Of Mice and Men

Testosterone Properly Timed: the schedule makes a difference!

Some recent research provided information about successful reproduction that has wide potential application for therapies. Elizabeth Pennisi,(1) writing an important brief article for Science NOW Daily News, 31 January 2007 reports what more than a few people have suspected for years.

When it comes to reproductive sex, the developmental timing is an overwhelming aspect of a successful outcome. In mammalian sexual reproduction, the schedule for testosterone production is critical to success. The regulatory system in mammals often works in complex and subtle ways.

Not long ago, David Volle, a postdoctoral researcher in Johan Auwerx’s lab at the Louis Pasteur University in Strasbourg, France, looking for a mechanism to apply leverage on the molecular switches that control testosterone production, looked at a protein called Small Heterodimer Partner (SHP). (Small Heterodimer Partner, is an orphan nuclear receptor which acts as a co-repressor in Helix-Loop-Helix transcription, among other activities.)

The work is reported in the 1 February issue of Genes and Development.

SHP clearly helps regulate the formation of liver bile – but is also present in small amounts in the testis. What happens there in the testis is the important timing of male sexual maturation – and the production of testosterone.

Well before the sexual maturation process, the most significant developments early on occur in gestation. In all mammals, the gestational role, played out well before birth, establishes the foundation for the eventual male sexual maturity to occur. During gestation testosterone produced by the pregnancy and circulated is drawn into the fetal cytoplasm, and converted to dihydrotestosterone(3) by the enzyme 5-alpha-reductase. Dihydrotestosterone is 4 times as potent as testosterone, and propels the developmental script in the formation of the male genital structural architecture.

From the purely biological perspective, reproductive success is the most important process for any species survival and shows itself in every level of mammalian development. In humans, by the seventh week of gestation, the genital swellings in male and female embryos are formed and are identical. By the ninth week, and under the influence of testosterone the male fetus’s genital tubercle starts lengthening. As the genital tubercle develops, two sets of tissues fold and develop on either side forming a trough, called the urethral groove. These endodermal folds fuse in the ventral midline to form the male urethra. Cells programmed as ectodermal will fuse over the developing urethra to form the penile shaft skin and the prepuce. As these two layers fuse and join from back to front, they leave behind a skin line: the median raphe, traversing the scrotum, and ascending the fetal penile shaft to the urethral exit. All of the receptor structures within the urethra have been in place in human males since about the 13th week of gestation where the urethra is almost complete. An ectoderm ring is built just proximal to the developing glans penis. This skin advances over the glandis, eventually covering the glans entirely as the prepuce or foreskin.

Near male maturity, in human males, at puberty, SHP’s dual role almost imperceptibly comes into play. The subtle double duty comes from SHP’s moderating testosterone output and its affects on the testis, where it influences the onset of male fertility. The production of testosterone initiates and directs the maturation of the male reproductive tract.

This puberty thing is a real timing issue. Because the release of testosterone orchestrates the maturation of the male reproductive tract--including the mature development of testis, the epididymis (the coils and tubes on the testicles), and the seminal vesicles, as well as enlargement of the penis, and its architecture. SHP’s influence on testosterone production also to some extent, affects the sperm themselves. Too much of this hormone too soon can disrupt normal reproductive patterns, leading, for example, to parents producing offspring before they can care for them.

To study SHP's role in the timing, Volle and colleagues compared the testosterone production and the fertility in mice. Two mice groups were used, one with and one without functional testosterone regulating SHP genes.

Testosterone levels were higher, and the epididymis and seminal vesicles grew faster, in the mice with the missing SHP-genes. Those mice with the SHP gene intact, the team reported, grew and developed appropriately, and reached reproductive maturity, timed for a more favorable rearing of the young.

The SHP-deficient mice were sexually precocious, fertilizing females a week earlier than mice with intact SHP.

Volle’s group of colleagues researched the molecular role and showed SHP puts a damper on the genes and on the transcription factor protein that spurs testosterone manufacture. They also discovered that SHP plays yet another role. This role involves reducing the production of retinoic acid which ensure the correct timing of sperm differentiation.

Much more work needs to be done, but the discovery of this new player in maturity suggests a novel way to control male fertility. In infertile men, one day, drugs that interfere with SHP's actions may help improve sperm production. Volle also suggests drugs that promote SHP regulating activity might be useful for treating premature puberty.

It is surprising how little SHP there is in the testes to find the molecule so influential in the timing of these key aspects of male reproduction.

Cell biologist, Bert O'Malley, Baylor College of Medicine in Houston, Texas, sees a potential new drug target for male fertility problems, and says "the work has implications for therapies.”

Clearly, there are implications for mice and men.

(1) http://sciencenow.sciencemag.org/cgi/content/full/2007/131/4

(2) http://www.just.edu.jo/~mafika/733_Reproductive%20Endocrinology/Male%20Reproductive%20System_733.htm

(3) http://www.endotext.org/male/male3/male3.htm