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.

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.

Using helium-oxygen to improve regional deposition of inhaled particles: mechanical principles.

BACKGROUND: Helium-oxygen has been used for decades as a respiratory therapy conjointly with aerosols. It has also been shown under some conditions to be a means to provide more peripheral, deeper, particle deposition for inhalation therapies. Furthermore, we can also consider deposition along parallel paths that are quite different, especially in a heterogeneous pathological lung. It is in this context that it is hypothesized that helium-oxygen can improve regional deposition, leading to more homogeneous deposition by increasing deposition in ventilation-deficient lung regions. METHODS: Analytical models of inertial impaction, sedimentation, and diffusion are examined to illustrate the importance of gas property values on deposition distribution through both fluid mechanics- and particle mechanics-based mechanisms. Also considered are in vitro results from a bench model for a heterogeneously obstructed lung. In vivo results from three-dimensional (3D) imaging techniques provide visual examples of changes in particle deposition patterns in asthmatics that are further analyzed using computational fluid dynamics (CFD). RESULTS AND CONCLUSIONS: Based on analytical modeling, it is shown that deeper particle deposition is expected when breathing helium-oxygen, as compared with breathing air. A bench model has shown that more homogeneous ventilation distribution is possible breathing helium-oxygen in the presence of heterogeneous obstructions representative of central airway obstructions. 3D imaging of asthmatics has confirmed that aerosol delivery with a helium-oxygen carrier gas results in deeper and more homogeneous deposition distributions. CFD results are consistent with the in vivo imaging and suggest that the mechanics of gas particle interaction are the source of the differences seen in deposition patterns. However, intersubject variability in response to breathing helium-oxygen is expected, and an example of a nonresponder is shown where regional deposition is not significantly changed.

Peripheral resistance: a link between global airflow obstruction and regional ventilation distribution.

Airflow obstruction and heterogeneities in airway constriction and ventilation distribution are well-described prominent features of asthma. However, the mechanistic link between these global and regional features has not been well defined. We speculate that peripheral airway resistance (R(p)) may provide such a link. Structural and functional parameters are estimated from PET and HRCT images of asthmatic (AS) and nonasthmatic (NA) subjects measured at baseline (BASE) and post-methacholine challenge (POST). Conductances of 35 anatomically defined proximal airways are estimated from airway geometry obtained from high-resolution computed tomography (HRCT) images. Compliances of sublobar regions subtended by 19 most distal airways are estimated from changes in regional gas volume between two lung volumes. Specific ventilations (sV) of these sublobar regions are evaluated from 13NN-washout PET scans. For each pathway connecting the trachea to sublobar region, values of R(p) required to explain the sV distribution and global airflow obstruction are computed. Results show that R(p) is highly heterogeneous within each subject, but has average values consistent with global values in the literature. The contribution of R(p) to total pathway resistance (R(T)) increased substantially for POST (P < 0.0001). The fraction R(p)/R(T) was higher in AS than NA at POST (P < 0.0001) but similar at BASE (range: 0.960-0.997, median: 0.990). For POST, R(p)/R(T) range was 0.979-0.999 (NA) and 0.981-0.995 (AS). This approach allows for estimations of peripheral airway resistance within anatomically defined sublobar regions in vivo human lungs and may be used to evaluate peripheral effects of therapy in a subject specific manner.

A multicentre randomized controlled trial of expectant management versus IVF in women with Fallopian tube patency.

BACKGROUND: Although observational studies suggest that IVF is more effective than no treatment for women with Fallopian tube patency, this has not been tested rigorously in a randomized controlled trial (RCT). METHODS: Eligible consenting couples planning their first treatment cycle in five Canadian fertility clinics received either IVF, within 90 days of randomization, or a period of 90 days with no treatment. Random allocation was stratified by female age and sperm quality, and administered using numbered, opaque, sealed envelopes. Follow-up assessed live birth and associated morbidity. RESULTS: Sixty-eight couples were randomized to a first cycle of IVF and 71 couples had 3 months without treatment. The live birth rates were 20/68 (29%) and 1/71 (1%), respectively. The single delivery in the untreated group was of twins, as were six of the 20 IVF deliveries (30%). An average of 2.0 embryos were transferred and no triplet pregnancies resulted. The relative likelihood of delivery after allocation to IVF was 20.9-fold higher than after allocation to no treatment [95% confidence interval (CI) 2.8-155]. The presence of abnormal sperm did not reduce this likelihood. Treating four women (95% CI 3-6) with one cycle of IVF is required to achieve a single additional birth. CONCLUSIONS: This study provides a valid and up-to-date comparison for policy makers and patients as they make choices around IVF, accurately measuring and confirming a major benefit from treatment.

Divergence of volatile anesthetic effects in inhibitory neurotransmitter receptors.

