Predictive value of postwashed total progressively motile sperm count using CASA estimates in 6871 non-donor intrauterine insemination cycles.

PURPOSE: To determine whether postwashed total progressively motile sperm count (TPMSC) obtained by CASA estimates could predict positive pregnancy test result in non-donor IUI cycles. METHODS: Six thousand eight hundred and seventy one (6,871) IUI cycles with non-donor semen were retrospectively analyzed. Patient, cycle characteristics and prewashed and postwashed semen parameters were included in analysis. The main outcome measure was the positive pregnancy test result. RESULTS: The pregnancy rate per cycle (PR/cycle) when postwashed TPMSC is between 0-0.5 million, 0.51-1 million, 1.01-5 million, 5.01-10 million and greater than 10 million were 8.1% (42/520), 14.4 % (41/285), 16.1% (237/1,469), 18.4% (193/1,046) and 18.8% (668/3,551) respectively. The predicted odd of positive pregnancy result is statistically significantly higher when TPMSC is >0.51 million compared to the TPMSC of <0.51 million (OR = 1.68, 95% CI: 1.04-2.71). The predicted odd of positive pregnancy result is greatest when TPMSC is at least 5 million (OR = 2, 95% CI: 1.38 to 2.9). CONCLUSION: TPMSC is an independent predictor of pregnancy test result and TPMSC of half million or greater is adequate to achieve statistically similar pregnancy test results after non-donor IUI cycles.

Using the oocyte donation model to identify early trophoblast pregnenolone production.

PURPOSE: To investigate production of progesterone's precursor, pregnenolone, in the early oocyte donation pregnancy. METHODS: Pregnenolone and progesterone were measured on luteal days 21, 28, 35, 60 and 80. Progesterone was measured via the Immulite system, pregnenolone by liquid chromatography separation with tandem mass spectrometric detection. RESULTS: Progesterone rose significantly from days 35 today 60. Pregnenolone likewise rose significantly from days 35-60, but at a much higher rate, with an increase of 57% by day 60, 75% to day 80. The increase in pregnenolone was statistically more significant than the increase in progesterone (p < .05). CONCLUSIONS: This is the first report describing that progesterone's precursor, pregnenolone, increases with time in the very early pregnancy. Because no corpus luteum is present in oocyte recipients, the main source of pregnenolone is the early placenta. Measurements of pregnenolone may provide information concerning early trophoblast function and may represent a method of assessing placental competency.

The extrapituitary effects of GnRH antagonists and their potential clinical implications: a narrated review.

Potential roles of gonadotropin-releasing hormone (GnRH) antagonists on GnRH/GnRH receptor systems and their effects on the extrapituitary tissues are largely elusive. In this narrated review, we summarized the systemic effects of GnRH antagonists on ovary, endometrium, embryo implantation, placental development, fetal teratogenicity, reproductive tissue cancer cells, and heart while briefly reviewing the GnRH and GnRH receptor system. GnRH antagonists may have direct effects on ovarian granulosa cells. Data are conflicting regarding their effects on endometrial receptivity. The GnRH antagonists may potentially have detrimental effect on early placentation by decreasing the invasive ability of cytotrophoblasts if the exposure to them occurs during early pregnancy. The GnRH antagonists were not found to increase the rates of congenital malformations. Comparative clinical data are required to explore their systemic effects on various extrapituitary tissues such as on cardiac function in the long term as well as their potential use in other human cancers that express GnRH receptors.

The impact of bariatric surgery on obesity-related infertility and in vitro fertilization outcomes.

Obesity-related infertility is one of the most common problems of reproductive-age obese women who desire childbearing. The various types of bariatric surgeries have proved effective in controlling excessive weight gain, improving fertility, and preventing certain maternal and fetal complications in these women. This article summarizes the current evidence regarding the impact of bariatric surgery on obesity-related infertility and in vitro fertilization (IVF) outcomes. We have also attempted to draw conclusions about maternal and fetal risks and the benefits of bariatric surgery. Laparoscopic adjustable gastric banding and Roux-en-Y procedures are the two most commonly performed bariatric surgeries. Bariatric surgery was believed to improve menstrual irregularity and increase ovulation rate in anovulatory obese women, which lead to increased pregnancy rates. Although there are data in the literature suggesting the improvement of both the ovulatory function and the spontaneous pregnancy rates in obese women who lost weight after bariatric surgery, most of these are case-control studies with a small number of patients. The data are insufficient to determine an ideal time interval for pregnancy after bariatric surgery; however, the general consensus is that pregnancy should be delayed 12 to 18 months after bariatric surgery to avoid nutritional deficiencies. Few data exist regarding IVF success rates in women who have undergone bariatric surgery. One pairwise study discussed five patients who underwent bariatric surgery followed by IVF that resulted in three term pregnancies in three patients after the first IVF cycle. Many studies reported reductions in obesity-related pregnancy complications such as gestational diabetes and hypertensive disorders after bariatric surgery. Although data are inconsistent, some studies reported increased rate of preterm delivery and small for gestational age infants after bariatric surgery. Pregnancies after bariatric surgery may be considered high risk due to the concerns for vitamin deficiencies and gastrointestinal symptoms related to the surgery. Therefore the follow-up of these pregnancies might require a team approach including a maternal fetal medicine specialist, bariatric surgeon, and nutritionist.

Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review.

OBJECTIVE: Menopause and its transition represent significant risk factors for the development of vulvovaginal atrophy-related sexual dysfunction. The objective of this study was to review the hormonal and nonhormonal therapies available for postmenopausal women with vulvovaginal atrophy-related sexual dysfunction, focusing on practical recommendations through a literature review of the most relevant publications in this field. METHODS: This study is a literature review. RESULTS: Available vaginal estrogen preparations are conjugated equine estrogens, estradiol vaginal cream, a sustained-release intravaginal estradiol ring, or a low-dose estradiol tablet. Vaginal estrogen preparations with the lowest systemic absorption rate may be preferred in women with history of breast cancer and severe vaginal atrophy. Vaginal lubricants and moisturizers applied on a regular basis have an efficacy comparable with that of local estrogen therapy and should be offered to women wishing to avoid the use of vaginal estrogens. CONCLUSIONS: Oral, transdermal, or vaginal estrogen preparations are the most effective treatment options for vulvovaginal atrophy-related sexual dysfunction. Selective estrogen receptor modulators such as lasofoxifene and ospemifene showed a positive impact on vaginal tissue in postmenopausal women. Vaginal dehydroepiandrostenedione, vaginal testosterone, and tissue selective estrogen complexes are also emerging as promising new therapies; however, further studies are warranted to confirm their efficacy and safety.

Expression and activation of the membrane-cytoskeleton protein ezrin during the normal endometrial cycle.

OBJECTIVE: To examine total ezrin expression (ezrin and phospho-ezrin) through the normal endometrial cycle and to correlate ezrin activation and localization with cytologic changes. DESIGN: Experimental laboratory study. SETTING: University medical centers. PATIENT(S): Reproductive-age women. INTERVENTION(S): A total of 36 samples of normal early, mid-, and late proliferative- and secretory-phase endometrium were studied for immunoreactive total ezrin (ir-T-ezrin) and phospho-ezrin (ir-p-ezrin) expression by histology, immunohistochemistry, and Western blotting. MAIN OUTCOME MEASURE(S): Total ezrin and phospho-ezrin expressions through the normal endometrial cycle. RESULT(S): Throughout the cycle ir-T-ezrin is present in the epithelium. The intensity and localization of both ir-ezrin and ir-p-ezrin vary greatly throughout the cycle. The main findings include the following: lateral localization of ir-ezrin/ir-p-ezrin in association with membrane specializations; dense staining around secretory vacuoles (secretory phase); dense staining of the apical surfaces, including microvilli and pinopodes of epithelial cells, especially during the mid- to late secretory phases; and the presence of ezrin in the glandular secretions. Immunoreactive total ezrin and ir-p-ezrin were not expressed by stromal fibroblasts. CONCLUSION(S): Ezrin is a prominent protein in the cycling endometrium. The most striking findings were the gravitation of ir-ezrin/ir-p-ezrin to the periphery of secretory vacuoles, localization on apical surfaces of the luminal epithelium, dense ezrin staining in secretory-phase epithelial cell plumes, and the presence of ir-ezrin/ir-p-ezrin in secretory-phase luminal secretions. These findings may have functional implications, especially for implantation biology.

Biochemistry, molecular biology and cell biology of gonadotropin-releasing hormone antagonists.

