Functional Anatomy: Gynecology

Clinical Proteomics: A Novel Diagnostic Tool for the New Biology of Preterm Labor, Part I: Proteomics Tools.
Buhimschi CS, Weiner CP, Buhimschi IA
Obstet Gynecol Surv. 2006 Jul;61(7):481-486.

The molecular mechanisms regulating myometrial contractility and preterm premature rupture of the membranes leading to preterm birth are poorly understood. The completion of the human genome sequence led to the development of functional genomics and gene array technology to simultaneously identify candidate genes potentially involved in regulation of human parturition. However, the study of living systems can now be expanded past genomics based on the rationale that it is the protein products of the genes, not simply gene expression, that have effects and cause disturbances at the cellular level. Therefore, identification of disease biomarkers, followed by a description of their functional networks, has the potential to significantly aid the development of new strategies for the prediction, diagnosis, and prevention of preterm birth. Interest in mass spectrometry and its use as a new clinical diagnostic tool has grown rapidly and is poised to become an important medical field for the next century. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to state the general concept of proteomics, summarize the use of proteomics as a potential clinical tool as a biomarker of disease, and recall that proteomics can be a means for understanding mechanisms of disease states.

Gabapentin, Estrogen, and Placebo for Treating Hot Flushes: A Randomized Controlled Trial.
Reddy SY, Warner H, Guttuso T Jr, Messing S, Digrazio W, Thornburg L, Guzick DS
Obstet Gynecol. 2006 Jul;108(1):41-48.

OBJECTIVE: To compare the efficacy of gabapentin, estrogen, and placebo in the treatment of hot flushes. METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 postmenopausal women to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe hot flushes. Participants were randomly assigned to receive either 0.625 mg/d of conjugated estrogens (n = 20), placebo (n = 20), or gabapentin titrated to 2,400 mg/d (n = 20) for 12 weeks. Participants recorded frequency and severity of baseline hot flushes on a hot flush diary for 2 weeks before randomization and for 12 weeks after randomization. The primary outcome measure was the weekly hot flush composite score, which takes into account both severity and frequency of hot flushes. Secondary outcome measures were differences in pre- and posttreatment scores pertaining to depression (Zung Depression Scale) and other climacteric symptoms (Greene Climacteric Scale). RESULTS: Intention-to-treat analysis showed that the reduction in the hot flush composite score for both estrogen (72%, P = .016) and gabapentin (71%, P = .004) was greater than the reduction associated with placebo (54%) at the conclusion of the 12th week. The extent of reduction in hot flush composite score, however, was not significantly different between estrogen and gabapentin (P = .63). No differences were seen between groups in the Zung Depression Scale, or in any of the Greene Climacteric subscales except for the Somatic Symptom cluster, which was significantly greater in the gabapentin arm than in the placebo arm. Despite a lack of group differences in adverse events, the Headache, Dizziness, and Disorientation cluster appeared with greater frequency in the gabapentin group. Estimation of the number needed to harm in this cluster suggests that these symptoms may occur with every fourth patient treated with gabapentin. CONCLUSION: Despite the small scale of this study, gabapentin appears to be as effective as estrogen in the treatment of postmenopausal hot flushes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT 00276081. LEVEL OF EVIDENCE: I.

Changes in u.s. Prescribing patterns of menopausal hormone therapy, 2001-2003.
Hing E, Brett KM
Obstet Gynecol. 2006 Jul;108(1):33-40.

