Hypothalamic–pituitary–gonadal axis

The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

The HPG axis plays a critical part in the development and regulation of a number of the body's systems, such as the reproductive and immune systems. Fluctuations in this axis cause changes in the hormones produced by each gland and have various local and systemic effects on the body.

The axis controls development, reproduction, and aging in animals. Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus by GnRH-expressing neurons. The anterior portion of the pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the gonads produce estrogen and testosterone.

In oviparous organisms (e.g. fish, reptiles, amphibians, birds), the HPG axis is commonly referred to as the hypothalamus-pituitary-gonadal-liver axis (HPGL-axis) in females. Many egg-yolk and chorionic proteins are synthesized heterologously in the liver, which are necessary for ovocyte growth and development. Examples of such necessary liver proteins are vitellogenin and choriogenin.

The HPA, HPG, and HPT axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function.

The hypothalamus is located in the brain and secretes GnRH. GnRH travels down the anterior portion of the pituitary via the hypophyseal portal system and binds to receptors on the secretory cells of the adenohypophysis. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.

The pulsatile release of GnRH by hypothalamic neurons is necessary for adequate gonadotropin production by the pituitary. Continuous secretion of GnRH uncouples the gonads from pituitary regulation and leads to decreased synthesis of gonadotropins and hypogonadism. The frequency and amplitude of GnRH pulses are tightly regulated, particularly in women, over the course of the reproductive cycle. For instance, the FSHβ gene exhibits ultrasensitive behavior in response to GnRH pulse frequency, with its expression sharply increasing at lower pulse frequencies and decreasing at higher frequencies. This ultrasensitive response is enhanced by the involvement of multiple mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK, p38, and ERK5, which form a complex network of feedback and feedforward loops. Different pulse frequencies of GnRH affect the production of gonadotropins, with rapid GnRH pulsatility promoting LH synthesis and slower pulsatility favoring FSH production. This ultrasensitive mechanism ensures that small changes in GnRH pulse frequency can lead to significant alterations in gonadotropin synthesis, thereby fine-tuning the reproductive endocrine system.

These two hormones play an important role in communicating to the gonads. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells. Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis. Interestingly, follistatin has been shown to also be upregulated by exercise to inhibit the inhibition of muscle growth by myostatin. This role of exercise in modulating activin inhibition and influencing the HPO axis presents a compelling direction for future exercise physiology research.