PURPOSE OF REVIEW: Gonadotropin-releasing hormone (GnRH) receptors are not only detected in the central nervous system but also in tissues such as ovary, endometrium, breast, gastrointestinal system, placenta and malignant tumors of ovary and breast. The direct role of GnRH-antagonists in ovarian function, implantation, cancer pathogenesis and treatment is under extensive investigation. This study reviews the biochemistry and molecular and cellular biology of GnRH-antagonists as well as GnRH types and their receptors. RECENT FINDINGS: The best clinical evidence with GnRH-antagonists has accumulated in controlled ovarian hyperstimulation protocols for prevention of premature luteinizing hormone surge (cetrorelix, ganirelix) and in the treatment of advanced-stage prostate cancer (abarelix and degarelix). GnRH-GnRH receptor pathways may have a role in the embryo implantation. The controversy still exists whether GnRH antagonist protocols result in slightly decreased clinical pregnancy rates compared with the GnRH agonist protocols. GnRH-antagonists could be used in the near future to treat some cancer types that express GnRH receptors. SUMMARY: GnRH-antagonists have various clinical applications in gynecology, reproductive medicine, urology and oncology. The emergence of well tolerated, orally active GnRH-antagonists may provide an alternative to long-term injections and is likely to have a major impact on the utility of GnRH analogues in the treatment of human diseases.

Estradiol regulates expression of polysialated neural cell adhesion molecule by human vascular endothelial cells.

RATIONALE: The mechanism of atherogenesis includes leukocyte adhesion to endothelial cells followed by migration into the subendothelial space. The polysialylated neural cell adhesion molecules (PSA-nCAMs) are a group of hydrophilic neural cell adhesion molecule (NCAM) isoforms that inhibit NCAM: NCAM association, thereby blocking cell: cell adhesion. During previous studies, we demonstrated that sialylation of specific NCAMs are upregulated at proestrus in the rat and that PSA-nCAM is expressed by the rat vascular endothelium. METHODS AND RESULTS: In this study, we sought the presence of PSA-nCAM in human vessels and regulation of its expression in estradiol-treated human umbilical vascular endothelial cells (HUVEC). Immunoreactive PSA-nCAM (ir-PSA-nCAM) was shown in blood and lymph vessels of adult rats and human brain, skin, liver, lung, cervix, endometrium, and ovary. Staining for ir-PSA-nCAM was present on the glycocalyceal surface of estradiol-treated HUVEC, but not in the presence of the estrogen receptor (ER)-blocker fulvestrant. Western blotting confirmed these findings. CONCLUSIONS: PSA-nCAM is widely present in the glycocalyx of human and rat vascular endothelium. It also is expressed by HUVEC, in which it is induced by estradiol. The estrogen-regulated presence of vascular PSA-nCAM could diminish NCAM-dependent interactions between vessels and circulating leukocytes, thereby impeding vascular inflammation and atherogenesis, and, contributing to estrogen-induced cardioprotection. This hypothesized action is presently under study.

Impact of developmental stage at cryopreservation and transfer on clinical outcome of frozen embryo cycles.

Although several early IVF successes were achieved after transferring fully formed blastocysts, the majority of embryos replaced worldwide over the past 30 years have been at the cleavage stage. The programme at this study centre has previously found that delaying an embryo transfer to day 5 can reduce the chance for a high-order multiple gestation without compromising the pregnancy rate because fewer embryos can be replaced. To evaluate the impact of transfer day and embryonic stage at cryopreservation on cycle outcome, 6069 fresh and 706 frozen transfers from 2000-2006 performed at this study centre were retrospectively analysed. Approximately half of the fresh transfers were performed on day 3, with a shift to day-5 transfer over the study period with no change in cryopreservation incidence. Implantation, clinical pregnancy and live birth rates were significantly higher following day-5 transfer. When frozen-thawed embryos (2-cell to day-6 blastocysts) were transferred, acceptable pregnancy and live birth rates were achieved at all stages but thawed embryos transferred as day-5 blastocysts generated consistently higher clinical pregnancy and live birth rates. Transfer of embryos frozen on day 6 had the highest miscarriage and lowest live birth rates. Barring government regulation, an IVF programme's day for cryopreservation generally depends on its management of and success with fresh embryo transfer.

What can we learn from design faults in the Women's Health Initiative randomized clinical trial?

Design faults resulted in the inability of the Women's Health Initiative (WHI) randomized clinical trial to test the level of cardioprotection conferred by timely hormone treatment of women seeking help for menopausal complaints. Adopting a design constructed around the avoidance of symptomatic subjects and recruitment of older subjects who were more likely to manifest cardiovascular events during the life of the WHI resulted in recruitment of older, sicker subjects than are normally treated for complaints around the time of menopause. The lack of cardioprotection in subjects that began treatment a decade or more after menopause diluted cardioprotection in subjects starting treatment close to the menopausal transition. As a result, despite having the largest number of subjects ever, there were not enough women in the WHI who were comparable to those in the observational trials that showed cardioprotection. This led the WHI to report that there was no cardioprotection in the trial, a position that has been qualified after further analysis. Misapprehension of the initial WHI conclusions by the media, professionals, and regulatory agencies led to a major shift away from menopausal hormone treatment. This remains problematic since the evidence continues to favor cardioprotection and other benefits that are denied under present regulations and guidelines. Regulatory agencies and professional organizations need to better understand the faws in the WHI design and results in order to properly consider its results and the sustainability of their earlier conclusions and recommendations. Additionally, new trials are needed to test the validity of menopausal hormone-related cardioprotection.