OBJECTIVE: In 2002, the combination estrogen-progestin hormone therapy (HT) treatment arm of the Women's Health Initiative was terminated early because cardiovascular and cancer risks were identified, while the estrogen-only therapy (ET) arm of this trial continued. We investigated hormone therapy prescription practice changes between 2001 and 2003 to explore the effects of the clinical trial results. METHODS: Data were obtained from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey for the years 2001 through 2003. These nationally representative surveys sample medical encounters in nonfederally employed physician's offices and outpatient departments of nonfederal short-stay and general hospitals. The proportion and rate of visits with ET and HT prescriptions were calculated. Logistic regression was used to estimate change over time accounting for patient and provider characteristics. RESULTS: Between 2001 and 2003, the number of visits with menopausal hormone prescriptions fell from 26.5 million to 16.9 million. Almost three-quarters of hormone visits were for ET prescriptions. The decrease in the rate of visits was slightly larger for HT prescription visits (44%) than ET prescription visits (35%). The rate of decline was highest among women 50 years of age and over. After controlling for covariates, there was no significant difference in the decline by hormone type. CONCLUSION: These nationally representative data indicate substantial declines in menopausal hormone prescriptions coinciding with clinical trial results on HT. These declines occurred among all types of therapy and patient characteristics. LEVEL OF EVIDENCE: II-3.

May

Relationship of the uterosacral ligament to the sacral plexus and to the pudendal nerve.
Siddique SA, Gutman RE, Schon Ybarra MA, Rojas F, Handa VL
Int Urogynecol J Pelvic Floor Dysfunct. 2006 May 30;.

We describe the anatomy of the uterosacral ligament with respect to the sacral plexus. In six adult female embalmed cadavers, we identified the uterosacral ligament and its lateral nerve relations. Using the ischial spine as the starting point and measuring along the axis of the uterosacral ligament, we noted that the S1 trunk of the sacral plexus passes under the ligament 3.9 cm [95% confidence interval (CI), 2.1-5.8 cm] superior to the ischial spine. The S2 trunk passes under the ligament at 2.6 cm (95% CI; 1.5, 3.6 cm), the S3 trunk passes under the ligament at 1.5 cm (95% CI; 0.7, 2.4 cm), and the S4 trunk passes under the ligament at 0.9 cm (95% CI; 0.3, 1.5 cm) superior to the ischial spine. The pudendal nerve forms lateral to the uterosacral ligament. Our data demonstrate that the S1-S4 trunks of the sacral plexus, not the pudendal nerve, are vulnerable to injury during uterosacral ligament suspension.

Lactobacilli in the female genital tract in relation to other genital microbes and vaginal pH.
Ronnqvist PD, Forsgren-Brusk UB, Grahn-Hakansson EE
Acta Obstet Gynecol Scand. 2006;85(6):726-35.

Background. The relationship between lactobacilli and other microbes and the association with vaginal pH in the female genital tract were examined. The study also included evaluation of the possibility of supplying probiotics to the genital tract by using panty liners impregnated with the probiotic strain Lactobacillus plantarum LB931. Methods. This was a randomized, placebo-controlled, double-blind, multicenter study involving 191 healthy fertile women. Specified microbes were counted and vaginal pH was measured once a month for five consecutive months. Results. Major individual variations in the genital microflora composition and the vaginal pH were found among the women. The number of lactobacilli was significantly related to vaginal pH (p<0.001) and approximately 70% of the women were permanent carriers of individual lactobacilli strains. Women with high numbers of lactobacilli were less prevalent with Group B streptococci than women with low numbers (p=0.036), and these women had a lower mean vaginal pH. The number of lactobacilli also correlated with the prevalence of yeast. LB931 could be found in 86% of the labial samples and 54% of the vaginal samples. Conclusions. High numbers of lactobacilli may contribute to a low vaginal pH and seem to have a negative influence on Group B streptococci. LB931 could be transferred from the panty liners to both the vagina and the labial fold.

April

Unopposed estrogen therapy and the risk of invasive breast cancer.
Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, Colditz GA
Arch Intern Med. 2006 May 8;166(9):1027-32.

