Endometriosis in a 22-Year-Old with Premature Ovarian Insufficiency Secondary to Pre-Pubertal Bone Marrow Transplant: a Case Report.

Endometriosis is often diagnosed in reproductive aged women with spontaneous ovarian activity. Here we described a case of endometriosis diagnosed in a patient with premature ovarian insufficiency (POI) due to prepubertal bone marrow transplant (BMT). The patient is a 22-year-old nulligravid female who presented with chronic pelvic pain. She had an inherited bone marrow failure syndrome (Diamond-Blackfan anemia), which required gonadotoxic chemotherapy for BMT at a young age prior to puberty. At age 13, she received hormone therapy with transdermal estrogen with subsequent addition of cyclic progestin and was later transitioned to combined oral contraceptive pills (COC). Endometriosis was suspected due to progressive dysmenorrhea and multiple cyclic systemic symptoms. She underwent a trial of elagolix, but could not tolerate it due to worsened arthralgia. Norethindrone acetate (NET-A) was then started, and she underwent diagnostic laparoscopy. Laparoscopy revealed scattered superficial endometriotic lesions in the pelvis. Histological studies showed florid endometriosis. Patient continues on NET-A 10mg and oral estradiol 0.5mg daily since the surgery and has experienced sustained improvement in her symptoms. Endometriosis should be considered as a possible cause for progressive dysmenorrhea or pelvic pain, even in the setting of POI. The balance between HT for overall health benefits in young women with POI and the risk of endometriosis exacerbation is delicate, but achievable.

hMG addition affects the change in progesterone level during IVF stimulation and LBR: a retrospective cohort study.

BACKGROUND: Premature progesterone (P) rise during IVF stimulation reduces endometrial receptivity and is associated with lower pregnancy rates following embryo transfer (ET), which can influence provider recommendation for fresh or frozen ET. This study aimed to determine whether change in P level between in IVF baseline and trigger (𝚫P) is predictive of pregnancy outcome following fresh ET, and whether the ratio of gonadotropins influences P rise and, as a result, clinical pregnancy outcomes: clinical pregnancy rate (CPR) and live birth rates (LBR). METHODS: Retrospective cohort study at a single fertility center at an academic institution. The peak P level and 𝚫P were modeled in relation to prediction of CPR and LBR, and the ratios of hMG:rFSH were also modeled in relation to prediction of peak P level on day of trigger, 𝚫P, and CPR/LBR in a total of 291 patients undergoing fresh embryo transfer after controlled ovarian hyperstimulation-IVF (COH-IVF). RESULTS: 𝚫P correlates with CPR, with the most predictive range for success as 𝚫P 0.7-0.85 ng/mL (p = 0.005, 95% CI 0.635, 3.636; predicting CPR of 88.9%). The optimal range for peak P in regard to pregnancy outcome was 0.15-1.349 ng/mL (p = 0.01; 95% CI for coefficient in model 0.48-3.570). A multivariable logistic model for prediction of CPR and LBR using either peak or 𝚫P supported a stronger association between 𝚫P and CPR/LBR as compared to peak P. Furthermore, an hMG:rFSH ratio of > 0.6 was predictive of lowest peak P (p = 0.010, 95% CI 0.035, 0.256) and smallest 𝚫P (p = 0.012, 95% CI 0.030, 0.243) during COH-IVF cycles. Highest CPRs were observed within hMG:rFSH ratios of 0.3-0.4 [75.6% vs. 62.5% within and outside of the range, respectively, (p = 0.023, 95% CI 0.119, 1.618)]. Highest LBRs were seen within the range of 0.3-0.6 hMG:rFSH, [LBR of 55.4% vs. 41.4% (p = 0.010, 95% CI 0.176, 1.311)]. CONCLUSIONS: Our data supports use of 𝚫P to best predict pregnancy rates and therefore can improve clinical decision making as to when fresh ET is most appropriate. Furthermore, we found optimal gonadotropin ratios can be considered to minimize P rise and to optimize CPR/LBR, emphasizing the importance of luteinizing hormone (LH) activity in COH-IVF cycles.

