Providers' perspectives on the reproductive decision-making of BRCA-positive women.

BACKGROUND: Reproductive decision-making is difficult for BRCA-positive women. Our objective was to assess the complexities of decision-making and identify decisional supports for patients and providers when discussing reproductive options prior to risk-reducing salpingo-oophorectomy (RRSO). METHODS: This study was of qualitive design, using data collection via semi-structured interviews conducted from November 2018 to October 2020. Individuals were included if they were identified to provide care to BRCA-positive women. In total, 19 providers were approached and 15 consented to participate. Providers were recruited from three clinics in Toronto, Ontario located at academic centers: [1] A familial ovarian cancer clinic, [2] A familial breast cancer clinic and [3] A fertility clinic, all of which treat carriers of the BRCA1/BRCA2 genetic mutation. The interview guide was developed according to the Ottawa Decision Support Framework and included questions regarding reproductive options available to patients, factors that impact the decision-making process and the role of decisional support. Interviews were transcribed and transcripts were analyzed thematically using NVIVO 12. RESULTS: Providers identified three major decisions that reproductive-aged women face when a BRCA mutation is discovered: [1] "Do I want children?"; [2] "Do I want to take the chance of passing on this the mutation?"; and [3] "Do I want to carry a child?" Inherent decision challenges that are faced by both providers and patients included difficult decision type, competing options, scientifically uncertain outcomes, and challenging decision timing. Modifiable decisional needs included: inadequate knowledge, unrealistic expectations, unclear values and inadequate support or resources. Identified clinical gaps included counselling time constraints, lack of reliable sources of background information for patients or providers and need for time-sensitive, geographically accessible, and centralized care. CONCLUSION: Our study identified a need for a patient information resource that can be immediately provided to patients who carry a BRCA genetic mutation. Other suggestions for clinical practice include more time during consultation appointments, adequate follow-up, value-centric counseling, access to psychosocial support, and a specialized decisional coach.

A synopsis of global frontiers in fertility preservation.

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of "Oncofertility Around the Globe" to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.

Risk of infertility in female adolescents and young adults with cancer: a population-based cohort study.

STUDY QUESTION: Do female adolescents and young adults (AYAs) with cancer have a higher risk of subsequent infertility diagnosis than AYAs without cancer? SUMMARY ANSWER: Female AYAs with breast, hematological, thyroid and melanoma cancer have a higher risk of subsequent infertility diagnosis. WHAT IS KNOWN ALREADY: Cancer therapies have improved substantially, leading to dramatic increases in survival. As survival improves, there is an increasing emphasis on optimizing the quality of life among cancer survivors. Many cancer therapies increase the risk of infertility, but we lack population-based studies that quantify the risk of subsequent infertility diagnosis in female AYAs with non-gynecological cancers. The literature is limited to population-based studies comparing pregnancy or birth rates after cancer against unexposed women, or smaller studies using markers of the ovarian reserve as a proxy of infertility among female survivors of cancer. STUDY DESIGN, SIZE, DURATION: We conducted a population-based cohort study using universal health care databases in the province of Ontario, Canada. Using data from the Ontario Cancer Registry, we identified all women 15-39 years of age diagnosed with the most common cancers in AYAs (brain, breast, colorectal, leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, thyroid and melanoma) from 1992 to 2011 who lived at least 5 years recurrence-free (Exposed, n = 14,316). Women with a tubal ligation, bilateral oophorectomy or hysterectomy previous to their cancer diagnosis were excluded. We matched each exposed woman by age, census subdivision, and parity to five randomly selected unexposed women (n = 60,975) and followed subjects until 31 December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertility diagnosis after 1 year of cancer was identified using information on physician billing codes through the Ontario Health Insurance Plan database (ICD-9 628). Modified Poisson regression models were used to assess the risk of infertility diagnosis (relative risk, RR) adjusted for income quintile and further stratified by parity at the time of cancer diagnosis (nulliparous and parous). MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at cancer diagnosis was 31.4 years. Overall, the proportion of infertility diagnosis was higher in cancer survivors compared to unexposed women. Mean age of infertility diagnosis was similar among cancer survivors and unexposed women (34.8 years and 34.9 years, respectively). The overall risk of infertility diagnosis was higher in cancer survivors (RR 1.30; 95% CI 1.23-1.37). Differences in infertility risk varied by type of cancer. Survivors of breast cancer (RR 1.46; 95% CI 1.30-1.65), leukemia (RR 1.56; 95% CI 1.09-2.22), Hodgkin lymphoma (RR 1.49; 95% CI 1.28-1.74), non-Hodgkin lymphoma (RR 1.42; 95% CI 1.14, 1.76), thyroid cancer (RR 1.20; 95% CI 1.10-1.30) and melanoma (RR 1.17; 95% CI 1.01, 1.35) had a higher risk of infertility diagnosis compared to women without cancer. After stratification by parity, the association remained in nulliparous women survivors of breast cancer, leukemia, lymphoma and melanoma, whereas it was attenuated in parous women. In survivors of thyroid cancer, the association remained statistically significant in both nulliparous and parous women. In survivors of brain or colorectal cancer, the association was not significant, overall or after stratification by parity. LIMITATIONS, REASONS FOR CAUTION: Non-biological factors that may influence the likelihood of seeking a fertility assessment may not be captured in administrative databases. The effects of additional risk factors, including cancer treatment, which may modify the associations, need to be assessed in future studies. WIDER IMPLICATIONS OF THE FINDINGS: Reproductive health surveillance in female AYAs with cancer is a priority, especially those with breast cancer, leukemia and lymphoma. Our finding of a potential effects of thyroid cancer (subject to over-diagnosis) and, to a lesser extent, melanoma need to be further studied, and, if an effect is confirmed, possible mechanisms need to be elucidated. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Faculty of Health Sciences and Department of Obstetrics and Gynecology, Queen's University. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Ovarian function after chemotherapy in young breast cancer survivors.

