In chronic stress, the reproductive axis is inhibited at all levels by various components of the activated hypothalamic-pituitary-adrenal (HPA) axis. CRH suppresses the secretion of GnRH either directly or indirectly, by stimulating the arcuate nucleus POMC peptide-secreting neurons. Glucocorticoids also exert an inhibitory effect on the GnRH neuron, the pituitary gonadotroph, and the gonads, and render target tissues of gonadal steroids resistant to these hormones. During inflammatory stress, the elevated concentrations of cytokines also result in suppression of reproductive function via inhibition of both GnRH pulsatile secretion from the hypothalamus and ovarian/testicular steroidogenesis. Suppression of gonadal function secondary to chronic stress-related activation of the HPA axis has been demonstrated in highly trained runners of both sexes and ballet dancers. These subjects display elevated concentrations of serum cortisol and plasma ACTH in the evening, increased 24-hour urinary free cortisol excretion, and diminished ACTH responses to exogenous CRH administration. Males have low LH and testosterone concentrations, and females have amenorrhea. Interestingly, obligate athletes develop withdrawal symptoms and signs following discontinuation of their exercise routine, which may reflect withdrawal from the daily exercise-induced elevation of opioid peptides and stimulation of the mesocorticolimbic system. Hypothalamic oligo-amenorrhea, improper folliculogenesis, oligo-anovulation, corpus luteum insufficiency and hypofertility have been associated with chronic stress. Defective blastocyst implantation, miscarriages, and premature labor and delivery can also occur in stressful pregnancies. From the side of the embryo and fetus, stress during gestation can lead to intrauterine size restriction and prenatal programming for a stressful extra-uterine environment. This entails acquisition of epigenetic vulnerability to later stress hyper-responsive and metabolic syndrome manifestations. Very early stress related to assisted reproductive technologies also entails later risks, such as metabolic syndrome manifestations, for the pregnancy product. The interaction between CRH and the hypothalamic-pituitary-gonadal axis is bi-directional, given that estrogen increases CRH gene expression via estrogen-response elements in the promoter region of the CRH gene. Therefore, the CRH gene is an important target of gonadal steroids and a potential mediator of sex-related differences in the stress-response and the activity of the HPA axis. Also, the dependence of the stress system upon estrogen explains estrogen withdrawal-related mood disorders, such as luteal phase dysphoric syndrome, postpartum blues and depression and climacteric depression.