Eleni A. Greenwood

Older Age Is Associated With Similar Improvements in Semen Parameters and Testosterone After Subinguinal Microsurgical Varicocelectomy

PURPOSE It is generally accepted that men with clinically palpable varicocele are at high risk for a progressive decrease in fertility and testosterone levels with time. Varicocelectomy is thought to improve testicular function or at least halt the accelerated decrease in testicular function associated with varicocele. Substantial controversy exists as to whether varicocelectomy is effective in older men, possibly due to irreversible testicular damage or limited potential for recovery from varicocele induced damage. MATERIALS AND METHODS We retrospectively reviewed the records of men who underwent microsurgical subinguinal varicocelectomy, as done by a single surgeon. Demographics, patient questionnaires, operative notes, charts, testosterone and semen analysis were reviewed. Patients were divided into 3 groups based on age at surgery, including less than 30, 30 to 39 and 40 years or greater. RESULTS A total of 272 men met study inclusion criteria. In all 3 age groups we noted similar testosterone and baseline semen analysis parameters. There were significant increases in sperm concentration and total sperm count in all age groups. When analysis was restricted to men with baseline testosterone 400 ng/dl or less, there was a mean 110, 133 and 136 ng/dl increase in 21 men who were 40 years old or older, in 30 who were 30 to 39 years old and in 21 who were younger than 30 years, respectively. CONCLUSIONS Microsurgical varicocelectomy resulted in significant increases in sperm concentration, total sperm count and testosterone in all age groups studied, including men in the fifth and sixth decades of life. Microsurgical varicocelectomy should be offered to older men for infertility and/or hypogonadism.

Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers

Prostate‐specific membrane antigen (PSMA) has been found to be expressed in the tumor‐associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor‐associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0‐IV breast cancer were identified. Ninety‐two of these patients had primary breast cancer [invasive breast carcinoma with or without co‐existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor‐associated vascular endothelial cell PSMA immunoreactivity was semi‐quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor‐associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5–50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor‐associated vasculature was PSMA‐positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue‐associated vasculature. The 10‐year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10‐year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores of 0 and 1 were compared with 2, there was a statistically significant difference in OS (96.0% vs 79.7%, respectively, p = 0.05). Patients with a PSMA score of 2 had a significantly higher median tumor size compared with patients in the lower PSMA score groups (p = 0.04). Patients with higher nuclear grade were more likely to have a PSMA score of 2 compared with patients with lower nuclear grade (p < 0.0001). Patients with a PSMA score of 2 had a significantly higher median Ki‐67 proliferation index compared with patients in the lower PSMA score groups (p < 0.0001). Patients with estrogen receptor (ER)‐negative tumors were more likely to have a PSMA score of 2 compared with patients with ER‐positive tumors (p < 0.0001). Patients with progesterone receptor (PR)‐negative tumors were more likely to have a PSMA score of 2 compared with patients with PR‐positive tumors (p = 0.03). No significant association was observed between PSMA score group status and lymph node involvement (p = 0.95). Too little variability was present in Human epidermal growth factor receptor‐2 (Her2/neu) amplified tumors to correlate with PSMA score group status. To date, this is the first detailed assessment of PSMA expression in the tumor‐associated vasculature of primary and metastatic breast carcinomas. Further studies are needed to evaluate whether PSMA has diagnostic and/or potential therapeutic value.

Putative role for insulin resistance in depression risk in polycystic ovary syndrome

OBJECTIVE To evaluate whether insulin resistance is associated with depression risk in women with polycystic ovary syndrome (PCOS), independent of other factors, including body mass index (BMI). DESIGN Cross-sectional. SETTING Tertiary university center. PATIENT(S) A total of 301 women, aged 14-52 years, with PCOS by Rotterdam criteria, consecutively examined between 2006 and 2013. INTERVENTION(S) Complete history and physical examinations, including endovaginal ultrasounds, dermatologic assessments, completion of Beck Depression Inventory Fast Screen (BDI-FS), and serum testing. MAIN OUTCOME MEASURE(S) Scores >4 on BDI-FS indicated a positive screen for depression. Scores were further subdivided into mild (5-8), moderate (9-12), and severe (>12) depression risk. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). RESULT(S) A total of 131 women (44%) were at risk for depression, determined by positive BDI-FS screening. These patients had higher BMI (32.3 vs. 28.5), and elevated insulin resistance, assessed by HOMA-IR (5.2 vs. 2.6), compared with patients with negative depression screening. In a stratified analysis by BMI category, obese women with positive depression screens had elevated HOMA-IR, compared with obese women with normal BDI-FS scores (7.4 vs. 4.1). In a multivariate logistic regression analysis, HOMA-IR was independently related to the odds of depression risk after controlling for age, ethnicity, BMI, and exercise (odds ratio: 1.07). CONCLUSION(S) Depression is common in PCOS. After controlling for confounders in multivariate regression analyses, we found HOMA-IR to be significantly associated with depression risk. Our data suggest a complex interplay among insulin resistance, obesity, and depression in PCOS, warranting additional investigation. Mental health assessment is indicated in comprehensive care of patients with PCOS.

