As more women conceive later in life, the risk of having a child with a genetic disorder increases (1). Prenatal screening provides the opportunity to discontinue such pregnancies. Despite medical advances that allow early detection of developmental abnormalities in pregnancy, recent changes in abortion access in many US states will soon eliminate this option for millions of women. Combining the reduced access to abortion with the rise in maternal age will undoubtedly lead to more children born with genetic abnormalities, including Down syndrome, which occurs in 1 in 30 pregnancies for women aged 45 (1, 2). Thus, approaches to improve the challenges of living with genetic disorders are needed. On page 1064 of this issue, Manfredi-Lozano et al. (3) demonstrate that gonadotropin-releasing hormone (GnRH) improves cognitive function in mouse models of Down syndrome and Alzheimer’s disease and in men with Down syndrome.

 

Down syndrome is characterized by cognitive disability and is often associated with reduced or loss of olfaction. The loss of olfaction in Down syndrome is frequently associated with deficits in fertility, both of which start around puberty. Coexpression of infertility with loss of olfaction is called Kallmann syndrome (4). This is caused by developmental impairments of the olfactory placode, an area in the head that gives rise to the olfactory system and where GnRH-expressing neurons are born. During development, GnRH neurons migrate from the olfactory placode into the brain and locate primarily in the ventral forebrain within the hypothalamus. From the hypothalamus, the majority of GnRH neurons project to the median eminence to release GnRH in a pulsatile pattern, which is required for GnRH to promote its effects on reproductive function (5).

 

Throughout life, GnRH release onto the pituitary gland promotes release of the gonadotropin hormones luteinizing hormone and follicle stimulating hormone, which act on the testes in males and on the ovaries in females. Fine-tuning of GnRH release patterns is required throughout life, whereby GnRH release is substantially increased in the pubertal period. After puberty, GnRH continues to promote gonadotropin release, which in adulthood is required for testosterone and sperm production in males and ovarian follicle maturation and ovulation in females. Loss of GnRH or its receptor causes hypogonadism and infertility.