Impact of embryo quality and endometrial thickness on implantation in natural cycle IVF.

PURPOSE: The aim of this study is to assess the effect of the endometrial thickness and embryo quality on the implantation potential in natural cycle IVF (NC-IVF). METHODS: A retrospective single-center study was performed on 552 single embryo transfers after NC-IVF. The 'quality' of the embryos was evaluated trough the number and regularity of blastomeres, degree of fragmentation, and nuclear content of cells. Endometrial thickness was measured in millimeters with transvaginal ultrasound on the day of hCG application. RESULTS: Our findings showed a statistically significant difference in successful implantation until a plateau of 10 mm is reached (p = 0.001). Only one pregnancy was achieved where endometrial thickness was less than 7 mm, and this resulted in an early miscarriage. The predictors of favorable implantation were fragmentation (≤ 10%, p < 0.05) and the number of blastomeres (preferably 8-cell, p < 0.01) on day 3. Embryo quality (R = 0.052) and endometrial thickness (R = 0.18) were closely related to pregnancy rate. The overall implantation rate per embryo transfer was 18.8%. CONCLUSIONS: Embryo quality and endometrial thickness have a significant impact on implantation in NC-IVF. Highest implantation potential has an 8-cell embryo with ≤ 10% fragmentation in the third day following oocyte retrieval. Endometrial thickness of at least 7 mm seems to be the optimal edge of successful pregnancy.

FERTILITY PRESERVATION IN YOUNG WOMEN WITH EARLY-STAGE BREAST CANCER.

Although breast cancer (BC) occurs more often in older women, it is the most commonly diagnosed malignancy in women of childbearing age. Owing to the overall advancement of modern medicine and the growing global trend of delaying childbirth until later age, we find ever more younger women diagnosed and treated for BC who have not yet completed their family. Therefore, fertility preservation has emerged as a very important quality of life issue for young BC survivors. This paper reviews currently available options for fertility preservation in young women with early-stage BC and highlights the importance of a multidisciplinary approach to fertility preservation as a very important quality of life issue for young BC survivors. Pregnancy after BC treatment is considered not to be associated with an increased risk of BC recurrence; therefore, it should not be discouraged for those women who want to achieve pregnancy after oncologic treatment. Currently, it is recommended to delay pregnancy for at least 2 years after BC diagnosis, when the risk of recurrence is highest. However, BC patients of reproductive age should be informed about the potential negative effects of oncologic therapy on fertility, as well as on the fertility preservation options available, and if interested in fertility preservation, they should be promptly referred to a reproductive specialist. Early referral to a reproductive specialist is an important factor that increases the likelihood of successful fertility preservation. Embryo and mature oocyte cryopreservation are currently the only established fertility preservation methods but they require ovarian stimulation (OS), which delays initiation of chemotherapy for at least 2 weeks. Controlled OS does not seem to increase the risk of BC recurrence. Other fertility preservation methods (ovarian tissue cryopreservation, cryopreservation of immature oocytes and ovarian suppression with gonadotropin-releasing hormone agonists) do not require OS but are still considered to be experimental techniques for fertility preservation.

Importance of ovarian tissue cryopreservation in fertility preservation and anti-aging treatment.

Various oncological and non-oncological diseases, as well as their treatments, can cause premature ovarian insufficiency and reduce a woman's reproductive potential. Fertility preservation is, therefore, becoming an emerging field of reproductive medicine allowing these patients to have their own biological children. The aim of this review is to analyze the importance of ovarian tissue cryopreservation as a fertility preservation method as well as its new role as a hormone replacement treatment. Although ovarian tissue cryopreservation is currently regarded as an experimental procedure, it is rapidly advancing and may become an established fertility preservation method in the near future. This method does not require ovarian stimulation or a subsequent delay in the initiation of cancer treatment. Furthermore, orthotopic ovarian tissue transplantation offers the unique opportunity of spontaneous conception. Due to the restoration of endocrine function following the procedure, ovarian tissue cryopreservation may also be used as tissue hormone replacement therapy in cases of premature ovarian insufficiency, to postpone menopause and prevent its troublesome symptoms and diseases. Even though the role of ovarian tissue cryopreservation as a new anti-aging treatment modality is quite promising, the safety and efficacy of this approach should be investigated in clinical settings.

The role of luteal support during IVF: a qualitative systematic review.

