Metformin and progestins in women with atypical hyperplasia or endometrial cancer: systematic review and meta-analysis.

PURPOSE: To assess metformin's effectiveness in adding it to progestin-based hormone therapy for treating atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC). METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines (registration number CRD42023399094). We searched databases for studies up to March 2023, including randomized and non-randomized clinical trials in English. RESULTS: Out of 280 studies, 9 studies (1104 patients) were eligible. A total of 408 patients were allocated to receive metformin, and 696 patients entered the control group. Primary analysis focused on evaluating the CR showed a significant difference in patients with AEH treated with metformin (RR = 1.10, 95% CI 1.02-1.20, p = 0.02). Relapse rate (RR = 0.62, 95% CI 0.33-1.17, p = 0.14) was also evaluated. Secondary analysis indicated higher pregnancy rates (RR = 1.28, 95% CI 1.04-1.57, p = 0.02) with no significant difference in live birth rates (RR = 0.56, 95% CI 0.29-1.10, p = 0.09). CONCLUSION: Combined therapy is effective. Metformin shows superiority to the standard regimen in achieving better CR rate in patients with AEH and benefits pregnancy rates but not recurrence or live birth rates. Therefore, the ideal fertility-sparing treatment for EC has not yet been determined and further clinical trials are needed.

Diagnostic Value of Autoantibodies against Steroidogenic Enzymes and Hormones in Infertile Women with Premature Ovarian Insufficiency.

The objective of the study was to evaluate the profile and diagnostic significance of serum autoantibodies in infertile patients with premature ovarian insufficiency (POI). The pilot study included 26 patients of reproductive age with POI and diminished ovarian reserve who received complex treatment using new surgical technologies (Group 1) and 18 patients without POI (Group 2). The profile of serum autoantibodies, including anti-ovarian antibodies, antibodies against thyroid peroxidase (TPO), steroidogenic enzymes, and steroid and gonadotropic hormones, was studied using modified ELISAs and human recombinant steroidogenic enzymes (CYP11A1, CYP19A1, CYP21A2). Patients in Group 1 had higher levels of IgG autoantibodies against steroidogenic enzymes, estradiol, progesterone, and TPO than those in Group 2. Tests for IgG antibodies against CYP11A1, CYP19A1, and CYP21A2 exhibited high sensitivity (65.4-76.9%), specificity (83.3-89.9%), and AUC values (0.842-0.910) for POI, the highest in the first test. Three-antibodies panel screening showed higher diagnostic accuracy (84.1% versus 75-79.6%). The levels of these antibodies correlated with menstrual irregularities and a decrease in the antral follicle count. Thus, antibodies against CYP11A1, CYP19A1, and CYP21A2 have a high diagnostic value for POI. Three-antibody panel screening may improve the accuracy of POI diagnosis and be useful for identifying high-risk groups, early stages of the disease, and predicting POI progression.

Altered Glycolysis, Mitochondrial Biogenesis, Autophagy and Apoptosis in Peritoneal Endometriosis in Adolescents.

Energy metabolism plays a pivotal role in the pathogenesis of endometriosis. For the initial stages of the disease in adolescents, this aspect remains unexplored. The objective of this paper was to analyze the association of cellular and endosomal profiles of markers of glycolysis, mitochondrial biogenesis, apoptosis, autophagy and estrogen signaling in peritoneal endometriosis (PE) in adolescents. We included 60 girls aged 13-17 years in a case-control study: 45 with laparoscopically confirmed PE (main group) and 15 with paramesonephric cysts (comparison group). Samples of plasma and peritoneal fluid exosomes, endometrioid foci and non-affected peritoneum were tested for estrogen receptor (Erα/ß), hexokinase (Hex2), pyruvate dehydrogenase kinase (PDK1), glucose transporter (Glut1), monocarboxylate transporters (MCT1 and MCT2), optic atrophy 1 (OPA1, mitochondrial fusion protein), dynamin-related protein 1 (DRP1, mitochondrial fission protein), Bax, Bcl2, Beclin1, Bnip3, P38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (Hif-1α), mitochondrial voltage-dependent anion channel (VDAC) and transforming growth factor (TGFß) proteins as markers of estrogen signaling, glycolysis rates, mitochondrial biogenesis and damage, apoptosis and autophagy (Western-Blot and PCR). The analysis identified higher levels of molecules associated with proliferation (ERß), glycolysis (MCT2, PDK1, Glut1, Hex2, TGFß and Hif-1α), mitochondrial biogenesis (OPA1, DRP1) and autophagy (P38, Beclin1 and Bnip3) and decreased levels of apoptosis markers (Bcl2/Bax) in endometrioid foci compared to non-affected peritoneum and that in the comparison group (p < 0.05). Patients with PE had altered profiles of ERß in plasma and peritoneal fluid exosomes and higher levels of Glut1, MCT2 and Bnip3 in plasma exosomes (p < 0.05). The results of the differential expression profiles indicate microenvironment modification, mitochondrial biogenesis, estrogen reception activation and glycolytic switch along with apoptosis suppression in peritoneal endometrioid foci already in adolescents.

