Pinar H. Kodaman

Oxidative stress and the ovary.

Superoxide (O2-), hydrogen preoxide (H2O2), and lipid peroxides are generated in luteal tissue during natural and prostaglandin-induced regression in the rat, and this response is associated with reversible depletion of ascorbic acid. Reactive oxygen species immediately uncouple the luteinizing hormone receptor from adenylate cyclase and inhibit steroideogenesis by interrupting transmitochondrial cholesterol transport. The cellular origin of oxygen radicls in regressing corpora lutea is predominately from resident and infiltrated leukocytes, notably neutrophils. Reactive oxygen species are also produced within the follicle at ovulation and, like the corpus luteum, leukocytes are the major source of the products. Antioxidants block the resumption of meiosis, whereas the generation of reactive oxygen induces oocyte maturation in the follicle. Although oxygen radicals may serve important physiologic roles within the ovary, the cyclic production of these damaging agents over years may lead to an increased cumulative risk of ovarian pathology that would probably be exacerbated under conditions of reduced antioxidant status.

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.

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.

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.

Endocrine-Regulated and Protein Kinase C-Dependent Generation of Superoxide by Rat Preovulatory Follicles1

The ovulatory LH surge results in follicular inflammation with an increase in cytokines and PGs. Reactive oxygen species (ROS) are also produced during inflammatory processes. To study ROS generation during the ovulatory cascade, preovulatory follicles were dissected from immature female rats primed with PMSG. Follicles were isolated, and ROS generation was assessed by luminol-amplified chemiluminescence. Immature rat granulosa cells were also subjected to luminometry after isolation from immature rats treated with diethylstilbestrol. Phorbol ester-stimulated ROS generation by follicular cells was completely suppressed by superoxide dismutase and the NADPH/NADH oxidase inhibitor diphenylene iodonium bisulfate, whereas catalase was without effect. Fractionation of granulosa cells with an antibody against leukocyte common antigen-1 showed that leukocyte-enriched cells produced more than 95% of the superoxide measured. In vivo treatment with LH produced a 5-fold increase in phorbol-stimulated superoxide production by isolated follicles. This response was maximal within 4 h and was blocked by indomethacin. In vivo administration of PGE2 and PGF2a did not reverse the blockade by indomethacin; however, isolated follicles incubated with PGE2 produced a time-dependent increase in phorbol-stimulated superoxide generation. Thus, a superoxide generator is present in the preovulatory follicle that is leukocytic in origin, hormone regulated, and activated by a protein kinase C-dependent pathway. The regulated generation of superoxide by preovulatory follicles may indicate a role for ROS in the periovulatory period. (Endocrinology 142: 687–693, 2001) T OVULATORY SURGE of LH results in follicular hyperemia, edema, vasodilatation, and extravasation of leukocytes, all of which are characteristic of an inflammatory response (1). Various inflammatory mediators play a role in ovulation, including cytokines (2–4), peptides (5), PGs (6), and other phospholipid-derived compounds, such as platelet-activating factor (7–9). The importance of PGs for ovulation was first demonstrated by blockade of ovulation with cyclooxygenase inhibitors (10, 11), and similar studies have subsequently shown that antihistamines (12), antagonists of platelet-activating factor (7–9) and lipoxygenase (13), and antibodies directed against interleukin-8 (IL-8) (4) are also able to block or at least suppress the ovulatory rate. At the time of ovulation, follicular macrophages increase by 5-fold, whereas neutrophils increase by 8-fold (14), and this may be influenced by the local production of various chemotactic cytokines, including IL-1, tumor necrosis factor-a, IL-8, monocyte chemotactic protein-1, and granulocyte monocyte colony stimulating factor (2, 15, 16). The significance of ovarian leukocytes is underscored by the finding that infusion of leukocytes into the perfused rat ovary produced an increased ovulatory rate compared with infusion of LH alone (17), and subsequent studies by Brannstrom et al. (18) demonstrated that IL-1 and tumor necrosis factor-a also increased the ovulation rate in this model. Therefore, in addition to their traditional roles in scavenging cell debris, antigen processing, and promoting repair, leukocytes appear to enhance the physiological processes of follicle growth and ovulation (19). One important consequence of leukocyte infiltration is the generation of reactive oxygen species (ROS) that are associated with acute inflammation. There is indirect evidence that ROS play a role in ovulation; for example, the expression of superoxide dismutase isozymes (Mn-SOD and Cu/Zn-SOD) varies during the periovulatory period (20, 21), and Mn-SOD activity decreases during this time (21). Furthermore, inactivation of superoxide (SO) by long-acting SOD administration blocks ovulation (21, 22). Yet, there is no information regarding the generation of SO during the periovulatory period and its source. Therefore, the objectives of the present studies were to examine the nature and regulation of ROS production by the preovulatory follicle in response to LH and other mediators of ovulation. Materials and Methods

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.

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.

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.

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.

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.