Polycystic ovary syndrome and iron overload: biochemical link and underlying mechanisms with potential novel therapeutic avenues.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder in women with components of significant genetic predisposition and possibly multiple, but not yet clearly defined, triggers. This disorder shares several clinical features with hemochromatosis, a genetically defined inheritable disorder of iron overload, which includes insulin resistance, increased adiposity, diabetes, fatty liver, infertility, and hyperandrogenism. A notable difference between the two disorders, however, is that the clinical symptoms in PCOS appear at much younger age whereas they become evident in hemochromatosis at a much later age. Nonetheless, noticeable accumulation of excess iron in the body is a common finding in both disorders even at adolescence. Hepcidin, the iron-regulatory hormone secreted by the liver, is reduced in both disorders and consequently increases intestinal iron absorption. Recent studies have shown that gut bacteria play a critical role in the control of iron absorption in the intestine. As dysbiosis is a common finding between PCOS and hemochromatosis, changes in bacterial composition in the gut may represent another cause for iron overload in both diseases via increased iron absorption. This raises the possibility that strategies to prevent accumulation of excess iron with iron chelators and/or probiotics may have therapeutic potential in the management of polycystic ovary syndrome.

Diagnosis and Management of an Adenomatoid Uterine Tumor: Ultrasound, Magnetic Resonance Imaging, Surgical Appearance, and Pathology Correlation.

Adenomatoid uterine tumors are rare, and their appearance on medical imaging modalities is not well established. We present a case of an adenomatoid uterine tumor reviewing a unique sonographic presentation, magnetic resonance imaging (MRI), gross surgical appearance of the tumor, and microscopic pathology images. A 29-year-old gravida 0 Caucasian woman presented with dysmenorrhea, menorrhagia, and desire to conceive. Transvaginal ultrasound revealed a 2.7 cm round, well-circumscribed posterior intramural uterine mass. The mass was hyperechoic centrally with a thin hypoechoic rim. Color Doppler imaging revealed a prominent vascular rim around the periphery of the mass as well as central vascularity not typical for a leiomyoma. MRI, with and without intravenous gadolinium, was obtained showing a 2.7 cm posterior fundal mildly enhancing uterine mass suggestive of leiomyoma. The mass had a heterogeneous signal pattern on T2-weighted images, and no fat component was noted within the mass. Repeat transvaginal ultrasound showed interval growth of the mass to 3.5 cm with a lipomatous appearance. Adenomatoid uterine tumors are rare and may be mistaken for uterine leiomyomata. Unique features include sonographic appearance of central hyperechogenicity with a hypoechoic rim and prominent peripheral and central vascularity in conjunction with MRI revealing a heterogeneous signal pattern on T2-weighted images without fat component. Gross surgical appearance reveals a nondiscrete capsule and secretion of mucoid material when the mass is exposed. We present a case of adenomatoid tumor providing sonographic, MRI, surgical, and pathological correlation. The patient subsequently conceived spontaneously and delivered at term by cesarean section. The patient underwent a preoperative evaluation with complete blood count, comprehensive metabolic panel, blood type with antibody screen, and pregnancy test. She underwent laparoscopic excision with robotic assistance for removal of the tumor. Grossly, the uterine mass had a very soft consistency atypical for a uterine leiomyoma making dissection more challenging. During dissection the mass diffusely secreted a mucoid material although the capsule was not disrupted. The lesion was excised intact and was removed from the peritoneal cavity in an endocatch bag without internal morcellation. Microscopic examination revealed an adenomatoid tumor.

Primary cervico-uterine anastomosis in a patient with agenesis of the uterine isthmus: A case report and review.

Arrested caudal extension of the fused Müllerian ducts, either complete or segmental, causes obstruction of the outflow tract. We describe a case of agenesis of the uterine isthmus and the procedure to establish the continuity of the outflow tract. A 15-year-old girl with cyclic pelvic pain and amenorrhea was found to have a 3-cm gap between the uterine body and the cervix. After cervico-uterine anastomosis via laparotomy she menstruated normally and was pain-free. Selected cases of arrested Müllerian duct extension can be corrected by primary anastomosis, which establishes anatomical continuity and restores menstruation and, possibly, future fertility.

Effects of a Delphi consensus acupuncture treatment protocol on the levels of stress and vascular tone in women undergoing in-vitro fertilization: a randomized clinical trial protocol.

