Reproductive surgery remains an essential element of reproductive medicine.

Background: Reproductive surgery has long been neglected and is perceived to be simple surgery that can be undertaken by all gynaecologists. However, given the ever-expanding knowledge in the field, reproductive surgery now comprises surgical interventions on female reproductive organs that need to be carefully planned and executed with consideration given to the individuals symptoms, function of the organ and fertility concerns. Objectives: To discuss the different perspectives of reproductive surgeons and other gynaecological surgeons, e.g., gynaecological oncologists, and advanced minimally invasive surgeons, regarding diagnosis and management of pelvic pathology that affects reproductive potential. Furthermore, to highlight the gaps in knowledge and numerous controversies surrounding reproductive surgery, while summarising the current opinion on management. Materials and Methods: Narrative review based on literature and the cumulative experience of the authors. Main outcome measures: The paper does not address specific research questions. Conclusions: Reproductive surgery encompasses all reproductive organs with the aim of alleviating symptoms whilst restoring and preserving function with careful consideration given to alternatives such as expectant management, medical treatments, and assisted reproductive techniques. It necessitates utmost technical expertise and sufficient knowledge of the female genital anatomy and physiology, together with a thorough understanding of and respect to of ovarian reserve, tubal function, and integrity of the uterine anatomy, as well as an up-to-date knowledge of alternatives, mainly assisted reproductive technology. What is new?: A holistic approach to infertile women is only possible by focusing on the field of reproductive medicine and surgery, which is unattainable while practicing in multiple fields.

The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

Adhesions and Anti-Adhesion Systems Highlights.

The peritoneal and intrauterine cavities are lined by fragile membranes with a high-wound healing capacity, e.g. repairing the endometrium in its cyclical "injury and scar-free repair process" during menstruation. However, peritoneal and intrauterine fibrosis and adhesions can develop after surgical trauma through activation of molecular, immune and genetic mechanisms. During procedures with a high-risk of adhesions, the use of new peritoneal and intrauterine conditions in combination with anti-adhesion substances are promising measures to preserve peritoneal and endometrial function and avoid the most common complication of gynecological surgery. Highlights of adhesions and anti-adhesion prevention techniques in laparoscopic, laparotomic and hysteroscopic surgeries are discussed in this paper. Unfortunately, evidence is lacking to prove the superiority of one technique over its counterparts in terms of postoperative adhesions, such as instrumentation, type of energy, distending media, and intracavitary pressure. Additionally, there is limited evidence about the efficacy and outcomes of techniques and adjuvant measures used during adhesiolysis. The definition of a universal intrauterine adhesions classification scheme as well as a prognostic scoring system to identify women at high risk of postoperative adhesions are necessary for advising those who could benefit the most of the use of antiadhesion barriers.

GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study.

BACKGROUND: GnRH agonist administration in the luteal phase was reported to beneficially affect the clinical outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This double blind, randomized, placebo controlled trial evaluates whether a single dose GnRH agonist administered 6 days after ICSI increases ongoing pregnancy rates following ET in cycles stimulated with the long GnRH agonist protocol. METHODS: Five hundred and seventy women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of ET according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. RESULTS: There were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval -5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. CONCLUSIONS: Single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase >or=12% in ongoing pregnancy rates.

An alternative to PVP for slowing sperm prior to ICSI.

BACKGROUND: There is a growing awareness of potential problems in exposing sperm to polyvinylpyrrolidone (PVP) to slow their motility, a procedure commonly used prior to ICSI. The study presented here evaluates an alternative product for slowing sperm motility, which contains hyaluronate, a substance found naturally in the reproductive tract. METHODS: Computerized sperm motility analysis was used to compare the motilities of sperm exposed to either a PVP-containing product (ICSI-100), or a hyaluronate-containing product (SpermCatch), or control sperm resuspended in a sperm maintenance medium. A subjective assessment was made of the ease with which sperm could be isolated and be drawn into, and expelled from, an injection pipette after having their tails nicked. Sperm exposed to either ICSI-100 or SpermCatch were used for ICSI. Fertilization rate, zygote development, grading, and outcome of transfer were recorded for the two treatment groups. RESULTS: The hyaluronate-containing product slowed sperm motility sufficiently for the sperm to be captured in an injection pipette, was easy to draw into and expel from the pipette, prevented sperm sticking to plastic or glassware, and did not affect post-injection zygote development. Clinical pregnancy rates were similar for the two groups. CONCLUSIONS: This product represents an alternative to PVP for slowing sperm motility prior to ICSI.