The aim of this review is to provide qualitative evidence-based synthesis regarding efficacy of luteal-phase support on fertility outcome in women undergoing in vitro fertilization (IVF) with respect to clinical or live birth rates and pregnancy loss rates. Although the need of luteal phase support in IVF/ICSI cycles is well-known, the optimal start, dosage, route and the duration of the luteal phase support is still subject of debate. Data suggest that the optimal period to start with the luteal phase support would be between 24-72 hours after oocyte-retrieval and should continue at least until a positive pregnancy test is achieved. However, the majority of IVF-centers worldwide provide progesterone support up to 8 weeks of pregnancy. Among the well-established routes of luteal support, oral dydrogesterone and subcutaneous progesterone represent new and interesting routes of progesterone administration. The current studies support these routes of progesterone administration use in terms of comparable pregnancy rates and pregnancy loss rates to vaginal and intramuscular progesterone. Furthermore, the acceptance and tolerability among patients seems to be even better. In the frozen-thawed embryo transfer, dydrogesterone and vaginal progesterone are not effective as monotherapy treatments; however, when combined there is no reason to avoid one or the other in this setting.

Altered leptin, adiponectin, resistin and ghrelin secretion may represent an intrinsic polycystic ovary syndrome abnormality.

The aim of the study was to investigate whether altered adipose tissue secretion of various adipokines is secondary to obesity, hyperandrogenism, and hyperinsulinemia or intrinsic to polycystic ovary syndrome (PCOS). This cross-sectional study included 151 women diagnosed with PCOS by the Rotterdam criteria and 95 healthy women matched by age, body mass index (BMI), and waist-to-hip ratio (WHR). Clinical, biochemical, and hormonal characteristics were assessed. Serum concentrations of ghrelin and adiponectin were found to be significantly lower and concentrations of leptin and resistin significantly higher in women with PCOS than in healthy women matched by age, BMI, and WHR. A PCOS diagnosis made the largest contribution to predicting serum levels of leptin, adiponectin, resistin, and ghrelin in all stepwise multiple regression models, which included PCOS diagnosis, BMI, WHR, luteinizing hormone, total testosterone, free testosterone and homeostatic model assessment of insulin resistance as independent predictors. Leptin, adiponectin, ghrelin and resistin levels may serve as independent biomarkers for the diagnosis of PCOS.

Improvement of Sexual and Reproductive Function in Men with Spinal Cord Lesion.

The aim of the review is to establish sexual and reproductive functions in men with spinal cord lesion (SCL). Many sexual and reproductive dysfunctions may be found in these patients including individual's low self-esteem, delay of orgasm, erectile or ejaculatory disorder and abnormalities of semen, which are characterized by lower sperm motility or viability. Owing to improvements in physical medicine and rehabilitation, the focus has been shifted from keeping patients alive towards ensuring the quality of life and improvements of sexual dysfunctions and later reproduction. Erectile dysfunction can be treated by using phosphodiesterase-5 inhibitors, intracavernosal injections, vacuum devices and penile prostheses. Semen can be retrieved from anejaculatory patients by medically assisted methods utilizing penile vibratory stimulation, electroejaculation, prostate mas-sage, or surgically. Although there is low chance for pregnancy in natural way in most of SCL pa-tients, fatherhood is possible through the introduction of assisted medical management. By use of various medical, technical and surgical procedures for sperm retrieval combined with assisted reproductive methods, high pregnancy rates have been reported comparable to those in able-bodied subfertile patients. Nevertheless, future studies are needed to improve semen quality and methods of assisted ejaculation in patients with SCL.

The cardiometabolic effect of current management of polycystic ovary syndrome: strategies of prevention and treatment.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder amongst women of reproductive age, which is characterized by reproductive and cardiometabolic disturbances with long-term health repercussions. Insulin resistance (IR), impaired glucose tolerance, type 2 diabetes mellitus (DM2), obesity and dyslipidemia occur more in women with PCOS than in age-comparable women without PCOS. Long term data regarding risks or benefits of medical intervention for metabolic dysfunction of PCOS are lacking. Therapies, such as oral contraceptives (OCPs) and anti-androgenic medications used to manage the reproductive manifestations of PCOS, may themselves be the cause of cardiometabolic perturbations. Hence, strategies regarding the management of reproductive issues in PCOS encompass a patient-specific tailored approach. Factors that influence the cardiometabolic side effects arising during treatment of the reproductive manifestations of PCOS (hirsutism/anovulation) are also discussed in this paper in order to build future strategies to minimize the overall cardiometabolic risk.

The role of female obesity on in vitro fertilization outcomes.

