The three components
HPG axis = Hypothalamus + Pituitary + Gonads. Three organs in sequence with feedback loops:
- Hypothalamus releases GnRH (gonadotropin-releasing hormone)
- GnRH stimulates anterior pituitary to release LH and FSH
- LH and FSH stimulate gonads (testes in men, ovaries in women)
- Gonads produce sex hormones (T, E2, progesterone) and gametes
- Sex hormones feed back to hypothalamus and pituitary, suppressing GnRH/LH/FSH
- The loop maintains homeostasis
GnRH from hypothalamus
GnRH is a 10-amino acid peptide released by neurons in the medial preoptic area and arcuate nucleus of the hypothalamus. Released in pulses every 60-120 minutes. The pulse frequency and amplitude encode information that determines downstream LH/FSH ratios.
Upstream of GnRH neurons are kisspeptin neurons, the actual master regulators that integrate inputs from leptin, sex hormones, stress, nutrition, and sleep before triggering GnRH pulses.
LH and FSH from pituitary
The anterior pituitary contains gonadotrope cells that respond to GnRH pulses by releasing:
- LH (luteinizing hormone), stimulates testicular Leydig cells (testosterone production) or ovarian theca cells (androgen production for ovarian estrogen)
- FSH (follicle stimulating hormone), stimulates testicular Sertoli cells (sperm production) or ovarian granulosa cells (follicle development)
The ratio of LH to FSH varies based on GnRH pulse pattern and feedback signals.
Gonadal output
In men:
- LH → Leydig cells → testosterone (~95% of total T)
- FSH → Sertoli cells → spermatogenesis support
- Testes also produce small amounts of estradiol via aromatase
In women:
- LH → theca cells → androgen production (precursor for estrogen)
- FSH → granulosa cells → estradiol via aromatase
- After ovulation, corpus luteum produces progesterone
Negative feedback loops
Sex hormones suppress upstream signaling:
- Testosterone suppresses GnRH (hypothalamus) and LH/FSH (pituitary)
- Estradiol does the same in women
- The negative feedback maintains homeostasis
- Exception: in women, the mid-cycle estradiol peak triggers a positive feedback LH surge that triggers ovulation (transient feedback reversal)
Pulsatile release
The whole axis is pulsatile, GnRH every 60-120 min, LH following, T peaking. Continuous (non-pulsatile) GnRH actually downregulates the axis (used therapeutically with GnRH agonists for prostate cancer treatment, suppressing T).
Where treatments act
| Treatment | Mechanism | HPG axis effect |
|---|---|---|
| TRT | Exogenous T | Suppresses entire axis (negative feedback) |
| HCG | Mimics LH | Stimulates testes directly; bypasses pituitary |
| Enclomiphene | Blocks E2 feedback at hypothalamus | Raises LH/FSH/T endogenously |
| Clomiphene | Mixed estrogen agonist/antagonist | Similar to enclomiphene with more side effects |
| Anastrozole | Blocks aromatase | Reduces E2; raises T/LH (less feedback) |
| HRT | Exogenous E2/progesterone | Suppresses HPG axis in women |
Understanding where each acts explains why fertility, testicular function, and post-treatment recovery differ across approaches.
The clinical insight: The HPG axis is one of the most elegant feedback systems in physiology. Different therapies target different points. Knowing the axis explains why TRT suppresses fertility while enclomiphene preserves it, and why post-cycle recovery varies.
Bottom line
The HPG axis is hypothalamus → pituitary → gonads with feedback. GnRH pulses drive LH/FSH which drive sex hormone production. Different treatments act at different points. Understanding the axis explains why interventions produce different patterns of effect.