Pregnancy induces maternal metabolic adaptations including mild glucose intolerance and weight gain in order to support fetal development and lactation. Adipose tissue (AT) function in gestation is featured by reduced insulin sensitivity and fat mass accrual which partly accounts for the weight gain in pregnant women and adaptation of glucose metabolism. A common metabolic pregnancy complication is gestational diabetes mellitus (GDM), a disease characterized by impaired glucose tolerance with onset in gestation. However, the relationship between AT expandability and glucose metabolism in gestation is not well understood. The goal of this thesis was to investigate the adaptations of human AT expansion induced by pregnancy, how these changes are reflected in pregnancies complicated with GDM and characterize a mouse model to study the mechanisms underlying this disease. This dissertation illustrates that pregnancy promotes AT expandability by a signaling mechanism between placental pregnancy-associated plasma protein-A (PAPP-A) and AT- insulin-like growth factor binding protein-5 (IGFBP5). In addition, gravidas with GDM showed impaired AT expansion. Studies investigating the relationship between PAPP-A and glycemic state demonstrated that low levels of PAPP-A in the 1sttrimester are highly associated with the development of GDM. Moreover, PAPP-A knockout mice exhibit reduced insulin sensitivity and impaired AT growth exclusively in gestation. These results expand the knowledge of AT biology in gestation and have the potential to improve maternal care by proposing PAPP-A as an early biomarker and possible therapeutic for GDM. It also introduces a new mouse model to study the etiology of gestational diabetes.

Background: Symptomatic knee osteoarthritis (OA) is an incurable condition that affects nearly 50% of adults, and women are twice as likely as men to develop OA. Throughout pregnancy, women experience large changes in morphology and gait mechanics, as well as changes in joint loading. It is possible these adaptations could cause lasting changes postpartum, which may potentially contribute to initiation of OA, thereby increasing the overall risk of OA for women. Purpose: This exploratory study looked to identify differences between lower limb gait mechanics of healthy nulliparous women and healthy parous women. Methods: 28 healthy female participants (14 parous, 14 nulliparous) were recruited for the study. Nulliparous participants had never given birth to a child, and were self-reported not pregnant. Parous participants had given birth to at least one full term infant (37 – 42 weeks) without complications between one to five years before data collection. Kinematic and kinetic data was collected for the lower body, using motion capture and in-ground force plates. Participants completed one quiet standing trial, and walked over-ground through the motion capture space at their preferred, fast, and set walking speeds (1.4 m/s). An ANOVA was performed to test if there were significant differences in between groups. Results: Q angle did not differ between groups. There was a significant main effect of group indicating a larger knee flexion angle at toe off (p = 0.060), smaller knee extension moment at heel strike (p = 0.0006), smaller first peak knee flexion moment (p = 0.040), and smaller peak hip adduction moment for the parous group compared to the nulliparous group (p = 0.003). Conclusions: Our data revealed a decrease in the moments experienced, which could possibly lead to degradation of cartilage due to under loading of the joint. We think this may be an indication that pregnancy could increase risk of OA, and therefore more research into this possibility is warranted.

Chlamydia is the most common bacterial sexually transmitted infection in the United States and worldwide. It often goes unnoticed due to lack of symptoms and left untreated it can ascend the female genital tract to cause sequelae like pelvic inflammatory disease and irreversible tubal infertility. In reproductive-aged women, female sex hormones estrogen (E2) and progesterone (P4) concentrations fluctuate during the menstrual cycle and are influenced by hormonal contraceptives and hormone replacement therapy. E2 and P4 influence genital Chlamydia infection in women and mice, but these multifactorial interactions are not entirely mapped out. The complex interplay of E2 and P4 with Chlamydia and the host response demand further study to determine the effect of hormonal environment and host susceptibility to Chlamydia. E2 primarily signals through estrogen receptors (ER) ERα and ERβ. We used ERα or ERβ knockout (KO) mice to study the role of E2 and ERs in chlamydial progression and examined the host immune response at day 9 post-infection, when we expected the immune response to be the most robust. ERαKO, but not ERβKO mice had significant differences in the progression of Chlamydia and the host immune response. Future studies should test the immune response at additional timepoints, and a model should be utilized wherein ERα and ERβ are simultaneously silenced by chemical knockdown of ERβ in ERα knockout mice using ER agonist ICI 182, 680. 3 Mice are widely used in Chlamydia research, but due to its short estrus cycle, infection cannot be established naturally before infected cells are shed. To overcome this, mice are pretreated with depot medroxyprogesterone acetate (DMPA), an exogenous progesterone that halts the estrus cycle. However, a mouse model not reliant on DMPA pretreatment is needed because 1.) DMPA can affect the immune response and 2.) the hormonal environment in women is not static. Our model uses mice that are ovariectomized to stop the production of endogenous E2 and P4, then treated with physiologically relevant levels of E2 and P4 via implantation of a hormone-filled capsule. We observed that E2 protected mice from Chlamydia, making our model a good alternative for in vivo Chlamydia studies.