Predictive Value of Ultrasound Imaging for Diagnosis and Surgery of Deep Endometriosis: A Systematic Review.

OBJECTIVE: To calculate the predictive value and thus the clinical usefulness of transvaginal ultrasound (US) imaging for the management of deep endometriosis, knowing that the positive predictive value (PPV) varies with the prevalence and probably with the volume and location of the disease. DATA SOURCES: After registration on PROSPERO (CRD42022366323), PubMed was searched for all reports describing the diagnostic accuracy of US imaging for deep endometriosis published between January 1, 2000, and October 20, 2022. METHODS OF STUDY SELECTION: The 536 articles on "endometriosis AND US And diagnosis" were hand searched, and 30 reports describing sensitivity and specificity of deep endometriosis were found. Besides sensitivity and specificity, the prevalence, localization, and size of deep endometriosis lesions were collected. TABULATION, INTEGRATION, AND RESULTS: Prevalences of deep endometriosis were reported only twice as 12% and 32% by ultrasonographers. In women undergoing surgery, prevalences vary between 40% and 100% because of the variable inclusion criteria. Specificity is higher than sensitivity for all locations: rectovaginal (97% [86-100] vs 74% [31-95], p = .0002), rectosigmoid (97% [63-100] vs 88% [37-97], p = .0082), vesicouterine (100% [97-100] vs 63% [22-100], p = .0021), and uterosacrals (91% [77-99] vs 68% [18-83], p = .0005). Notwithstanding improved equipment, accuracy did not vary over the last 20 years. Sensitivities or specificities have not been stratified by the size of the lesion, and thus, the lower detection limits are not known. In the absence of blinding, the usefulness for surgery could not be established. CONCLUSION: The reported sensitivities and specificities of transvaginal US are not only those of imaging but include symptoms and clinical examinations. In referral centers, the reported PPVs are high (94%-100%) given that prevalences are >10% and specificities are >95%. However, the extrapolation of the clinical use before surgical interventions should be considered with care, given that PPVs for smaller lesions and the lower detection limit are unknown and surgeons were not blinded to US results.

Laser vaporization compared with other surgical techniques in women with ovarian endometrioma: a systematic review and meta-analysis.

OBJECTIVE: To compare outcomes after laparoscopic cystectomy versus laser vaporization in women of reproductive age with ovarian endometrioma. EVIDENCE REVIEW: Our systematic review and meta-analysis was registered in PROSPERO (CRD42021281781) and was done according to the PRISMA 2020 checklist. Studies (published until October 2021) were identified by searching PubMed, Cochrane Library, Google Scholar, and ClinicalTrials.gov databases (key words "cystectomy", "laser vaporization", and "endometrioma"). The search was conducted independently by two investigators (L.P. and S.I.). Inclusion criteria were: women of reproductive age undergoing surgery for symptomatic endometriomas larger than 30 mm. The exclusion criteria were: women who undergo conservative treatment. Outcomes were: risk ratio for recurrence, ovarian reserve and pregnancy rates. The studies included were randomized clinical trials (RCTs) and nonrandomized clinical trials (prospective controlled, prospective cohort, retrospective studies, and other types of studies) that included a minimum of 10 patients and written in English. Tools recommended by the Cochrane Society achieved risk-of-bias assessment. RESULTS: Totally, 874 studies were found, 9 studies were included in qualitative synthesis (822 patients). All the authors compared the efficacy and safety of cystectomy or laser vaporization in reproductive-aged women with ovarian endometrioma. The overall risk of bias for the randomized trials was 80% 'some concerns' and 20% 'low', and for the cohort studies, 50% 'some concerns' and 50% 'low'. The primary meta-analysis focused on recurrence rates (4 studies included) with no statistically significant differences found between these two interventions (RR = 0.53, 95% CI 0.24 to 1.21, P = 0.13). The next meta-analysis estimated antral follicle count (3 studies) which was significantly lower in cystectomy group (RR = - 2.56, 95% CI - 3.71 to - 1.42, P < 0.0001). Pregnancy rates were analyzed in 3 studies with no statistically significant difference (RR = 0.96, 95% CI 0.81 to 1.14, P = 0.64). CONCLUSIONS: There was no statistical difference in the recurrence rate and pregnancy rates, but the antral follicle count was higher in the laser vaporization group. However, we need more clinical trials to make stronger recommendations.

