Understanding the male Hypothalamic-Pituitary-Gonadal axis (HPG axis)

Introduction to the HPG axis

The hypothalamic-pituitary-gonadal axis (HPG axis) alludes to the connection between the hypothalamus, pituitary gland, and gonads, of which in males are the testes.

This is the system that is understood to govern the release of the gonadal steroids testosterone and hence oestradiol in the testes via a cascade of hormones, including gonadotropin-releasing hormone (GnrH), follicle-stimulating hormone (FSH),and luteinising hormone (LH).

The system works in a negative feedback loop manner to have an outcome of moderating free circulating testosterone and therefore also oestradiol as a downstream product of testosterone .

It is an important control system important to the development and regulation of the reproductive system, mood and cognition, immune system, as well as having implications on rate of aging.

The HPG feedback loop

In the brain
1. The hypothalamus produces gonadotrophin releasing hormone (GnRH), which it then secretes in a pulsatile pattern, which enters the hypophyseal portal system (a direct line blood vessel from hypothalamus to pituitary) in order to reach the pituitary gland.
  - ASIDE: pulsing patterns and relationship to LF & FSH
    
    “it is differing pulses in GnRH that lead to gonadotrope expression of LH over FSH, or vice versa, with LH synthesis being induced by fast GnRH pulses (>1 pulse per hour) and FSH by slower pulse frequencies (<1 pulse per 2–3 hours)”
    
    Clavijo and Hsiao. Update on male reproductive endocrinology (2018)
2. GnRH binds to GnRH receptors located on pituitary “gonadotrope cells” in the anterior pituitary. This stimulates the pituitary gland to secrete two hormones vital for reproduction, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), as well as adrenocorticotropin, growth hormone (GH), prolactin, and thyroid-stimulating hormone(TSH). These hormones will all enter the peripheral circulatory system to reach corresponding receptor sites.
In the gonads (testes in males)

LH and FSH act on receptors in cells in the testes including Leydig, Sertoli and germ cells.
1. In Leydig cells, LH will stimulate the conversion of cholesterol to testosterone.
  1. Some testosterone undergoes aromatisation by the enzyme aromatase to convert to oestradiol.
2. while Sertoli cells produce inhibin B.
  1. Some testosterone undergoes aromatisation by the enzyme aromatase to convert to oestrodial.
In peripheral circulation and other tissues

Testosterone, once released into the peripheral circulation may be converted to estradiol by the enzyme aromatase which is present throughout many tissues but in highest concentrations in fat tissue.
In the brain
1. The hormones inhibin B, oestradiol, testosterone and dihydrotestosterone will bind to androgen receptors in the pituitary and the hypothalamus, which respond in a negative feedback relationship. According to recent research, it appears oestradiol is the steroid hormone of greatest inhibition on hypothalamus GnRH, while the combination of oestadiol and androgens is more of a factor on pituitary release of LH and FSH.
  1. This is such that higher testosterone, dihydrotestosterone, oestradiol, or inhibin B will result in decreasing the output of the regulatory hormones gonadotropin-releasing hormone (GnrH), follicle-stimulating hormone (FSH),and luteinising hormone (LH).
  2. Correspondingly, lower testosterone, dihydrotestosterone, oestradiol, or inhibin B will result in increasing the output of the regulatory hormones gonadotropin-releasing hormone (GnrH), follicle-stimulating hormone (FSH),and luteinising hormone (LH).
And as such the feedback loop is complete and begins over again from step 1.

It is important to note that precise role and receptors for hypothalamus and pituitary inhibitory actions are still be be fully understood and identified. Even though oestradiol has a significant role in the male HPG feedback loop, it has only been identified as such in the last two decades, and prior understanding placed testosterone as the primary regulator.
As such many medical professionals and education resources are still out of date. According to emerging research it appears to be a primary lever of influence, while the androgens testosterone and dihydrotestosterone have comparatively much lower impact.

Hormone regulation is a complex system

A point should be made very clear from understanding the HPG system: regulation of male hormone production is complex and has many gates to self regulate or create points of failure.

Pharmaceutical, supplementary, or other lifestyle interventions will be varied in effect between individuals and should not be applied with a “one size fits all” attitude. This is a prime example of a complex system that will have complex responses to intervention. To add, much is still to be understood about the fine tuning of the system, fore example, that even differences in the rate of GnRH release can have a significant impact on the ratio of LH to FSH released by the pituitary.

Regarding herbal interventions such as Fadogia agrestis, Bulbine natalensis, Tongkat ali, Cistanche tubulosa, Epemedium, and others; some indications are present but precise and comprehensive understanding is not yet available. For example with both Fadogia and Bulbine, animal research, and human anecdotal outcomes of increased serum LH and testosterone occur, however conclusive points are not established as to how these herbs interject into the HPG axis.

What about the female HPG axis?

This discussion is exclusively in attention to the male HPG axis and it is important to understand that the female HPG axis operates in a different manner with altered calibration along the menstrual cycle. The female HPG axis will be a topic of future discussion.

Parting statement

The intention of this article was to provide a foundational understanding of how male GnRH, LH, FSH, and testosterone production and secretion is regulated via the HPG axis. This knowledge can be a valuable aid in vetting and selection of the proper tools to address your own hormonal goals and interests.

If you are interested in further reading, reference articles are listed below.

Published - 6th August 2023
Edited - 2nd December 2023: Video added and formatting adjusted