BACKGROUND: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal. METHODS: We conducted a cross-sectional study evaluating anti-Müllerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing. RESULTS: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy (p = 0.002) and in the subgroup reporting normal cycles (p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh (p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older. CONCLUSIONS: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist.

Obesity-related health status is a better predictor of pregnancy with fertility treatment than body mass index: a prospective study.

This study assessed whether an obesity-related health status instrument (Edmonton obesity scoring system - EOSS) or body mass index (BMI) better predicted pregnancy rates in overweight women undergoing fertility treatments. A prospective cohort study was conducted on patients with a BMI ≥ 25 kg m(-2) undergoing a fertility treatment cycle (ovulation induction, superovulation, or in vitro fertilization). Obesity-related health status including blood pressure, blood work, health history, and functional assessment were assessed. A total of 101 patients were included in the study with an average age of 36.3 ± 4.2 years and a mean BMI of 31.8 ± 5.2 kg m(-2) . EOSS was found to be statistically predictive of pregnancy rate/cycle (OR 0.51, 95% CI 0.27-0.94; P = 0.03), whereas BMI was not (OR 0.95, 95% CI 0.86-1.05). A similar trend was seen for clinical pregnancy rate/cycle started. However, the association between clinical pregnancy rates and EOSS or BMI did not reach statistical significance (OR 0.53, P = 0.06 and OR 0.98, P = 0.62 respectively). Our results demonstrated that EOSS better predicted pregnancy rates after fertility treatments than BMI. In fact, for every EOSS stage increased by one unit, the odds of pregnancy were approximately halved. A multi-centre study powered for live birth is warranted to establish effective pre-fertility management of overweight women.

Evidence for a common binding cavity for three general anesthetics within the GABAA receptor.

The GABA(A) receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABA(A) receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABA(A) receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 A(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.

Mcl-1 is a key regulator of the ovarian reserve.

A majority of ovarian follicles are lost to natural death, but the disruption of factors involved in maintenance of the oocyte pool results in a further untimely follicular depletion known as premature ovarian failure. The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia-1 (MCL-1) has a pro-survival role in various cell types; however, its contribution to oocyte survival is unconfirmed. We present a phenotypic characterization of oocytes deficient in Mcl-1, and establish its role in maintenance of the primordial follicle (PMF) pool, growing oocyte survival and oocyte quality. Mcl-1 depletion resulted in the premature exhaustion of the ovarian reserve, characterized by early PMF loss because of activation of apoptosis. The increasingly diminished surviving cohort of growing oocytes displayed elevated markers of autophagy and mitochondrial dysfunction. Mcl-1-deficient ovulated oocytes demonstrated an increased susceptibility to cellular fragmentation with activation of the apoptotic cascade. Concomitant deletion of the pro-apoptotic Bcl-2 member Bcl-2-associated X protein (Bax) rescued the PMF phenotype and ovulated oocyte death, but did not prevent the mitochondrial dysfunction associated with Mcl-1 deficiency and could not rescue long-term breeding performance. We thus recognize MCL-1 as the essential survival factor required for conservation of the postnatal PMF pool, growing follicle survival and effective oocyte mitochondrial function.

