Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation

BACKGROUND: Ovarian antibodies as detected by indirect immunofluorescence have been used to detect ovarian autoimmunity, but to our knowledge the rate of false positive findings using this method has never been reported. METHODS: Here we examine whether a commercially available ovarian antibody test system, using cynomologous monkey ovary, might be useful in the diagnosis of autoimmune premature ovarian failure. The test was performed in a blinded manner in 26 young women with 46,XX spontaneous premature ovarian failure, in 26 control women with regular menstrual cycles (matched for age, race, and parity) and 26 control men (matched for age and race). We also compared the frequency of other autoantibodies associated with ovarian autoimmunity. RESULTS: As a group young women with premature ovarian failure had an increased incidence of thyroid and gastric parietal cell autoimmunity (p < 0.05). Unexpectedly, however, nearly one third (31%) of normal control women had ovarian antibodies using the commercially available test. One half of young women with premature ovarian failure were found to have ovarian antibodies (P = 0.26). In our own laboratory we found similar results and we were unable to improve the specificity of the test. None of 26 men were found to have ovarian antibodies (P < 0.001). CONCLUSION: Since approximately one third of normal women were found to have ovarian antibodies using the system under study, we conclude that ovarian antibodies as detected by this indirect immunofluorescence method have poor specificity. The specificity of any ovarian antibody test should be established before it is used clinically

Biological therapies for premature ovarian insufficiency: what is the evidence?

Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies

Anti-Müllerian hormone for the diagnosis and prediction of menopause:a systematic review

Background: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman’s circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause. Objective and Rationale: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI). Search Methods: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded. Outcomes: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (&gt;22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged &lt;40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]). Wider Implications: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis

The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes

Maternal chronic stress correlates with serum levels of cortisol, glucose and C-peptide in the fetus, and maternal non chronic stress with fetal growth

Introduction: During pregnancy, maternal stressors cause changes in both maternal and fetal HPA axes. We therefore investigated the impact of maternal non chronic and chronic stress on fetal glucose metabolism and growth, and serum levels of cortisol in the fetus. Materials and methods: Normal weight pregnant women (n = 192; mean ± SD 27.9 ± 4.2 years old, and; 26.9 ± 2.4 kg/m²) were assessed during the 2nd and 3rd trimester with anthropometry, fetal ultrasound, blood samples for serum CRH, cortisol and IL6, and STAI trait and state stress questionnaires. We measured serum cortisol, insulin and c-peptide, and plasma glucose from cord blood. Neonates underwent anthropometry at the 3rd post-delivery day. Results: In both 2nd and 3rd trimesters, women with STAI trait scores ≥40 had significantly greater levels of fasting serum CRH and cortisol than those with STAI trait scores<40. 2nd trimester: STAI trait scores correlated positively with cord blood glucose and c-peptide. Maternal serum CRH correlated negatively with U/S fetal biparietal head diameter, while serum cortisol correlated positively with abdominal circumference. Maternal serum IL6, CRH and cortisol all correlated positively with birth waist circumference. 3rd trimester: Women with STAI state scores ≥40 had fetuses with larger U/S abdominal and smaller head circumferences compared to those of women with STAI scores <40. Women with STAI trait scores ≥40 had greater levels of cord blood cortisol, glucose, and c-peptide compared to women with STAI scores <40. STAI state scores ≥40 correlated positively with maternal CRH and U/S fetal abdominal circumference, and negatively with fetal head circumference and biparietal diameter. STAI trait scores correlated positively with cord blood c-peptide, glucose, insulin and cortisol. Maternal serum levels of CRH correlated positively with U/S fetal abdominal circumference and cord blood cortisol, and negatively with fetal head circumference and biparietal head diameter. Maternal serum levels of both CRH and cortisol correlated positively with cord blood c-peptide, glucose, and insulin. STAI trait was the best positive predictor of cord blood cortisol, glucose and c-peptide, whilst STAI state was the best positive and negative predictor, respectively of fetal abdominal circumference and fetal head circumference or biparietal diameter. Conclusions: Increased maternal chronic stress (reflected by the STAI trait score) associates with increased fetal cortisol, glucose, c-peptide secretion and thus, insulin resistance. Maternal non chronic stress (STAI state) in the 3rd trimester associates with changes in fetal growth pattern, including increased and decreased measurements of fetal abdominal and head growth respectively

Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency

Low androgen levels occur in women with primary ovarian insufficiency(POI) and could contribute to mood and behavioral symptoms in this condition. We examined the effects of physiologic testosterone (T) replacement therapy added to standard estrogen/progestin replacement therapy (EPT) on quality of life, self-esteem, and mood in women with POI

ART in Europe, 2016 : results generated from European registries by ESHRE

STUDY QUESTION: What are the reported data on cycles in ART, IUI and fertility preservation (FP) interventions in 2016 as compared to previous years, as well as the main trends over the years? SUMMARY ANSWER: The 20th ESHRE report on ART and IUI shows a progressive increase in reported treatment cycle numbers in Europe, with a decrease in the number of transfers with more than one embryo causing a reduction of multiple delivery rates (DR), as well as higher pregnancy rates and DR after frozen embryo replacement (FER) compared to fresh IVF and ICSI cycles, while the outcomes for IUI cycles remained stable. WHAT IS KNOWN ALREADY: Since 1997, ART aggregated data generated by national registries, clinics or professional societies have been collected, analysed by the European IVF-monitoring Consortium (EIM) and reported in 19 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN, SIZE, DURATION: Yearly collection of European medically assisted reproduction (MAR) data by EIM for ESHRE. The data on treatments performed between 1 January and 31 December 2016 in 40 European countries were provided by either National Registries or registries based on personal initiatives of medical associations and scientific organizations. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 1347 clinics offering ART services in 40 countries reported a total of 918 159 treatment cycles, involving 156 002 with IVF, 407 222 with ICSI, 248 407 with FER, 27 069 with preimplantation genetic testing, 73 927 with egg donation (ED), 654 with IVM of oocytes and 4878 cycles with frozen oocyte replacement (FOR). European data on IUI using husband/partner’s semen (IUI-H) and donor semen (IUI-D) were reported from 1197 institutions offering IUI in 29 and 24 countries, respectively. A total of 162 948 treatments with IUI-H and 50 467 treatments with IUI-D were included. A total of 13 689 FP interventions from 11 countries including oocyte, ovarian tissue, semen and testicular tissue banking in pre-and postpubertal patients were reported. MAIN RESULTS AND THE ROLE OF CHANCE: In 20 countries (18 in 2015) with a total population of approximately 325 million inhabitants, in which all ART clinics reported to the registry, a total of 461 401 treatment cycles were performed, corresponding to a mean of 1410 cycles per million inhabitants (range 82–3088 per million inhabitants). In the 40 reporting countries, after IVF the clinical pregnancy rates (PR) per aspiration and per transfer in 2016 were similar to those observed in 2015 (28.0% and 34.8% vs 28.5% and 34.6%, respectively). After ICSI, the corresponding rates were also similar to those achieved in 2015 (25% and 33.2% vs 26.2% and 33.2%). After FER with own embryos, the PR per thawing is still on the rise, from 29.2% in 2015 to 30.9% in 2016. After ED, the PR per fresh embryo transfer was 49.4% (49.6% in 2015) and per FOR 43.6% (43.4% in 2015). In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and 4 embryos in 41.5%, 51.9%, 6.2% and 0.4% of all treatments, respectively (corresponding to 37.7%, 53.9%, 7.9% and 0.5% in 2015). This resulted in a proportion of singleton, twin and triplet DRs of 84.8%, 14.9% and 0.3%, respectively (compared to 83.1%, 16.5% and 0.4%, respectively in 2015). Treatments with FER in 2016 resulted in twin and triplet DR of 11.9% and 0.2%, respectively (vs 12.3% and 0.3% in 2015). After IUI, the DRs remained similar at 8.9% after IUI-H (7.8% in 2015) and at 12.4% after IUI-D (12.0% in 2015). Twin and triplet DRs after IUI-H were 8.8% and 0.3%, respectively (in 2015: 8.9% and 0.5%) and 7.7% and 0.4% after IUI-D (in 2015: 7.3% and 0.6%). The majority of FP interventions included the cryopreservation of ejaculated sperm (n¼7877 from 11 countries) and of oocytes (n¼4907 from eight countries). LIMITATIONS, REASONS FOR CAUTION: As the methods of data collection and levels of completeness of reported data vary among European countries, the results should be interpreted with caution. A number of countries failed to provide adequate data about the number of initiated cycles and deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 20th ESHRE report on ART and IUI shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Being already the largest data collection on MAR in Europe, continuous efforts to stimulate data collection and reporting strive for future quality control of the data, transparency and vigilance in the field of reproductive medicine.The study has no external funding and all costs were covered by ESHRE.peer-reviewe

