The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 4 • August 2015

Reversal of Androgen Inhibition of Estrogen-Activated Sexual Behavior by Cholinergic Agents

We have previously written about the interaction of the cholinergic nervous system and estrogens in our hypothesis (also shared by others) that it is the decline in the cholinergic nervous system with age that is largely responsible for the fact that restoration of estrogen in ovariectomized animals after a certain period of time no longer provides the cognitive advantages of estrogen that occur when it is given right after ovariectomy (Hammond, 2011).

Now, we have come across a relatively early paper from 1989 (Dohanich, 1989) that reports that the inhibition by androgens of estrogen-induced sexual activity in ovariectomized female rats can be reversed by cholinergic agonists, which included in this study carbachol and the acetylcholinesterase inhibitor physostigmine. The nutrient choline also increases cholinergic activity (Mike, 2000) and, of course, galantamine (an acetylcholinesterase inhibitor) would be expected to act in a similar manner as the acetylcholinesterase inhibitor physostigmine.

This is a very interesting study that shows that the decline of the cholinergic system is likely to play a major role in the decline in sexual activity with age in post-menopausal women. Both testosterone and its 5-alpha reductase product dihydrotestosterone have been shown to inhibit diverse responses regulated by estrogens, including functions of the female reproductive system such as ovarian growth, follicular development, and progestin receptor induction, as well as inhibiting estrogen-activated female sexual behavior (such as lordosis) in female rats, mice, and hamsters. Cholinergic antagonists have been found to inhibit sexual behavior in ovariectomized females treated with estrogen and progesterone.

The cholinergic agonists that activate lordosis in the animals are mediated by the muscarinic type cholinergic receptors and lordosis is prevented by blockers of these receptors (Dohanich, 1989). Note that muscarinic cholinergic antagonists are very widely used for treating urinary urgency and incontinence in older women and these drugs may be impairing the libido of these older women.

Thus, the purpose of this study was to test the ability of cholinergic agents to reverse the inhibitory effects of dihydrotestosterone on estrogen-induced lordosis in female Long-Evans rats.

Interestingly, the acetylcholinesterase inhibitor physostigmine was more effective in increasing the incidence of lordosis in the rats than the cholinergic receptor agonist carbachol. Both physostigmine and carbachol were administered via intracerebral intraventricular infusion but these agents pass through the blood-brain barrier so this may have been done to ensure that a specific dose was received in the target tissue, whereas with oral treatment, there is not as much certainty on how much of the ingested treatment reaches the target tissue, especially when it is in the brain.


  • Hammond and Gibbs. GPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performance. Brain Res. 1379:53-60 (2011).
  • Dohanich and Cada. Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents. Horm Behav. 23:503-13 (1989).
  • Mike, Castro, Albuquerque. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res. 882:155-68 (2000).

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