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

Derivatives of 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine as central nervous system agents.

Four 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepines were prepared and evaluated as central nervous system agents. All were active psychotropic agents as determined by animal screening tests. The most interesting compound, 11-(1-piperazinyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, showed dual activity as an antidepressant against tetrabenazine depression and as a neuroleptic as measured by protection vs. amphetamine lethality in grouped mice.

Derivatives of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione as anxiolytic agents.

A study of the pharmacological properties of pyrrolo[2,1-c][1,4]benzodiazepine derivatives led to the choice of (+)-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolol[2,1-c][1,4]benzodiazepine-5,11)10H)-dione as a candidate for anxiolytic evaluation in a limited clinical trial in man. Metabolism studies in laboratory animals have pointed to rapid hydroxylation, possibly in the 3 and 11a positions. A series of compouds containing methyl groups in one or more of these positions has been prepared in an effort to block metabolism and thereby obtain more active or longer acting compounds. All of these derivatives were less active than the parent compound.

Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines.

The synthesis of a series of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines (VIII) is reported. Some of these derivatives show activity in tests predictive of anxiolytic activity [(a) protection against pentylenetetrazole-induced convulsions; (b) thirsty rat conflict procedure]. They also represent a new class of compound which inhibits [3H]diazepam binding. Structure--activity correlations, as well as the ability of structures VIII to inhibit [3H]diazepam binding (in vitro), are discussed.

10-(Alkylamino)-4H-thieno[3,4-b][1,5]benzodiazepines. A novel class of potential neuroleptic agents.

An investigation of the structural requirements for CNS activity of the title compounds was undertaken. A synthesis of the precursor dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-ones was achieved and three routes for their conversion to the title compounds were developed. The compounds were tested for neuroleptic activity by means of the blockade or d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the compounds were found to be potent neuroleptic agents with several exhibiting additional antidepressant activity.

Thiophene systems. 5. Thieno[3,4-b][1,5]benzoxazepines, thieno[3,4-b][1,5]benzothiazepines, and thieno[3,4-b][1,4]benzodiazepines as potential central nervous system agents.

10-(Alkylamino)thieno[3,4-b][1,5]benzoxazepines (3) and 10-(alkylamino)thieno[3,4-b][1,5]benzothiazepines (4) were prepared by derivatization of the respective lactams (7 and 8) via phosphorus pentachloride and subsequent condensation with the appropriate alkylamines. 9-(Alkylamino)-4H-thieno[3,4-b][1,4]benzodiazepines (5) were prepared by titanium tetrachloride catalyzed condensation of the lactam 11 with alkylamines. 9-(Alkylamino)-4-methylthieno[3,4-b][1,4]benzodiazepines (6) were prepared by reductive alkylation of 5. The compounds were tested for potential neuroleptic activity by means of the blockade of d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the title compounds 3-6 were found to have neuroleptic activity. In addition, introduction of a 3-chloro substituent in the oxygen and sulfur systems (3p and 4c), as well as introduction of an N-alkyl in the dinitrogen system (6), was found to produce antidepressant effects. Structure-activity relationships are discussed.

Assessment and psychotherapeutic intervention for an HIV-infected preschool child.

Pediatric acquired immunodeficiency syndrome (AIDS) is becoming more common. Moreover, human immunodeficiency virus (HIV) positive status in multiple family members is common and complicates disease management. Practitioners treating these children are often unaware of the effect of the virus on the child's psychological, cognitive, and emotional functioning. In addition, children with AIDS frequently come from families facing pressing social problems, including homelessness, poverty, and drug addiction. HIV-positive children thus confront such diverse issues as the deterioration of developmental skills, social ostracism, and the possibility of imminent death, placing them in a socioemotional crisis. This paper presents a comprehensive psychotherapeutic intervention for such children.

The Cornell Interview of Peers and Friends: development and validation.

The Cornell Interview of Peers and Friends (CIPF), a 30-minute semistructured interview, evaluated 7- to 11-year-old children's perceptions of their social relationships. Significant differences on the CIPF were found between clinical and nonclinical groups and between boys and girls. Three CIPF subscales, Developmental Appropriateness, Social Skills, and Self-esteem, were assessed and significantly differentiated between clinical and nonclinical populations. Satisfactory interrater reliability is reported for the interview's total score and the three subscale scores. The CIPF offers potential for screening children at risk for emotional disturbance and for assessing outcomes of therapeutic interventions.