Peritoneal fluid progesterone and progesterone resistance in superficial endometriosis lesions.

Peritoneal fluid in ovulatory women is an ovarian exudate with higher estrogen and progesterone concentrations than in plasma. In the follicular phase, progesterone concentrations are as high as plasma concentrations in the luteal phase. After ovulation, estrogen and progesterone concentrations in the peritoneal fluid are 5-10 times higher than in plasma, both in women with and without endometriosis. The histologically proliferative aspect without secretory changes of most superficial subtle lesions is not compatible with the progesterone concentrations in the peritoneal fluid. Therefore, we have to postulate a strong progesterone resistance in these lesions. The mechanism is unclear and might be a peritoneal fluid effect in women with predisposing defects in the endometrium, or isolated endometrial glands with progesterone resistance, or subtle lesions originating from the basal endometrium: the latter hypothesis is attractive since in basal endometrium progesterone does not induce secretory changes while progesterone withdrawal, not occurring in peritoneal fluid, is required to resume mitotic activity and proliferation. Hormone concentrations in the peritoneal fluid are an important factor in understanding the medical therapy of endometriosis. The effect of oestro-progestin therapy on superficial endometriosis lesions seems to be a consequence of the decreased estrogen concentrations rather than a direct progestin effect. In conclusion, the peritoneal fluid, being a secretion product of the ovarian follicule, deserves more attention in the pathophysiology and treatment of endometriosis.

A Review of Recent Studies on the Effects of SARS-CoV-2 Infection and SARS-CoV-2 Vaccines on Male Reproductive Health.

According to world statistics, men are more susceptible to the coronavirus disease 2019 (COVID-19) than are women. Considering the interconnection between infections and male infertility, investigation of the potential impact of COVID-19 on men's reproductive health is now a particularly relevant topic. Published data indicate decreased sperm quality and orchitis development in patients with COVID-19, including reduced sperm count, decreased sperm motility, and elevated DNA fragmentation index. Although mass vaccination against COVID-19 is currently being carried out worldwide using available authorized vaccines, the effect of these vaccines on men's reproductive health has not yet been investigated. There is currently no evidence that SARS-CoV-2 can be transmitted in semen, but available data suggest that it can infect spermatogonia, spermatids, Leydig cells, and Sertoli cells. Therefore, SARS-CoV-2 orchitis and reduced male fertility may be long-term complications of COVID-19, which requires further investigation. Currently, there is also no evidence that vaccines against SARS-CoV-2 have any pathological effects on spermatogenesis or male reproductive health. Thus, further studies are needed to determine the effects of COVID-19 and COVID-19 vaccines on men's reproductive health, which will help to optimize the management and rehabilitation of these patients. This review aims to discuss recent studies on the impact of the COVID-19 and COVID-19 vaccines on men's reproductive health. The article addresses various issues such as the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on testosterone biosynthesis, semen parameters, testicular tissue, and epididymis.

Gene Expression Signature of Endometrial Samples from Women with and without Endometriosis.