Nomograms to Predict Patency After Microsurgical Vasectomy Reversal

PURPOSE After undergoing vasectomy up to 6% of men will elect to undergo vasectomy reversal. For these men paternity can be achieved with vasectomy reversal or surgical sperm retrieval coupled with assisted reproduction. Nevertheless, it remains difficult for surgeons to accurately counsel men on the chance of patency after vasectomy reversal. MATERIALS AND METHODS A retrospective review was conducted of 548 patients who underwent microsurgical vasectomy reversal. Surgery was considered successful if sperm concentration was 100,000 or more sperm per ml, total count was 100,000 or more sperm per ejaculate, motile sperm were present and there was no evidence of subsequent failure. A multivariate logistic regression model was constructed to calculate the probability of having a successful vasectomy reversal and nomograms for patency were generated from this model. RESULTS A total of 548 patients met the inclusion criteria for this study. Mean followup was 1.8 ± 0.10 years. Mean patient age was 43.4 ± 0.3 years and mean duration of obstruction was 10.4 ± 0.2 years. Two nomograms to predict patency were generated, one for preoperative counseling and a second for postoperative counseling. The factors with the largest effect on patency were average testicular volume and obstruction duration. The factor with the least effect was the presence of sperm granuloma. The concordance index for the preoperative and the postoperative nomograms was 0.64 and 0.66, respectively. CONCLUSIONS To our knowledge this represents the first use of nomograms to predict the likelihood of patency after microsurgical vasectomy reversal. These nomograms may prove useful to guide further treatment decisions.

Transforming growth factor β-1 (TGF-β1) is a serum biomarker of radiation induced fibrosis in patients treated with intracavitary accelerated partial breast irradiation: preliminary results of a prospective study.

PURPOSE To examine a relationship between serum transforming growth factor β -1 (TGF-β1) values and radiation-induced fibrosis (RIF). METHODS AND MATERIALS We conducted a prospective analysis of the development of RIF in 39 women with American Joint Committee on Cancer stage 0-I breast cancer treated with lumpectomy and accelerated partial breast irradiation via intracavitary brachytherapy (IBAPBI). An enzyme-linked immunoassay (Quantikine, R&D, Minneapolis, MN) was used to measure serum TGF-β1 before surgery, before IBAPBI, and during IBAPBI. Blood samples for TGF-β1 were also collected from 15 healthy, nontreated women (controls). The previously validated tissue compliance meter (TCM) was used to objectively assess RIF. RESULTS The median time to follow-up for 39 patients was 44 months (range, 5-59 months). RIF was graded by the TCM scale as 0, 1, 2, and 3 in 5 of 20 patients (25%), 6 of 20 patients (30%), 5 of 20 patients (25%), and 4 of 20 patients (20%), respectively. The mean serum TGF-β1 values were significantly higher in patients before surgery than in disease-free controls, as follows: all cancer patients (30,201 ± 5889 pg/mL, P=.02); patients with any type of RIF (32,273 ± 5016 pg/mL, P<.0001); and women with moderate to severe RIF (34,462 ± 4713 pg/mL, P<0.0001). Patients with moderate to severe RIF had significantly elevated TGF-β1 levels when compared with those with none to mild RIF before surgery (P=.0014) during IBAPBI (P≤0001), and the elevation persisted at 6 months (P≤.001), 12 months (P≤.001), 18 months (P≤.001), and 24 months (P=.12). A receiver operating characteristic (ROC) curve of TGF-β1 values predicting moderate to severe RIF was generated with an area under the curve (AUC)ROC of 0.867 (95% confidence interval 0.700-1.000). The TGF-β1 threshold cutoff was determined to be 31,000 pg/mL, with associated sensitivity and specificity of 77.8% and 90.0%, respectively. CONCLUSIONS TGF-β1 levels correlate with the development of moderate to severe RIF. The pre-IBAPBI mean TGF-β1 levels can serve as an early biomarker for the development of moderate to severe RIF after IBAPBI.

