BONES AND MALE FERTILITY

Skeleton regulates male fertility

February 17, 2011

Researchers at Columbia University Medical Center have discovered that the skeleton acts as a regulator of fertility in male mice through a hormone released by bone, known as osteocalcin.

The research, led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University Medical Center, is slated to appear online on February 17 in Cell, ahead of the journal's print edition, scheduled for March 4.
Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass.
"Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone really begs the question: Does bone regulate the gonads?" said Dr. Karsenty.
Dr. Karsenty and his team found their first clue to an answer in thereproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete a hormone called osteocalcin were poor breeders.
The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility. As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.
Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.
Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.
If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone.
Skeleton Regulates Male Fertility, But Not Female
Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that theskeleton influences female reproduction.
Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis.
Sex hormones, namely estrogen in women and testosterone in men, have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.
"We do not know why the skeleton regulates male fertility, and not female. However, if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males," said Dr. Karsenty. "This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."
Other Novel Functions of Osteocalcin Reported Earlier
The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.
"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process. As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well."
Next Steps and Potential Drug Development
Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.
And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected.
Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.
"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty.

Provided by Columbia University Medical Center

anti TB drug

2 in 1: Multi-tasking protein provides new approaches for anti-tuberculosis drugs

February 15, 2011

In a paper published today in PNAS, scientists from the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, reveal new insights into the workings of enzymes from a group of bacteria including Mycobacterium tuberculosis, the bacterium that causes tuberculosis. The new findings present possible new opportunities for developing organism-specific drugs, which target the pathogen but leave other microorganisms, which are beneficial to us, untouched.

Tuberculosis remains one of the largest threats to human health worldwide, and one of the most frequent causes of death in HIV patients. With the increasing emergence of strains of Mycobacterium tuberculosis that are hyper-resistant to drugs, it becomes ever more urgent that novel treatments be developed, and the search for novel strategies for drug development is an important step in this process.
In the current study, Matthias Wilmanns and his group at EMBL identified a multi-tasking enzyme from Mycobacterium tuberculosis that catalyses reactions on two different molecules, or substrates. In most organisms, cells need two specific enzymes, known as HisA and TrpF, in order to produce two essential amino acids – histidine and tryptophan. However, in Mycobacterium tuberculosis, the encoding gene for TrpF is missing, and the two reactions are instead catalysed by a single enzyme, which is able to recognize and bind to two different substrates. This enzyme is known as PriA.
Using the Mycobacterium tuberculosis version of the PriA enzyme as a model, the researchers were able to unravel the hitherto unknown mechanism of bi-substrate specific binding observed in this group of bacteria.
"When we solved the three-dimensional structure of PriA, we found that it has the unique ability to form two different substrate-specific active sites," Wilmanns says: "it can form a reaction-specific active site, or undergo what we call 'substrate-induced metamorphosis' to form a different active site."
To further verify these observations, Wilmanns and colleagues screened 20,000 small molecule compounds, and identified a handful which inhibited both PriA-catalysed reactions but had no effect on TrpF activity.
"We believe that this ability for bi-substrate catalysis in Mycobacterium tuberculosis could be a new opportunity for future drug development," Wilmanns concludes: "This organism-specific reaction process could be exploited, since only the pathogen but none of the other bacteria living in or on humans, many of which are important for our well being, would be targeted."

Provided by European Molecular Biology Laboratory

Losing hair at 20

Losing hair at 20 is linked to increased risk of prostate cancer in later life

February 15, 2011

Men who start to lose hair at the age of 20 are more likely to develop prostate cancer in later life and might benefit from screening for the disease, according to a new study published online in the cancer journal, Annals of Oncology today.

The French study compared 388 men being treated for prostate cancer with a control group of 281 healthy men and found that those with the disease were twice as likely as the healthy men to have started going bald when they were 20. However, if the men only started to lose their hair when they were 30 or 40, there was no difference in their risk of developing prostate cancer compared to the control group. The study found no association between early hair loss and an earlier diagnosis of prostate cancer, and nor was there any link between the pattern of hair loss and the development of cancer.
Until now there has been conflicting evidence about the link between balding and prostate cancer; this is the first study to suggest a link between going bald at the young age of 20 and the development of prostate cancer in later life.
Professor Philippe Giraud (M.D., PhD), Professor of Radiation Oncology at the Paris Descartes University (Paris, France) and at the European Georges Pompidou Hospital (Paris, France), who led the research, said: "At present there is no hard evidence to show any benefit from screening the general population for prostate cancer. We need a way of identifying those men who are at high risk of developing the disease and who could be targeted for screening and also considered for chemo-prevention using anti-androgenic drugs such as finasteride. Balding at the age of 20 may be one of these easily identifiable risk factors and more work needs to be done now to confirm this."
Androgenic alopecia, sometimes known as male pattern baldness, is common in men, affecting 50% throughout their lifetime. A link has been established between baldness and androgenic hormones, and androgens also play a role in the development and growth of prostate cancer. Finasteride blocks the conversion of testosterone to an androgen called dihydrotestosterone, which is thought to cause hair loss, and the drug is used to treat the condition. It has also been shown to decrease the incidence of prostate cancer.
From September 2004 Prof Giraud and his colleagues asked the men in their study to answer a questionnaire about their personal history of prostate cancer (if any) and to indicate on four pictures any balding patterns that they had at ages 20, 30 and 40. The pictures showed four stages of hair loss: no balding (stage I), frontal hair loss (receding hairline around the temples), vertex hair loss (a round bald patch at the top of the head), or a combination of both types of hair loss (stage IV). The men's doctors were also asked to provide a medical history of their patients, including any diagnosis of prostate cancer, age at diagnosis, stage of the disease and treatment. The study ran for 28 months. The men with prostate cancer were diagnosed with the disease between the ages of 46 and 84.
Dr Michael Yassa (M.D.), currently Assistant Professor at the University of Montreal (Montreal, Canada) and a radiation oncologist at the Maisonneuve-Rosemont Hospital in Montreal, but who previously worked as a radiation oncology Fellow at the European Georges Pompidou Hospital, said: "There were only three men with stage III and none with stage IV hair loss at the age of 20, but the data revealed that any balding at stages II-IV (37 cases and 14 controls) was associated with double the risk of prostate cancer later in life. This trend was lost at ages 30 and 40.
"We were unable to find an association between the type or pattern of hair loss and the development of cancer. This might be due to the very low prevalence of stage III and IV hair loss at the ages of 20 and 30 in our study."
The researchers say the link between baldness and the development of prostate cancer is still unclear. "Further work should be done, both at the molecular level and with larger groups of men, to find the missing link between androgens, early balding and prostate cancer," said Dr Yassa.

More information: "Male pattern baldness and the risk of prostate cancer".Annals of Oncology. doi:10.1093/annonc/mdq695

Provided by European Society for Medical Oncology