PCa Commentary | Volume 215 – July 2026

Posted by Edward Weber, MD | July 2026

Low Testosterone after Successful Treatment — Is Replacement Testosterone Safe?

Any man who has undergone androgen deprivation therapy – ADT – to suppress his prostate cancer will have suffered some or all the associated adverse effects of diminished testosterone: fatigue, hot flushes, cognitive decline, bone density loss, erectile dysfunction, loss of libido, irritability, fragility fractures, and gynecomastia. These are the consequences of lowering the normal T level from 300 – 1000 ng/dL to 20 ng/dL, the desired target, or even lower with combination therapy of Lupron and one of the androgen receptor signaling inhibitors, i.e., Xtandi, Zytiga, Nubeqa, and Erleada.

The Biology of Testosterone and Estradiol (E2) Suppression.

The persistence of testosterone suppression after stopping ADT lengthens in relation to the duration of prior exposure and the patient’s age. The biology of suppression results from the anti-androgen (i.e., Lupron, an LHRH agonist) shutting down the signal from the pituitary gland to the testes, thus reducing testicular testosterone production and resulting in a lowering of T to <50 ng/dL within 4 weeks and, in most men, subsequently to ~ 20 ng/dL. Serum estradiol (E2) is also suppressed along with the lowered T because of its linkage to the serum T level.

The normal range of E2 (estradiol) in men is between 10 and 40 pg/mL, with half coming from the testes and half arising from the enzymatic conversion of serum T to E2. Lupron causes E2 to drop to 20 pg/mL or lower. Diminished E2 is associated with an accelerated loss of bone mineral density and osteoporosis, increased fragility fractures, hot flashes, loss of muscle mass, diminished libido, erectile function, and potentially cardiovascular risk.

Abraham Morgentaler, Division of Urology, Harvard Medical School, has studied and written extensively about T replacement. He concludes that, in contrast to popular opinion, androgens do not drive PC.

How Long Does it Take To Recover Baseline Testosterone After Stopping ADT?

The extent to which T is suppressed depends on a patient’s age and the duration of anti-androgen exposure, and both those factors also influence the rate of T recovery after ADT is ceased. At a T level of <230 ng/dL, a man is said to be “hypogonadal,” and symptoms from a diminished T commence – to different degrees in different men. After a 3- to 6-month duration of Lupron or Relugolix treatment, 65% of men will still be below <230 ng/dL at 12 months after stopping.

Caveat:  Bone mineral density should be evaluated with a DEXA scan before and after ADT, even in asymptomatic men, since asymptomatic bone density loss occurs until a fragility fracture.

Examples of the relationship of the duration of ADT exposure to subsequent recovery to their original T levels after stopping ADT are as  follows:

• After 3 – 9 months of ADT, nearly all men fully recover by about 10 months.
• After 18 – 24 months of ADT, only 60% fully recover by about 3 years.
• After 36 months of ADT exposure, only 50% fully recover by ~ 5 years.

After receiving ADT for longer than 6-9 months, many men never fully return to their T baseline. This raises the very important question of whether it is safe to offer replacement testosterone in symptomatic men who have been rendered persistently hypogonadal (<230 ng/dL).

Is Replacement Testosterone Therapy (TTh) Safe in Persistently Hypogonadal Men After Successful Primary Treatment?

TTh Post  Prostatectomy:  The largest study in the literature is “Testosterone Therapy in Men After Radical Prostatectomy for Low-Intermediate Organ-Confined Disease,”  Flores et. al., J. Urol. Jan. 2025. The study followed 5199 men, Gleason Grade Group 1-3, with 198 receiving TTh and 5001 not. The end point was the rate of biochemical recurrence (PSA > 0.1 ng/mL) at 18 months following surgery in men whose PSAs at the start of the study were undetectable and whose T levels were below 300 ng/dL. Follow-up was 10 years. “Overall rates of biochemical recurrence (BCR) were low, with a probability of BCR at 5 years of less than 2% in both groups.” Authors’ conclusion: TTh seems to be safe in this highly specific population and does not seem to be a factor associated with BCR …”

TTh Post-Radiation Therapy: The most-cited study is “Testosterone Therapy after Radiation Therapy for Low, Intermediate and High-Risk Prostate Cancer,” Pastuszak et al., J Urol. 2015. Ninety-eight hypogonadal men were treated. The median initial T was 209, rising to a median 420 ng/dL after TTh. Their PSAs rose minimally from a baseline of 0.08 to 0.09 ng/mL. Gleason scores were 5 and 6 in 50% and 7 in 26%. The authors point out that the safety of TTh after radiotherapy is more uncertain than post-surgery because of possible residual microscopic cancer after RT. At 41-month follow-up, 6.1% (6 of 98) had BCR (at PSA > nadir + 2 ng/mL). The Gleason Scores in men who recurred were 7, 8, and 9, suggesting a higher risk of BCR at higher Gleason scores. Authors’ conclusion: “Patient selection should be diligent and limited to men with quality-of-life impairment…who are at risk from untreated hypogonadism.” Their data suggest special concern for men with Gleason scores of 7 or greater.

BOTTOM LINE: Testosterone Replacement Therapy is safe in carefully selected men who are symptomatic due to low testosterone following successful primary therapy.

“We appreciate the unfailing assistance of the librarians at Providence/Swedish.”