DEOXYRIBONUCLEASE I (DNASE I) ACTIVITY IN THE AMNIOTIC FLUID AT THE SECOND TRIMESTER OF PREGNACY AND LABOR

OBJECTIVE. TO INVESTIGATE THE PRESECE, THE NORMAL VALUES AND THE SIGNIFICANCE OF DEOXYRIBONUCLEASE I (DNASE I), AN EZYME CATALYZING DNA, IN HUMAN PREGNANCY AND LABOR. STUDY DESIGN. SIXTY SIX PREGNANT WOMEN AT 16 TO 24 WEEKS OF GESTATION AND 89 WOMEN IN SPONTANEOUS LABOR AT TERM WERE RECRUITED TO THE STUDY. A SPECTROPHOTOMETRIC TECHNIQUE (DNA PRECIPITATION ASSAY) AND NUCLEIC ACID ELECTROPHORESIS, FOLLOWING DEGRADATION BY THE ENZYME, WERE USED TO MEASURE DNASE IACTIVITY IN AMNIOTIC FLUID. THE STUDENT T-TEST WAS USED FOR STATISTICAL ANALYSIS. RESULTS. DNASE I ACTIVITY IS DETECTABLE (2.3+-0.64*10^5 U/L) IN THE SECOND TRIMESTER OF PREGNANCY. DNASE I ACTIVITY IS SIGNIFICANTLY DECREASED DURING LABOR (1.9+-0.44* 10^5 U/L, P < 0.001), WITH SIGNIFICANTLY HIGHER VALUES OCCURED IN THE PRESENCE OF MECONIUM-STAINED AMNIOTIC FLUID (11.4+-4.1*10^5 U/L, P < 0.001). CONCLUSION. DNASE I ACTIVITY IS PRESENT IN THE AMNIOTIC FLUID OF NORMAL PREGNANCIES. HIGHER DNASE I ACTIVITY MAY PLAY A ROLE IN THE PRESENCE OF MECONIUM DURING LABOR.ΣΚΟΠΟΣ. Η ΑΝΙΧΝΕΥΣΗ ΤΗΣ ΠΑΡΟΥΣΙΑΣ, Ο ΠΡΟΣΔΙΟΡΙΣΜΟΣ ΤΗΣ ΔΡΑΣΤΙΚΟΤΗΤΑΣ ΚΑΙ Η ΔΙΕΡΕΥΝΗΣΗ ΤΗΣ ΣΗΜΑΣΙΑΣ ΤΗΣ ΔΕΟΞΥΡΙΒΟΝΟΥΚΛΕΑΣΗΣ Ι (DNASE I), ΕΝΟΣ ΕΝΖΥΜΟΥ ΚΑΤΑΒΟΛΙΣΜΟΥ ΤΩΝ ΝΟΥΚΛΕΙΚΩΝ ΟΞΕΩΝ, ΣΤΟ ΑΜΝΙΑΚΟ ΥΓΡΟ ΣΤΟ 2Ο ΤΡΙΜΗΝΟ ΤΗΣ ΚΥΗΣΗΣ ΚΑΙ ΚΑΤΑ ΤΟΝ ΤΕΛΕΙΟΜΗΝΟ ΚΟΛΠΙΚΟ ΤΟΚΕΤΟ. ΥΛΙΚΟ ΚΑΙ ΜΕΘΟΔΟΣ. ΛΗΨΗ ΑΜΝΙΑΚΟΥ ΥΓΡΟΥ ΕΓΙΝΕ ΣΕ 66 ΕΓΚΥΕΣ ΣΤΟ 2Ο ΤΡΙΜΗΝΟ ΚΑΙ ΣΕ 89 ΕΠΙΤΟΚΕΣ ΚΑΤΑ ΤΟΝ ΤΟΚΕΤΟ. ΜΙΑ ΤΕΧΝΙΚΗ ΦΩΤΟΜΕΤΡΗΣΗΣ (ΚΑΤΑΚΡΗΜΝΙΣΗΣ DNA) ΚΑΙ ΗΛΕΚΤΡΟΦΟΡΗΣΗ DNA, ΜΕΤΑ ΑΠΟ ΠΕΨΗ ΑΠΟ ΤΗΝ DNASE Ι, ΧΡΗΣΙΜΟΠΟΙΗΘΗΚΑΝ ΓΙΑ ΤΟΝ ΠΡΟΣΔΙΟΡΙΣΜΟ ΤΗΣ ΔΡΑΣΤΙΚΟΤΗΤΑΣ ΤΟΥ ΕΝΖΥΜΟΥ. Η ΣΤΑΤΙΣΤΙΚΗ ΑΝΑΛΥΣΗ ΕΓΙΝΕ ΜΕ ΤΟ STUDENT T-TEST. ΑΠΟΤΕΛΕΣΜΑΤΑ. ΔΙΑΠΙΣΤΩΘΗΚΕ Η ΠΑΡΟΥΣΙΑ ΤΗΣ DNASE I ΣΕ ΟΛΑ ΤΑ ΔΕΙΓΜΑΤΑ ΑΜΝΙΑΚΟΥ ΥΓΡΟΥ. Η ΔΡΑΣΤΙΚΟΤΗΤΑ ΤΟΥ ΕΝΖΥΜΟΥ ΣΕ ΦΥΣΙΟΛΟΓΙΚΕΣ ΚΥΗΣΕΙΣ ΣΤΟ 2Ο ΤΡΙΜΗΝΟ ΗΤΑΝ 2.3+-0.64*10^5 U/L. ΜΕΙΩΣΗ ΤΗΣ ΔΡΑΣΤΙΚΟΤΗΤΑΣ ΔΙΑΠΙΣΤΩΘΗΚΕ ΚΑΤΑ ΤΟΝ ΤΟΚΕΤΟ (1.9+-0.44*10^5 U/L, P < 0.001) ΣΕ ΣΧΕΣΗ ΜΕ ΤΟ 2Ο ΤΡΙΜΗΝΟ, ΕΝΩ ΣΤΑΤΙΣΤΙΚΑ ΣΗΜΑΝΤΙΚΗ ΑΥΞΗΣΗ (P < 0.001)ΠΑΡΑΤΗΡΗΘΗΚΕ ΣΤΙΣ ΠΕΡΙΠΤΩΣΕΙΣ ΠΑΡΟΥΣΙΑΣ ΜΗΚΩΝΙΟΥ ΣΤΟ ΑΜΝΙΑΚΟ ΥΓΡΟ (11.4+-4.1*10^5 U/L). ΣΥΜΠΕΡΑΣΜΑΤΑ. Η DNASE I ΥΠΑΡΧΕΙ ΦΥΣΙΟΛΟΓΙΚΑ ΣΤΟ ΑΜΝΙΑΚΟ ΥΓΡΟ, Η ΔΡΑΣΤΙΚΟΤΗΤΑ ΤΗΣ ΜΕΙΩΝΕΤΑΙ ΣΤΟΝ ΤΟΚΕΤΟ ΚΑΙ ΑΥΞΑΝΕΤΑΙ ΣΤΙΣ ΠΕΡΙΠΤΩΣΕΙΣ ΠΑΡΟΥΣΙΑΣ ΜΗΚΩΝΙΟΥ