STUDY OBJECTIVE: To develop a prototype of a complex gene expression biomarker for the diagnosis of endometriosis on the basis of differences between the molecular signatures of the endometrium from women with and without endometriosis. DESIGN: Prospective observational cohort study. Evidence obtained from a well-designed, controlled trial without randomization. SETTING: Department of reproductive medicine and surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry. PATIENTS: A total of 33 women (aged 32-38 years) were included in this study. Patients with and without endometriosis were divided into 2 separate groups. The group composed of patients with endometriosis included 19 living patients with endometriosis who underwent laparoscopic excision of endometriosis. The control group included 6 living patients who underwent laparoscopic excision of incompetent uterine scar after cesarean section, with both surgically and histologically confirmed absence of endometriosis and adenomyosis. An additional control/verification group included various previously RNA-sequencing-profiled tissue samples (endocervix, ovarian surface epithelium) of 8 randomly selected healthy female cadaveric donors aged 32 to 38 years. The exclusion criteria for all patients were hormone therapy and any intrauterine device use for more than 1 year preceding surgery, as well as absence of other diseases of the uterus, fallopian tubes, and ovaries. INTERVENTIONS: Laparoscopic excision of endometriotic foci and hysteroscopy with endometrial sampling were performed. The cadaveric tissue samples included endocervix and ovarian surface epithelium. Endometrial sampling was obtained from the women in the control group. RNA sequencing was performed using Illumina HiSeq 3000 equipment (Illumina, Inc., San Diego, CA) for single-end sequencing. Unique bioinformatics algorithms were developed and validated using experimental and public gene expression datasets. MEASUREMENTS AND MAIN RESULTS: We generated a characteristic signature of 5 genes downregulated in the endometrium and endometriotic tissue of the patients with endometriosis, selected after comparison with the endometrium of the women without endometriosis. This gene signature showed a capacity for nearly perfect separation of all 52 analyzed tissue samples of the patients with endometriosis (endometrial as well as endometriotic samples) from the 14 tissue samples of both living and cadaveric donors without endometriosis (area under the curve = 0.982, Matthews correlation coefficient = 0.832). CONCLUSION: The gene signature of the endometrium identified in this study may potentially serve as a nonsurgical diagnostic method for endometriosis detection. Our data also suggest that the statistical method of 5-fold cross-validation of differential gene expression analysis can be used to generate robust gene signatures using real-world clinical data.

Prevalence of Endometriosis and Peritoneal Pockets in Women with Infertility and/or Pelvic Pain.

OBJECTIVE: To evaluate the prevalence of endometriosis and peritoneal pockets and to analyze whether these pockets are associated with pain. METHODS: Analysis of prospectively registered data of all women undergoing laparoscopy for infertility or pelvic pain between 1988 and 2011 at KU Leuven University Hospital. RESULTS: Of 4497 women, 191 had 238 pockets, with a prevalence of 4.7% in women with infertility only, 4.9% in women with infertility and pelvic pain, and 3.5% in women with pelvic pain only (P = 0.045 for all infertility vs. pelvic pain only). Prevalence did not vary by age. Pockets were associated with endometriosis (P < 0.0001), which was found in 77% of women with pockets. Among women with infertility only, the prevalence of endometriosis was higher in women with pockets (P = 0.0001) than in women without. The prevalence of endometriosis was similar in women with infertility and pelvic pain or pelvic pain only. Pelvic pain as an indication for surgery was associated simultaneously (through logistic regression) with endometriosis (P < 0.0001) and pockets (P = 0.040). Pelvic pain severity was associated simultaneously with pockets (P = 0.0026) and the severity of subtle (P = 0.001), typical (P = 0.030), cystic ovarian (P = 0.051), and deep endometriosis (P < 0.0001). Pelvic pain severity was not associated with endometriosis in the pockets or the diameter or location of pockets. CONCLUSIONS: The prevalence of pockets was low, at between 3.5% and 5%. Women with infertility only and pockets had more endometriosis than women without. Severe pelvic pain and pelvic pain as an indication for surgery were associated with the presence of pockets as well as the presence and severity of endometriosis.

Which Knots Are Recommended in Laparoscopic Surgery and How to Avoid Insecure Knots.