BACKGROUND: The mechanism of volatile anesthetic (VA) action is unknown. Inhibitory receptors for the neurotransmitters gamma-aminobutyric acid (GABA) or glycine are typically positively modulated by VAs and may be important targets for their action. The existence of a GABA receptor subtype (p), which is uniquely inhibited by VAs, suggested a chimeric receptor approach to identify portions of these proteins that may be necessary for anesthetic effects. METHODS: A silent mutation resulting in the addition of a unique restriction enzyme recognition site was introduced in GABA receptor type A alpha2, glycine alpha1, and p subunit cDNAs. Chimeras were constructed by rejoining restriction digest fragments and were expressed in Xenopus oocytes. Modulation of submaximal agonist-evoked peak currents by the VAs chloroform, enflurane, halothane, or isoflurane was measured using two-electrode voltage clamp. RESULTS: Four chimeras were constructed and designated glyrho, rhogly, alpha2rho, and rhoalpha2. Glyrho formed glycine-gated receptors with currents that were enhanced by chloroform or halothane but were inhibited by enflurane or isoflurane. Chimeras rhogly and rhoalpha2 each formed GABA-gated receptors with currents that were inhibited by chloroform or halothane but enhanced by enflurane or isoflurane. CONCLUSIONS: These data show, for the first time, functional divergence of VA action on a single protein target. The VAs in this study fall into two distinct groups with respect to their effects on these receptors. This grouping parallels the chemistry of these compounds. Our results support the involvement of multiple protein domains in the mechanism of VA modulation of GABA and glycine receptors.

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.

Fertility-sparing surgery, with subsequent pregnancy, in persistent gestational trophoblastic neoplasia: case report.

Gestational trophoblastic neoplasia (GTN) is primarily a disease of women of reproductive age. In most instances, it is cured by surgical evacuation of the uterus, with persistent disease being very sensitive to chemotherapy. Hysterectomy, recommended for persistent chemotherapy-resistant uterine disease, may be unacceptable to the woman who wishes to maintain her fertility. Uterine resection of localized disease, with uterine reconstruction, may be a viable alternative. A case is presented of a woman with persistent uterine GTN, treated with localized uterine resection and reconstruction, followed by two successful pregnancies and deliveries. The literature is reviewed and potential pregnancy complications of this management, particularly uterine rupture, are discussed.

The choice of embryo transfer catheter affects embryo implantation after IVF.

OBJECTIVE: Comparison of two transfer catheters in an IVF program. DESIGN: Prospective, randomized clinical study. SETTING: A private tertiary care center for ART. PATIENT(S): 66 patients < 38 years of age undergoing IVF and/or ICSI. INTERVENTION(S): Patients were randomly assigned to undergo ET using the Tomcat catheter (n = 32) or the TDT catheter (n = 34). MAIN OUTCOME MEASURE(S): Primary outcome measures were implantation and pregnancy rates. Secondary outcome measures were contamination with blood and/or mucus on the tip of the catheter, cramping or patient discomfort, and time required to complete ET. RESULT(S): Use of the Tomcat catheter resulted in significantly higher implantation (25.2% vs. 8.4%) and clinical pregnancy rates (47% vs. 14.7%) compared with the TDT catheter. All secondary outcome measures were similar for both catheters. CONCLUSION(S): The choice of ET catheter may affect the success of IVF-ET cycles. Use of the Tomcat catheter compared with the TDT catheter seems to result in significantly better efficiency of the ET procedure and is more cost effective.

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.

Successful twin pregnancy in a dual-transplant couple resulting from in-vitro fertilization and intracytoplasmic sperm injection: case report.

There are numerous reports of successful pregnancy following liver transplantation. Little information is available regarding the incidence and management of infertility in transplant recipients, particularly the use of artificial reproductive technologies. We present a case of a successful twin pregnancy resulting from in-vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) in a liver transplant recipient, whose partner was a renal transplant recipient with severe oligozoospermia. With careful evaluation and monitoring, and the involvement of appropriate consultants, artificial reproductive technologies can be safely used in transplant recipient couples experiencing infertility.

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.

Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse.

Xenogeneic transplantation of ovarian cortex into an immunodeficient animal host may be an approach toward fertility preservation for young female patients undergoing cancer therapy. Our objective was to evaluate the development of follicles in human ovarian cortex placed s.c. in non-obese diabetic-severe combined immune deficiency (NOD-SCID) mice (n = 54). The following variables were compared: 1) male versus female mice as hosts, 2) intact versus pituitary down-regulated mice, and 3) warm versus cold tissue transport. After 2 wk, 37 of 50 (74%) of the human xenografts contained follicles. At 12 wk after transplantation, exogenous gonadotropin stimulation resulted in follicle growth in 19 of 37 (51%) of the grafts, including the development of antral follicles, which could be palpated and visualized through the mouse skin. Significantly more developing follicles were identified in male versus female mice (13 of 17 vs. 6 of 20, respectively; p = 0.013) after stimulation. No difference was found between intact and pituitary down-regulated mice as hosts. Follicular survival was significantly increased by warm versus cold tissue transport. Our results suggest that s.c. ovarian cortex xenografting into NOD-SCID mice is feasible. Primordial follicles in ovarian xenografts retain their developmental potential and form antral follicles following gonadotropin stimulation.

Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.

Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of inhaled anaesthetics. The function of GABA(A) and glycine receptors is enhanced by a number of anaesthetics and alcohols, whereas activity of the related GABA rho1 receptor is reduced. We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric receptor constructs, we have identified a region of 45 amino-acid residues that is both necessary and sufficient for the enhancement of receptor function. Within this region, two specific amino-acid residues in transmembrane domains 2 and 3 are critical for allosteric modulation of both GABA(A) and glycine receptors by alcohols and two volatile anaesthetics. These observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetics.