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Study Into Protein Activity Could Open Door for Male Contraceptives

Researchers in China have used mass spectrometry to study how molecular mechanisms of certain hormones affect sperm production, potentially opening the door to new forms of male contraceptives.
To date the only forms of male contraception are condoms and vasectomies, which are often irreversible. Pharmaceutical firms have been working on developing alternatives, most of them hormone-based, and though some have shown some promise, to date none have made it to market.
In an article published Aug. 15 in the online edition of the Journal of Proteome Research describing their work, the authors said that while earlier studies have looked into the “suppressive effects of exogenous hormone treatment on testicular function,” less research has been directed at the underlying molecular mechanisms of such effects, and as a result they are “poorly understood.”
Their research builds on a study they published last year in the Journal of Clinical Endocrinology & Metabolism looking at the suppressive effects of exogenous testosterone and testosterone with progestin on sperm production. In that study they showed that testosterone undecanoate alone and in combination with oral levonorgestrel reduced sperm production over time.
In the current article, they sought to move a step further to “clarify the underlying molecular mechanism(s) involved in hormone-induced suppression of spermatogenesis and to understand the initial response of the testicular cells to exogenous hormone administration.”
Using mass spectrometry, the researchers found “significant“ differences in the expression levels of proteins that are associated with both cell assembly and cell survival, and identified six proteins they said may serve as potential early molecular targets “responsible for spermatogenesis suppression induced by hormone treatment.”
The six proteins, they added, could lay the groundwork for further work into male contraception and provide novel targets for male contraceptive development.
Six Degrees of Contraception
For their study, the research team performed a protein profile of 36 men, evenly split between those who received injections of just testosterone undecanoate and those who received injections of testosterone undecanoate combined with oral levonorgestrel. As in their earlier study, they found that in both groups sperm concentration “severely” declined over time.
Testicular biopsies were obtained with each specimen divided in two and analyzed by immunohistochemistry, and 2D gel electrophoresis and Western blotting. Histological examination was done on the biopsies at baseline as a control.

“Further studies on their function in the testis will provide more information about the exact mechanisms of male hormonal contraception.”

No changes were found in testicular morphology between baseline and at two weeks after treatment with the hormones were found. However, an analysis of testicular proteins using 2-DE found that among men who had been treated with testosterone undecanoate, 17 protein spots were expressed “significantly” differently compared to the control group. Fourteen of the spots were identified through database searching, corresponding to 13 proteins.
In the group of men who had been treated with testosterone undecanoate and oral levonorgestrel, 46 protein spots had significant differential expressions, compared to the control group, corresponding to 31 proteins.
The researchers then analyzed the proteins for their involvement in a “relevant molecular network.” Among the 13 differential proteins that were regulated by testosterone undecanoate treatment, eight were observed to participate in the complex functional network. Three were considered “key proteins that participated in most of cellular/molecular events induced by exogenous testosterone treatment, including ‘assemble,’ ‘cell survival,’ proliferation,’ and ‘death,’” the researchers said — superoxide dismutase mitochondrial precursor, or SOD2; heterogeneous nuclear ribonucleoprotein K, or hnRNP K; and proteasome inhibitor PI31 subunit, or PSMF1.
Among the 46 proteins regulated by treatment with testosterone undecanoate combined with oral levonorgestrel, 20 proteins were identified in the complex functional network, a majority of them participating in proliferation, cell survival, and apoptosis. Of those, four — SOD2; parvalbumin alpha, or Pvalb; protein disulfide-isomerase precurson (proly 4-hydroxylase beta subunit, P4HB; and Annexin II — were identified to be “key proteins” due to their participation in most of the cellular and/or molecular events induced by hormone treatment, including proliferation, cell survival, and apoptosis.  
Of the six “key” proteins, hnRNP K and PSMF1 were found by the researchers to be upregulated in their study. hnRNP K has been observed to have a pro-apoptotic role and may help to suppress spermatogenesis, they said. Upregulation of PSMF1, they added, could lead to cell dysfunction and death.  
SOD2, which improves cell survival, was also found to be upregulated in the study, leading the researchers to surmise that this may be a “defensive or reparative response to protect the testis against enhanced oxidative stress generated from withdrawal of intratesticular testosterone,” the researchers said. Pvalb also was found to express more highly in the study.
Previous studies suggest that the protein may delay cell death and accelerate cell proliferation, and the upregulation observed in the current study may be a defensive or reparative response, the researchers said.
P4HB has been shown to protect against apoptosis, but in the study its expression was downregulated in men treated with testosterone undecanoate and oral levonorgestrel. Similar treatment also lowered the expression of Annexin II, which has been associated with cell proliferation, hampering sperm production.
“Thus the altered expression of P4HB and Annexin II … can inhibit cell proliferation and cause apoptosis in human testis,” the authors wrote.
While the researchers found upregulation in proteins that promote cell survival as well as those that induce cell death, they said that those that promote survival may only delay spermatogenesis.
Continuous treatment with the hormones, they said, may have weakened the reparative response in the testis before eventually disrupting spermatogenesis.
In an e-mail, John Amory, an associate professor of medicine at the University of Washington who has been studying male contraception and who did not participate in the Journal of Proteome Research study, said that there is value to the researchers’ approach to studying the molecular mechanisms of hormonal male contraception. But said he would like to see further characterization of the proteins and more research into their potential “drugability.”
One question about hormonal treatment as a form of male contraception is efficacy, and some studies indicate that up to 15 percent of men don’t respond to it. Amory said that the study is a first step toward addressing that issue but “doesn’t answer the big question initially.”
The authors of the study agreed that additional research is necessary but said that the six proteins they identified could serve as targets for future development of male contraceptives as well as “provide new avenues for the management of human infertility.”
“Further studies on their function in the testis will provide more information about the exact mechanisms of male hormonal contraception,” they said.

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