BACKGROUND: Although short-term unopposed estrogen use does not seem to increase breast cancer risk, the effect of longer-term estrogen use remains unclear. We sought to assess the relationship between longer-term use of unopposed estrogen and the risk of invasive breast cancer over an extended follow-up period. METHODS: Within the Nurses' Health Study, a prospective cohort study, we observed 11 508 postmenopausal women who had a hysterectomy and reported information on estrogen use at baseline (1980). The study population was expanded every 2 years to include women who subsequently became postmenopausal and had a hysterectomy, so that 28 835 women were included in the final follow-up period (2000-2002). Estrogen use was assessed from self-reported data on biennial questionnaires. The main outcome was invasive breast cancer. RESULTS: A total of 934 invasive breast cancers were included in the analysis. Breast cancer risk increased with duration of unopposed estrogen use among longer-term users with the highest risk seen in cancers positive for estrogen receptor (ER+) and progesterone receptor (PR+). The multivariate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer with current use of unopposed estrogen for less than 5 years, 5 to 9.9 years, 10 to 14.9 years, 15 to 19.9 years, and 20 years or longer were, respectively, 0.96 (95% CI, 0.75-1.22), 0.90 (95% CI, 0.73-1.12), 1.06 (95% CI, 0.87-1.30), 1.18 (95% CI, 0.95-1.48), and 1.42 (95% CI, 1.13-1.77) (P for trend <.001). The risk of ER+/PR+ breast cancers was noted to be statistically significant after 15 years of current use (RR, 1.48; 95% CI, 1.05-2.07). CONCLUSION: Users of unopposed estrogen were at increased risk of breast cancer but only after longer-term use.

Alternatives to estrogen for treatment of hot flashes: are they effective and safe?
Tice JA, Grady D
JAMA. 2006 May 3;295(17):2076-8.

Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis.
Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L
JAMA. 2006 May 3;295(17):2057-71.

CONTEXT: Concern regarding the adverse effects of estrogen and other hormones for treating menopausal symptoms has led to demand for other options; however, the efficacy and adverse effects of nonhormonal therapies are unclear. OBJECTIVE: To assess the efficacy and adverse effects of nonhormonal therapies for menopausal hot flashes by reviewing published randomized controlled trials. DATA SOURCES: MEDLINE (1966-October 2005), PsycINFO (1974-October 2005), and the Cochrane Controlled Clinical Trials Register Database (1966-October 2005) were searched for relevant trials that provided data on treatment of menopausal hot flashes using 1 or more nonhormonal therapies. STUDY SELECTION: All English-language, published, randomized, double-blind, placebo-controlled trials of oral nonhormonal therapies for treating hot flashes in menopausal women measuring and reporting hot flash frequency or severity outcomes. DATA EXTRACTION: Trials were identified, subjected to inclusion and exclusion criteria, and reviewed. Data on participants, interventions, and outcomes were extracted and trials were rated for quality based on established criteria. A meta-analysis was conducted for therapies with sufficient trials reporting hot flash frequency outcomes. DATA SYNTHESIS: From 4249 abstracts, 43 trials met inclusion criteria, including 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescribed medications, and 17 trials of isoflavone extracts. The number of daily hot flashes decreased compared with placebo in meta-analyses of 7 comparisons of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (mean difference, -1.13; 95% confidence interval [CI], -1.70 to -0.57), 4 trials of clonidine (-0.95; 95% CI, -1.44 to -0.47), and 2 trials of gabapentin (-2.05; 95% CI, -2.80 to -1.30). Frequency was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Evidence of the efficacy of other therapies is limited due to the small number of trials and their deficiencies. Trials do not compare different therapies head-to-head and relative efficacy cannot be determined. CONCLUSION: The SSRIs or SNRIs, clonidine, and gabapentin trials provide evidence for efficacy; however, effects are less than for estrogen, few trials have been published and most have methodological deficiencies, generalizability is limited, and adverse effects and cost may restrict use for many women. These therapies may be most useful for highly symptomatic women who cannot take estrogen but are not optimal choices for most women.

Right ovarian vein drainage variant: Is there a relationship with pelvic varices?
Koc Z, Ulusan S, Oguzkurt L
Eur J Radiol. 2006 Apr 24;.

