What happens to progesterone levels in males undergoing testosterone (testosterone replacement therapy) therapy?

Effects of Testosterone Therapy on Male Progesterone Levels

Testosterone replacement therapy (TRT) does not significantly affect progesterone levels in males, as progesterone is not a primary focus of monitoring during TRT according to current clinical guidelines.

Hormonal Effects of Testosterone Therapy

Testosterone therapy primarily affects the hypothalamic-pituitary-gonadal (HPG) axis through negative feedback mechanisms. When examining the hormonal changes that occur during TRT:

• Gonadotropins: TRT significantly suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through negative feedback on the hypothalamus and pituitary 1, 2

  • LH suppression occurs in approximately 73% of men at some point during TRT, though only 22% maintain suppressed levels throughout treatment 2
  • FSH suppression is also common but less consistent than LH suppression 1

• Testosterone: Exogenous testosterone increases serum testosterone levels, with target ranges typically aimed at 450-600 ng/dL (middle tertile of normal range) 3

• Estradiol: Testosterone therapy can lead to increased estradiol levels in some men due to aromatization of testosterone to estrogen, particularly in those with higher body fat 4

  • Approximately 20.2% of men on injectable testosterone therapy develop high estradiol levels (≥42.6 pg/ml) 4

Progesterone in Males

Despite the significant attention paid to testosterone, estradiol, LH, and FSH in men receiving TRT, progesterone is notably absent from monitoring recommendations in major clinical guidelines 1, 3:

• Progesterone is present in men at levels similar to those in women outside the luteal phase 5
• Progesterone plays roles in male physiology including:
  • Influencing spermatogenesis
  • Affecting sperm capacitation/acrosome reaction
  • Contributing to testosterone biosynthesis in Leydig cells
  • Effects on the central nervous system, immune system, and cardiovascular system 5

Monitoring Recommendations During TRT

Current guidelines recommend monitoring several parameters during TRT, but progesterone is not among them 3:

• Initial monitoring (3-6 months):

  • Testosterone levels
  • Hematocrit
  • PSA
  • Symptom response

• Long-term monitoring (annually):

  • Testosterone levels
  • Hematocrit
  • PSA (in men ≥40 years)
  • Symptom evaluation

Clinical Implications

The absence of progesterone from monitoring guidelines suggests that:

1. Changes in progesterone levels during TRT are not clinically significant enough to warrant routine monitoring
2. There is insufficient evidence that TRT meaningfully impacts progesterone levels in a way that affects clinical outcomes

Potential Pitfalls and Considerations

• When evaluating hormonal changes in men on TRT, clinicians should focus on parameters known to affect morbidity and mortality:

  • Hematocrit (discontinue therapy if exceeds 54%) 3
  • PSA (biopsy if >4.0 ng/mL or increases >1.0 ng/mL/year) 3
  • Cardiovascular risk factors 1, 3

• The route of testosterone administration may influence hormonal responses:

  • Intramuscular testosterone is associated with greater LH suppression than transdermal formulations 2
  • Transdermal formulations provide more stable serum testosterone levels with fewer fluctuations in mood and sexual function 3

While progesterone plays various physiological roles in men, current clinical guidelines do not identify it as a key parameter to monitor during testosterone replacement therapy, suggesting that any changes in progesterone levels during TRT are not considered clinically significant for patient outcomes related to morbidity, mortality, or quality of life.