Multiple physiological mechanisms are involved in mediating libido in male mammals. The most well understood process is the hypothalamic-pituitary-gonadal (HPG) axis. The hypothalamus secretes gonadotropic-releasing hormone (GnRH) that causes the pituitary to release luteinizing hormone (LH), which in turn causes the testis to secrete testosterone (T) (see FIG. 1). The HPG axis responds to sexual stimuli in adult males (visual and olfactory) and is dependent on a minimum concentration of plasma testosterone. Yet, individual variation of testosterone concentrations is not predictive of libido or sexual performance once minimum levels are present. It appears that the ability to increase plasma testosterone concentrations in response to sexual opportunities, rather than base line concentrations of testosterone is more important for predicting libido. The ability to change levels of hormones is under the influence of endogenous opiates. Based on data collected mostly in rodents, we know that the HPG axis is influenced by a complex interaction of endogenous opiates and neurotransmitters in the brain. It is well established that endorphins have an inhibitory influence on the release of hypothalamic gonadotropic hormone-releasing hormone (GnRH). Naloxone (an opiate antagonist) can reverse the inhibitory effects of naturally-occurring endorphins on luteinizing hormone. Hence, treatment with naloxone causes significant elevations in serum LH concentrations in rats (Meites et al., 1979) and rams (Ebling et al. 1987). A scheme for this is represented in FIG. 1.
In 1979, Gessa et al. gave injections of naloxone to sexually inactive male rats. The injections induced copulatory behavior. The authors suggested that endogenous opiates were the cause of the sexual inhibition and that the drug naloxone removed the opiate driven sexual inhibition. We gave naloxone to sexually inactive rams, but were unable to induce sexual behavior (Fitzgerald and Perkins, 1994). Unexpectedly, we noticed that the LH response to the naloxone treatment was greater in the sexually active rams versus the sexually inactive rams. So, although naloxone treatments did not alter libido or sexual performance, it did predict which rams would be most likely to demonstrate sexual activity based on their LH concentrations.
There is a great deal of variation in the sexual performance of male sheep. In 1964, Hulet et al. described rams that failed to mate with estrus females during behavioral testing. Since then, several scientists, as well as producers, have observed poor sexual performing rams. Standardized sexual behavior tests have been developed that can evaluate sexual performance in rams (Kilgour and Whale, 1980). These behavioral tests involve observations of sexual activity. The average number of ejaculations that a ram achieves over several sexual performance tests correlates to pasture breeding efficiency (Perkins et al., 1992). These tests, however, are labor intense, costly and impractical for the producer to conduct. The purpose of this project was to develop a more practical tool (a drug test) that could be used by veterinarians or producers to predict sexual performance in rams or other species for which maximizing reproductive success is a concern.
The first and most obvious place to look for a predictor of sexual performance is basal concentrations of testosterone. Testosterone is critical to both the development and execution of sexual behavior in all male mammals. Yet once minimal concentrations of testosterone are present, increasing testosterone concentration will not increase sexual performance (D'Occhio and Brooks, 1976). Most rams, including sexually inactive rams, have the minimal amounts of testosterone needed to execute sexual behavior (Perkins et al., 1992). In addition, variations in testosterone concentrations beyond minimal values are not correlated to sexual performance (Knight, 1973). Therefore, physiological mechanisms located elsewhere (perhaps in the brain and not the gonads) are more likely to be responsible for variations in libido and sexual performance.
We have observed reduced LH responses by poor sexual performing rams to estrus ewes (Perkins et al., 1992). Therefore, we chose to investigate the effect of naloxone, on both sexual behavior and the pituitary-gonadal response among rams that vary in sexual performance. Our original goal was to increase the libido and the sexual performance of low performing rams by increasing LH responses with Naloxone. Although we were unsuccessful in improving the sexual behavior of sexually inactive rams (Fitzgerald and Perkins, 1994), we have now established a predictor (77% accuracy) of sexual performance by measuring the luteinizing hormone and testosterone response to an IV injection of naloxone. We recommend that veterinarians or producers as a tool for screening out low libido or poor sexual performing rams use this protocol. This naloxone test will also help in the identification of high sexual performing rams, but it will not screen for sexual orientation. This same prediction might be true for any male mammal that expresses individual variations in both libido and endogenous opiate levels in mammals such as: humans, primates (such as monkeys), felines, canids, rodents, marine mammals, ungulates (such as elk, deer, antelope, caribou, among others), and livestock such as rams, bulls, stallions, boars, among others. The ram has been an excellent model for examining this system.
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USPTO Backgrounds