BACKGROUND: The variability of published acupuncture protocols for patients undergoing In-Vitro Fertilization (IVF) complicates the interpretation of data and hinders our understanding of acupuncture's impact. In 2012, an acupuncture treatment protocol developed by a Delphi consensus process was published to describe the parameters of best practice acupuncture for Assisted Reproductive Technology and future research. However, there has been no clinical trial utilizing this protocol to assess the effects of acupuncture. This study aims to assess the implementation of Dephi consensus acupuncture protocol and to examine the impact of acupuncture on stress and uterine and ovarian blood flow among women between ages 21-42 years seeking IVF. METHODS/DESIGN: This study is a one site prospective, two-arm randomized controlled non-blind clinical trial conducted in a medical school-affiliated fertility center . Participants will be randomized 1:1 into either the acupuncture group or the standard of care (no acupuncture) group using computer generated tables. Both groups will have 3 regular clinical visits as their standard IVF care during an approximately 2 to 3 weeks window. Women who are randomized into the acupuncture group would receive three sessions based on the Delphi consensus acupuncture protocol in addition to the standard care. The first treatment will be administered between days 6 to 8 of the stimulated IVF cycle. The second session will be performed on the day of embryo transfer at least 1 h prior to the transfer. The third session will be performed within 48 h post-embryo transfer. Participants will be followed for their pregnancy test and pregnancy outcome when applicable. The outcomes stress and blood flow will be measured by a validated perceived stress scale and vasoactive molecules, respectively. DISCUSSION: Although recruitment and scheduling could be challenging at times, the Delphi consensus acupuncture protocol was implemented as planned and well-accepted by the patients. Because of the time-specified sessions around patients' IVF cycle, it is highly recommended to have on-site study acupuncturist(s) to accommodate the schedule. TRIAL REGISTRATION: ClinicalTrials NCT02591186 registered on October 7, 2015.

Environmental determinants of polycystic ovary syndrome.

In this review, we summarize existing research on a variety of environmental factors potentially involved in the etiology, prevalence, and modulation of polycystic ovary syndrome (PCOS), and we suggest avenues for future research. The main environmental factors we consider include environmental toxins, diet and nutrition, socioeconomic status, and geography. There is some evidence that environmental toxins play a role in disrupting reproductive health, but there is limited research as to how these toxins may affect the development of PCOS. Although research has also shown that PCOS symptoms are reduced with certain dietary supplements and with weight loss among obese women, additional research is needed to compare various approaches to weight loss, as well as nutritional factors that may play a role in preventing or mitigating the development of PCOS. Limited studies indicate some association of low socioeconomic status with certain PCOS phenotypes, and future research should consider socioeconomic conditions during childhood or adolescence that may be more relevant to the developmental onset of PCOS. Finally, the limited scope of comparable international studies on PCOS needs to be addressed, because global patterns of PCOS are potentially valuable indicators of cultural, environmental, and genetic factors that may contribute to excess risk in certain regions of the world.

Low Starch/Low Dairy Diet Results in Successful Treatment of Obesity and Co-Morbidities Linked to Polycystic Ovary Syndrome (PCOS).

BACKGROUND: Polycystic Ovary Syndrome (PCOS) affects approximately 15% of reproductive-age women and increases risk of insulin resistance, type 2 diabetes mellitus, cardiovascular disease, cancer and infertility. Hyperinsulinemia is believed to contribute to or worsen all of these conditions, and increases androgens in women with PCOS. Carbohydrates are the main stimulators of insulin release, but research shows that dairy products and starches elicit greater postprandial insulin secretion than non-starchy vegetables and fruits. The purpose of this study was to determine whether an 8-week low-starch/low-dairy diet results in weight loss, increased insulin sensitivity, and reduced testosterone in women with PCOS. METHODS: Prospective 8-week dietary intervention using an ad libitum low starch/low dairy diet in 24 overweight and obese women (BMI ≥ 25 kg/m2 and ≤ 45 kg/m2) with PCOS. Diagnosis of PCOS was based on the Rotterdam criteria. Weight, BMI, Waist Circumference (WC), Waist-to-Height Ratio (WHtR), fasting and 2-hour glucose and insulin, homeostasis model assessment of Insulin Resistance (HOMA-IR), HbA1c, total and free testosterone, and Ferriman-Gallwey scores were measured before and after the 8-week intervention. RESULTS: There was a reduction in weight (-8.61 ± 2.34 kg, p<0.001), BMI (-3.25 ± 0.88 kg/m2, p<0.001), WC (-8.4 ± 3.1 cm, p<0.001), WHtR (-0.05 ± 0.02 inches, p<0.001), fasting insulin (-17.0 ± 13.6 µg/mL, p<0.001) and 2-hour insulin (-82.8 ± 177.7 µg/mL, p=0.03), and HOMA-IR (-1.9 ± 1.2, p<0.001) after diet intervention. Total testosterone (-10.0 ± 17.0 ng/dL, p=0.008), free testosterone (-1.8 pg/dL, p=0.043) and Ferriman-Gallwey scores (-2.1 ± 2.7 points (p=0.001) were also reduced from pre- to post-intervention. CONCLUSION: An 8-week low-starch/low-dairy diet resulted in weight loss, improved insulin sensitivity and reduced testosterone in women with PCOS.

Effect of a low-starch/low-dairy diet on fat oxidation in overweight and obese women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects between 4%-18% of reproductive-aged women and is associated with increased risk of obesity and obesity-related disease. PCOS is associated with hyperinsulinemia, which is known to impair fat oxidation. Research shows that carbohydrates from dairy and starch-based foods cause greater postprandial insulin secretion than carbohydrates from nonstarchy vegetables and fruits. The purpose of this study was to determine whether an ad libitum 8-week low-starch/low-dairy diet would improve fasting and postprandial fat oxidation after a high saturated fat liquid meal (HSFLM) in overweight and obese women with PCOS. Prospective 8-week dietary intervention using a low-starch/low-dairy diet in 10 women (body mass index ≥25 kg/m(2) and ≤45 kg/m(2)) with PCOS. Indirect calorimetry was used at fasting and for 5 h following consumption of the HSFLM to determine respiratory exchange ratio (RER), macronutrient oxidation, and energy expenditure (EE) at week 0 and week 8. Participants had a reduction in body weight (-8.1 ± 1.8 kg, p < 0.05) and fasting insulin (-19.5 ± 8.9 µg/mL, p < 0.05) after dietary intervention; however, these were not significantly correlated with improved fat oxidation. There was a reduction in fasting RER, and fasting and postprandial carbohydrate oxidation, and an increase in fasting and postprandial fat oxidation after adjusting for body weight. There was also significant difference in incremental area under the curve from pre- to post-diet for fat (0.06 ± 0.00 g/kg per 5 h; p < 0.001) and carbohydrate oxidation (-0.29 ± 0.06 g/kg per 5 h; p < 0.001), but not for RER or EE. In conclusion, an 8-week low-starch/low-dairy diet increased fat oxidation in overweight and obese women with PCOS.

Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization.

CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. PATIENTS: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Diagnosis of polycystic ovaries by three-dimensional transvaginal ultrasound.

OBJECTIVE: To study diagnostic thresholds for polycystic ovary (PCO). DESIGN: Retrospective cohort study. SETTING: Academic hospital. PATIENT(S): Normoandrogenic ovulatory women and patients with polycystic ovary syndrome (PCOS). INTERVENTION(S): Two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound. MAIN OUTCOME MEASURE(S): The mean follicle number per ovary (FNPO) of both ovaries and the maximum number follicles in a single sonographic plane (FSSP) of either ovary were determined using 3D transvaginal ultrasound. Ovarian volume was determined using 2D transvaginal ultrasound. RESULT(S): Twenty-nine normoandrogenic ovulatory women were compared with 10 patients with PCOS. Diagnostic thresholds for PCO with 100% specificity as determined by receiver operator characteristic (ROC) curves were > or =20 for mean FNPO, > or =10 for maximum FSSP, and > or =13 cm3 for ovarian volume. Both 2D and 3D transvaginal ultrasound were highly accurate in the diagnosis of PCO as determined by areas under the curve (AUC) that were >90% for all three measures. CONCLUSION(S): Mean FNPO and maximum FSSP by 3D transvaginal ultrasound have comparable high accuracy for diagnosis of PCO. The diagnostic threshold with 100% specificity for mean FNPO is > or =20, which is greater than suggested by the Rotterdam Consensus Workshop in 2003. Use of the consensus standard, consequently, may result in overdiagnosis of PCO. A threshold of > or =20 mean FNPO using 3D transvaginal ultrasound may be appropriate to minimize false-positive diagnoses of PCO.

Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients.

