In the United States, nearly one in three women of childbearing age is obese. As maternal obesity impacts the health of offspring, it is imperative to obtain a better understanding of the mechanisms that drive these influences. It remains unclear whether the underlying pathophysiology is related to abnormal hypothalamic- pituitary dynamics, abnormal ovarian environment, or both. Obesity is associated with decreased pituitary output of luteinizing hormone (LH) and FSH, inadequate folliculogenesis and reduced ovarian steroid and protein production. The persistent deficit in FSH secretion, despite the lack of restraint and normal pituitary FSH reserve, remains unexplained. FSH is secreted intermittently in pulses, which are important for hypothalamic-pituitary-ovarian (HPO) axis regulation. FSH pulsatile secretion has been challenging to characterize. We hypothesize that one reason a lack of clarity still exists is that current analytic methods fail to appropriately characterize the hormone secretion dynamics of FSH and its feedback. The overriding objective is to define essential characteristics of FSH-ovarian interactions using a multi- disciplinary approach. We build upon (1) our existing Bayesian approaches to modeling pulsatile hormones to develop a biologically relevant and flexible model, and (2) transgenic FSH mouse model showing that pulsatile FSH secretion dramatically enhances ovarian function.
AIM 1 focuses on showing how new joint models leverage the clearer information about LH pulses to clarify FSH pulses. Associations between pulse locations and amplitudes of both hormones will be used to differentiate between constitutive and pulsatile secretion of FSH. We will utilize existing experimental data from the PI's previously conducted NIH-funded obesity studies in a cost-effective way.
In AIM 2, we will determine if exogenous FSH administered in a pulsatile fashion results in a significant increase of ovarian hormones in obese women. Serial inhibin B and E2 levels will be measured in obese and normal weight women undergoing frequent blood sampling studies before and after GnRH antagonist blockade.
AIM 3 will determine the FSH pulse characteristics and effects of diet-induced obesity on FSH and its secretagogues in a transgenic mouse model. Serial blood sampling and a multiplex assay that simultaneously measures LH and FSH in low volumes of mouse serum will be used. We will also measure how FSH-responsive ovarian genes would be affected, perform fertility analysis, and test the oocyte quality. Ultimately, we anticipate that our results will pinpoint the component of the HPO axis (central vs. ovary) that is primarily affected in hormonal dysregulation in obese women. Identification of a direction will inform future studies of interactions between altered HPO dynamics and possible molecular mechanisms. We will also develop a general analytic framework to clarify pulsatile secretion in any linked hormones.
Excess maternal weight, especially obesity, influences almost every aspect of fertility, from conception to problems during pregnancy. We will use novel statistical methods as well as clinical and animal studies to clarify the hormonal changes behind reproductive health conditions. A better understanding of reproductive hormonal changes in obese women may offer a way to identify new treatments.
|Roy, Sambit; Gandra, Divya; Seger, Christina et al. (2018) Oocyte-Derived Factors (GDF9 and BMP15) and FSH Regulate AMH Expression Via Modulation of H3K27AC in Granulosa Cells. Endocrinology 159:3433-3445|
|Kumar, T Rajendra (2018) Fshb Knockout Mouse Model, Two Decades Later and Into the Future. Endocrinology 159:1941-1949|
|Das, Nandana; Kumar, T Rajendra (2018) Molecular regulation of follicle-stimulating hormone synthesis, secretion and action. J Mol Endocrinol 60:R131-R155|
|Liu, Huayu; Carlson, Nichole E; Grunwald, Gary K et al. (2018) Modeling associations between latent event processes governing time series of pulsing hormones. Biometrics 74:714-724|
|Gilbert, Sara Babcock; Roof, Allyson K; Rajendra Kumar, T (2018) Mouse models for the analysis of gonadotropin secretion and action. Best Pract Res Clin Endocrinol Metab 32:219-239|
|Liu, Huayu; Polotsky, Alex J; Grunwald, Gary K et al. (2018) Bayesian analysis improves pulse secretion characterization in reproductive hormones. Syst Biol Reprod Med 64:80-91|
|Kallen, Amanda; Polotsky, Alex J; Johnson, Joshua (2018) Untapped Reserves: Controlling Primordial Follicle Growth Activation. Trends Mol Med 24:319-331|
|Kumar, T Rajendra (2018) Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models. Endocrinology 159:2-8|
|Kumar, T Rajendra (2017) The SO(H)L(H) ""O"" drivers of oocyte growth and survival but not meiosis I. J Clin Invest 127:2044-2047|
|Horton, K W; Carlson, N E; Grunwald, G K et al. (2017) A population-based approach to analyzing pulses in time series of hormone data. Stat Med 36:2576-2589|