Variation in collagenase Clostridium histolyticum practice patterns: a Survey of ISSM Members.

Collagenase clostridium histolyticum (CCH, Xiaflex, Xiapex) is the only FDA-approved medication for treatment of Peyronie's disease. It is unclear how practitioners actually use CCH in their own practices. The objectives of the study were: (1) to identify variability in practice patterns for CCH among practitioners, (2) to assess adherence to the package insert instructions, and (3) to evaluate whether provider satisfaction was associated with adherence to instructions. A 30-question online survey was distributed to 1270 members of the International Society for Sexual Medicine (ISSM) from the EU, USA, Canada and Australia. Of the 30 questions, 10 survey questions had only one response consistent with the CCH package insert recommendations. An "adherence" score was calculated for each survey participant depending on how many of these questions were answered correctly. The average adherence scores of various groups were compared using a student's t-test. A chi-squared test was used to determine association between categorical variables. Of 202 total responses, 132 practitioners reported using CCH out of 1270 ISSM members from countries where CCH is available (10.4% response rate). Practitioners from outside the USA were more likely to be satisfied with CCH (p = 0.006), and more experienced users (>20 uses) were more likely to be satisfied than less experienced users (<10 uses) (p = 0.046). Satisfied users of CCH did not have significantly different adherence scores than non-satisfied users. Even though 67% of practitioners believed they followed the package insert guidelines, only 11% adhered to all the recommendations evaluated by the survey. Treatment adherence to package insert guidelines does not appear to be associated with provider satisfaction. We believe there is utility in seeing a snapshot of these practice patterns so practitioners may feel more comfortable adapting their own practice in light of newer data supporting alternative administration methods.

The association between seminal vesicle size and duration of abstinence from ejaculation.

There are few data describing the relationship between seminal vesicle (SV) size and duration of abstinence between ejaculations. This study evaluates the association between SV size and duration of abstinence from ejaculation using pelvic magnetic resonance imaging (MRI). Sexually active men 18-68 years old who underwent pelvic MRI for various medical indications were included. The date of last ejaculation was recorded, and the cross-sectional areas of the right and left seminal vesicles were calculated separately using mediolateral and anteroposterior measurements on T2-weighted MRI images. The association between SV area and duration of abstinence between ejaculations was determined via linear regression analysis. The study cohort consisted of 104 men with a mean age of 46.45 ± 11.4 (range 18-68) years old. Mean right and left SV cross-sectional areas were 744.1 ± 351.1 (range: 149.9-1794.7) mm2 and 727.6 ± 359.2 (range 171.4-2248.4) mm2 respectively. The mean duration of abstinence between ejaculations in the cohort was 3.6 ± 2.6 (range 1-15) days. Although no correlation between age and SV area was observed (r = .007, p = .947), linear regression analysis demonstrated a positive correlation between SV area and the duration of abstinence from ejaculation (r = .372, p = .0001). SV cross-sectional area increases with duration of abstinence from ejaculation and can be assessed using MRI. The use of SV size estimation may be applicable in diagnosis, risk stratification and treatment of urological diseases.

Depression is correlated with the psychological and physical aspects of sexual dysfunction in men.

Few studies have objectively examined the relationship between depression and various stages of sexual function. Here we associate depression and sexual function using validated questionnaires. A retrospective review of 186 men was performed; demographics and serum hormone levels were obtained. Responses to questionnaires evaluating depressive symptoms (Patient Health Questionnaire (PHQ-9)), sexual function (International Index of Erectile Function (IIEF)) and hypogonadal symptoms (quantitative Androgen Decline in the Aging Male (qADAM)) completed by each patient were correlated using Spearman's rank correlation. Mean±s.d. subject age: 52.6±12.7 years; mean serum hormone levels: TT 429.8±239.2 ng dl(-1), free testosterone 9.72±7.5 pg ml(-1) and estradiol 34.4±22.8 pg ml(-1). Negative correlations were observed between total PHQ-9 score and the sexual desire (ρ=-0.210, P=0.006), intercourse satisfaction (ρ=-0.293, P<0.0001) and overall satisfaction (ρ=-0.413, P<0.0001) domains of the IIEF and individual IIEF questions pertaining to erectile function. Men with a PHQ-9 score 10 (mild depression or worse), had lower sexual desire and sex life satisfaction. A negative correlation between PHQ-9 score and qADAM score (ρ=-0.634, P<0.0001) was observed and men with higher PHQ-9 score had lower qADAM scores. Depressive symptoms in men correlate with both psychological as well as physical aspects of sexual function.