STUDY OBJECTIVE: To investigate why security of identical knot sequences is variable and how to avoid occasionally insecure knots. DESIGN: A factorial design was used to assess factors affecting the security of half knot (H) and half-hitch (S) knot combinations. The effect of tying forces and the risk factors to transform H knots into S knots were investigated. The risk factors evaluated were as follows: starting with an H1 or H2 instead of an H3 knot, inexperience, short sutures, and monomanual knot tying. Security of transformed knots, S2S1 and S2S2 knots, and their recuperation with 2 additional half hitches, SSb or SbSb, were evaluated. SETTING: Training center for laparoscopic suturing. PATIENTS: Not applicable. INTERVENTIONS: Security of knots was evaluated in vitro. MEASUREMENTS AND MAIN RESULTS: The forces that caused knot combinations to open before breaking of the suture were used to calculate the risk of opening with low forces. Tying more strongly increased the security of half knots (H2H1sH1s) (p <.02) and half hitches (p <.001). The forces needed to transform an H3 into an S3 are higher than those for an H2 (p <.001), and the risk increases when the surgeon is inexperienced (p <.001), when sutures are short (p <.001), and when monomanual knot tying (p <.001) is used. Inadvertently made S2S1 and S2S2 knots are dangerous, with the exception of the symmetric S2S2, which is stable. Unstable knots such as S2S1a and S2S2a knot combinations improve with 2 additional blocking half hitches (SbSb), but S2S2aSbSb remains occasionally insecure. CONCLUSION: To reduce the risk of accidentally transforming a first H into an S knot, it is recommended to start with an H3, tie with force, avoid short sutures, and use bimanual suturing. This permits the recommendation to use preferentially H3H2 knots or 5 half hitches (SSSbSbSb). When in doubt, half knot combinations should be secured with at least 2 blocking half hitches.

Direct Mass Spectrometry Differentiation of Ectopic and Eutopic Endometrium in Patients with Endometriosis.

STUDY OBJECTIVE: To introduce a method for the rapid assessment of endometriotic tissues using direct mass spectrometry (MS)-based lipidomics. DESIGN: A prospective observational cohort study (Canadian Task Force classification II2). SETTING: Department of Operative Gynecology of the Research Centre for Obstetrics, Gynecology and Perinatology. PATIENTS: Fifty patients with ovarian cysts and peritoneal endometriosis who underwent laparoscopic surgery between 2014 and 2016. INTERVENTION: Differences in mass spectrometric profiles of ectopic endometria (endometriosis) and eutopic endometria were analyzed for each patient in combination with morphohistologic evaluation. The lipidomic approach was applied using a direct high-resolution MS method. MEASUREMENTS AND MAIN RESULTS: Of 148 metabolites, 15 showed significant differences between endometriotic tissue and a healthy endometrium of the same patient, considered as a control in this study. The main lipids prevalent in endometriotic tissues were phosphoethanolamine (PE O-20:0), sphingomyelin (SM 34:1), diglycerides (DG 44:9), phosphatidylcholines (PC 32:1, PC O-36:3, PC 38:7, PC 38:6, PC 40:8, PC 40:7, PC 40:6, PC 40:9, and PC O-42:1), and triglycerides (TG 41:2, TG 49:4, and TG 52:3). Using partial least squares discriminant analysis models, MS showed that the lipidomic profile of endometriotic tissue (peritoneal endometriosis and ovarian endometriomas) was clearly separated from the eutopic endometrium, indicating tissue-type differentiation. CONCLUSION: Our results suggest that direct MS may play an important role for endometriotic tissue identification. Such an approach has potential usefulness for real-time tissue determination and differentiation during surgical treatment. Lipids of 3 important classes, sphingolipids, phospholipids, and the fatty acids (di- and triglycerides), were identified. Validation is required to determine whether these lipids can be used to discriminate between patients with endometriosis and those with other gynecologic diseases.

Preimplantation genetic testing for aneuploidy in patients of different age: a systematic review and meta-analysis.

This study aimed to summarize the current knowledge on the benefits of in vitro fertilization/intracytoplasmic sperm injection with preimplantation genetic testing for aneuploidy (PGT-A) and to discuss the role of PGT-A in patients of different ages undergoing assisted reproduction. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist. Registration number: CRD42022354697. Studies were identified by searching the PubMed, Cochrane Library, Google Scholar, Scopus, Embase, and ClinicalTrials databases. Seven meta-analyses were performed with additional stratification of age and prognosis of the women studied. Clinical pregnancy rate per embryo transfer in patients aged >35 years was higher in the PGT-A group (P=0.0002) than in controls. Live birth rate (LBR) per embryo transfer in women 35 years old or younger (P=0.002) was higher in the PGT-A group. The LBR per patient in women aged >35 years was higher in the PGT-A group (P=0.004). The effects of PGT-A on LBR in patients with poor prognosis showed a statistically significant increase (P=0.003). There was no significant difference in the rate between the two groups. PGT-A is effective and can be recommended for patients aged >35 years undergoing assisted reproduction to improve their reproductive outcomes. Moreover, our study showed the possible benefits of PGT-A in patients with a poor prognosis. Overall, our findings suggest that PGT-A is a valuable tool for improving the reproductive outcomes of assisted reproductive procedures in older women and those with a history of pregnancy complications.

