The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–testicular/ovarian 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 testosterone and estrogen.
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.
Location and regulation
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 inh ibit 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.
Kisspeptin helps to regulate the HPO axis by acting as a mediator. This neuropeptide, encoded by the KISS1 gene, primarily exerts its effects by binding to its receptor, KISS1R (also known as GPR54), on GnRH neurons in the hypothalamus. By stimulating GnRH release, kisspeptin indirectly promotes the secretion of LH and FSH from the pituitary gland. Two main populations of kisspeptin neurons have been identified in the hypothalamus: one in the arcuate nucleus (ARC) and another in the anteroventral periventricular nucleus (AVPV) in rodents, or the preoptic area (POA) in humans. These neurons are involved in both the negative and positive feedback mechanisms of estrogen on GnRH secretion, with ARC kisspeptin neurons mediating negative feedback and AVPV/POA neurons facilitating the preovulatory LH surge. Kisspeptin's influence extends beyond the hypothalamus, as it has been shown to have direct effects on the pituitary and ovaries, regulating processes such as follicle development, oocyte maturation, and ovulation. Dysregulation of the kisspeptin system has been implicated in various reproductive disorders, including polycystic ovary syndrome (PCOS) and infertility, highlighting its importance in maintaining normal reproductive function. These kisspeptin neurons act as central processors for relaying signals from the periphery to GnRH neurons and are essential for the onset of puberty and maintenance of normal reproductive function.
In addition, leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. Kisspeptin also influences GnRH secretion.
Leptin, an adipocyte-derived hormone, exerts a stimulatory effect on GnRH secretion through multiple mechanisms. While GnRH neurons do not express leptin receptors directly, leptin influences GnRH neuronal activity indirectly via regulation of downstream mediators such as neuropeptide Y, α-melanocyte-stimulating hormone, and agouti-related peptide. Furthermore, leptin promotes GnRH function by acting on kisspeptin neurons, which regulate GnRH release as discussed previously. In the hypothalamus, leptin has been shown to accelerate GnRH secretion dose-dependently, specifically affecting pulse frequency rather than amplitude. At the pituitary level, leptin directly stimulates the release of LH and, to a lesser extent, FSH via nitric oxide synthase activation in gonadotropes.
Insulin, another metabolic hormone, also plays a significant role in modulating GnRH secretion. Central infusion of insulin has been associated with increased LH secretion in diabetic male sheep and female rats, suggesting a neuronal action of insulin in regulating LH release. Insulin receptor signaling in GnRH neurons has been shown to increase GnRH pulsatile secretion and consequent LH secretion, particularly in the context of obesity. This effect appears to be sexually dimorphic, with a more pronounced response observed in female rodents compared to males.
In contrast to the stimulatory effects of leptin and insulin, ghrelin exerts predominantly inhibitory effects on GnRH secretion. Ghrelin, commonly known as the "hunger hormone," has been shown to decrease the firing rate and burst frequency of GnRH neurons in a sex- and estrous cycle-dependent manner. This inhibitory effect is mediated through the growth hormone secretagogue receptor (GHS-R) expressed on GnRH neurons. Ghrelin's action on GnRH neurons involves a decrease in the frequency of GABAergic miniature postsynaptic currents and is dependent on retrograde endocannabinoid signaling. At the hypothalamic level, ghrelin has been demonstrated to inhibit GnRH secretion from hypothalamic fragments of ovariectomized female rats.
The integration of these metabolic signals ensures that reproduction occurs under favorable energetic conditions. Leptin serves as a permissive signal for puberty onset, with a threshold level necessary for normal pubertal progression. Insulin sensitivity in GnRH neurons is important for maintaining normal reproductive function, particularly in the face of metabolic challenges such as obesity. Ghrelin, on the other hand, acts as a signal of energy insufficiency, with persistently elevated levels potentially delaying the normal timing of puberty. Evolutionarily speaking, this makes sense as it is unwise for the body to spend excess energy that it does not have to grow the body larger. Additionally, the effects of these hormones on GnRH secretion can vary depending on the stage of the estrous cycle, nutritional status, and other physiological factors.
From a larger picture, the HPO axis exhibits a concept known as bistability which is responsible for the maintenance of a cyclical pattern in ovarian activity. This bistability is most obvious in the transition between the follicular and luteal phases, and arises from interactions between positive and negative feedback loops involving GnRH, LH, FSH, estrogen, and progesterone. The kisspeptin system creates a switch-like mechanism driving the transition from negative to positive feedback. The distinct hormone profiles characterizing each phase represent two stable states, with sharp transitions between them ensuring proper timing of ovulation and endometrial preparation.
As previously stated, during the follicular phase, estrogen and LH levels rise, and entry into the luteal phase does not occur unless a surge in these hormones occurs up to a certain threshold. Progesterone levels remain low until after the surge, when they rise in the luteal phase. Throughout this cycle, inhibins provide a clear picture of bistability. These dimeric glycoprotein hormones, primarily produced by granulosa cells in the ovary, act as negative feedback regulators of FSH secretion from the anterior pituitary. During the follicular phase, inhibin B is the predominant form, with its levels rising in parallel to the growth of the dominant follicle. This increase in inhibin B, along with rising estrogen levels, contributes to the suppression of FSH secretion, which is critical for the selection of a single dominant follicle. As the cycle progresses to the luteal phase, inhibin A becomes the primary form produced by the corpus luteum. The declining steroid production by the corpus luteum and the dramatic fall of inhibin A towards the end of the luteal phase allow for FSH to rise during the last few days of the menstrual cycle. This elevation in FSH is important for the recruitment of a new cohort of ovarian follicles in the subsequent cycle.
After menstruation begins, FSH levels decrease due to estrogen's negative feedback and inhibin B produced by the developing follicle. FSH stimulates aromatase activity in granulosa cells, converting androgens to estrogen. As FSH levels drop, the surrounding follicles develop a more androgen-rich environment. Additionally, the granulosa cells of the dominant follicle release peptides that may inhibit the growth of nearby follicles through autocrine and paracrine mechanisms. The development of the dominant follicle occurs in three stages: recruitment, selection, and dominance. Recruitment happens during the first four days of the menstrual cycle when FSH stimulates the recruitment of a group of follicles from the non-growing pool. Between days 5 and 7, one follicle is selected to continue development while the others undergo atresia, a process influenced by anti-Müllerian hormone (AMH). By day 8, the selected follicle dominates by promoting its growth and inhibiting the development of others.