CXCL12 Attracts Bone Marrow-Derived Cells to Uterine Leiomyomas.

Uterine leiomyomas, also known as fibroids or myomas, are a common benign gynecologic tumor found in women of reproductive age. Though advances have been made in understanding leiomyomas, the etiology and pathogenesis of this disease are not fully characterized. Current evidence supports a role of putative human uterine stem/progenitor cells in the onset of uterine disease such as uterine myomas. In this study, we report that increased expression of CXCL12 in leiomyomas recruits bone marrow-derived cells (BMDCs) that may contribute to leiomyoma growth. Tissue was collected from leiomyomas or control myometrium from women with or without leiomyomas. qRT-PCR analysis showed increased expression of CXCL12 and decreased CXCR4 expression in the leiomyoma and myometrium of women with leiomyoma compared with normal myometrium. Increased CXCL12 protein secretion from cultured myoma cells was confirmed by ELISA. Further, we found that BMDCs migration was increased toward leiomyoma conditioned medium compared with conditioned medium from normal myometrium. CXCR4 antagonist AMD3100 completely blocked this migration. Engraftment of BMDCs significantly increased in myoma of mouse uteri treated with CXCL12 compared with placebo. We conclude that CXCL12 may play a role in leiomyomas growth by attracting bone marrow-derived cells to leiomyoma. Therefore, CXCL12 and its receptors are novel targets for leiomyoma therapy.

H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas.

Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting ~80% of women, and symptomatic in 25%, UFs bring tremendous suffering and are an economic burden worldwide; they cause severe pain and bleeding, and are the leading cause of hysterectomy. Yet, UFs are severely understudied with few effective treatment options available; those that are available frequently have significant side effects such as menopausal symptoms. Recently, integrated genome-scale studies have revealed mutations and fibroid subtype-specific expression changes in key driver genes, with MED12 and HMGA2 together contributing to nearly 90% of all UFs, but their regulation of expression is poorly characterized. Here we report that the expression of H19 long noncoding RNA (lncRNA) is aberrantly increased in UFs. Using cell culture and genome-wide transcriptome and methylation profiling analyses, we demonstrate that H19 promotes expression of MED12, HMGA2, and key ECM-remodeling genes via multiple mechanisms including a new class of epigenetic modification by TET3. Our results mark the first example of an evolutionarily conserved lncRNA in pathogenesis of UFs and regulation of TET expression. Given the link between a H19 single-nucleotide polymorphism (SNP) and increased risk and tumor size of UFs, and the existence of multiple fibroid subtypes driven by key pathway genes regulated by H19, we propose a unifying mechanism for pathogenesis of uterine fibroids mediated by H19 and identify a pathway for future exploration of novel target therapies for uterine leiomyomas.

Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2.

Context: Glycogen synthesis is a critical metabolic function of the endometrium to prepare for successful implantation and sustain embryo development. Yet, regulation of endometrial carbohydrate metabolism is poorly characterized. Whereas glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of the insulin receptor is maximally expressed in secretory-phase endometrium, indicating a potential role of insulin in glucose metabolism. Objective: We sought to determine whether insulin or progesterone regulates glycogen synthesis in human endometrium. Design, Participants, Outcome Measurements: Endometrial epithelial cells were isolated from 28 healthy women and treated with insulin, medroxyprogesterone (MPA), or vehicle. Intracellular glycogen and the activation of key enzymes were quantified. Results: In epithelia, insulin induced a 4.4-fold increase in glycogen, whereas MPA did not alter glycogen content. Insulin inactivated glycogen synthase (GS) kinase 3α/ß (GSK3α/ß), relieving inhibition of GS. In a regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GS 2 (GYS2) gene expression. Conclusions: We demonstrate that insulin, not progesterone, directly regulates glycogen synthesis through canonical acute inactivation of GSK3α/ß and noncanonical stimulation of GYS2 transcription. Persistently elevated GS enables endometrium to synthesize glycogen constitutively, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests that insulin plays a key, physiological role in endometrial glucose metabolism and underlines the need to delineate the effect of maternal obesity and hyperinsulinemia on fertility and fetal development.