Progression to the blastocyst stage of embryos derived from testicular round spermatids.

Progression to the blastocyst stage of embryos derived from testicular round spermatids in men with non-obstructive azoospermia was studied. A total of 56 men were studied in whom partial spermatogenesis failure had occurred where only very few spermatozoa (fewer than the number of oocytes retrieved) were extracted from multiple testicular biopsy specimens. Oocytes remaining after intracytoplasmic injection of testicular spermatozoa (group 1) were injected with round spermatids (ROSI, group 2). Only embryos derived from group 1 were transferred. Remaining embryos were observed under culture for 8 days and their progression to the blastocyst stage was recorded. Of the 546 oocytes injected with testicular spermatozoa, 404 (73.9%) showed evidence of 2-pronuclear (2PN) fertilization. Injection of testicular round spermatids resulted in 2PN fertilization rate of 50% (P < 0.05). Using a four-point grading system, 53% of the good quality embryos (grade 1 or 2) in group 1 reached the blastocyst stage compared with 25% in group 2 (P < 0.05). The rate of progression to the blastocyst stage of grade 3 and grade 4 embryos was 46 and 8.5% in the two groups respectively (P < 0.05). Using a different three-point grading system for the blastocysts, 75.3% of the blastocysts in group 1 were either grade 1 or grade 2 and 24.7% were grade 3. However, in group 2 all blastocysts were grade 3. All embryos observed in group 1 reached the blastocyst stage by day 5 or 6 compared with 25% of the embryos reaching the blastocyst stage by this time in group 2. While 31.2% of the blastocysts in group 1 showed evidence of spontaneous hatching in vitro, none of the blastocysts in group 2 hatched. In conclusion, progression to the blastocyst stage occurred at a much lower and slower rate in embryos derived from testicular round spermatids. Furthermore, all blastocysts resulting from ROSI were of poor quality and none showed spontaneous hatching. These results may explain the dismal outcome associated with ROSI.

Outcome of testicular sperm retrieval procedures in non-obstructive azoospermia: percutaneous aspiration versus open biopsy.

The aim of this study was to evaluate whether the extraction of testicular spermatozoa with percutaneous versus open biopsy has an effect on the treatment outcome with intracytoplasmic sperm injection (ICSI) in men with non-obstructive azoospermia. Regardless of testicular size, follicle stimulating hormone concentration, and previous biopsy result, percutaneous testicular sperm aspiration (PTSA) using a 21-gauge butterfly needle was attempted first and if this failed testicular sperm extraction (TESE) was performed. In 63 men spermatozoa were found with PTSA whereas in 228 men TESE had to be undertaken. More men in the PTSA group had previously been diagnosed with hypospermatogenesis (82 versus 50%). Compared with the PTSA group, more men in the TESE group had germ cell aplasia (27 versus 10%) or maturation arrest (22 versus 8%). There was no difference between the groups regarding mean age of men and their partners, duration of stimulation, oestradiol concentration on the day of human chorionic gonadotrophin, number of oocytes retrieved, fertilization rate, and embryo quality between the two groups. The number of embryos transferred (4.38 versus 3.90) was significantly higher in the PTSA group (P < 0.05), reflecting the increased number of embryos available for transfer. Implantation rate per embryo was 20.7% in the PTSA and 13.3% in the TESE group (P < 0.05). Clinical pregnancy rates were 46 and 29% in the PTSA and TESE groups respectively (P < 0.05). Clinical abortion rates were similar (21.2 versus 24%). It is concluded that in men with non-obstructive azoospermia, easier sperm retrieval, which is most likely indicative of a more favourable histopathology, is associated with higher implantation rates per embryo.