Posthumous sperm utilization in men presenting for sperm banking: an analysis of patient choice.

The question remains as to whether or not men would agree to posthumous sperm use for pregnancy initiation. Often, these individuals' lives are suddenly interrupted and prior consent is rarely given. Therefore, post-mortem retrieval or use of these spermatozoa remains controversial and the incidence of consent for post-mortem sperm use is not clear. Men who bank spermatozoa, however, represent a cohort that can be examined for frequency of consent for post-mortem sperm use. We performed a retrospective chart review for 364 patients presenting for sperm banking at a single institution from 2009 to 2011. Banked specimens represented either ejaculated or surgically retrieved spermatozoa. Demographic information was obtained for each patient and men were grouped by reason for sperm banking, relationship and paternity status, and consent for post-mortem sperm use. The frequency of post-mortem consent was determined within each group. Men were grouped based on reason for banking, including infertility ('Infertility') or malignancy prior to treatment ('Cancer'). Mean ± SD age of the infertility and cancer groups were 40.1 ± 9.9 years and 27.1 ± 9.6 years, respectively. Of the 364 men, 85.9% provided consent for post-mortem sperm use. In the infertility group, 87.4% of men consented. Of these, 92.9% men in a relationship and 62.5% single men consented. Regarding paternity status, 64.7% men with and 56.6% men without children consented. Within the cancer cohort, 83.8% men consented. Of men <18 years old and ≥18 years old, 65.2 and 85.8% consented, respectively. Relationship status yielded 93.2% men in relationships and 79.4% single men consenting. Paternity status in the cancer group yielded 95.8% with and 82.4% men without children consenting. In summary, most men presenting for sperm banking provided consent for post-mortem sperm use, irrespective of reason for banking. Men who are in a relationship or who are fathers were more likely to agree to post-mortem sperm use.

Testosterone replacement therapy in the setting of prostate cancer treated with radiation.

A lack of consensus and few data support testosterone replacement therapy (TRT) in hypogonadal men who have been treated for prostate cancer (CaP), particularly those who have received radiation therapy. We performed retrospective review of 13 hypogonadal men with CaP, treated with brachytherapy or external beam radiotherapy who were subsequently treated with testosterone (T) between 2006 and 2011. Serum T, free T (FT), estrogen (E), sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), hemoglobin (Hgb) and hematocrit (Hct) values were evaluated approximately every 3 months after TRT initiation up to 67 months of follow-up. Prostate biopsies demonstrated four men with Gleason (Gl) 6, 7 with Gl 7 and 2 with Gl 8 disease. Median (interquartile range) age at TRT initiation was 68.0 (62.0-77.0) years, initial T 178.0 (88.0-263.5) ng dl(-1), FT 10.1 (5.7-15.0) pg ml(-1) and PSA 0.30 (0.06-0.95) ng ml(-1). Median follow-up after TRT initiation was 29.7 months (range 2.3-67.3 months). At median follow-up, a significant increase in mean T (368.0 (281.3-591.0) ng dl(-1), P=0.012) and SHBG were observed, with no significant increases in Hgb, Hct, E, FT, or PSA (0.66 (0.16-1.35) ng ml(-1), P=0.345). No significant increases in PSA or CaP recurrences were observed at any follow-up interval. TRT in the setting of CaP after treatment with radiation therapy results in a rise in serum T levels and improvement in hypogonadal symptoms without evidence of CaP recurrence or progression.

IGF-1 levels are significantly correlated with patient-reported measures of sexual function.