Premature Ovarian Insufficiency - an update on recent advances in understanding and management.

Premature ovarian insufficiency is a complex and relatively poorly understood entity with a myriad of etiologies and multisystem sequelae that stem from premature deprivation of ovarian sex hormones. Timely diagnosis with a clear understanding of the various comorbidities that can arise from estrogen deficiency is vital to appropriately counsel and treat these patients. Prompt initiation of hormone therapy is critical to control the unsolicited menopausal symptoms that many women experience and to prevent long-term health complications. Despite ongoing efforts at improving our understanding of the mechanisms involved, any advancement in the field in recent decades has been modest at best and researchers remain thwarted by the complexity and heterogeneity of the underpinnings of this entity. In contrast, the practice of clinical medicine has made meaningful strides in providing assurance to the women with premature ovarian insufficiency that their quality of life as well as long-term health can be optimized through timely intervention. Ongoing research is clearly needed to allow pre-emptive identification of the at-risk population and to identify mechanisms that if addressed in a timely manner, can prolong ovarian function and physiology.

Hysteroscopic polypectomy for women undergoing IVF treatment: when is it necessary?

PURPOSE OF REVIEW: The objectives of the present review are to discuss the role of endometrial polyps in infertility and to analyze the evidence for hysteroscopic polypectomy prior to IVF. RECENT FINDINGS: Endometrial polyps are frequently found during routine workup for infertility and are known to negatively impact endometrial receptivity through various mechanisms. Overall, most studies to date point to a favorable effect of hysteroscopic polypectomy on subsequent fertility. A recent meta-analysis showed a four-fold increase in expected pregnancy rates following hysteroscopic polypectomy in women planning to undergo intrauterine insemination, and although there are no randomized controlled trials specifically addressing hysteroscopic polypectomy prior to IVF, several large studies suggest a beneficial effect of hysteroscopy both prior to initial IVF and after failed IVF as intrauterine abnormalities, mostly endometrial polyps, are found in a significant proportion of the infertile population. There may be an added benefit of hysteroscopy itself in facilitating subsequent embryo transfer via dilation of the cervix or by increasing endometrial receptivity through endometrial injury. SUMMARY: Hysteroscopic polypectomy is a minimally invasive procedure with little risk of complication and therefore should be performed prior to IVF to optimize chances for successful implantation.

Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma.

CONTEXT: Type 2 diabetes and obesity are risk factors for endometrial hyperplasia and cancer, suggesting that hyperinsulinemia contributes to pathogenesis. Insulin action through insulin receptor (IR) splice variants IR-A and IR-B regulates cellular mitogenesis and metabolism, respectively. OBJECTIVE: We hypothesized that IR-A and IR-B are differentially regulated in normal endometrium, according to mitogenic and metabolic requirements through the menstrual cycle, as well as in endometrial hyperplasia and cancer. DESIGN: IR-A, IR-B, and IGF-1 receptor (IGF-1R) mRNA was quantified in endometrium, endometrial epithelial and stromal cells, and in vitro after hormone stimulation. SETTING: Academic center. PATIENTS: Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11). INTERVENTION(S): In vitro sex-steroid treatment. MAIN OUTCOME MEASURE(S): IR-A and IR-B expression Results: IR-A increased dramatically during the early proliferative phase, 20-fold more than IR-B. In early secretory phase, IR-B and IGF-1R expression increased, reaching maximal expression, whereas IR-A decreased. In adenocarcinoma, IR-B and IGF-1R expression was 5- to 6-fold higher than normal endometrium, whereas IR-A expression was similar to IR-B. Receptor expression was unrelated to body mass index. CONCLUSION: IR-A was elevated during the normal proliferative phase, and in endometrial hyperplasia and adenocarcinoma. The dramatic early rise of IR-A in normal endometrium indicates IR-A is the predominant isoform responsible for initial estrogen-independent endometrial proliferation as well as that of cancer. IR-B is elevated during the normal secretory phase when glucose uptake and glycogen synthesis support embryo development. Differing from other cancers, IR-B expression equals mitogenic IR-A in endometrial adenocarcinoma. Differential IR isoform expression suggests a distinct role for each in endometrial physiology and cancer.