The 10 "Cardinal Sins" in the Clinical Diagnosis and Treatment of Endometriosis: A Bayesian Approach.

Evidence-based data for endometriosis management are limited. Experiments are excluded without adequate animal models. Data are limited to symptomatic women and occasional observations. Hormonal medical therapy cannot be blinded if recognised by the patient. Randomised controlled trials are not realistic for surgery, since endometriosis is a variable disease with low numbers. Each diagnosis and treatment is an experiment with an outcome, and experience is the means by which Bayesian updating, according to the past, takes place. If the experiences of many are similar, this holds more value than an opinion. The combined experience of a group of endometriosis surgeons was used to discuss problems in managing endometriosis. Considering endometriosis as several genetically/epigenetically different diseases is important for medical therapy. Imaging cannot exclude endometriosis, and diagnostic accuracy is limited for superficial lesions, deep lesions, and cystic corpora lutea. Surgery should not be avoided for emotional reasons. Shifting infertility treatment to IVF without considering fertility surgery is questionable. The concept of complete excision should be reconsidered. Surgeons should introduce quality control, and teaching should move to explain why this occurs. The perception of information has a personal bias. These are the major problems involved in managing endometriosis, as identified by the combined experience of the authors, who are endometriosis surgeons.

Novel Approaches to Possible Targeted Therapies and Prophylaxis of Uterine Fibroids.

Uterine leiomyomas are the most common benign tumors in women of childbearing age. They may lead to problems of conception or complications during the gestational period. The methods of treatment include surgical (myomectomy and hysterectomy, embolization of arteries) and therapeutic treatment (ulipristal acetate, leuprolide acetate, cetrorelix, goserelin, mifepristone). Both approaches are efficient but incompatible with pregnancy planning. Therefore, there is a call for medical practice to develop therapeutical means of preventing leiomyoma onset in patients planning on becoming pregnant. Based on the analysis of GWAS data on the search for mononucleotide polymorphisms associated with the risk of leiomyoma, in meta-transcriptomic and meta-methylomic studies, target proteins have been proposed. Prospective therapeutic treatments of leiomyoma may be based on chemical compounds, humanized recombinant antibodies, vaccines based on markers of the uterine leiomyoma cells that are absent in the adult organism, or DNA and RNA preparations. Three different nosological forms of the disease associated with driver mutations in the MED12, HMGA2, and FH genes should be considered when developing or prescribing drugs. For example, synthetic inhibitors and vaccines based on matrix metalloproteinases MMP11 and MMP16 are expected to be effective only for the prevention of the occurrence of MED12-dependent nodules.

Endometriosis in Adolescents: Diagnostics, Clinical and Laparoscopic Features.

BACKGROUND: The early diagnosis of endometriosis in adolescents is not developed. OBJECTIVE: We aim to conduct clinical, imaging, laparoscopic and histological analyses of peritoneal endometriosis (PE) in adolescents in order to improve early diagnosis. METHODS: In total, 134 girls (from menarche to 17 years old) were included in a case-control study: 90 with laparoscopically (LS) confirmed PE, 44 healthy controls underwent full examination and LS was analyzed in the PE group. RESULTS: Patients with PE were characterized with heredity for endometriosis, persistent dysmenorrhea, decreased daily activity, gastrointestinal symptoms, higher LH, estradiol, prolactin and Ca-125 (<0.05 for each). Ultrasound detected PE in 3.3% and MRI in 78.9%. The most essential MRI signs are as follows: hypointense foci, the heterogeneity of the pelvic tissue (paraovarian, parametrial and rectouterine pouch) and sacro-uterine ligaments lesions (<0.05 for each). Adolescents with PE mostly exhibit initial rASRM stages. Red implants correlated with the rASRM score, and sheer implants correlated with pain (VAS score) (<0.05). In 32.2%, foci consisted of fibrous, adipose and muscle tissue; black lesions were more likely to be histologically verified (0.001). CONCLUSION: Adolescents exhibit mostly initial PE stages, which are associated with greater pain. Persistent dysmenorrhea and detected MRI parameters predict the laparoscopic confirmation of initial PE in adolescents in 84.3% (OR 15.4; <0.01), justifying the early surgical diagnostics and shortening the time delay and suffering of the young patients.