Growth hormone (GH) supplementation may help to preserve erectile function. We assessed whether serum insulin-like growth factor 1 (IGF-1) levels, a surrogate for GH levels, correlate with sexual function scores in 65 men who completed the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires, and had serum IGF-1 and testosterone levels determined. Median±s.d. IGF-1 level, SHIM and EPIC scores were 235.0±86.4, 19.5±8.7 and 56.4±28.3 mg ml(-1), respectively. IGF-1 levels and total SHIM score correlate significantly (r=0.31, P=0.02), as do IGF-1 levels and all individual SHIM question scores, and IGF-1 levels and the sexual domain of the EPIC questionnaire (r=0.30, P=0.02). No correlation was observed between IGF-1 levels and Gleason score, IGF-1 and testosterone level or SHIM score and testosterone level. These data support a potential role for the GH axis in erectile function.

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.

BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. METHODS: We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. RESULTS: In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

Preconception counseling and women's compliance with folic acid supplementation.

QUESTION: I am counseling patients to take folic acid when they plan pregnancy and during early pregnancy. Is there any proof that counseling really causes women to comply? ANSWER: A recent Motherisk study showed that counseling women who were planning pregnancy about folic acid use is very effective: 71% of those counseled took folic acid, compared with only 17% of those who were not counseled.

Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study.

BACKGROUND: Misoprostol, a synthetic prostaglandin E1 analog is labeled for the treatment of gastric and duodenal ulcers. In Brazil, where abortion is not a legal procedure, there is a widespread popular misuse of this drug in abortion attempts. This misuse and the fact that, in many cases the desired pregnancy termination does not occur, raise concerns about fetal safety. Case reports of congenital anomalies after maternal use of misoprostol have been published. The objective of this work was to compare pregnancy outcome following misoprostol exposure with a matched control group. This is the first prospective controlled study on fetal safety after misoprostol use. METHODS: A prospective, observational cohort study with 86 exposed and 86 pair-matched, non-exposed controls. RESULTS: There was no significant difference in the rates of major or minor birth between exposed compared to non-exposed infants (2/67 vs 2/81, major defects; 7/67 vs. 3/81, minor anomalies) There were significantly more miscarriages in the exposed group (17.1% vs. 5.8%; relative risk, 2.97; 95% confidence interval, 1.12 to 7.88). There was no statistical difference in gestational age at delivery, birth weight, sex ratio, rate of prematurity, low birth weight, or rates of cesarean section between groups. CONCLUSIONS: Our study, despite its limited statistical power, does not suggest a potent teratogenic action of misoprostol exposure during pregnancy.

Are the new SSRIs safe for pregnant women?

QUESTION: More and more of my female patients are switching to the new selective serotonin reuptake inhibitors. Are they safe during pregnancy? ANSWER: Our data suggest these drugs do not increase the malformation rate, but there are no data on neurodevelopment. Because such data do exist on fluoxetine and tricyclic antidepressants, those drugs should be considered first.

Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: a meta-analysis.

The objective was to determine the association of moderate to heavy caffeine consumption during pregnancy on spontaneous abortion and birth weight in humans. Data sources used included a computerized literature search of MEDLINE (1966-July 1996); EMBASE (1988-November 1996); Psychlit I (1974-1986); Psychlit II (1987-1996); CINAHL (1982-May 1996) and manual search of bibliographies of pertinent articles. Inclusion criteria were: English language research articles; pregnant human females; case control or cohort design; documented quantity of caffeine consumption during pregnancy; control group with minimal or no caffeine consumption (0 to 150 mg caffeine/d); documented data regarding spontaneous abortion and/or fetal growth. The exclusion criteria were: case reports; editorials; review papers. The methods section of each study was examined independently by two blinded investigators with a third investigator adjudicating disagreements. Two independent investigators extracted data onto a standardized form. A third investigator adjudicated discrepancies. We compared a caffeine-exposed group (>150 mg/d) and controls (0 to 150 mg/d), using Mantel-Haenszel pooling. Of the 32 studies meeting inclusion criteria, 12 had extractable data (6 for spontaneous abortion, 7 for low birth weight, 1 common study). Mantel-Haenszel odds ratio (CI95%) was 1.36 (1.29-1.45) for spontaneous abortion in 42,988 pregnancies. The overall risk ratio was 1.51 (1.39-1.63) for low birthweight (<2500 g) in 64,268 pregnancies. Control for confounders such as maternal age, smoking, and ethanol use was not possible. We concluded that there is a small but statistically significant increase in the risks for spontaneous abortion and low birthweight babies in pregnant women consuming >150 mg caffeine per d. A possible contribution to these results of maternal age, smoking, ethanol use, or other confounders could not be excluded.