The aim of this review is to analyze the role of obesity on fertility outcome in women undergoing in vitro fertilization (IVF) with respect to clinical or live birth rates and pregnancy loss rates. Despite findings from several earlier and newer studies that obesity does not adversely affect pregnancy outcome in women attempting conception, numerous reports from mostly recent studies suggest that obesity undoubtedly impairs IVF outcomes. Obesity impairs ovarian responsiveness to gonadotrophin stimulation, requiring higher doses of medication, increased risk of cycle cancelation, pre-term delivery, low birth weight or miscarriage, and decreases implantation, clinical pregnancy or live birth rates compared to women of normal weight. The mechanisms underlying the adverse effects of female obesity on IVF outcome may be primarily explained by functional alterations to the hypothalamic-pituitary-ovarian axis. Additionally, obesity appears to affect deleteriously the number and quality of oocytes or embryos, and impairs endometrial decidualization which is necessary for uterine receptivity. Nevertheless, attaining normal body weight by the use of lifestyle modifications, including a healthy diet and exercise over time of several months before and during an IVF treatment, may be successful in achievement of gradual and sustainable weight loss with improvement of IVF outcome.

Laboratory and clinical significance of macroprolactinemia in women with hyperprolactinemia.

The role of macroprolactinemia in women with hyperprolactinemia is currently controversial and can lead to clinical dilemmas, depending upon the origin of macroprolactin, the presence of hyperprolactinemic symptoms and monomeric prolactin (PRL) levels. Macroprolactinemia is mostly considered an extrapituitary phenomenon of mild and asymptomatic hyperprolactinemia associated with normal concentrations of monomeric PRL and a predominance of macroprolactin confined to the vascular system, which is biologically inactive. Patients can therefore be reassured that macroprolactinemia should be considered a benign clinical condition, resistant to antiprolactinemic drugs, and that no diagnostic investigations or prolonged follow-up should be necessary. However, a significant proportion of macroprolactinemic patients appears to suffer from hyperprolactinemia-related symptoms and radiological pituitary findings commonly associated with true hyperprolactinemia. The symptoms of hyperprolactinemia are correlated to the levels of monomeric PRL excess, which may be explained as coincidental, by dissociation of macroprolactin, or by physiological, pharmacological and pathological causes. The excess of monomeric PRL levels in such cases is of primarily importance and the diagnosis of macroprolactinemia is misleading or inadequate. However, macroprolactinemia of pituitary origin associated with radiological findings of pituitary adenomas may rarely occur with similar hyperprolactinemic manifestations, exclusively due to bioactivity of macroprolactin. Therefore, in such cases with hyperprolactinemic signs and pituitary findings, macroprolactinemia should be considered a pathological biochemical condition of hyperprolactinemia. Accordingly, individualized diagnostic investigations with the introduction of dopamine agonists, or other treatment with prolonged follow-up, should be mandatory. The review analyses the laboratory and clinical significance of macroprolactinemia in hyperprolactinemic women suggesting clinically useful diagnostic and treatment strategies.

Current Medical Strategies in the Prevention of Ovarian Hyperstimulation Syndrome

The purpose of this review is to analyze current medical strategies in the prevention of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation for in vitro fertilization. Owing to contemporary preventive measures of OHSS, the incidence of moderate and severe forms of the syndrome varies between 0.18% and 1.40%. Although none of medical strategies is completely effective, there is high-quality evidence that replacing human chorionic gonadotropin (hCG) by gonadotropin-releasing hormone (GnRH) agonists after GnRH antagonists and moderate- quality evidence that GnRH antagonist protocols, dopamine agonists and mild protocols reduce the occurrence of OHSS. Among various GnRH agonists, buserelin 0.5 mg, triptorelin 0.2 mg and leuprolide acetate (0.5-4 mg) have been mostly utilized. Although GnRH trigger is currently regarded as the best tool for OHSS prevention, intensive luteal support with exogenous administration of estradiol and progesterone or low-dose hCG on the day of oocyte retrieval or on the day of GnRH agonist trigger are required to achieve optimal conception rates due to early luteolysis. Among currently available dopamine agonists, cabergoline, quinagolide and bromocriptine are the most common drugs that should be used for prevention of both early and late OHSS. Mild stimulation protocols offer attractive option in OHSS prevention with satisfactory pregnancy rates.

Kisspeptin as a promising oocyte maturation trigger for in vitro fertilisation in humans.