Tissue Compliance Meter is a More Reproducible Method of Measuring Radiation-Induced Fibrosis than Late Effects of Normal Tissue–Subjective Objective Management Analytical in Patients Treated with Intracavitary Brachytherapy Accelerated Partial Breast Irradiation: Results of a Prospective Trial

Identification of radiation‐induced fibrosis (RIF) remains a challenge with Late Effects of Normal Tissue–Subjective Objective Management Analytical (LENT‐SOMA). Tissue compliance meter (TCM), a non‐invasive applicator, may render a more reproducible tool for measuring RIF. In this study, we prospectively quantify RIF after intracavitary brachytherapy (IB) accelerated partial breast irradiation (APBI) with TCM and compare it with LENT‐SOMA. Thirty‐nine women with American Joint Committee on Cancer Stages 0‐I breast cancer, treated with lumpectomy and intracavitary brachytherapy delivered by accelerated partial breast irradiation (IBAPBI), were evaluated by two raters in a prospective manner pre‐IBAPBI and every 6 months post‐IBAPBI for development of RIF, using TCM and LENT‐SOMA. TCM classification scale grades RIF as 0 = none, 1 = mild, 2 = moderate, and 3 = severe, corresponding to a change in TCM (ΔTCM) between the IBAPBI and nonirradiated breasts of ≤2.9, 3.0–5.9, 6.0–8.9, ≥9.0 mm, respectively. LENT‐SOMA scale employs clinical palpation to grade RIF as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Correlation coefficients—Intraclass (ICC), Pearson (r), and Cohens kappa (κ)—were employed to assess reliability of TCM and LENT‐SOMA. Multivariate and univariate linear models explored the relationship between RIF and anatomical parameters [bra cup size], antihormonal therapy, and dosimetric factors [balloon diameter, skin‐to‐balloon distance (SBD), V150, and V200]. Median time to follow‐up from completion of IBAPBI is 3.6 years (range, 0.8–4.9 years). Median age is 69 years (range, 47–82 years). Median breast cup size is 39D (range, 34B–44DDD). Median balloon size is 41.2 cc (range, 37.6–50.0 cc), and median SBD is 1.4 cm (range, 0.2–5.5 cm). At pre‐IBAPBI, TCM measurements demonstrate high interobserver agreement between two raters in all four quadrants of both breasts ICC ≥ 0.997 (95% CI 0.994–1.000). After 36 months, RIF is graded by TCM scale as 0, 1, 2, and 3 in 10/39 (26%), 17/39 (43%), 9/39 (23%), and 3/39 (8%) of patients, respectively. ΔTCM ≥6 mm (moderate‐severe RIF) is statistically different from ΔTCM ≤3 mm (none‐mild RIF) (p < 0.05). At 36 months post‐IBAPBI, TCM measurements for two raters render ICC = 0.992 (95% CI 0.987–0.995) and r = 0.983 (p < 0.0001), whereas LENT‐SOMA demonstrates κ = 0.45 (95% CI 0.18–0.80). SBD and V150 are the only factors closest to 0.05 significance of contributing to RIF. This prospective study indicates that TCM is a more reproducible method than LENT‐SOMA in measuring RIF in patients treated with IBAPBI. This tool renders a promising future application in assessing RIF.

Antimüllerian hormone levels and antral follicle counts are not reduced compared with community controls in patients with rigorously defined unexplained infertility

OBJECTIVE To test the hypothesis that women with unexplained infertility demonstrate evidence of diminished ovarian reserve when compared with a population of community controls. DESIGN Cross-sectional study. SETTING Multicenter university-based clinical practices. PATIENT(S) Study participants included 277 healthy, normo-ovulatory female partners with rigorously defined unexplained infertility randomly selected from a multicenter trial (Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation). Controls included 226 healthy, normo-ovulatory women not seeking treatment for fertility from a community-based cohort (Ovarian Aging study). INTERVENTION(S) Serum antimüllerian hormone (AMH) assay at a central laboratory, FSH, fasting serum metabolic testing, transvaginal ultrasonography for antral follicle counts (AFCs), anthropometric measurements. MAIN OUTCOME MEASURE(S) Average AMH, AFC, and AMH/AFC were compared between infertile and control women by age. Analyses of covariance compared these outcomes while controlling for confounders, including age, race, body mass index, smoking history, and study site. RESULT(S) In our models, AMH, AFC, and AMH/AFC ovarian reserve indices did not differ between infertile women and community-based controls, after controlling for age, race, body mass index, smoking history, and study site. CONCLUSION(S) Currently utilized predictors of ovarian reserve do not discriminate women with rigorously defined unexplained infertility from healthy community-based women of similar demographic characteristics. Contrary to our hypothesis, among women with FSH in the normal range (≤12 IU/L), women with unexplained infertility did not show evidence of decreased ovarian reserve as measured by AMH and AFC. Ovarian reserve markers in isolation may not serve as predictors of future fertility.

