Testosterone, Dihydrotestosterone, and Prostate Cancer: The Saturation Model and the Inverse Relationship with Androgen Deficiency

Testosterone, Dihydrotestosterone, and Prostate Cancer: The Saturation Model and the Inverse Relationship with Androgen Deficiency

A Review Supporting the Clinical Use of Testosterone in the Context of Age-Related Androgen Decline

Abstract

The traditional paradigm that higher circulating testosterone (T) drives prostate cancer (PCa) risk and progression has been substantially revised by the saturation model of androgen action. Prostate tissue, both benign and malignant, is exquisitely sensitive to androgens only at very low concentrations. Maximal androgen receptor (AR) occupancy occurs near or below the lower end of the physiologic range (approximately 250 ng/dL). Above this saturation point, further increases in serum T produce little additional prostatic stimulation. Consistent with this framework, men with near-zero T (historical eunuchs and men undergoing androgen deprivation) have a markedly reduced incidence of PCa, while low but non-castrate T is associated with higher-grade, more aggressive disease. Dihydrotestosterone (DHT), the 5α-reduced metabolite of T, is the predominant intraprostatic androgen. Age-related declines in T can alter the local hormonal milieu, and restoring physiologic T normalizes the androgen environment without increasing PCa risk above the saturation threshold. These observations support the use of testosterone therapy to address the consequences of low T, including potential shifts toward a relatively DHT-dominant or estrogen-influenced inflammatory state within the prostate.

Introduction

Circulating testosterone (T) and its more potent metabolite dihydrotestosterone (DHT) are the principal androgens regulating prostatic growth and function. DHT is formed intracellularly by 5α-reductase and binds the androgen receptor (AR) with higher affinity than T. As men age, serum T declines while the relative contribution of local DHT production and the T-to-estrogen ratio can shift. The longstanding clinical teaching that T “feeds” prostate cancer has been challenged by both mechanistic and clinical data. The saturation model, articulated by Morgentaler and Traish, provides a coherent framework that reconciles the dramatic effects of castration with the absence of increased PCa risk from higher physiologic or even supraphysiologic T in non-castrate men.1

The Saturation Model of Androgen Action in the Prostate

Prostate growth and AR-mediated signaling are highly sensitive to changes in androgen concentration only in the near-castrate range. Maximal AR binding is achieved at serum T concentrations well below the normal physiologic range. Once the receptors are saturated, additional ligand produces little further transcriptional activation or proliferative stimulus.1 Clinical data place the approximate saturation point near 250 ng/dL (8 nmol/L). Below this threshold, PSA and prostatic volume respond markedly to changes in T; above it, further increases in serum T do not raise PSA or prostate volume in healthy men or in most men receiving testosterone therapy.1,2

This model explains several otherwise paradoxical observations: (1) androgen deprivation therapy produces profound PSA declines and disease control; (2) administration of T to castrated men rapidly restores prostatic stimulation; and (3) T therapy in eugonadal or moderately hypogonadal men does not increase PCa incidence or progression rates in the available observational literature.1,3

Low Testosterone and Prostate Cancer Aggressiveness

Multiple independent series have demonstrated that low serum T is associated with higher Gleason grade, higher pathologic stage, and greater risk of upgrading or upstaging at radical prostatectomy. Schatzl et al. reported that men with high-grade PCa had significantly lower T (and estradiol) and that mean T declined with increasing Gleason score.4 Subsequent studies have confirmed that low total, free, or bioavailable T independently predicts predominant Gleason pattern 4 disease and adverse pathologic features.5,6 These findings are the inverse of the older linear “androgen hypothesis” and are consistent with the saturation model: once the prostate is no longer androgen-starved, further T does not drive more aggressive disease, whereas profound androgen deficiency may select for or permit higher-grade clones.