The aim of this review is to analyse the effectiveness of exogenous kisspeptin administration as a novel alternative of triggering oocyte maturation, instead of currently used triggers such as human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) agonist, in women undergoing in vitro fertilisation (IVF) treatment. Kisspeptin has been considered a master regulator of two modes of GnRH and hence gonadotropin secretion, pulses and surges. Administration of kisspeptin-10 and kisspeptin-54 induces the luteinising hormone (LH) surge required for egg maturation and ovulation in animal investigations and LH release during the preovulatory phase of the menstrual cycle and hypothalamic amenorrhoea in humans. Exogenous kisspeptin-54 has been successfully administered as a promising method of triggering oocyte maturation, following ovarian stimulation with gonadotropins and GnRH antagonists in women undergoing IVF, due to its efficacy considering achieved pregnancy rates compared to hCG and GnRH agonists. Also, its safety in patients at high risk of developing ovarian hyperstimulation syndrome is noteworthy. Nevertheless, further studies would be desirable to establish the optimal trigger of egg maturation and to improve the reproductive outcome for women undergoing IVF treatment.

Fertility in men with spinal cord injury.

Young men comprise the overwhelming majority of men with spinal cord injury (SCI), the incidence of which has been growing over the years. Due to advances in physical medicine and rehabilitation, remarkable improvements in survival rates have been reported, leading to life expectancies similar to those of the general population. However, many sexual and reproductive functions may be impaired due to erectile or ejaculatory dysfunction and semen abnormalities, characterised by low-sperm motility or viability in SCI males who have not become parents yet. Nevertheless, fatherhood is still possible through the introduction of specialised medical management, by using various medical, technical and surgical methods for sperm retrieval in combination with assisted reproductive techniques. Erectile dysfunction can be managed by the use of phosphodiesterase-5 inhibitors, intracavernosal injections, vacuum devices and penile prostheses. Semen can be obtained from the vast majority of anejaculatory men by medically assisted ejaculation through the use of penile vibratory stimulation or electroejaculation and via prostate massage or surgical procedures. Despite impaired sperm parameters, reasonable pregnancy rates similar to those in able-bodied subfertile cohorts have been reported. However, future research should focus on the optimisation of semen quality in these men and on improving natural ejaculation.

Combined ovulation triggering with GnRH agonist and hCG in IVF patients.

The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ''dual trigger'' combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ''double trigger" represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ''double trigger" has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

Current Preventive Strategies for Preovulatory Progesterone Elevation During Ovarian Stimulation for In Vitro Fertilization

The purpose of this review is to present contemporary measures for preventing the increase in preovulatory progesterone (P) and its adverse effects on ovarian stimulation in in vitro fertilization (IVF). For the last 20 years, the increase of preovulatory P has been a topic of numerous discussions because its role is not fully understood in terms of its impact on pregnancy outcome after IVF. Some studies failed to establish a connection between the preovulatory P increase and successful IVF outcome regardless of the level of P, while, conversely, most other studies have reported on adverse effects of elevated P concentrations. Current strategies to prevent the increase in preovulatory P include an individualized approach with the use of mild stimulation protocols and early application of human chorionic gonadotropin for ovulation induction among good responders, delay in the transfer of fresh embryos from 3rd to 5th day, and cryopreservation of all embryos with the thawed embryo transfer in the natural cycle. Nevertheless, further studies are needed to confirm the current preventive methods or enable the application of new strategies in order to lower or eliminate the detrimental effects of preovulatory P rise during ovarian stimulation in IVF.

Pneumothorax and Pneumomediastinum as a Rare Complication of Laparoscopic Surgery

Occurrence of bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema during gynecologic laparoscopic procedure is very rare. We report a case of a 23-year-old woman who developed bilateral pneumothorax, pneumomediastinum and subcutaneous emphysema during laparoscopic ovarian cystectomy. Carbon dioxide extravasations outside the peritoneal cavity during laparoscopy may have fatal consequences. Careful monitoring, immediate diagnosis and proper treatment are crucial for patient safety.

INFLUENCE OF MALE OBESITY ON FERTILITY.