Elevated serum progesterone level on the day of human chorionic gonadotropin administration does not adversely affect implantation rates after intracytoplasmic sperm injection and embryo transfer.

OBJECTIVE: To evaluate the association between serum P levels on the day of hCG administration and the outcome of intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective case study. SETTING: Assisted reproduction unit of a tertiary care private hospital. PATIENT(S): Nine hundred eleven ICSI cycles that proceeded to ET were studied. INTERVENTION(S): The decision to administer hCG was based on serum E2 levels and follicle size. Serum P was measured from frozen sera obtained on the day of hCG administration. Cycles were stratified according to serum P levels of <0.9 ng/mL (n = 298) or > or =0.9 ng/mL (n = 613). This cutoff level was selected because it yielded the highest sensitivity and specificity according to a receiver operator characteristic curve. MAIN OUTCOME MEASURE(S): Implantation and clinical pregnancy rates. RESULT(S): In cycles with high serum P levels, more oocytes were retrieved and more embryos were available for transfer. Clinical pregnancy rates per ET in the low and high P groups were 36.9% and 45.4%, respectively (P<.05). The implantation rate per embryo was similar in the two groups (14.9% and 16.4%, respectively, in cycles with P levels <0.9 vs > or =0.9 ng/mL). Abortion rates were 22.7 and 25.8%, respectively (P>.05). CONCLUSION(S): Our data showed no adverse effect of high serum P levels on the day of hCG administration on implantation rates after ICSI and ET.

Evaluation of uterine cavity by sonohysterography in women scheduled for intracytoplasmic sperm injection.

A prospective study was performed to determine the feasibility of evaluating the uterine cavity by sonohysterography (SHG) in women who were scheduled for intracytoplasmic sperm injection (ICSI) due to severe male factor infertility and who had not had a previous hysterosalpingography (HSG). Sonohysterography was performed in 80 women scheduled for ICSI. A subsequent hysteroscopy was undertaken in patients with intracavitary lesions. The outcome of ICSI for the women undergoing SHG was compared with that of 240 cycles performed (during the same time period) in patients who had a normal HSG before admission to the clinic. There were no complications attributable to the SHG procedure. Hysteroscopy correctly identified all lesions depicted by SHG. SHG and HSG groups were comparable with regard to female age and duration of infertility. Clinical pregnancy rates per transfer were 40.2% and 42.5% in the SHG and HSG groups, respectively. Abortion rates in the two groups were also similar (14.8 and 11.0%, respectively). In conclusion, sonohysterography appears to be a simple, inexpensive, and safe alternative to HSG for evaluation of the uterine cavity in women scheduled for ICSI.

Methylation levels at selected CpG sites in the factor VIII and FGFR3 genes, in mature female and male germ cells: implications for male-driven evolution.

Transitional mutations at CpG dinucleotides account for approximately a third of all point mutations. These mutations probably arise through spontaneous deamination of 5-methylcytosine. Studies of CpG mutation rates in disease-linked genes, such as factor VIII and FGFR3, have indicated that they more frequently originate in male than in female germ cells. It has been speculated that these sex-biased mutation rates might be a consequence of sex-specific methylation differences between the female and the male germ lines. Using the bisulfite-based genomic-sequencing method, we investigated the methylation status of the human factor VIII and FGFR3 genes in mature male and female germ cells. With the exception of a single CpG, both genes were found to be equally and highly methylated in oocytes and spermatocytes. Whereas these observations strongly support the notion that DNA methylation is the major determining factor for recurrent CpG germ-line mutations in patients with hemophilia and achondroplasia, the higher mutation rate in the male germ line is apparently not a simple reflection of sex-specific methylation differences.

Performing testicular or epididymal sperm retrieval prior to the injection of hCG.

PURPOSE: Our purpose was to determine the feasibility and efficacy of performing testicular or epididymal sperm retrieval prior to the injection of human chorionic gonadotropin (hCG). METHODS: This report deals with 87 sperm-positive percutaneous epididymal sperm aspiration (PESA), percutaneous testicular sperm aspiration (PTSA), or testicular sperm extraction (TESE) cycles. All sperm retrieval procedures were performed prior to administration of hCG to the women. Retrieved spermatozoa were cultured in vitro in simple medium for approximately 40 hr prior to intracytoplasmic sperm injection. RESULTS: In all but one cycle in which TESE was performed for nonobstructive azoospermia, motile sperm were available for ICSI. The overall fertilization rate was 53%. Pregnancy rate per transfer and implantation rate per embryo were 41.2 and 15.7%, respectively. CONCLUSIONS: Satisfactory fertilization and pregnancy rates can be achieved when PESA, PTSA, or TESE is performed prior to the injection of hCG followed by in vitro culture of spermatozoa approximately 40 hr before ICSI. Scheduling of testicular or epididymal sperm retrieval cases in this way appears to ease the workload on laboratory and operating room personnel. Furthermore, withholding hCG when sperm is absent may obviate the unnecessary risk of ovarian hyperstimulation when spermatozoa cannot be retrieved.

Pregnancy in infertile PCOD patients. Complications and outcome.

OBJECTIVE: To evaluate the complications and outcome of pregnancy in women with polycystic ovary disease (PCOD). STUDY DESIGN: The course and outcome of 47 singleton pregnancies in women with well-documented PCOD were compared with those in 100 healthy controls. RESULTS: Women with PCOD had a significantly higher body mass index as compared to the control group (P < .05); however, the proportion of lean versus obese subjects in the two groups was similar. The incidence of an abnormal glucose challenge test, gestational diabetes mellitus and pregnancy-induced hypertension was significantly increased in pregnant women with PCOD (P < .05). When lean PCOD subjects were compared with lean control subjects, the difference in the incidence of the above complications was still significant (P < .05). The incidence of pregnancy complications was similar when obese PCOD subjects were compared with obese controls. CONCLUSION: Women with PCOD were at increased risk of gestational diabetes and pregnancy-induced hypertension, and this risk appeared to be independent of body mass index.

Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation and fertility.

OBJECTIVE: To assess the safety and efficacy of hysteroscopic adhesiolysis in patients with recurrent pregnancy loss and infertility. DESIGN: Retrospective case report series. SETTING: The obstetrics and gynecology clinic of a medical school. PATIENT(S): Forty women with recurrent pregnancy loss or infertility resulting from intrauterine adhesions. INTERVENTION(S): Hysteroscopic adhesiolysis in patients with recurrent pregnancy loss and infertility. MAIN OUTCOME MEASURE(S): Postoperative adhesion formation, intraoperative complication, conceivement after surgery, pregnancy rate, and pregnancies resulted in term or viable preterm infants. RESULT(S): Most patients with minimal or moderate adhesions were free of adhesions when compared with postoperative control subjects. However, adhesion re-formation was noted in 60% of the patients who initially had severe adhesions. Normal menstrual flow was restored in 81% of the patients. All the patients who had recurrent pregnancy loss conceived after treatment, and 71% of the pregnancies resulted in a term or viable preterm infant. Of the 16 infertile patients treated, 10 (63%) conceived and 6 (37%) were delivered of viable infants. CONCLUSION(S): Hysteroscopic adhesiolysis is a safe and effective procedure for restoring the normal menstrual pattern and fertility. The initial severity of the adhesions appears to correlate best with the reproductive outcome.

Adhesion formation and reformation after laparoscopic removal of ovarian endometriomas.