OBJECTIVE: To correlate right ovarian vein (ROV) variations that drain into the right renal vein (RRV) with the presence of pelvic varices. MATERIALS AND METHODS: Routine abdominal multidetector-row computed tomography scans of 324 women were analyzed for the presence and type of ROV variations in this retrospective study. The subjects were divided into 2 groups: those with ROV variations and those without such variations. The diameters of the subjects' ROV, left ovarian vein (LOV), and parauterine veins were measured. Pelvic varices and the presence and degree of ovarian vein reflux were noted and compared between the 2 groups. The chi(2)-test and the Pearson correlation test were used for statistical analysis. RESULTS: Thirty-two (9.9%) of 324 women studied exhibited ROV variant that drained into the right renal vein, and the remaining subjects (90.1%) exhibited a normal pattern of ROV drainage that flowed directly into the inferior vena cava. Pelvic varices were identified in 59 (18%) of the subjects. Reflux was not observed in any patient without pelvic varices. Fifty-seven of 59 women exhibited ovarian vein reflux. In 56 of those 57 individuals, reflux occurred only in the LOV, and in 1 subject, reflux was noted predominantly in the ROV. No significant relationship between the presence of an ROV that drained into the right renal vein and pelvic varices was noted. CONCLUSION: Although right-sided pelvic varices associated with right ovarian vein drainage variations are rare, anatomic variations of the right ovarian vein are not. This study did not find an association between the presence of right ovarian vein and pelvic varices.

Appearance of the levator ani muscle subdivisions in magnetic resonance images.
Margulies RU, Hsu Y, Kearney R, Stein T, Umek WH, Delancey JO
Obstet Gynecol. 2006 May;107(5):1064-9.

OBJECTIVE: Identify and describe the separate appearance of 5 levator ani muscle subdivisions seen in axial, coronal, and sagittal magnetic resonance imaging (MRI) scan planes. METHODS: Magnetic resonance scans of 80 nulliparous women with normal pelvic support were evaluated. Characteristic features of each Terminologia Anatomica-listed levator ani component were determined for each scan plane. Muscle component visibility was based on pre-established criteria in axial, coronal, and sagittal scan planes: 1) clear and consistently visible separation or 2) different origin or insertion. Visibility of each of the levator ani subdivisions in each scan plane was assessed in 25 nulliparous women. RESULTS: In the axial plane, the puborectal muscle can be seen lateral to the pubovisceral muscle and decussating dorsal to the rectum. The course of the puboperineal muscle near the perineal body is visualized in the axial plane. The coronal view is perpendicular to the fiber direction of the puborectal and pubovisceral muscles and shows them as "clusters" of muscle on either side of the vagina. The sagittal plane consistently demonstrates the puborectal muscle passing dorsal to the rectum to form a sling that can consistently be seen as a "bump." This plane is also parallel to the pubovisceral muscle fiber direction and shows the puboperineal muscle. CONCLUSION: The subdivisions of the levator ani muscle are visible in MRI scans, each with distinct morphology and characteristic features. LEVEL OF EVIDENCE: III.

March

Estrogen induces lung metastasis through a host compartment-specific response.
Banka CL, Lund CV, Nguyen MT, Pakchoian AJ, Mueller BM, Eliceiri BP
Cancer Res. 2006 Apr 1;66(7):3667-72.

Direct proliferative effects of estrogen (E(2)) on estrogen receptor-positive tumors are well documented; however, the potential for E(2) to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E(2) to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E(2) action in tumor growth and metastasis by analysis of E(2)-nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E(2)-containing slow-release pellets (OVX + E(2)). We show that the D121 lung carcinoma cell line is E(2)-nonresponsive, and following s.c. implantation in OVX versus OVX + E(2) mice, E(2) action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E(2)-nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E(2) mice. These results suggest that the E(2) status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E(2) in the tumor versus host compartments.

Changes in the extracellular matrix in the anterior vagina of women with or without prolapse.
Lin SY, Tee YT, Ng SC, Chang H, Lin P, Chen GD
Int Urogynecol J Pelvic Floor Dysfunct. 2006 Mar 18;.