The aim of this review is to analyze current diagnostic approaches to obesity in adult men, the potential mechanisms linking obesity to infertility, and treatment options aimed at improving reproductive health. Obesity has become a worldwide epidemic with the estimated prevalence increasing from 28.8% to 36.9% between 1980 and 2013. In terms of diagnosis, numerous simple techniques have been developed including body mass index, waist to hip ratio, waist circumference, bioelectrical impedance analysis, ultrasound and skinfold measurements. Additionally, several other less available but more accurate techniques have been suggested, such as air displacement plethysmography, dual energy x-ray absorptiometry, computed tomography and magnetic resonance imaging. In addition to cardiovascular and other disorders, male obesity can negatively affect the male reproductive potential through abnormal reproductive hormone levels, reduced semen quality, increased release of adipose-derived hormones and adipokines, as well as thermal, genetic and sexual mechanisms. In the management of obesity related male infertility, natural weight loss is the cornerstone and regular exercise the first-line treatment. Although bariatric surgery results in greater improvements in weight loss outcomes when compared to non-surgical interventions, further research is required to clarify its overall influence on male fertility.

Fertility preservation options in breast cancer patients.

The purpose of this review is to analyse current options for fertility preservation in young women with breast cancer (BC). Considering an increasing number of BC survivors, owing to improvements in cancer treatment and delaying of childbearing, fertility preservation appears to be an important issue. Current fertility preservation options in BC survivors range from well-established standard techniques to experimental or investigational interventions. Among the standard options, random-start ovarian stimulation protocol represents a new technique, which significantly decreases the total time of the in vitro fertilisation cycle. However, in patients with oestrogen-sensitive tumours, stimulation protocols using aromatase inhibitors are currently preferred over tamoxifen regimens. Cryopreservation of embryos and oocytes are nowadays deemed the most successful techniques for fertility preservation in BC patients. GnRH agonists during chemotherapy represent an experimental method for fertility preservation due to conflicting long-term outcome results regarding its safety and efficacy. Cryopreservation of ovarian tissue, in vitro maturation of immature oocytes and other strategies are considered experimental and should only be offered within the context of a clinical trial. An early pretreatment referral to reproductive endocrinologists and oncologists should be suggested to young BC women at risk of infertility, concerning the risks and benefits of fertility preservation options.

THE RISK OF HYPERCOAGULABILITY IN OVARIAN HYPERSTIMULATION SYNDROME.

Ovarian hyperstimulation syndrome (OHSS) is a rare and potentially life-threatening complication of infertility treatment occurring during either the luteal phase or early pregnancy. An increasing number of thromboembolic complications associated with the increased use of assisted reproductive techniques have been reported in the literature. Identification of the risk factors is crucial for prevention of thromboembolic events in OHSS patients. Alterations in the hemostatic system cause hypercoagulability in women affected by severe OHSS. Coexistence of inherited hypercoagulable conditions increases the risk of thromboembolism. The role of clinical parameters that can help predict development of thrombosis is controversial. Patients with a personal or family history of thrombosis undergoing infertility treatment should be considered for thrombophilia screening, while routine examination of inherited thrombophilic mutations is not indicated in infertile patients. Antithrombotic primary prevention is not indicated in healthy women undergoing assisted reproductive procedures or in women with thrombophilia. Anticoagulant therapy is indicted if there is clinical evidence of thrombosis or laboratory evidence of hypercoagulability. In this review, the risks of hypercoagulability in the OHSS are discussed.

Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial.

OBJECTIVES: To compare efficacy, satisfaction and tolerability of oral dydrogesterone and micronized vaginal progesterone gel used for luteal supplementation. STUDY DESIGN: Randomized controlled trial. A total of 853 infertile women undergoing IVF/ICSI treatment in University Hospital Center "Sisters of Mercy", Zagreb, Croatia. Luteal support was provided as Crinone 8%(®) vaginal progesterone gel (90mg) administered daily, or oral dydrogesterone Duphaston(®) (2× 10mg) administered two times daily. Progesterone was administered from the day of oocyte retrieval (day 0) till pregnancy test or in a case of pregnancy, until week 10. RESULTS: The on-going pregnancy rates were comparable between Crinone 8%(®) vaginal progesterone gel and oral dydrogesterone - Duphaston(®) (28.1% versus 30.3%; OR 1.11 (0.82-1.49 with 95% CI)). Overall satisfaction and tolerability were significantly higher in the dydrogesterone group than in the Crinone group. Vaginal bleeding, interference with coitus and local adverse side effects such as vaginal irritation and discharge occurred significantly more in Crinone group than in dydrogesterone group. CONCLUSIONS: Oral dydrogesterone is effective drug, well tolerated and accepted among patients and can be considered for routine luteal support. CLINICAL TRIAL REGISTRATION NUMBER: NCT01178931; www.clinicaltrials.gov.

Subsequent pregnancy and prognosis in breast cancer survivors.

An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. Because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. In the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. Ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required.