Peripubertal Vitamin D3 Deficiency Delays Puberty and Disrupts the Estrous Cycle in Adult Female Mice1

Abstract

The mechanism(s) by which vitamin D(3) regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D(3) deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D(3)) null mice to study the effect of vitamin D(3) deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D(3)-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D(3) deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D(3)-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D(3)-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D(3)-replete diet. Estrous cycles were restored when vitamin D(3)-deficient Cyp27b1 null young adult females were transferred to a vitamin D(3)-replete diet. This study is the first to demonstrate that peripubertal vitamin D(3) sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D(3) is a key regulator of neuroendocrine and ovarian physiology.

Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

“…The timing of puberty was assessed by monitoring vaginal opening (VO) (Danilovich, et al 1999; Fernandez-Fernandez, et al 2006; Krewson, et al 2004; Sanchez-Garrido, et al 2013; Seminara, et al 2003) and preputial separation (PS) (Deboer and Li 2011; Korenbrot, et al 1977; Nathan, et al 2006; Novaira, et al 2014; Sanchez-Garrido et al 2013; Smith and Spencer 2012; Takashima-Sasaki, et al 2006) every day post-weaning. VO and PS are estradiol- and testosterone-dependent processes, respectively, and altered day of VO correlates with other measures of pubertal timing (Caron, et al 2012; Chehab, et al 1997; Dicken, et al 2012; Divall, et al 2010; True, et al 2015; Zhu et al 2010). Body weights were measured to 0.1 grams.…”

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology

“…Therefore, a more accurate picture of the association between PCOS and obesity might arise from the studies where PCOS would be detected through the screening of an unselected or minimally biased population. In addition, the studies performed so far do not make it possible to establish the direction of the association between PCOS and obesity, and the causes of this association (66,105). It is possible that environmental factors such as energy intake, energy expenditure or quality of diet, particularly the amount of AGEs, are somehow involved in PCOS pathogenesis (123), but the lack of rigorous methodology and carefully controlled direct observation of the lifestyle of patients leave the question unresolved.…”

Lower plasma 25-hydroxyvitamin D is associated with irregular menstrual cycles in a cross-sectional study

“…Knock-out mice missing the enzyme for converting vitamin D to its active form show estrus cycle disturbances including arrested follicular development, prolonged estrous cycles, and anovulation [6,7]. …”