Estrogens regulate posttranslational modification of neural cell adhesion molecule during the estrogen-induced gonadotropin surge.

Estrogen-induced synaptic plasticity (EISP) in the periventricular area (PVA) of the hypothalamus is necessary for the preovulatory gonadotropin surge. Because in situ enzymatic desialization of hypothalamic polysialylated (PSA) neural cell adhesion molecule (NCAM) blocked EISP, we examined the presence and amount of NCAM isotopes, PSA-NCAM, and sialylation enzymes in microdissected mouse hypothalamus tissues from proestrous afternoon [peak of estrogens and nadir of arcuate nucleus (AN) synapses] and metestrous morning (nadir of estrogens and highest AN synapses). Immunohistochemistry confirmed immunoreactive (ir) PSA-NCAM staining in the perineural spaces of the PVA. The extent of staining was cycle dependent, with more dense and complete profiles of individual neurons limned by the ir-PSA-NCAM staining on proestrus and less on metestrus. Western blots showed that high levels of ir-PSA-NCAM on proestrus are accompanied by diminished ir-NCAM-140 and -180 but not ir-NCAM-120 and the reverse on metestrus (P < 0.05). To evaluate the increase of sialylated NCAM at the expense of desialylated protein, expression of the responsible polysialyltransferase enzymes polysialyltransferase (ST8Sia IV) and sialyltransferase (ST8Sia II) mRNA levels were measured using RT-PCR. Both polysialyltransferase and sialyltransferase mRNA are more abundant on proestrus than metestrus (P < 0.05), indicating that these enzymes are regulated by estrogens. These results support estrogen-regulated formation and extrusion of hydrophilic PSA-NCAM into perineural spaces in the PVA as part of the mechanism of EISP.

Peritoneal tuberculosis with elevated serum Ca-125 level mimicking advanced stage ovarian cancer: a case report.

BACKGROUND: Tuberculosis is still a common problem in immigrant population with peritoneal tuberculosis as the most common presentation of extrapulmonary disease. CASE: A 36-year-old woman presented with abdominal distention, night sweats and weight loss. Physical examination and radiologic studies revealed ascites, omental caking and bilateral enlarged ovaries with an elevated serum Ca-125 of 353 U/mL. Acid-fast stain and culture were negative for Mycobacterium tuberculosis. Diagnostic laparoscopy and biopsy revealed multiple granulomas with epithelioid cells and caseification necrosis confirming tuberculosis. Treatment with anti-tuberculin drugs resulted in resolution of symptoms with a reduction in Ca-125 to normal. CONCLUSION: Laparoscopic biopsy with frozen section evaluation would spare patients with peritoneal tuberculosis from unnecessary extensive surgery. Serum Ca-125 level may be useful in monitoring treatment response.

Tenascin is highly expressed in endometriosis and its expression is upregulated by estrogen.

OBJECTIVE: To investigate the localization of tenascin expression in the endometrium of women without endometriosis and in endometriotic implants, and to determine the in vitro regulation of tenascin by E(2) in these tissues. DESIGN: Experimental laboratory study. SETTING: University medical center. PATIENT(S): Reproductive age women with or without endometriosis. INTERVENTION(S): Proliferative (n = 14), and secretory (n = 14) endometrium from women without endometriosis and endometriosis implants (n = 14) were used for immunohistochemical analysis. Endometrial and endometriotic stromal cells were grown in culture and treated with E(2), the estrogen receptor antagonist ICI 182 780 (ICI) alone, E(2) in combination with ICI, or vehicle (control) for 24 hours, and tenascin expression was analyzed by Western blotting. MAIN OUTCOME MEASURE(S): Expression levels of tenascin in normal endometrium and endometriotic implants and its regulation by E(2). RESULT(S): Tenascin immunostaining revealed an increasing intensity in the stromal cells, starting from normal secretory endometrium, then normal proliferative endometrium, and reaching the highest expression in endometriotic implants. Estradiol induced a significant increase in tenascin protein levels in the endometriotic stromal cells in culture. CONCLUSION(S): The modulation of tenascin as an extracellular matrix protein by E(2) in endometriotic stromal cells may be one of the factors playing a role in the development of endometriosis.