Hypothalamic–pituitary–gonadal axis

One of the most important functions of the HPG axis is to regulate reproduction by controlling the uterine and ovarian cycles.[7] In females, the positive feedback loop between estrogen and luteinizing hormone help to prepare the follicle in the ovary and the uterus for ovulation and implantation. When the egg is released, the empty follicle sac begins to produce progesterone to inhibit the hypothalamus and the anterior pituitary thus stopping the estrogen-LH positive feedback loop. If conception occurs, the placenta will take over the secretion of progesterone; therefore the mother cannot ovulate again. If conception does not occur, decreasing excretion of progesterone will allow the hypothalamus to restart secretion of GnRH. These hormone levels also control the uterine (menstrual) cycle causing the proliferation phase in preparation for ovulation, the secretory phase after ovulation, and menstruation when conception does not occur. The activation of the HPG axis in both males and females during puberty also causes individuals to acquire secondary sex characteristics.

In males, the production of GnRH, LH, and FSH are similar, but the effects of these hormones are different.[8] FSH stimulates sustentacular cells to release androgen-binding protein, which promotes testosterone binding. LH binds to the interstitial cells, causing them to secrete testosterone. Testosterone is required for normal spermatogenesis and inhibits the hypothalamus. Inhibin is produced by the spermatogenic cells, which, also through inactivating activin, inhibits the hypothalamus. After puberty these hormones levels remain relatively constant.

The activation and deactivation of the HPG axis also helps to regulate life cycles.[7] At birth FSH and LH levels are elevated, and females also have a lifetime supply of primary oocytes. These levels decrease and remain low through childhood. During puberty the HPG axis is activated by the secretions of estrogen from the ovaries or testosterone from the testes. This activation of estrogen and testosterone causes physiological and psychological changes. Once activated, the HPG axis continues to function in men for the rest of their life but becomes deregulated in women, leading to menopause. This deregulation is caused mainly by the lack of oocytes that normally produce estrogen to create the positive feedback loop. Over several years, the activity the HPG axis decreases and women are no longer fertile.[9]

Although males remain fertile until death, the activity of the HPG axis decreases. As males age, the testes begin to produce less testosterone, leading to a condition known as post-pubertal hypogonadism.[8] The cause of the decreased testosterone is unclear and a current topic of research. Post-pubertal hypogonadism results in progressive muscle mass decrease, increase in visceral fat mass, loss of libido, impotence, decreased attention, increased risk of fractures, and abnormal sperm production.

Sex steroids also affect behavior, because sex steroids affect the brains structure and functioning. During development, hormones help determine how neurons synapse and migrate to result in sexual dimorphisms.[10] These physical differences lead to differences in behavior. While GnRH has not been shown to have any direct influence on regulating brain structure and function, gonadotropins, sex steroids, and activin have been shown to have such effects. It is thought that FSH may have an important role in brain development and differentiation.

Testosterone levels have been shown to relate to prosocial behavior.[11] This helps create synaptogenesis by promoting neurite development and migration. Activin promotes neural plasticity throughout the lifespan and regulates the neurotransmitters of peripheral neurons. Environment can also affect hormones and behavior interaction.[12]

Disorders of the hypothalamic–pituitary–gonadal axis are classified by the World Health Organization (WHO) as:[13]

• WHO group I of ovulation disorders: Hypothalamic–pituitary failure
• WHO group II of ovulation disorders: Hypothalamic–pituitary dysfunction. WHO group II is the most common cause of ovulation disorders, and the most common causative member is polycystic ovary syndrome (PCOS).[14]

Genetic mutations and chromosomal abnormalities are two sources of HPG axis alteration.[15] Single mutations usually lead to changes in binding ability of the hormone and receptor leading to inactivation or over activation. These mutations can occur in the genes coding for GnRH, LH, and FSH or their receptors. Depending on which hormone and receptor are unable to bind different effects occur but all alter the HPG axis.

For example, the male mutation of the GnRH coding gene could result in hypogonadotrophic hypogonadism. A mutation that cause a gain of function for LH receptor can result in a condition known as testotoxicosis, which cause puberty to occur between ages 2–3 years. Loss of function of LH receptors can cause male pseudohermaphroditism. In females mutations would have analogous effects. Hormone replacement can be used to initiate puberty and continue if the gene mutation occurs in the gene coding for the hormone. Chromosomal mutations tend to affect the androgen production rather than the HPG axis.

The HPG axis can be suppressed by hormonal birth control administration. Although often described as preventing pregnancy by mimicking the pregnancy state, hormonal birth control is effective because it works on the HPG axis to mimic the luteal phase of a woman's cycle. The primary active ingredients are synthetic progestins, which mimic biologically derived progesterone. The synthetic progestin prevents the hypothalamus from releasing GnRH and the pituitary from releasing LH and FSH; therefore it prevents the ovarian cycle from entering the menstrual phase and prevents follicle development and ovulation. Also as a result, many of the side effects are similar to the symptoms of pregnancy. Alzheimer's has been shown to have a hormonal component, which could possibly be used as a method to prevent the disease.[16] Male contraceptives utilizing sex hormones approach the problem in a similar way.

The HPG axis can also be suppressed by GnRH antagonists or continuous administration of GnRH agonist, such as in the following applications

• Ovarian suppression as breast cancer management, to prevent the body's formation of estrogen which may stimulate breast cancer cells. This is generally done by continuous administration of GnRH agonist.
• Ovulation suppression as part of controlled ovarian hyperstimulation in in vitro fertilization, in order to prevent the spontaneous ovulation of ovarian follicles before they can be harvested.

Ovulation induction is usually initially performed by giving an antiestrogen such as clomifene citrate or letrozole in order to decrease negative feedback on the pituitary gland, resulting in an increase in FSH with the aim of increasing folliculogenesis. It is the main initial medical treatment for anovulation.