To investigate the changes in the connective tissues located in the upper portion of the anterior vaginal wall, which are associated with anterior vaginal wall prolapse, 23 women with anterior vaginal wall prolapse were included in the study group and 15 women with normal genital support served as control group. The anterior vaginal wall tissue samples were obtained for immunohistochemical staining of collagen (type I, III, IV, V, VI), elastin, and glycoproteins from the extracellular matrix (fibronectin, vitronectin, laminin). The number of capillaries per arteriole and mitochondria numbers per smooth muscle cell were evaluated for demonstrating whether the anatomical prolapse affect on blood supply to these tissues. Collagen III was significantly less in the anterior vaginal wall of patients with anterior vaginal wall prolapse. Quantitative immunoreactivity of collagen I and III had significant positive correlations with ageing.

February

Baseline dimensions of the human vagina.
Barnhart KT, Izquierdo A, Pretorius ES, Shera DM, Shabbout M, Shaunik A
Hum Reprod. 2006 Feb 14;.

BACKGROUND: Vaginal anatomy has been poorly studied. This study aimed to measure baseline dimensions of the undistended vagina of women of reproductive age. METHODS: We combined baseline information collected from five clinical trials using magnetic resonance imaging (MRI) to quantify distribution of a vaginal gel. Seventy-seven MRI scans were performed on 28 women before gel application to establish baseline vaginal measurements. Average dimensions were calculated for each woman and for the population. The influence of potential covariates (age, height, weight and parity) on these dimensions was assessed. RESULTS: MRI measurements are reproducible. The SD surrounding the mean at each anatomical site, and with summary measurements, was significantly smaller with each subject compared with the population. Mean vaginal length from cervix to introitus was 62.7 mm. Vaginal width was largest in the proximal vagina (32.5 mm), decreased as it passed through the pelvic diaphragm (27.8 mm) and smallest at the introitus (26.2 mm). Significant positive associations were parity with vaginal fornix length, age with pelvic flexure width and the height with width at the pelvic flexure. CONCLUSION: No one description characterized the shape of the human vagina. Although there is variation among women, variables such as parity, age and height are positively associated with differences in baseline dimensions.

Experimental contributions to the study of the embryology of the vagina.
Sanchez-Ferrer ML, Acien MI, Del Campo FS, Mayol-Belda MJ, Acien P
Hum Reprod. 2006 Feb 13;.

BACKGROUND: Acien's hypothesis, deduced from patients with malformations of the female genital tract, especially those with renal agenesis and ipsilateral blind hemivagina, affirms the embryology of the human vagina as deriving from the Wolffian ducts and the Mullerian tubercle and could explain the embryological origin of all the female genital malformations reported. In this study, we investigated the hypothesis in rats. METHODS: Twenty-five pregnant rats were used to analyse female embryos (64) from day 15 (stage indifferent) to day 20 postcoitum (vagina completely formed). We performed transverse and longitudinal sections of embryos, haematoxylin-eosin tinction and immunohistochemical staining using markers specific to Wolffian derivatives. We also analysed the presence of these markers in the vagina of four adult rats. RESULTS: The Muller ducts converge until they fuse into one tube, but caudally they diverge and finally they fuse with the 'urogenital sinus bulbs' that are actually the distal portion of the Wolffian ducts according to the immunohisto-chemical marking with GZ1 and GZ2. The Mullerian tubercle is observed between those elements. Then, the immunohistochemical staining can be seen all along the completely formed vagina, which is also observed in the vagina of the adult rat. CONCLUSION: We prove the participation of Muller tubercle and Wolffian ducts in the formation of the vagina in rats, so we confirm experimentally Acien's hypothesis about the human vagina embryology.

January

Re: Clitoral anatomy in nulliparous, healthy, premenopausal volunteers using unenhanced magnetic resonance imaging.
Puppo V
J Urol. 2006 Feb;175(2):790-1.

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