Mutations in low-density lipoprotein receptor-related protein 5 have been found to be significantly associated with PLO.[12–14] Low-estrogen status after long-term anorexia, stress, excessive exercise and even premature ovarian failure, have been documented to be correlated with PLO.[15] Some studies have shown that increased calcium requirement for fetal skeletal development may also contribute to the development of PLO. This evidence concerns the gene LRP5 and primary ovarian failure.