Weight Status as a Moderator of Low Self-Esteem and Poor Sexual Functioning

Researchers have found that self-esteem and weight status can impact numerous aspects of an individual’s life, including reproductive health issues. However, there has been limited research specifically examining how self-esteem may affect female sexual functioning. The current study aims to examine whether self-esteem is a significant predictor of sexual functioning, and whether this relationship may change as a function of women’s weight status. Participants consisted of 730 women ranging from 18 to 49 years of age, who were recruited through an online questionnaire. Results indicate that higher levels of self-esteem predict better sexual functioning and weight status was found to be a significant moderator of this relationship; specifically, self-esteem was only found to predict sexual functioning for individuals at average or below-average weight status, and not for individuals who were of higher-than-average weight status. Findings have potential implications for physical and mental health professionals working with individuals trying to improve their sexual functioning

Effects of Prenatal Testosterone on Metabolic Dysfunction in Female Sheep

Excess androgen exposure during fetal life in the ewe permanently alters the number of agouti-related peptide (AgRP) neurons and their projections, suggesting a possible mechanism by which prenatal testosterone may contribute to insulin resistance and an increased risk of obesity in women with polycystic ovarian syndrome (PCOS). Using immunocytochemistry, we found a decrease of insulin receptors colocalized with AgRP in the arcuate nucleus of the hypothalamus in prenatal testosterone treated sheep, but no changes in colocalization with proopiomelanocortin (POMC). In addition, characterization of leptin-induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin signalling, was mapped in the hypothalamus and preoptic area of control sheep. We found that pSTAT3 colocalizes with POMC-ir neurons, minimally with kisspeptin, and is not co-expressed with GnRH. Overall, these results may lay the foundation for manipulation studies that will attempt to help address the metabolic and reproductive deficits seen in women with PCOS

Effects of Prenatal Testosterone on the Reproductive and Metabolic Neurons of the Sheep Hypothalamus

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting reproductively aged women. Women with PCOS and ewes prenatally exposed to testosterone (T) show similar reproductive and metabolic defects, including anovulatory dysfunctions stemming from abnormal gonadotropin releasing hormone (GnRH) secretion and insulin resistance. For this dissertation, I examined the effects of prenatal T treatment on androgen receptor (AR) and insulin receptor (IR) expression with the reproductive and metabolic neurons of the hypothalamus, the ARC KNDy (co-expressing kisspeptin, neurokinin B/dynorphin), AgRP (agouti-related peptide) and proopiomelanocortin (POMC) neurons, and the preoptic area (POA) kisspeptin neurons, and the GnRH neurons. I show that prenatal T treatment increases AR-immunoreactivity in several brain areas of the sheep brain and colocalization of AR with ARC KNDy and AgRP and POA kisspeptin neurons. Conversely, prenatal T treatment decreases IR colocalization with ARC KNDy and AgRP neurons, but not POMC neurons. Prenatal, but not postnatal interventions blocking androgen action (Flutamide, F) or increasing sensitivity to insulin (Rosiglitazone, R) prevent the prenatal T induced alterations in these populations. Lastly, leptin, an important metabolic signal that can influence GnRH secretion, indirectly activates ARC KNDy neurons through a pathway that may include AgRP and POMC neurons. Overall, these results show that prenatal exposure to T masculinizes the female brain and alters insulin signalling in the reproductive and metabolic neurons of the ARC and highlights the importance of prenatal interventions in blocking these effects. These changes may contribute the reproductive and metabolic dysfunctions associated with the PCOS phenotype

The Role of Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) in Normal and Neoplastic Physiology of Diet-Induced Obese Mouse Models

Obesity is a risk factor for various endocrine diseases including metabolic syndrome, cancer, and infertility, and its increasing incidence in society poses a major health concern. INPP4B is a tumor suppressor in breast cancer and a metabolic regulator that was shown to protect male mice from obesity and type 2 diabetes. Despite the wide expression pattern of INPP4B, its role in normal physiology is not fully described. It is also not known whether loss of INPP4B plays a role in obesity-associated increase in breast cancer initiation and progression or whether it alters tumor metabolism. In this dissertation, I showed that INPP4B loss affects the metabolic health of female mice, mammary gland development, and ERBB2- driven tumorigenesis in females. I found that Inpp4b-/- females develop high-fat diet (HFD) induced obesity, hyperglycemia, nonalcoholic fatty liver disease (NAFLD), and adipose tissue inflammation. I determined that NAFLD is due to increased hepatic lipid synthesis, while hyperglycemia is caused by insulin resistance, increased gluconeogenesis, and reduction in hypothalamic FGF21/FGFR1 signaling. Increased de novo lipogenesis in liver, decreased fat combustion in adipose tissue, and hypothalamic leptin resistance contributed to diet- induced obesity and inflammation of visceral adipose tissue. In mammary glands, I showed that INPP4B stimulates ductal branching by stabilizing progesterone receptor levels and inducing its transcriptional activity. The mammary glands of Inpp4b- knockout females on an HFD have elevation of AKT and p53 levels, as well as dysregulated leptin signaling and inflammation. In ERBB2 driven mammary gland tumorigenesis, both INPP4B loss of function and HFD accelerate tumor incidence and progression by reducing p53 expression and activity and increasing lipid synthesis. I also found that INPP4B plays an important role in male reproductive function. Inpp4b-/- males exhibit smaller testis and fewer sperm due to reduced rates of meiosis and increased apoptosis. In men, the expression of INPP4B is highest in post-meiotic germ cells and it declines significantly in testes of infertile men that lack mature sperm. Thus, INPP4B emerges as a new regulator of metabolic and reproductive health as well as in obesity-induced tumorigenesis

