, and S1PR5 but not S1PR4 in hGCs and HGL5 cells. The FF-HDL- and S1P-induced granulosa lutein cell migration was emulated by FTY720, an agonist of S1PR1, S1PR3, S1PR4, and S1PR5, and by VPC24191, an agonist of S1PR1 and S1PR3, but not by SEW2871 and phytosphingosine 1-phosphate, agonists of S1PR1 and S1PR4, respectively. In addition, blockade of S1PR3 with CAY1044, suramine, or pertussis toxin inhibited hGC and HGL5 cell migration toward FF-HDL or S1P, while blockade of S1PR1 and S1PR2 with W146 and JTE013, respectively, had no effect. Both FF-HDL and S1P triggered activation of small G-protein RAC1 and actin polymerization in granulosa cells, and RAC1 inhibition with Clostridium difficile toxin B or NSC23766 abolished FF-HDL- and S1P-induced migration. The FF-HDL-associated S1P promotes granulosa lutein cell migration via S1PR3 and RAC1 activation. This may represent a novel mechanism contributing to the development of the corpus luteum.

Human luteinized granulosa cells secrete apoB100-containing lipoproteins.

Thus far, liver, intestine, heart, and placenta have been shown to secrete apolipoprotein (apo)B-containing lipoproteins. In the present study, we first investigated lipoproteins in human follicular fluid (FF), surrounding developing oocytes within the ovary, as well as in corresponding plasma samples (n = 12). HDL cholesterol within FF correlated well with plasma HDL cholesterol (r = 0.80, P < 0.01), whereas VLDL cholesterol did not, indicating that VLDL in FF might originate directly from the granulosa cells producing FF. Primary human granulosa cells expressed apoB, microsomal triglyceride transfer protein, and apoE, but not the apoB-editing enzyme apobec-1. Using (3)H-leucine, we show that granulosa cells secrete apoB100-containing lipoproteins and that secretion can be stimulated by adding oleate to the medium (+83%). With electron microscopy, apoB-containing lipoproteins within the secretory pathway of human granulosa cells were directly visualized. Finally, we found a positive relationship between apoB levels in FF and improved fertility parameters in a population of 27 women undergoing in vitro fertilization. This study demonstrates that human granulosa cells assemble and secrete apoB100-containing lipoproteins, thereby identifying a novel cell type equipped with these properties. These results might have important implications for female infertility phenotypes as well as for the development of drugs targeting the VLDL production pathway.

Primary peritoneal carcinoma in a young woman with suspected endometriosis.

OBJECTIVE: To describe the treatment of a 23-year-old patient with primary peritoneal carcinoma and preservation of her fertility. DESIGN: Case report. SETTING: University of Schleswig-Holstein, Campus Lübeck, Department of Gynecology and Obstetrics. PATIENT(S): A 23-year-old patient with primary peritoneal carcinoma. INTERVENTION(S): The patient was given treatment by first preserving her fertility with oocyte vitrification and cryoconservation of ovarian biopsy samples. Surgery was performed with radical resection of the peritoneal lesion, ovarian biopsies, omentectomy, and pelvic and para-aortic lymph node sampling before starting chemotherapy with carboplatin and paclitaxel (Taxol). Hysterectomy and bilateral salpingo-oophorectomy were not performed. MAIN OUTCOME MEASURE(S): Treatment of peritoneal carcinoma and number of vitrified oocytes. RESULT(S): Twenty-five oocytes of the patients were vitrified before chemotherapy was performed. CONCLUSION(S): Primary peritoneal carcinoma is a rare disease that laparoscopically resembles peritoneal endometriosis and histologically is very similar to primary epithelial ovarian cancer. The advised therapy is based on ovarian cancer treatment; however, it is unclear whether the radical operation improves prognosis. In this case, a 23-year-old patient underwent treatment preserving her fertility with oocyte vitrification and cryoconservation of ovarian biopsy samples before surgery and chemotherapy were performed.

Follicular and endocrine response to anastrozole versus clomiphene citrate administered in follicular phase to normoovulatory women: a randomized comparison.