Pregnancy outcome following first trimester exposure to sumatriptan.

We prospectively compared pregnancy outcome after exposure to sumatriptan with that of disease-matched controls and nonteratogen controls. There were no differences in the rates of live births, spontaneous abortions, therapeutic abortions, or major birth defects among the three groups. This first prospective report suggests that the use of sumatriptan during organogenesis is not associated with an apparent increased risk of major birth defects.

Use of misoprostol during pregnancy and Möbius' syndrome in infants.

BACKGROUND: Patients with upper gastrointestinal ulceration may be treated with misoprostol, but it is not recommended for pregnant women because it may stimulate uterine contractions and cause vaginal bleeding and miscarriage. Recent data from Brazil, where misoprostol is used orally and vaginally as an abortifacient, have suggested a relation between the use of misoprostol by women in an unsuccessful attempt to terminate pregnancy and Möbius' syndrome (congenital facial paralysis) in their infants. METHODS: We compared the frequency of misoprostol use during the first trimester by mothers of infants in whom Möbius' syndrome was diagnosed and mothers of infants with neural-tube defects in Brazil. All diagnoses in infants were made between January 16, 1990, and May 31, 1996, by clinical geneticists at seven hospitals who also interviewed the mothers and recorded information about the administration of misoprostol, among other data. RESULTS: We identified 96 infants with Möbius' syndrome and matched them with 96 infants with neural-tube defects. The mean age at the time of the diagnosis of Möbius' syndrome was 16 months (range, 0.5 to 78), and the diagnosis of neural-tube defects was made within 1 week of birth in most cases. Among the mothers of the 96 infants with Möbius' syndrome, 47 (49 percent) had used misoprostol in the first trimester of pregnancy, as compared with 3 (3 percent) of the mothers of the 96 infants with neural-tube defects (odds ratio, 29.7; 95 percent confidence interval, 11.6 to 76.0). Twenty of the mothers of the infants with Möbius' syndrome had taken misoprostol only orally (odds ratio, 38.8; 95 percent confidence interval, 9.5 to 159.4), 20 had taken misoprostol both orally and vaginally, 3 had taken the drug vaginally, and 4 did not report how they took the drug. CONCLUSIONS: Attempted abortion with misoprostol is associated with an increased risk of Möbius' syndrome in infants.

Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.

Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (+/- 3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.

Is topical tretinoin safe during the first trimester?

QUESTIONOne of my patients conceived while using a topical tretinoin preparation for acne. I know this drug is related to Accutane, which is teratogenic. How should I advise her?ANSWERAvailable evidence suggests that topical tretinoin does not increase teratogenic risk in humans.

Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study.

CONTEXT: Although a large number of women of reproductive age use new selective serotonin reuptake inhibitors (SSRIs) and half of all pregnancies are unplanned, no data exist on the safety of these agents for the human fetus. OBJECTIVE: To assess fetal safety and risk of fluvoxamine, paroxetine, and sertraline. DESIGN: A prospective, multicenter, controlled cohort study. SETTING: Nine Teratology Information Service centers in the United States and Canada. PATIENTS: All women who were counseled during pregnancy following exposure to a new SSRI and followed up by the participating centers. Controls were randomly selected from women counseled after exposure to nonteratogenic agents. MAIN OUTCOME MEASURES: Rates of major congenital malformations. RESULTS: A total of 267 women exposed to an SSRI and 267 controls were studied. Exposure to SSRIs was not associated with either increased risk for major malformations (9/222 live births [4.1%] vs 9/235 live births [3.8%] in the controls, relative risk, 1.06, 95% confidence interval, 0.43-2.62) or higher rates of miscarriage, stillbirth, or prematurity. Mean (SD) birth weights among SSRI users (3439 [505] g) were similar to the controls (3445 [610] g) as were the gestational ages (39.4 [1.7] weeks vs 39.4 [1.9] weeks). CONCLUSION: The new SSRIs, fluvoxamine, paroxetine, and sertraline, do not appear to increase the teratogenic risk when used in their recommended doses.

The safety of mesalamine in human pregnancy: a prospective controlled cohort study.

BACKGROUND & AIMS: Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS: The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS: This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.