The description and interpretation of Latinas’ experience with chemotherapyinduced premature menopause from breast cancer treatment were explored in this study, which utilized an interpretive descriptive method from a feminist lens, and Knobf’s (1998, 2002) “Carrying on” theory. The specific aims of the study and the interview questions were guided by the state of the science literature. Overall, the impact of physiological effects, psychosocial effects, barriers, influencing factors that made their experience easier or harder, and how participants adjusted to a cancer diagnosis, treatment course, and menopause transition were described as bigger than the menopause experience alone. Participants also described a period of uncertainty or “ever-changing landscape” that began at the time of diagnosis and continued through survivorship. The impact of information, access to healthcare, acculturation levels, support, and a sense of control were elucidated as important factors in “working through” the experience. A range of collateral data sources were employed. Study limitations and future implications for practice, research, and health policy were demarcated.

Background Female stress urinary incontinence (SUI) greatly affects quality of life. The midurethal sling (MUS) procedure has been widely accepted as the standard of care treatment for SUI, although there is little information regarding patients' subjective reports of symptom improvement. Objectives The objective of this study was to identify clinical and demographic characteristics that predict subjective symptom improvement following MUS procedures in women with SUI. Materials and Methods The study design was retrospective cohort. Subjects included women who underwent MUS between 2006 and 2008, returned mailed surveys and met our predefined inclusion criteria. Pre-operative data included demographics, prior surgery, co-morbid diseases, urodynamics and concomitant reconstructive surgery. Subjective improvement was measured by score improvement on the UIQ-7, UDI-6, the UDI stress subscale and Question 3 of the UDI, "Do you experience urine leakage related to physical activity, coughing, or sneezing?" Results The mean age of the study sample was 57 years, parity was 2.5 and BMI was 28. Subjects with lower MUCP demonstrated more improvement on the UIQ-7. ΔUDI-6 stress subscale scores were more sensitive to symptom change than either the ΔUDI-6 or ΔUIQ-7. Older, menopausal subjects with urethral hypermobility and concomitant vaginal suspension showed less improvement than subjects without these characteristics. After controlling for urethral straining angle, PVR, menopause and time out from surgery, older age and concomitant vaginal suspension were associated with persistent post-op symptoms on the UDI-6 Question 3 and age remained the only variable associated with persistent symptoms on the UDI-6 stress subscale. Conclusion Concurrent vaginal suspension and advancing age were risk factors for persistent symptoms following MUS procedures in patients with SUI. Symptoms may recur after 24 post-operative months. Clinicians are encouraged to provide additional preoperative counseling to those women who are at greatest risk for persistent symptoms.

Chlamydia trachomatiscauses a bacterial sexually transmitted infection, Chlamydia, that is often chronic and casues reproductive complications in women. We hypothesized that Chlamydia infection increases local acetylcholine (ACh) production, which regulates the host’s inflammatory response to the infection. Female mice infected with C. muridarumwere sacrificed at days 3, 9, 15, and 21 post-infection, genital tract tissues harvested, and immunohistochemistry performed to enumerate ACh-producing cells. Infection increased the number of ACh-producing cells in cervical tissue at days 3,15, and 21 post-infection (pi), uterine tissue at day 3 and 9 pi, and ovarian tissue day 3, 15, and 21 pi. These findings suggest that C. trachomatis increases ACh production, which may suppress the host’s immunity and aid in establishing chronic infection.

