Maternal Vitamin D Deficiency: Defective Programming of Hypothalamic-Pituitary Function Causes Reproductive Dysfunction in Female Offspring

Presentation Number: OR15-2
Date of Presentation: March 6th, 2015

Cari Nicholas*1, Andrew Wolfe2, Yan Sun1 and Genevieve S. Neal-Perry3
1Albert Einstein College of Medicine, Bronx, NY, 2Johns Hopkins University School of Medicine, Baltimore, MD, 3University of Washington, Seattle, WA

Abstract

Vitamin D deficiency (VD-) affects over one billion people worldwide. In the United States, more than 40% of pregnant women and nearly 20% of children are estimated to be vitamin D (vitD) deficient. The vitD receptor is expressed throughout the hypothalamic-pituitary-gonadal (HPG) axis raising the possibility that vitD signaling is important for normal HPG axis and reproductive function. We previously reported that in utero and lactational VD- results in programmed estrous cycle dysfunction. To determine the critical window of development when VD- programs reproductive dysfunction in adult females, we exposed female mice to dietary VD- at three specific developmental stages: 1) in utero, 2) lactation or 3) in utero and lactational (early life). We hypothesize that exposure to in utero VD- programs reproductive dysfunction in female mice through effects on the hypothalamus. We used vaginal opening and cytology to assess puberty and estrous cyclicity in females. Neither in utero, lactational nor early life VD- affected puberty. However, regardless of when in development female mice were exposed to VD-, they developed prolonged and irregular estrous cycles characterized by oligoovulation (P<0.05). These findings suggested that developmental vitD sufficiency is important for normal HPG axis function in adulthood. To determine how early life VD- disrupts HPG axis function, we collected serum samples during estrus, diestrus and proestrus and quantified serum LH. Females exposed to early life VD- released 40% less LH on the day of proestrus. To determine if the reduced LH surge amplitude in early life VD- resulted from abnormal hypothalamic responsiveness to excitatory input, we conducted kisspeptin (KISS; 10 pmol) challenges in ovariectomized and estradiol-benzoate and progesterone primed females. Briefly, control mice and mice exposed to early life VD- were infused intracerebroventricularly with KISS immediately after basal blood collection. Blood was collected 10 min after KISS infusion, and then at 20 min intervals for a total of 50 min. Despite similar gonadal steroid and baseline gonadotropin levels, peak LH release in females exposed to early life VD- was 31% less than controls infused with KISS (p <0.05). In contrast, FSH release was not affected. This study suggests that early life VD- resulting from maternal VD- may program estrous cycle dysfunction through effects on hypothalamic responsiveness to KISS excitatory input.

 

Nothing to Disclose: CN, AW, YS, GSN