OBJECTIVE: To compare the effect on follicular growth and endocrine parameters of follicular phase administration of anastrozole to healthy, normoovulatory women in doses of 1 or 5 mg, respectively, with the conventional dosing regimen for ovulation induction with clomiphene citrate (CC). DESIGN: Randomized, assessor-blinded, single-center, three-armed study. SETTING: University-affiliated, tertiary referral center. PATIENT(S): Thirty-two, normoovulatory, normogonadotropic women. INTERVENTION(S): Administration of anastrozole 1 mg (group A1), anastrozole 5 mg (group A5), or CC 50 mg (group CC50) from cycle days 3 to 7. MAIN OUTCOME MEASURE(S): Number of follicles >or=15 mm and >or=10 mm on the day of the endogenous LH surge. RESULT(S): The mean number of follicles >or=15 mm on the day of LH surge was 1.4 +/- 0.5, 1.0 +/- 0.4, and 0.8 +/- 0.4 in groups CC50, A1, and A5, respectively, which was statistically significant. Furthermore, a statistically significant difference between groups was found for the size of the growing follicular cohort (follicles >or=10 mm) on cycle days 8 and 10 and on the day of LH surge. The area under the curve (adjusted for baseline values on cycle day 3 and time frame of assessment) of follicular phase E(2) levels was significantly different among the groups that were compared (223.0 +/- 97.5, 69.2 +/- 40.0, and 83.4 +/- 36.4 for groups CC50, A1, and A5, respectively). CONCLUSION(S): CC 50 mg exerts a stronger stimulatory effect on follicular growth compared with anastrozole in doses of 1 or 5 mg. Anastrozole administration results in lower follicular phase E(2) levels.

159C>T CD14 genotype--functional effects on innate immune responses in term neonates.

Given the susceptibility of newborns to infection and the potential harm of overwhelming proinflammatory immune responses, the impact of genetic variation in innate immune molecules is of increasing interest for risk stratification and prevention. We studied the functional relevance of the 159C>T CD14 single nucleotide polymorphism in cord blood samples of n=135 healthy term neonates by investigation of sCD14, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations in whole-blood culture supernatants and intracellular assessment of IL-1beta, IL-6, and TNF-alpha expression by flow cytometry. The 159C>T CD14 genotype frequencies were n=42 (0.31) for homozygous CD14-159 CC, n=69 (0.51) for heterozygous CD14-159 CT, and n=24 (0.18) for homozygous CD14-159 TT. No genotype-associated differences were noted for ex vivo baseline expression of sCD14, IL-6, IL-10, and TNF-alpha. After in vitro stimulation of cord blood cultures with lipopolysaccharide, carriers of the CD14-159 T allele were determined to have higher levels of sCD14 compared with carriers of the CD14-159 C allele (p=0.04) and increased concentrations of IL-6 (p=0.009) in culture supernatants (one-way analysis of variance). The 159C>T CD14 polymorphism is associated with soluble CD14 expression and cytokine expression, which might influence the balance of pro- and anti-inflammatory immune responses in healthy term neonates. Further studies are needed to delineate whether the 159C>T CD14 genotype is a risk factor for severity of neonatal infection in the clinical setting and a potential target for prevention strategies.

Follicular fluid high density lipoprotein-associated sphingosine 1-phosphate is a novel mediator of ovarian angiogenesis.

Angiogenesis plays an important role in the development of the ovarian follicle and its subsequent transition into the corpus luteum. Accordingly, follicular fluid is a rich source of mitogenic and angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor secreted by granulosa cells. In the present study, we show that follicular fluid deprived of basic fibroblast growth factor or vascular endothelial growth factor by means of thermal denaturation or antibody neutralization retains its capacity to stimulate endothelial proliferation and angiogenesis. Mass spectrometric analysis of chromatographic fractions stimulating endothelial growth obtained from follicular fluid revealed that the heat-stable mitogenic activity is identical with the subfraction alpha of high density lipoproteins purified from follicular fluid (FF-HDL). Further investigations demonstrated that sphingosine 1-phosphate (S1P), one of the lysophospholipids associated with HDL, accounts for the capacity of this lipoprotein to stimulate endothelial growth and the formation of new vessels. Activation of mitogen-activated protein kinase (p42/44(ERK1/2)), protein kinase C, and protein kinase Akt represent signaling pathways utilized by FF-HDL and S1P to induce endothelial proliferation and angiogenesis. We conclude that FF-HDL represents a novel mitogenic and angiogenic factor present in follicular fluid and that S1P is one of the FF-HDL lipid components accounting for this activity.

Polymorphisms of haemostasis genes as risk factors for preterm delivery.

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant's factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infant's factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.

Lessons learned from introducing an in-vitro maturation programme into clinical practice.

The technology of in-vitro maturation (IVM) aims at maturing immature oocytes from the germinal vesicle (GV) stage to the metaphase 2 stage of the second meiotic division in vitro. Gametes are obtained by immature oocyte retrieval from small antral follicles (5-12 mm) present in polycystic ovarian syndrome patients or at the beginning of each cycle of normally menstruating woman. Maturation time in vitro takes about 28-36 h. After precise patient selection and adequate preparation, a high proportion of oocytes are able to resume meiosis in vitro. Intracytoplasmic sperm injection is the preferred method of fertilization. About 300 children have been born worldwide after IVM, and are reported to be healthy. Recent data suggests that IVM has the potential to replace standard ovarian stimulation in the near future. Nevertheless, several aspects of IVM regarding safety and efficacy remain unanswered and will have to be addressed. This paper reviews data concerning IVM in clinical practice and describesexperience from the establishment of an IVM programme that resulted in the first IVM pregnancy in Germany.