Chlamydia trachomatis is the most prevalent agent of bacterial sexually transmitted infections in the world. However, a profuse number of cases are unreported, as the infection is often asymptomatic. Sequelae such as pelvic inflammatory disease, an increased risk of cervical cancer, premature birth, and perinatal infections in pregnant women can occur. Inflammation occurs in the body in response to infection or injury. Although inflammation can lead to some unwanted secondary effects, such as pain, it serves to return the body to homeostasis by restoring injured tissues and eliminating pathogens. One recently identified connection between the central nervous system and the immune system that regulates inflammation is the cholinergic anti-inflammatory pathway (CAP). In the CAP, pathogen-associated molecular patterns stimulate the vagus nerve to activate the pathway, which ultimately results in acetylcholine (ACh) release, which down regulates inflammation. We hypothesized that genital chlamydial infection would increase the expression of choline acetyltransferase (ChAT), the enzyme that synthesizes ACh, in the female murine genital tract, therefore down regulating inflammation and promoting chlamydial infection. Transgenic female mice carrying a ChAT-promoter driven GFP reporter gene were vaginally infected with C. muridarum. Mice were sacrificed on days 3, 9, 15, and 21 post infection; cervical, uterine horn, and ovarian tissues were removed and embedded in paraffin. Small sections of each tissue were cut and mounted onto slides. The tissue sections were then stained for the expression of ChAT using immunohistochemical techniques. Finally, tissue sections were viewed under a microscope for positive staining and the data was analyzed. The results indicated that there is a significant increase in the number of cells that express ChAT in genital tract of chlamydia-infected mice versus non-infected mice.

Background: The Veterans Health Administration (VHA) encourages depression screening and treatment for pregnant veterans; however, rates of depression symptoms and treatment utilization during pregnancy have not been well-studied. Methods: We used data from the Maternity Care Coordination for Women Veterans cohort study. Specifically, our aims were to: 1) examine rates and correlates of depression symptoms in a sample of pregnant veterans; 2) understand mental health care treatment utilization and explore the experiences of veterans accessing mental health care at the VHA during pregnancy; and 3) examine VHA mental health provider's perspectives on depression screening and treatment in the perinatal period. Findings: Depression symptoms were present in 28% of pregnant veterans in our sample. Social support and employment decreased odds of symptoms; history of anxiety, antidepressant use, and active duty service resulted in increased odds of symptoms. Nearly 70% of women veterans with prenatal depression symptoms received at least one mental health visit or antidepressant prescription during pregnancy. However, symptomatic pregnant women without a history of depression were less likely to receive care. Mental health providers identified absence of screening protocols and referral procedures and variability in risk/benefit conversations surrounding antidepressant use as areas of weakness for VHA mental health care during the perinatal period. Conclusions: Depression symptoms were present in nearly one in every three pregnant veterans. Depression treatment during pregnancy is complex, requiring individualized care. Policies for depression screening, referrals to providers, and medication review could be better encouraged to improve standardized care across the VHA.