Utility of Magnetic Resonance Imaging in the Evaluation of Intraoperatively Confirmed Pelvic Adhesions.

OBJECTIVE: The aim of this study was to evaluate the ability of magnetic resonance imaging (MRI) to identify pelvic adhesions. DESIGN: This was an institutional review board-approved retrospective analysis. METHODS: Ninety-nine patients met inclusion criteria and constituted our study population. INCLUSION CRITERIA: patients who underwent MRI and subsequent gynecologic abdominal surgery within 6 months after MRI. All imaging and operative reports were reviewed for the presence of pelvic adhesions by independent and blinded specialists. The findings were compared to calculate MRI sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in the evaluation of pelvic adhesions. RESULTS: The specificity of MRI in the detection of pelvic adhesions was greater than 90% in all locations with the exception of the posterior cul-de-sac. Accuracy was highest in the anterior cul-de-sac at 88%. The positive predictive value was greater than 85% for prediction of non-location-specific adhesions. CONCLUSIONS: Magnetic resonance imaging is very specific in the evaluation of pelvic adhesions.

Current strategies for endometriosis management.

Endometriosis is a common gynecologic disorder that persists throughout the reproductive years. Although endometriosis is a surgical diagnosis, medical management with ovarian suppression remains the mainstay of long-term management with superimposed surgical intervention when needed. The goal of surgery should be excision or ablation of all visible disease to minimize risk of recurrence and need for repeat surgeries. When infertility is the presenting symptom, surgical therapy in addition to assisted reproductive technology can improve chances of conception; however, the treatment approach depends on stage of disease and other patient characteristics that affect fecundity.

Early menopause: primary ovarian insufficiency and surgical menopause.

Early menopause, whether a consequence of primary ovarian insufficiency or resulting from surgical removal of gonads in a premenopausal woman, offers unique health-related challenges. Premature deprivation of sex steroids sets into motion a cascade of events that preferentially target urogenital, skeletal, cardiovascular, and neurocognitive systems, and culminate in global health deterioration in a chronologically younger population of women compared with those undergoing age-appropriate, NATURAL menopause. Overtly, menopausal symptoms may be shared between those experiencing early menopause versus those undergoing a natural attrition of their reproductive physiology. Extrapolation of concerns emanating from recent randomized trials of menopausal hormone therapy may not be applicable to young women experiencing early menopause, however, and estrogen replacement remains a mainstay in the clinical management of this population.

Cesarean scar ectopic pregnancy: case series and review of the literature.

Cesarean scar ectopic pregnancy is becoming increasingly common at tertiary care hospitals around the world. It is a condition in which the embryo implants within the myometrium at the site of a previous cesarean hysterotomy, and it can occur in women with only one prior cesarean delivery. We present four cases of cesarean scar ectopic pregnancy diagnosed within a 6-month period between 2007 and 2008. Their initial presentations and management are discussed, followed by a review of the published literature summarizing both diagnostic and management recommendations.

Myoferlin is critical for endocytosis in endothelial cells.

Myoferlin is a member of the ferlin family of proteins that promotes endomembrane fusion with the plasma membrane in muscle cells and endothelial cells. In addition, myoferlin is necessary for the surface expression of vascular endothelial growth factor receptor 2 through the formation of a protein complex with dynamin-2 (Dyn-2). Since Dyn-2 is necessary for the fission of endocytic vesicles from the plasma membrane, we tested the hypothesis that myoferlin may regulates aspects of receptor-dependent endocytosis. Here we show that myoferlin gene silencing decreases both clathrin and caveolae/raft-dependent endocytosis, whereas ectopic myoferlin expression in COS-7 cells increases endocytosis by up to 125%. Interestingly, we have observed that inhibition of Dyn-2 activity or caveolin-1 (Cav-1) expression impairs endocytosis as well as membrane resealing after injury, indicating that Dyn-2 and Cav-1 also participate in both membrane fission and fusion processes. Mechanistically, myoferlin partially colocalizes with Dyn-2 and Cav-1 and forms a protein complex with Cav-1 solubilized from tissue extracts. Together, these data describe a new role for myoferlin in receptor-dependent endocytosis and an overlapping role for myoferlin-Dyn-2-Cav-1 protein complexes in membrane fusion and fission events.