Epidural stimulation for urogenital dysfunction in the spinal cord injured rat.

Spinal cord injury (SCI) is a devastating, life changing event that greatly impacts quality of life. SCI can have body-wide, multi-system consequences including dysfunction within the urogenital system. Challenges with the urinary system include urinary incontinence, urine retention, and detrusor-sphincter dyssynergia all of which require maintenance through the regular use of catheters. Sexual dysfunction in men, who comprise nearly 80% of the SCI population, includes erectile dysfunction, anejaculation, retrograde ejaculation, poor expulsive force during ejaculation, and poor sperm quality. The treatment for sexual function in SCI men is focused more on fertility through the collection of sperm for insemination procedures rather than restoration of function. Unfortunately, SCI-induced urogenital dysfunction and its potential treatment are largely understudied even though regaining both urinary function and sexual function are a top priority among persons with SCI. In a rodent model of SCI, this work sought to determine the efficacy of spinal cord epidural stimulation (scES) as an intervention for urogenital dysfunction. First, three centers within the spinal cord (T13, L3 and L6) were targeted in female, Wistar rats with incomplete SCI to determine the impact stimulation has on urinary function during urethane-anesthetized ii cystometry. Then, the spinal generator for ejaculation was targeted in male, Wistar rats with anatomically complete and incomplete SCI to determine if scES could be used to induce ejaculation. Finally, an additional intervention, locomotor training, was added to determine if training could improve frequency of response to scES in rats with incomplete SCI. Measures of sperm health were also taken during the studies that focused on sexual health to document the timeline behind SCI-induced changes in spermatogenesis in a rodent model. scES was found to not only be impactful for triggering urine storage and bladder voiding behaviors when configured for urinary function, but was also found to induce ejaculation following SCI, highlighting the multifunctional effects of this treatment. This dissertation sets the frame-work for stimulation intensities, frequencies, and locations that are optimal for the recovery of urogenital function. These findings can be used to guide the translation of scES from bench to bedside

A Comprehensive Exploration of Sexual Wellbeing in Women with Endometriosis

Endometriosis is an illness that impacts at least 1 in 10 women of reproductive age worldwide. It has been hypothesized to have an impact on sexual functioning and sexual satisfaction. This study aimed to better understand the levels of sexual functioning and satisfaction in women with endometriosis as well as explore the predictors of sexual satisfaction in this population. A sample of 162 cisgender women, either diagnosed via surgery or with a probable diagnosis based on symptoms and medical history provided by a healthcare professional, participated in an online survey. Participants completed questionnaires assessing their sexual functioning, sexual satisfaction, and various factors related to endometriosis symptoms, as well as emotional and sexual wellbeing. Findings revealed that overall levels of sexual functioning and sexual satisfaction were notably low in this population, with many participants meeting criteria for sexual dysfunction. A regression analysis identified high sexual functioning and high sexual self-esteem as strong predictors of sexual satisfaction. Low fatigue and low resilience emerged as small yet significant predictors of sexual satisfaction. No differences in sexual functioning or sexual satisfaction were observed between the group with a surgical diagnosis of endometriosis and those with a probable diagnosis. These findings emphasize the challenges women with endometriosis may face in maintaining sexual wellbeing, regardless of diagnosis method. The study contributes to a growing body of literature by highlighting the importance of addressing both physical and psychological factors, such as sexual functioning and sexual self-esteem, when developing interventions aimed at improving sexual satisfaction for women with endometriosis