The hypothalamo-neurohypophysial model has been studied for many years. Of note, when the axons of the magnocellular, peptidergic neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) are transected or crushed, varying degrees of polydipsia and polyuria ensue as the result of measurable losses of vasopressin (AVP) within the organism's circulation. Following insult, these hypothalamic cells show a remarkable capacity to reorganize themselves within the proximal areas of the infundibular stalk and median eminence and form what has come to be known as a new 'mini neural lobe' . While the surviving neurons sprout new projections toward the level of the external zone, vascular hypertrophy is marked throughout the new neurohypophysis and new neurohemal contacts have been identified (at the ultrastructural level) associated with these vessels. In parallel with this vascular hypertrophy is a measurable re-release of vasopressin into the circulation. This new 'mini neural lobe' now has the morphological and physiological appearance of an intact neural lobe and is capable of releasing AVP in response to changes in water balance. While the ability of these axons to reorganize is more characteristic of the peripheral nervous system (PNS), this model system provides an unique opportunity to study axonal regeneration of the central nervous system (CNS). Not only the mechanisms underlying the restoration of AVP function following axotomy but the extent to which various magnocellular neuron populations are involved in the regenerative process may also be analyzed. Before attempting to identify putative markers associated with this regenerative process, it was necessary to carefully characterize the system following axonal injury. Using Sprague Dawley rats, we repeated previous physiological studies which had examined the intake of water and output of urine following hypophysectomy. In addition, we also correlated the restoration of water balance with the return of AVP release, as measured by radioimmunoassay. These data defined a temporal framework in which magnocellular AVP regeneration occurs. As a result of repeating these physiological studies, we noted several inconsistencies between other previously published work. First, the time course of AVP recovery did not agree with other published results, nor did the first appearance of AVP immunoreactivity . We did not observe a complete recovery of water balance as previously reported and the degree of magnocellular death was inconsistent with other reports. In light of these many conflicting observations between several historical reports and our own results, we did a basic physiological re-characterization of the hypothalamo-neurohypohysial system following hypophysectomy. By means of immunohistochemistry, we also demonstrated the re-appearance of AVP within the new the 'mini neural lobe ' concomitant with the increased appearance of synapsin I, a marker associated with the presence of mature and presumably functioning synapses to be no sooner than 28 days following surgical removal of the hypophysis. Immunocytochemistry was also used in conjunction with retrograde fluorescent labeling to extend the previous studies and include a 2-D analysis of cell survival throughout the PVN and SON following hypophysectomy or neurohypophysectomy. As reported previously, magnocellular neuronal loss is greater within the SON, particularly the hypophysectomized subject, and less so within the PVN; again with the greater loss in the PVN of the hypophysectomized animal. Based upon our observations and other recent reports, we suggest the possibility that some cells of the hypothalamo-neurohypophysial system or some other extrahypothalamic cell population may be capable of expressing vasopressin in response to neurohypophysectomy. We provide initial evidence that glial cells of the third ventricle may indeed be involved. Finally, one of the ultimate goals of using this as a model system of CNS regeneration is to understand the underlying mechanisms and components essential to central nervous tissue regeneration. Toward that end I have been involved with the initial studies to optimize an adenovirus delivery system which will be capable of incorporating various putative neurotransmitter and/or peptide anti-sense messages, being injected into the neurohypophysis and transported back into the cells of the hypothalamo-neurohypophysial system. Once these antisense sequences are expressed by the cells following axotomy, the sequence of expression of various proteins in response to injury may be elucidated.

Background: One in ten people in the U.S. are affected by a substance use disorder (SUD), roughly one third of whom are women. Rates of unintended pregnancy are higher in this population than in the general public. Little is understood about how women with SUD use prescription contraception and think about pregnancy. Methods: By analyzing Medicaid claims data and conducting qualitative interviews with women with SUD, this doctoral thesis seeks to: 1) compare any use of and consistent, continued coverage by prescription contraceptives between women with and without SUD; 2) determine the extent to which SUD is associated with pregnancy, abortion, and adverse feto-maternal outcomes in women who use prescription contraception; and 3) explore facilitators of and barriers to contraceptive utilization by women with SUD, using qualitative interviews. Results: Compared to women without SUD, women with SUD are less likely to use any prescription contraceptive, particularly long-acting reversible methods. Among women who do use long-acting methods, SUD is associated with less continued, consistent coverage by a prescription contraceptive. Among women who use contraception, SUD is also associated with increased odds of abortion. When interviewed, women with SUD report fatalistic attitudes towards pregnancy planning, and have difficulty conceptualizing how susceptibility to pregnancy may change over time. Women with SUD also report that pregnancy has substantial impact on their drug treatment prospects. Conclusions: This study is the first to examine contraceptive utilization by women with SUD who are enrolled in Medicaid or state-subsidized insurance. Our study may help to inform clinical practice and policy development to improve the reproductive health and wellbeing of women with SUD.