Insulin action is mediated by two insulin receptor (IR) isoforms, differing in mitogenic and metabolic function. IR isoform expression might occur in human granulosa cells and could be altered in polycystic ovary syndrome (PCOS) from hyperinsulinemia. To determine the relationship between granulosa cell IR isoform expression and follicular fluid insulin concentration in individual follicles, 18 normal women and seven PCOS patients receiving gonadotropins for in vitro fertilization were studied. Glucose tolerance testing was performed before pituitary desensitization, and fasting serum insulin was measured at oocyte retrieval. Granulosa cells and fluid aspirated from the first follicle were used to determine IR isoform mRNA expression and insulin concentration, respectively. IR isoform A mRNA expression was greater than that of IR isoform B expression in normal mural granulosa and cumulus cells, without a cell type effect. Intrafollicular insulin levels increased with adiposity and serum insulin levels at oocyte-retrieval but did not predict IR mRNA expression. Total IR mRNA expression, but not intrafollicular insulin levels, was elevated in PCOS patients, whereas intrafollicular insulin levels were increased in women with impaired glucose tolerance. Granulosa cell IR heterogeneity, together with adiposity-dependent intrafollicular insulin availability, introduces a novel mechanism by which insulin may affect granulosa cell function within the follicle.

Hypersensitivity to progesterone-in-oil after in vitro fertilization and embryo transfer.

OBJECTIVE: To report the occurrence and management of pulmonary compromise, marked leukocytosis, and eosinophilia in a patient receiving P-in-oil after IVF and embryo transfer. DESIGN: Case report.A tertiary referral reproductive medicine unit. PATIENT(S): A 29-year-old patient receiving P-in-oil supplementation after IVF embryo transfer. INTERVENTION(S): Extensive diagnostic testing and surveillance for hypersensitivity to P in sesame oil; development of an alternative oil-based P-in-oil suspension. MAIN OUTCOME MEASURE(S): Tolerance of alternative P vehicle; clinical pregnancy. RESULT(S): The patient tolerated an alternative P oil vehicle and successfully achieved a clinical pregnancy after frozen embryo transfer. CONCLUSION(S): Although rare, hypersensitivity reactions may occur in patients receiving P-in-oil supplementation after IVF embryo transfer. Testing for tolerance and subsequent use of alternative P vehicles may be an effective strategy in managing patients with sensitivity to P-in-oil.

Successful elective single blastocyst transfer in a patient with prior repetitive high-order multiple gestations.

Multiple gestations remain one of the leading causes of morbidity related to infertility therapy. In the realm of assisted reproductive technologies, multiple gestations can be significantly limited by the reduction in the number of embryos transferred. Significant concern remains that a reduction in the number of embryos transferred may appreciably lower overall chances for pregnancy. Promising new developments are unfolding that may permit improved detection of a single human embryo with high implantation potential. One such development is the use of sequential culture media to allow prolonged culture of embryos to the blastocyst stage. We report a case in which sequential culture and elective transfer of one blastocyst was successfully used in a patient with a profoundly poor obstetrical history because of the complications of high-order multiple gestations.

Differences in steroidogenic acute regulatory protein expression from the luteinizing-granulosa cells of patients undergoing in vitro fertilization with embryo transfer: implications for cycle outcomes.

OBJECTIVE: Previous research has suggested a correlation between the subtle rise in progesterone induced by the administration of human chorionic gonadotropin (hCG) and cycle outcome in patients undergoing in vitro fertilization with embryo transfer (IVF-ET). The data suggest that patients who have <2-fold increase in progesterone levels will not conceive as a result of that IVF-ET attempt (poor responders). Further, if the luteinizing-granulosa cells of poor responders are placed in culture, their steroid hormone production will be significantly less than that of the luteinizing-granulosa cells of patients with a normal response to hCG (>3-fold; normal responders). Recent studies have demonstrated that steroidogenic acute regulatory protein (StAR) regulates the rate-limiting step in steroid hormone biosynthesis. The objective of the present study was to determine whether StAR expression differed in normal responders and poor responders undergoing IVF-ET. STUDY DESIGN: The luteinizing-granulosa cells of 6 patients were isolated after follicular aspiration and assayed for StAR expression. Three sets of cells were from patients exhibiting a normal response to hCG administration and 3 sets were from patients exhibiting a poor response. RESULTS: Data suggest a 17% drop in StAR protein in patients with a poor response to hCG administration when compared with those with a normal response. CONCLUSIONS: Although StAR protein was expressed in all 6 cellular extracts, expression appeared greatest in cells recovered from normal responders. Further, although two thirds of the patients with a normal response reported term pregnancies, no pregnancies were reported in the poor responders. Low levels of progesterone and absence of pregnancy may be due to a defect in the mechanism that converts granulosa and theca-lutein cells to luteal cells after the luteinizing hormone surge (or hCG administration). Data from the current study would suggest that the StAR protein may be involved.