STUDY OBJECTIVE: To evaluate the extent of adhesion formation after laparoscopic removal of endometriomas. DESIGN: Prospective case series. SETTING: A university hospital. PATIENTS: Nineteen infertile women with ovarian endometriomas. INTERVENTIONS: All patients underwent laparoscopic cystectomy with total stripping of the cyst capsule when possible. A second-look laparoscopy was performed after 3 months of postoperative treatment with a gonadotropin-releasing hormone analog. MEASUREMENTS AND MAIN RESULTS: The extent of adhesion reformation was dependent on the extent and severity of adhesions at initial laparoscopy. One (5.2%) woman had a residual ovarian endometrioma at second-look laparoscopy. De novo adhesion formation was not seen. Nine women (42.8%) conceived during the postoperative follow-up period (range 11-22 mo). CONCLUSIONS: Laparoscopic removal of endometriomas is effective in eradicating the disease. Adhesions at second-look laparoscopy depend on adhesions at the initial laparoscopy. Crude pregnancy rates are satisfactory in infertile women.

Results of in vitro fertilization and embryo transfer in women with infertility due to genital tuberculosis.

OBJECTIVE: To determine the results of IVF-ET in women with infertility due to genital tuberculosis. DESIGN: Retrospective case-control study. SETTING: In vitro fertilization and ET unit of a university hospital. PATIENTS: Forty-four cycles of IVF-ET were undertaken in 24 women with genital tuberculosis and the results were compared with 366 cycles in 274 nontuberculous tubal factor couples. INTERVENTIONS: All women with genital tuberculosis were evaluated with hysteroscopy, endometrial biopsy, and acid fast bacilli stain before treatment with IVF-ET. RESULTS: Subjects with genital tuberculosis had higher basal FSH levels, required more exogenous gonadotropins for controlled ovarian hyperstimulation, reached lower peak E2 levels, and yielded fewer oocytes and embryos when compared with tubal factor patients. Furthermore, in women with genital tuberculosis, clinical pregnancy rate per cycle was lower and spontaneous abortion rate was higher. CONCLUSIONS: Women with genital tuberculosis appear to represent a less favorable subset within other tubal factor patients when treated with IVF-ET.

PIP: At Hacettepe University Hospital in Ankara, Turkey, 24 women with genital tuberculosis had undergone 44 cycles of in vitro fertilization-embryo transfer (IVF-ET) and 274 women with tubal infertility not related to genital tuberculosis (controls) had undergone IVF-ET. Physicians compared the results of IVF-ET in these two sets of women. Women with genital tuberculosis had significantly higher day-3 follicle stimulating hormone (FSH) levels than the controls (11.6 vs. 7.7 mIU/ml; p 0.001). Thus, they had a higher number of ampules of hMG than the controls (27.3 vs. 18.4; p 0.05) to achieve peak estradiol levels on the day of human chorionic gonadotropin (hCG) and the number of days of follicle stimulation. Peak estradiol levels were lower among cases than controls (852 vs. 1141 pg/ml; p 0.05), while the number of days of follicle stimulation was higher among cases than controls (10.3 vs. 7.5; p 0.01). Women with genital tuberculosis also had a significantly lower number of aspirated oocytes and of transferred embryos than controls (5.8 vs. 7.7 and 2 vs. 2.9, respectively; p 0.01 for both). They also had a much lower clinical pregnancy rate than controls (9.1% vs. 21.3%; p 0.001). Women with genital tuberculosis also had a significantly higher spontaneous abortion rate than controls (75% vs. 19.2%; p 0.05). The only woman with genital tuberculosis who delivered a live infant had undergone hysteroscopic lysis of dense intrauterine synechia. The lower pregnancy rate was largely due to the fewer embryos available for transfer among the women with genital tuberculosis. The implantation rates per transferred embryo were not significantly different between the two groups (5.85% for cases vs. 8.6% for controls). These findings suggest that women with genital tuberculosis are a less favorable subset among tubal factor patients when treated with IVF-ET. Physicians should anticipate these women to have a reduced ovarian reserve, lower intrauterine pregnancy, and higher miscarriage rates.