COMPARATIVE SERUM PHTHALATE CONCENTRATIONS IN FERTILE VERSUS INFERTILE MEN AND WOMEN IN SASKATCHEWAN

Objective: To determine whether serum phthalate concentrations differ in men and women with infertility compared to those without infertility in Saskatchewan Hypothesis: Serum phthalate concentrations will be greater in men and women with infertility compared to fertile men and women Setting: Patients undergoing assisted reproduction for the treatment of infertility; healthy volunteers recruited from the community Recruitment and sample collection: Infertile couples were recruited prior to in vitro fertilization (IVF) therapy for treatment of unexplained infertility (n=15), polycystic ovarian syndrome (PCOS, n=13), and male factor infertility (n=12); fertile men (n=15) and women (n=15) were recruited using poster advertisements. Blood samples were collected by venipuncture for phthalate analysis. Main outcome measures: Serum phthalates concentrations (ng/mL) Design: Prospective cohort pilot study Methods: In infertile couples, blood samples were collected on the following 3 days of the IVF cycle: early during ovarian stimulation, day of oocyte retrieval and day of embryo transfer. In healthy volunteers, 3 blood samples were collected over a 2 week period. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) was conducted to quantify concentrations of four phthalates: di-n-butyl phthalate (DBP), diethyl phthalate (DEP), di-(2-ethylhexyl) phthalate (DEHP) and diisodecyl phthalate (DIDP). Phthalate concentrations were compared among the four study groups using non-parametric Kruskal-Wallis and Mann-Whitney U post hoc tests. Results: Serum DEHP and DEP concentrations did not differ among control, unexplained, PCOS, and male factor infertility groups in both men and women (p>0.05). DBP in women did not differ among study groups (p=0.205). In contrast, DBP was lesser in men with unexplained, PCOS, and male factor infertility compared to controls (p < 0.05). Similarly, DIDP was lesser in women of couples with unexplained, PCOS and male factor infertility groups compared to fertile women (p < 0.05). Less DIDP was detected in men with unexplained and male factor infertility compared to the control group (p < 0.05) Conclusion: Serum phthalate concentrations in serum were lesser or not different in infertility patients undergoing IVF compared to fertile volunteers. These findings do not support the notion that serum phthalate concentrations are associated with human infertility. Further research is needed to determine whether phthalate concentration in blood cells and adipose tissue differ in infertile versus fertile men and women

Investigating physiological effects of weight loss on male fertility

Infertility is an emotionally devastating condition for a couple. It is defined as the inability to conceive following 1 year of regular unprotected intercourse. Infertility affects 15% of couples with nearly 50% of cases due to poor sperm quality in the male partner. i.e. ‘male factor infertility’. There are currently no approved pharmacological therapies to directly stimulate spermatogenesis; anti-oestrogens and aromatase inhibitors have limited effectiveness for the treatment of oligospermia and their usage is not supported by current clinical guidelines. Consequently, the only therapeutic option for male factor infertility is assisted reproductive technologies (ART), such as intra-cytoplasmic sperm injection (ICSI) which although effective are resource limiting and unaffordable for many couples worldwide. Therefore, there exists an important and unmet need to develop practical and cost-effective therapies for male factor infertility. Over the last 50 years, whilst sperm quality has declined, obesity has doubled in prevalence. Evidence suggests an association between obesity and male infertility, which makes weight loss a plausible answer to this rising endemic problem. Currently, bariatric surgery is the most effective treatment for obesity leading to major weight loss. However, effects on semen parameters are controversial, with some studies suggesting that the acute starvation-like state induced by bariatric surgery paradoxically reduces sperm function. Recent observational reports have suggested that milder dietary weight loss is associated with improved semen quality and DNA fragmentation index (DFI) in men with obesity and infertility. Low energy diet (LED) is a safe, well-tolerated and established method of achieving modest weight loss which could therefore provide a novel, non-pharmacological therapy for men with obesity-related male factor infertility. However to date, there are currently no prospective randomised controlled studies investigating whether weight loss via LED can improve sperm quality in obese men. Additionally, it is unclear what level of weight loss would be ideal to optimise sperm quality in obese men. This thesis outlines the first ever three randomised controlled studies investigating the physiological effects of weight loss by LED on sperm quality in obese fertile (study 1 and 2) and infertile men (study 3) respectively. I hypothesized that some, but not all, degrees of weight loss would significantly improve sperm concentration in men with obesity, with a potential threshold of weight loss in men leading to improvements 3 in sperm quality. I have measured novel molecular markers, such as seminal reactive oxygen species (ROS) and DFI, associated with male infertility in obese men undergoing weight loss. Collectively, these results will extend our understanding of the physiological effects of weight loss on sperm quality in obese men. This could potentially lead to larger studies determining the effect of weight loss on live birth rates in couples affected by obesity-related male infertility.Open Acces