Adhesion formation after laparoscopic ovarian cautery for polycystic ovarian syndrome: lack of correlation with pregnancy rate.

OBJECTIVE: To assess adhesion formation after laparoscopic ovarian cautery in women with polycystic ovarian syndrome (PCOS) and the efficacy of Interceed Adhesion Barrier (Ethicon, Summerville, NJ) in their prevention. DESIGN: Prospective, randomized, blinded, clinical study of laparoscopic ovarian cautery with application of Interceed to one ovary, followed by short interval second-look laparoscopy, scoring of adhesions, and clinical follow-up. SETTING: Tertiary care clinic at a University teaching hospital. PATIENTS: Eight infertile women with PCOS who failed to conceive with previous clomiphene citrate (CC) therapy. RESULTS: Periovarian adhesions of varying severity developed in all women after laparoscopic ovarian cautery. Interceed showed no protective effect. Despite this finding, all women initiated regular menses after laparoscopic ovarian cautery and seven of eight women spontaneously conceived eight singleton pregnancies without any further therapy. CONCLUSION: Laparoscopic ovarian cautery should be considered in infertile women with PCOS who fail to respond to CC therapy. These women must be counseled with respect to the possible complication of postoperative adhesion formation.

Use of the internet by infertile couples.

OBJECTIVE: To evaluate and compare the extent of Internet use by infertile couples attending a government-funded and a private assisted reproductive technology clinic. DESIGN: A prospective study. SETTING: One private and one public tertiary care fertility clinic in Toronto. PATIENT(S): 250 patients were approached, and 150 (60%) responded. INTERVENTION(S): A self-administered questionnaire on socioeconomic status, fertility history, and computer and Internet use. MAIN OUTCOME MEASURE(S): The extent of Internet use on fertility-related issues was determined, correlated with socioeconomic status and fertility history, and compared between the two clinics. RESULT(S): Higher levels of education, employment, and combined family income characterized patients at the private clinic. A similarly high proportion of patients at both clinics had previous experience with the Internet (mean, 75.3%). Overall, 42% of the total study population and 55.8% of current Internet users had used the Internet for fertility-related issues. Using a logistic regression model, none of the patients' socioeconomic or clinical variables predicted Internet use. Thirty percent of the patients found the Internet helpful in their decision making process. CONCLUSION(S): A considerable proportion of infertile couples from all socioeconomic levels is actively using the Internet with regard to their fertility problems. Health care providers should consider the Internet an important tool for all aspects of their interaction with infertile persons.

In vitro fertilization outcome in the presence of severe male factor infertility.

OBJECTIVE: To assess the outcome of standard IVF treatment (nonmicromanipulated) with respect to total motile sperm number recovered by swim-up, particularly for couples with severe male factor infertility defined as total motile sperm number < 0.5 x 10(6). DESIGN: Retrospective study of patients who underwent successful oocyte retrieval in an IVF program from August 10, 1992 to December 31, 1993. SETTING: A university-based tertiary referral center (The Toronto Hospital). PATIENTS: All cycles (n = 672) were divided into four groups according to total motile sperm number recovered using standard swim-up: group 1, total motile sperm number < or = 0.50 x 10(6); group 2, total motile sperm number between 0.51 and 1.00 x 10(6); group 3, total motile sperm number between 1.01 and 1.50 x 10(6); and group 4, total motile sperm number > or = 1.51 x 10(6). All patients received the same controlled ovarian hyperstimulation protocol, which consisted of a GnRH analog flare-up followed by parenteral menotropins. Clinical and cycle characteristics in the four groups were analyzed and outcome was evaluated. RESULTS: There was no significant difference in clinical and cycle characteristics between the groups. The uniformity of the groups justified analysis of their outcome. A fertilization rate of 21.5% was achieved in couples with severe male factor (group 1). Fertilization rate and number of embryos transferred increased directly with the total motile sperm number. There was no significant difference in implantation rate per embryo between the groups. CONCLUSIONS: The results in couples with severe male factor infertility compare favorably with monospermic fertilization rates reported in the literature using partial zona dissection and subzonal insertion but is lower than with intracytoplasmic sperm injection. Therefore, we believe that couples with severe male factor infertility should be considered for standard IVF, as long as adequate total motile sperm can be recovered (100 x 10(3) per dish). If intracytoplasmic sperm injection is available, it should be offered to these couples.