Assessment of pain as a sequela in patients treated with intracavitary brachytherapy accelerated partial breast irradiation (IBAPBI): preliminary results of a prospective study.

To assess pain rates and relationship to radiation‐induced fibrosis (RIF) in patients treated with intracavitary brachytherapy accelerated partial breast irradiation (IBAPBI). Thirty‐nine patients treated with IBAPBI were assessed prospectively for development of pain pretreatment, 1 month post‐IBAPBI, and every 6 months thereafter. A qualitative subjective Late Effects of Normal Tissue–Subjective Objective Management Analytical (LENT‐SOMA) questionnaire assessed pain. Use of pain medications was assessed as “no”, “sometimes”, or “regularly”. A quantitative objective validated pressure threshold (PTH) measured pain in the site of IBAPBI breast (index) and its mirror‐image in the nonirradiated breast (control). A validated tissue compliance meter (TCM) quantitatively assessed RIF in the index and control breasts at all time points. Mean ΔPTH(kg) and ΔTCM(mm) values reflected mean difference between the index and control breasts. Median follow‐up is 44 months (range 5–59 months). According to LENT‐SOMA, pain occurred in 89% at 1 and 24 months, 67% at 30 months, 30% at 36 months, 29% at 40 months, and 20% at 48 months. No patient used pain medication “regularly” but the use “sometimes” decreased over time: 61% at 1 month, 42% at 18 and 24 months, 13% at 36 months, and 10% at 40 months. Mean ΔPTH values, compared to Δ0 kg at baseline, peaked in absolute value by 1 month to −1.36 kg (p < 0.0001), persisted after 18 months at −0.99 kg (p < 0.0001) and 24 months at −0.73 kg (p < 0.0001), and returned to nearly baseline by 40 months at −0.11 kg (p < 0.57). Mean ΔPTH and ΔTCM correlated significantly with subjective patient reports of pain at each time point (p < 0.0001). To date, this is the first report to prospectively assess pain employing quantitative and qualitative inventories in patients treated with IBAPBI. Pain is experienced in the majority of patients experienced pain within the first 2 years, sometimes requiring a medication, and though subsides, it may persist 4 years after IBAPBI.

Association among depression, symptom experience, and quality of life in polycystic ovary syndrome

BACKGROUND: Clinical stigmata of polycystic ovary syndrome include hirsutism, obesity, menstrual disturbances, and infertility. These symptoms impair health‐related quality of life. Depression is also common. The relationship among depression, symptom self‐perception, and quality of life in polycystic ovary syndrome is poorly understood. OBJECTIVE: We sought to investigate the relationship between health‐related quality of life and depression in women with polycystic ovary syndrome. STUDY DESIGN: We conducted a secondary analysis of a multicenter, randomized clinical trial (Pregnancy in Polycystic Ovary Syndrome II, NCT00719186) comparing clomiphene citrate vs letrozole in the treatment of infertility. Subjects included 732 women ages 18–40 years with polycystic ovary syndrome by modified Rotterdam criteria. The validated Polycystic Ovary Syndrome Health‐Related Quality of Life survey was self‐administered, assessing the following domains: emotions, body hair, body weight, menstrual problems, and infertility; scores range from 1–7, with lower numbers indicating poorer quality of life. Depression was evaluated via the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. Quality‐of‐life scores were compared between depressed and nondepressed women. Multivariate linear regression models analyzed the association between depression and quality‐of‐life scores, controlling for age, body mass index, hirsutism score, and duration of infertility. RESULTS: In all, 64 women (8.4%) met criteria for depression. Depressed women reported reduced quality of life in all domains compared to nondepressed women: mood (3.1 vs 4.6, P < .001), body hair (3.5 vs 4.2, P = .002), weight (2.0 vs 3.5, P < .001), menstrual problems (3.3 vs 4.1, P < .001), and infertility (1.9 vs 3.0, P < .001). Global quality‐of‐life score was reduced in depressed women (2.8 vs 3.9, P < .001). Impairments in quality of life in depressed women persisted in all domains after controlling for objective parameters including age, body mass index, hirsutism score, and infertility duration. CONCLUSION: Depression is associated with reduced quality of life related to polycystic ovary syndrome symptoms. Disturbances in health‐related quality of life in depressed women are not explained by objective measures including body mass index, hirsutism scores, and duration of infertility. Depression may color the experience of polycystic ovary syndrome symptoms and should be considered when there is significant discordance between subjective and objective measures in women with polycystic ovary syndrome.