by James J. Galligan,  Ph.D., Associate  Chair,
Department of Pharmacology and  ToxicologyFlibanserin

The medical and financial success of phosphodiesterase-5 (PDE5) inhibitors in treating male erectile dysfunction (ED) has led to the pursuit of a similar drug for the treatment of sexual dysfunction in women.  Although most people would not recognize these drugs by their specific target, anybody who watches television would recognize Viagra (sildenafil), Cialis (tadalafil) or Levitra (vardenafil).

An erection requires an increase in blood flow to the penis. This is caused by release of nitric oxide (NO) in the wall of the blood vessels in the penis.  NO activates the enzyme, guanylate cylcase which produces cyclic guanosine-5-monophosphate (cGMP) which then produces relaxation of the muscle cells in the blood vessels supplying the penis.  This allows for the increase in penile blood flow needed for an erection.  In ED the mechanisms responsible for increased penile blood flow are compromised.  This can be caused by diabetes, high blood pressure, some drugs or just old age.  This is where the PDE5 inhibitors are effective in ED, they can bypass the normal mechanisms leading to erection and stimulate blood flow to the penis more or less directly.  They do because PDE5 breaks down cGMP and inhibition of PDE5 increases cGMP levels in the muscle cells causing them to relax thereby increasing blood flow.  Early drug studies of the effectiveness of the PDE5 inhibitors were greatly simplified by one of the major endpoints measured: erection!  This is fairly unambiguous and is easy to measure.  The rest is history as the PDE5 inhibitors have become a successful and profitable class of drugs that are effective in treating a common problem.

Flibanserin

Flibanserin

This brings us to the results of a recent trial of a drug treatment for loss of sexual desire in women.    The drug under study was flibanserin which interacts with serotonin, norepinephrine and dopamine signaling in the brain.  Serotonin, norepinephrine and dopamine are neurotransmitters that are important for regulation of mood, reward and motivation.  Flibanserin was tested in women suffering from hypoactive sexual desire disorder (low sex drive).

The end points measured in the study were an increase in global desire and the number of sexually satisfying experiences per month.  Unlike the end point in the PDE5 trials, these are a little harder to define and quantify.  This might explain the failure of flibanserin to progress through the Food and Drug Administration (FDA) approval process recently.  In the trials, it was found that women taking flibanserin had an average of 4.5 sexually satisfying experiences per month while women taking placebo (an inert substance) had 2.8 similar experiences per month.  The difference in outcomes between flibanserin and placebo treatment was not compelling and the FDA turned down the company’s request for approval.

The discussion above brings us to the main conclusion: boys and girls are different!

For better or worse, sexual desire and arousal are relatively simple in men.  Measurement of arousal is also straightforward as is treatment of ED, a common cause of sexual dysfunction in men.  Pursuit of the “female Viagra” is likely to be futile as the problem that Viagra treats does not occur in women.

As all men know, piquing a woman’s interest and desire is complex, subtle and often frustrating.  The same frustrations await the pharmacologist pursuing this holy grail.