Testosterone implants in women: Pharmacological dosing for a physiologic effect

Objectives: The objectives of this study were to determine therapeutic serum testosterone (T) levels/ranges and inter-individual variance in women treated with subcutaneous T implants. Study design: In study group 1, T levels were measured at two separate time intervals in pre- and postmenopausal women treated with subcutaneous T for symptoms of androgen deficiency: (i) four weeks after pellet insertion, and (ii) when symptoms of androgen deficiency returned. In a separate pharmacokinetic study (study group 2), 12 previously untreated postmenopausal women each received a 100 mg T implant. Serum T levels were measured at baseline, 4 weeks and 16 weeks following T pellet implantation. In study ‘group’ 3, serial T levels were measured throughout a 26 h period in a treated patient. Results: In study group 1, serum T levels measured at ‘week 4’ (299.36 +/- 107.34 ng/dl, n = 154), and when symptoms returned (171.43 +/- 73.01 ng/dl, n = 261), were several-fold higher compared to levels of endogenous T. There was significant inter-individual variance in T levels at ‘week 4’ (CV 35.9%) and when symptoms returned (CV 42.6%). Even with identical dosing (study group 2), there was significant inter-individual variance in T levels at ‘week 4’ (CV 41.9%) and ‘week 16’ (CV 41.6%). In addition, there was significant intra-individual circadian variation (CV 25%). Conclusions: Pharmacologic dosing of subcutaneous T, as evidenced by serum levels on therapy, is needed to produce a physiologic effect in female patients. Safety, tolerability and clinical response should guide therapy rather than a single T measurement, which is extremely variable and inherently unreliable. (c) 2012 Elsevier Ireland Ltd. All rights reserved