Malignant Clinical Course of "Proliferative" Ovarian Struma: Diagnostic Challenges and Treatment Pitfalls.

Struma ovarii (SO) is a monodermal teratoma predominantly composed of thyroid tissue (TT) showing benign, "proliferative", or malignant histology. By imaging, a 38-year-old patient with lower backache revealed a 6.2-cm vertebral lesion (L5). Core biopsy showed well-differentiated TT without features of papillary carcinoma. A 3.5-cm left ovarian mature teratoma (lacking TT) and peritoneal nodules (showing well-differentiated TT) were also identified and surgically removed. Thyroid ultrasound and cytological examination resulted negative. Four years before, left ovarian cystectomy was performed for a histologically "proliferative" SO. According to the malignant clinical course and WHO classification, this case was overall reassessed as a recurring well-differentiated follicular carcinoma arising in SO (WD-FC-SO), despite lacking malignant histological features in any specimens. Immunophenotype: TTF-1+/PAX-8+/thyroglobulin+/CK7+/chromogranin-/synaptophysin-/inhibin-/calretinin-/HNF1B-; Ki-67 index < 5%. Polymerase chain reaction analysis resulted negative for BRAFV600E mutation. The patient refused further treatments, without recurrence after 17 months. The clinical behavior of SO may be unpredictable. Histologically benign or proliferative strumas extraordinarily metastasize, while SO with malignant features may not recur. The exceptional evidence of peritoneal implants of well-differentiated TT (peritoneal strumosis) in patients with histologically benign SO represents a metastasis of WD-FC-SO (like in our case). A multidisciplinary approach including clinical, laboratory, radiologic, and histopathological data is required.

Familial Predisposition to Leiomyomata: Searching for Protective Genetic Factors.

In order to determine genetic loci associated with decreasing risk of uterine leiomyomata (UL), a genome-wide association study (GWAS) was performed. We analyzed a group of patients with a family history of UL and a control group consisting of patients without uterine fibroids and a family predisposition to this pathology. Six significant single nucleotide polymorphisms were selected for PCR-genotyping of a large data set of patients with UL. All investigated loci (rs3020434, rs11742635, rs124577644, rs12637801, rs2861221, and rs17677069) demonstrated the lower frequency of minor alleles within a group of women with UL, especially in a subgroup consisting of patients with UL and a familial history of leiomyomata. We also found that the minor allele frequencies of these SNPs in our control group were higher than those across the Caucasian population in all. Based on the obtained data, an evaluation of the common risk of UL was performed. Further work will pave the way to create a specific SNP-panel and allow us to estimate a genotype-based leiomyoma incidence risk. Subsequent studies of genetic variability in a group of patients with a familial predisposition to UL will allow us to make the prediction of the development and course of the disease more individualized, as well as to give our patients personalized recommendations about individual reproductive strategies.

Surgical management of endometriosis-associated pain.

Endometriosis and pelvic pain are associated. However, only half of the subtle and typical, and not all cystic and deep lesions are painful. The mechanism of the pain is explained by cyclical trauma and repair, an inflammatory reaction, activation of nociceptors up to 2.7 cm distance, painful adhesions and neural infiltration. The relationship between the severity of lesions and pain is variable. Diagnosis of the many causes requires laparoscopy and expertise. Imaging cannot exclude endometriosis. Surgical removal is the treatment of choice. Medical therapy without a diagnosis risks missing pathology and chronification of pain if not 100% effective. Indications and techniques of surgery are described as expert opinion since randomised controlled trials were not performed for ethical reasons, since not suited for multimorbidity while a control group is poorly accepted. Subtle endometriosis needs destruction since some cause pain or progress to more severe disease. Typical lesions need excision or vaporisation since depth can be misjudged by inspection. Painful cystic ovarian endometriosis needs adhesiolysis and either destruction of the lining or excision of the cyst wall, taking care to avoid ovarian damage. Cysts larger than 6 cm need a two-step technique or an ovariectomy. Excision of deep endometriosis is difficult and complication prone surgery involving bladder, ureter, and bowel surgery varying from excision and suturing, disc excision with a circular stapler and resection anastomosis. Completeness of excision, prevention of postoperative adhesions and recurrences of endometriosis, and the indication to explore large somatic nerves will be discussed.