40% Increase in Total + 50% Increase in Free Testosterone - Two Not Necessarily Undesirable Side Effects of Sildenafil. Human Study Confirms Direct Effect of PDE-5 Inhibition

Either you buy one of the bazillion OTC test-boosters that will not do anything for your testosterone levels, but may have minimal effects on your libido; or, you get a script for the blue pills and accept that one of the side-effects of these proven libido-boosters is an increase in testicular testosterone production.
If you were all Germans, I would probably be cracking a joke about the lead author's name "Spitzer", but in view of the fact that you aren't and that it would be a saucy one I will stick to the news-piece alone - it's saucy enough, anyways ;-)

Actually you've heard Carl and me talk about the purported testosterone boosting effects of sildenafil aka Viagra on the Science Round Up in the past, but Mr. Spitzer and his colleagues from the Greenfield Health Center are the first to prove the potency of the testosterone response in male subjects who received "an optimized dose" (more on that later) of sildenafil, as well as its "direct action on the testes" in a controlled larger-scale trial (Spitzer. 2013).

More than just "spitz" (engl. "horny")

The data Matthew Spitzer et al. analyzed came from the Testosterone and Erectile Dysfunction Trial in the course of which 140 men, aged 40–70 years with erectile dysfunction, low serum total testosterone (<11.4 nmol/L; 330 ng/dL) and/or free testosterone (<173 pmol/L; 50 pg/mL) over received starting doses of
  • 25mg sildenafil, if they were on an alpha-blocker
  • 50mg sildenafil, if they never used sildenafil before, and
  • 100mg sildenafil, if they were viagra veterans
for  3–7 weeks. The men in the 25mg and 50mg groups had the chance to increase the dosage to up to 100mg "on occasion"; or, in other words, when their sexual desire did not match their physical function.
Figure 1: Changes of testosterone and other hormones rel. to baseline level (Spitzer. 2013)
As you can see in Figure 1 the ingestion of a handful of the infamous blue pills lead to significant increases of in total (+3.6 nmol/L = 103 ng/dL; p<0.001) and free (+110 pmol/L = 31.7 pg/mL; p<0.001) testosterone levels and were accompanied by parallel increases in serum DHT (0.17 nmol/L = 4.9 ng/dL; p<0.001) and oestradiol (14 pmol/L = 3.7 pg/mL; p<0.001) and significant suppression of luteinizing hormone (change 1.3 units/L; p=0.003) levels.

The latter, i.e. the reduced luteinizing hormone levels are what actually suggests that we are dealing with a direct effect at the testicular level and not some weird hyptohalamic feedback. A centrally mediated in crease in testosterone production would after all have gone hand in hand with in- not decreases in luteinizing hormone concentration.

Minimal changes in adrenal hormones

With small, but noticeable increases in androstenedione and oestrone increased by 1.3 nmol/L (38 ng/dL; p=0.011) and 10.7 pmol/L (2.9 pg/mL; p=0.012), Spitzer et al. cannot exclude that the sildenafil induced phosphodiesterase-5 inhibition did also affect the adrenal glands - or, to be precise, "late adrenal androgen synthesis" (Spitzer. 2013):
Gingko = Brain Viagra?
"The adrenal glands are the major site for production of androstenedione, which is converted to oestrone by aromatase. Enzyme 17,20 lyase, which converts 17a-hydroxyprogesterone to androstenedione, is upregulated with sildenafil treatment in rats.

This could explain the increase in serum androstenedione levels in our participants. However, an increase in 17,20-lyase activity should also result in an increase in DHEAS levels, which was not observed. Further investigation is needed to study the effect of sildenafil on adrenal androgens." (Spitzer. 2013)
While the exact mechanism that's responsible for the androstenedione increases must still be determined, it is, as previously mentioned, almost certain that the increase in testosterone levels was mediated by direct effects on the steroidigenic leydig cells in the testes. They are the ones that respond to the luteinizing hormone signalling from the brain have been reported to respond directly to PDE-5 inhibitors in previous studies by Andric et al. from 2007 & 2010, as well as Janjic et al. from 2012.

More sex = more testosterone?

Whether and to which extend the increase in testosterone has also been indirectly promoted by increases in sexual activity, which have been previously reported to lead to increases in testsosterone levels after successful treatment of erectile dysfunction (Aversa. 2013) remains to be seen. The data from the study at hand does at least not support this notion, because a "greater sexual activity did not predict greater change in serum total testosterone" (Spitzer. 2013).

Other studies have associated greater sexual arousal with acute increases in LH and subsequent increases in testosterone production (LaFerla. 1978; Rowland.1987). With decreasing not increasing LH levels being one of the main findings of the study at hand, it is however more or less impossible that the increased sexual desire was the horse, not the cart in the sildenafil-related increases in testosterone levels Spitzer et al. observed in their 140 borderline to full-blown hypogonadal man.
SuppVersity Suggested Read: "Will Sex Before a Competition Hamper Your Performance? Plus: How Can Estrogen, Cortisol, Quail and Muhammad Ali Help Us Answer This Important Question" | read more
Bottom line: It appears to be settled that it is the direct effect of PDE-5 inhibition on testicular testosterone production that's responsible for the Viagra induced increases in testosterone production. What is not settled, though and I guess that is something people tend to forget about, when they hear promising study results like  these is that the benefits were observed in a men whose testosterone production was already impaired.

In fact, the researchers' acknowledgment that "some portion of the observed increases in testosterone occurring during sildenafil administration is almost certainly attributable to regression to the mean" (Spitzer. 2013) would suggest that similarly pronounced effects cannot necessarily be expected in men with normal testosterone levels... but hey, the same goes for 99.9% of the OTC "test boosters" and people still buy them despite the fact that they do not even have produce those "nasty" boners as a side effect ;o)
  • Andric SA, Janjic MM, Stojkov NJ, Kostic TS. Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E544-50.
  • Aversa A, Jannini EA, Maggi M, Lenzi A. Effects of testosterone replacement on response to sildenafil citrate. Ann Intern Med. 2013 Apr 2;158(7):569-70.
  • Janjic MM, Stojkov NJ, Bjelic MM, Mihajlovic AI, Andric SA, Kostic TS. Transient rise of serum testosterone level after single sildenafil treatment of adult male rats. J Sex Med. 2012 Oct;9(10):2534-43.
  • LaFerla JJ, Anderson DL, Schalch DS. Psychoendocrine response to sexual arousal in human males. Psychosom Med. 1978 Mar;40(2):166-72.
  • Rowland DL, Heiman JR, Gladue BA, Hatch JP, Doering CH, Weiler SJ. Endocrine, psychological and genital response to sexual arousal in men. Psychoneuroendocrinology. 1987;12(2):149-58.
  • Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013 Nov;1(6):913-8.
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