HMG-CoA reductase inhibitors: do they have potential in the treatment of polycystic ovary syndrome?

Many women of reproductive age are affected by polycystic ovary syndrome (PCOS), a heterogeneous endocrinopathy characterized by androgen excess, chronic oligo-anovulation and/or polycystic ovarian morphology. In addition, PCOS is often associated with insulin resistance, systemic inflammation and oxidative stress, which, on one hand, lead to endothelial dysfunction and dyslipidaemia with subsequent cardiovascular sequelae and, on the other hand, to hyperplasia of the ovarian theca compartment with resultant hyperandrogenism and anovulation. Traditionally, HMG-CoA reductase inhibitors (statins) have been used to treat dyslipidaemia by blocking HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis); however, they also possess pleiotropic actions, resulting in antioxidant, anti-inflammatory and anti-proliferative effects. Statins offer a novel therapeutic approach to PCOS in that they address the dyslipidaemia associated with the syndrome, as well as hyperandrogenism or hyperandrogenaemia. These actions may be due to an inhibition of the effects of systemic inflammation and insulin resistance/hyperinsulinaemia. Evidence to date, both in vitro and in vivo, suggests that statins have potential in the treatment of PCOS; however, further clinical trials are needed before they can be considered a standard of care in the medical management of this common endocrinopathy.

Statins in the treatment of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive-aged women. The hyperandrogenemia associated with the syndrome is a result of excessive growth and steroidogenic activity of theca-interstitial tissues in response to various factors, including elevated gonadotropins, hyperinsulinemia, and oxidative stress. PCOS frequently coexists with other cardiovascular risk factors, such as dyslipidemia and systemic inflammation. Statins inhibit the synthesis of mevalonate, the key precursor to cholesterol biosynthesis, and reduce cardiovascular morbidity and mortality. Blockade of mevalonate production may also lead to decreased maturation of insulin receptors, inhibition of steroidogenesis (e.g., via limiting the amount of substrate: cholesterol), and alteration of signal transduction pathways that mediate cellular proliferation. The latter depend upon posttranslational modification of proteins (prenylation), a process mediated by mevalonate derivatives. Statins also have intrinsic antioxidant properties. Given the pleiotropic actions of statins, they are likely not only to improve the dyslipidemia associated with PCOS but may also exert other beneficial metabolic and endocrine effects.

HOX genes in implantation.

Implantation is a complex event requiring synchronization between a developing embryo and receptive endometrium. This process is governed by molecular mechanism mediated by homeobox (Hox) genes, which encode transcription factors. These factors guide embryologic development as well as regulate differential gene expression within the endometrium with each menstrual cycle. Spatiotemporal aberrations in HOX gene expression as seen with polycystic ovarian syndrome, endometriosis, hydrosalpinges, and endocrine disrupters compromise implantation. The role of HOX genes and their products continues to be explored as animal models that demonstrate implantation-specific infertile phenotypes continue to be investigated.

Intra-uterine adhesions and fertility outcome: how to optimize success?

PURPOSE OF REVIEW: To review the etiology, diagnosis, and clinical manifestations of intra-uterine adhesions and to address treatment with a specific focus on fertility outcome. RECENT FINDINGS: Intra-uterine adhesions can cause recurrent pregnancy loss and infertility. The gravid or recently postpartum uterus is particularly susceptible to adhesion formation following instrumentation. While sonohysterography and hysterosalpingography are useful as screening tests of intra-uterine adhesions, hysteroscopy remains the mainstay of diagnosis and treatment. Hysteroscopic lysis of adhesions with scissors, electrosurgery, or laser can restore the size and shape of the endometrial cavity. Significantly obliterated cavities may require multiple procedures to achieve a satisfactory anatomical result. Postoperative mechanical distention of the endometrial cavity and hormonal treatment to facilitate endometrial regrowth appear to decrease the high rate of adhesion reformation. Newer antiadhesive barriers may also prevent the recurrence of intra-uterine adhesions. Endometrial development can remain stunted due to a scant amount of residual functioning endometrium and fibrosis. Potential pregnancy complications, especially placenta accreta, after the treatment of intra-uterine adhesions should be anticipated and discussed with the patient. SUMMARY: Diagnosis and treatment of intra-uterine adhesions are integral to the optimization of fertility outcomes. Favorable results in terms of pregnancy and live birth rates can be expected after hysteroscopic adhesiolysis.

Ovarian cryopreservation with transposition of a contralateral ovary: a combined approach for fertility preservation in women receiving pelvic radiation.

OBJECTIVE: To describe a technique of fertility preservation by ovarian transposition combined with ovarian cryopreservation in the setting of oncologic pelvic radiation for a reproductive age woman. DESIGN: Case report. SETTING: IVF center at a tertiary care hospital. PATIENT(S): Thirty-year-old nulligravid women who previously underwent lumbar spinal cord tumor debulking requested fertility preservation before pelvic radiation. INTERVENTION(S): Laparoscopic ovarian transposition with cryopreservation of the contralateral ovary. MAIN OUTCOME MEASURE(S): New technique in fertility preservation. RESULT(S): Laparoscopic surgery was used to evaluate, select, and remove a single ovary that then underwent cryopreservation. Transposition of the remaining ovary was subsequently successfully performed, placing it of out of the pelvis. CONCLUSION(S): The combination of ovarian cryopreservation and ovarian transposition may maximize future fertility options for women facing pelvic irradiation. This combined approach should be included among the options offered to reproductive age women before pelvic radiation.

Hormonal regulation of implantation.

Implantation is a complex process that requires synchronization between the embryo and a receptive endometrium. Hormones, such as the female sex steroids, prostaglandins, and peptide hormones, regulate the cellular and molecular mediators of endometrial receptivity, which include pinopodes, cell adhesion molecules, cytokines, homeobox genes, and growth factors. These mediators can be altered, despite the presence of normal hormone levels and endometrial histology; this limits the usefulness of the luteal phase endometrial biopsy. Therefore, analysis of markers of endometrial receptivity may predict successful implantation better. Elevated androgen and estrogen levels, as seen with polycystic ovary syndrome and controlled ovarian hyperstimulation, respectively, also can have detrimental effects on the endometrium, and therefore, implantation.

Evidence-based diagnosis and management of tubal factor infertility.

PURPOSE OF REVIEW: The investigation for potential tubal disease is an essential step in the work-up of infertility. This review article provides an evidence-based overview of the diagnosis and management of tubal factor infertility. RECENT FINDINGS: While laparoscopic chromopertubation remains the gold standard in the diagnosis of tubal disease and hysterosalpingography is still widely used, newer modalities offer some advantages. Sonohysterography with the use of contrast medium is superior to hysterosalpingography and comparable to laparoscopic chromotubation in diagnosing tubal blockage. Chlamydia serology is the most cost-effective and least invasive diagnostic test for tubal disease, and it is comparable to, if not better than, hysterosalpingography. Depending on the nature and degree of tubal dysfunction as well as the age and ovarian reserve of the patient, various treatments for tubal infertility are available. For proximal tubal obstruction, transcervical tubal cannulation with tubal flushing is a reasonable first approach. Surgical techniques for tubal repair, such as salpingostomy or fimbrioplasty for distal tubal obstruction, can provide good results. Still, tubal factor remains a major indication for in-vitro fertilization and embryo transfer, which bypasses the tubal problem altogether. In certain situations, such as the presence of hydrosalpinx, prophylactic surgery can be used in conjunction with in-vitro fertilization and embryo transfer. SUMMARY: As with infertility in general, the diagnosis and management of tubal infertility should be tailored to the individual patient. Future studies should help to further clarify the role of the various diagnostic tests and therapeutic approaches for tubal infertility.