"Our sources tell us there were several factors," Peter Castro, deputy editor for People, told ABC News. "It's undeniable that his throat cancer and her bi-polar disorder created a perfect storm of tension and issues that were really hard to overcome."
According to People, the 68-year-old Douglas' frank comments about the cause of his throat cancer - he blamed it on a virus he contracted during oral sex - may have been one of the factors contributing to the alleged rift.
"He gave very candid interviews about his sexual past that she really bristled at. She was not happy about his comments and that sort of got the ball rolling in terms of the split," said Castro.
In May, Douglas told ABC News' Elizabeth Vargas that he admired his wife's openness about her battles with bi-polar disorder.
"She was smart to go public, you now," Douglas said. "[It] sort of reminded me of when I had to come out about the cancer. You know, [it] just clears up a lot of rumors."
The couple was last seen together publicly at a Barbra Streisand tribute in April.
The pair are Hollywood royalty, and for 13 years they've led a glamorous life, had two children and helped each other through their health crises.
The 43-year-old Zeta-Jones, an Academy Award-winning actress whose has starred in the films "Traffic," "Entrapment" and "The Mask of Zorro," announced in 2011 that she suffered from bi-polar disorder.
Douglas, a two-time Academy Award winner whose films include "Wall Street," "Fatal Attraction" and "Falling Down," has overcome stage four throat cancer.
People magazine also claims that the incarceration of Douglas' oldest son, Cameron, who pleaded guilty to selling bulk quantities of methamphetamine and cocaine, also created tension between Douglas and Zeta-Jones.
A representative for Michael Douglas had no comment on the allegations Thursday evening. A representative for Zeta-Jones did not immediately respond to a request for comment.