Historical and Castration Evidence

Men with lifelong near-castrate T levels (functional eunuchs from prepubertal orchitis or surgical castration) rarely develop clinically evident PCa. The few documented cases typically demonstrate residual intracrine androgen production capable of generating local DHT even when circulating T is undetectable.7 Androgen deprivation remains one of the most effective systemic therapies for advanced PCa precisely because it reduces androgens below the saturation threshold. The clinical corollary is that any T above true castrate levels preferentially saturates prostatic AR; once that limited capacity is filled, additional circulating T does not further stimulate the gland.1

Testosterone, DHT, and the Local Hormonal Environment

Within the prostate, T is efficiently converted to DHT. Intraprostatic DHT concentrations are normally 10- to 20-fold higher than T. Age-related declines in circulating T reduce the substrate available for both systemic and local androgen production and can alter the T:estradiol ratio. Relative estrogen excess, or an elevated estrogen-to-androgen ratio, has been shown in experimental models to promote prostatic inflammation and fibrosis; androgen replacement at doses that restore prostatic and seminal-vesicle growth is anti-inflammatory in these models.8,9 Although DHT can modulate macrophage cytokine production under specific in-vitro conditions, the dominant clinical observation is that physiologic androgen replacement does not increase, and may mitigate, the inflammatory milieu associated with hypogonadism. Restoring circulating T therefore rebalances the androgen–estrogen axis and supplies substrate for regulated local DHT production without exceeding the saturation capacity of prostatic AR.

Clinical Implications for Testosterone Therapy

Observational cohorts and systematic reviews of men receiving testosterone therapy after radical prostatectomy, radiotherapy, or while on active surveillance have not demonstrated increased rates of biochemical recurrence or progression compared with untreated controls, provided patients are carefully selected.3,10 Because the prostate is already saturated at low physiologic T, raising serum T into the mid-normal range does not provide additional trophic stimulus. In hypogonadal men, testosterone therapy addresses the systemic consequences of low T while normalizing, rather than unnaturally elevating, the prostatic androgen environment. This approach is consistent with both the saturation model and the observed association between low T and higher-grade disease.

Conclusion

The relationship between androgens and the prostate is nonlinear. Prostate tissue is sensitive to T and DHT only until AR saturation is reached, a point that lies near the lower limit of the normal male range. Below that threshold, androgen deficiency is linked to higher-grade prostate cancer and to a hormonal milieu that can favor inflammation. Historical and experimental castration data confirm that true absence of androgenic stimulation largely prevents clinical PCa, yet any T above castrate levels saturates the gland. Providing physiologic testosterone therefore corrects the deficiency state without increasing prostatic stimulation beyond the saturated baseline. These principles support the use of testosterone therapy in appropriately selected men as a rational intervention that restores androgen balance rather than driving prostate pathology.

References

  1. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55(2):310-321. doi:10.1016/j.eururo.2008.09.024
  2. Morgentaler A. Turning conventional wisdom upside-down: low serum testosterone and high-risk prostate cancer. Cancer. 2011;117(17):3885-3888. doi:10.1002/cncr.25975
  3. Santucci J, Stapleton P, Perera M, et al. Oncological safety of testosterone replacement therapy in men with localised prostate cancer: a systematic review of observational studies. BJU Int. 2025;136(5):788-799. doi:10.1111/bju.16870
  4. Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate. 2001;47(1):52-58. doi:10.1002/pros.1046
  5. Botto H, Roupret M, Mathieu F, Richard F. High incidence of predominant Gleason pattern 4 localized prostate cancer is associated with low serum testosterone. J Urol. 2011;186(4):1400-1405. doi:10.1016/j.juro.2011.05.084
  6. García-Cruz E, Piqueras M, Huguet J, et al. Low testosterone levels are related to poor prognostic factors in men with prostate cancer prior to treatment. BJU Int. 2012;110(11 Pt B):E541-E546. doi:10.1111/j.1464-410X.2012.11243.x
  7. Mohler JL, Gaston KE, Moore DT, et al. Characterization of prostate cancer in a functional eunuch. JNCCN. 2016;14(9):1054-1060. doi:10.6004/jnccn.2016.0125
  8. Yatkin E, Bernoulli J, Talvitie EM, Santti R. Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio. Int J Androl. 2009;32(4):399-410. doi:10.1111/j.1365-2605.2008.00930.x
  9. Vignozzi L, Cellai I, Santi R, et al. Anti-inflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells. J Endocrinol. 2012;214(1):31-43.
  10. Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol. 2014;65(1):115-123. doi:10.1016/j.eururo.2013.08.015