A second Foreign Office minister has resigned in the space of a week as Mark Simmonds quit the Government and announced he will leave Parliament at the next election.
The former Africa minister's departure, blamed on the "intolerable" pressure on his family life, follows Baroness Warsi's decision to quit in protest at Government policy on Gaza.
Downing Street insisted that Mr Simmonds' resignation was not triggered by a dispute over policy, and had been agreed with David Cameron at the time of the reshuffle last month but was delayed to allow him to chair a United Nations meeting on the situation in the Democratic Republic of Congo.
But Labour seized on the announcement, which followed Lady Warsi's shock exit on August 5, to claim the Government was "characterised by confusion" at a time when the Foreign Office faced major international crises.
Philip Hammond, who took over as Foreign Secretary in last month's reshuffle, insisted that Mr Simmonds' departure was merely a "delayed change" from Mr Cameron's shake-up of his ministerial team.
Father-of-three Mr Simmonds s aid: "Despite the enjoyment and personal fulfilment I have found in this role, the lack of support available to MPs with families outside of London and the sacrifice to my family life has become intolerable. At this stage, I need to focus on providing for my family."
In his resignation letter, the Boston and Skegness MP told Mr Cameron he would "remain supportive of you, your Government and the Conservative Party".
The Prime Minister said Mr Simmonds still had "much more to give" and had been an "incredibly loyal colleague, but also a good friend".
Mr Simmonds held his seat with a majority of 12,426 in 2010, but Ukip has made inroads in the region, with huge gains in Boston in last year's local elections.
In a letter to Ruth Street, who chairs the Boston and Skegness Conservative Association, Mr Simmonds said: "I have been concerned for some time about the view of many in the constituency that it is incompatible to be a Government minister and the local MP."
Mr Hammond insisted there was no comparison to be drawn between Mr Simmonds' departure and that of Lady Warsi.
He said: " Mark Simmonds agreed with the Prime Minister at the time of the reshuffle that he wanted to stand down, that he has made the decision to stand down from Parliament at the time of the next election.
"We are very grateful to him for agreeing to stay on to chair this very important meeting at the UN last week on the Democratic Republic of Congo.
"It's something that he has been working on for a very long time and which came to a head, as it were, with the British presidency of the Security Council.
"So he stayed on specifically for that purpose.
"This is a delayed change from the reshuffle."
He added: "Baroness Warsi's departure is in a different category altogether. She decided to resign for whatever reason and she left last week.
"Mr Simmonds' departure was agreed at the time of the reshuffle and would have been announced on the same day as William Hague's departure, had it not been for the fact that he had agreed to stay on and chair this very important meeting in New York last week."
A No 10 spokeswoman insisted that Mr Cameron was "very confident" in the team at the Foreign Office, with James Duddridge replacing Mr Simmonds.
She said Mr Duddridge, who served on the International Development Select Committee from 2006 to 2008, "had experience of dealing with international issues".
But s hadow Foreign Office minister John Spellar said the resignation raises further questions about Mr Cameron's judgment and is a "another blow to a Government already reeling" from Lady Warsi's departure.
He said: "The new Foreign Secretary has now lost two ministers in just a few days.
"At a time when the FCO (Foreign and Commonwealth Office) should be focused both on the crisis in Iraq and the situation in Gaza following the recent appalling violence there, David Cameron's Government instead risks looking increasingly rudderless and characterised by confusion.
"Even if Mark Simmonds' resignation is for understandable personal reasons, the Prime Minister should have announced his replacement at the time of the reshuffle to allow an orderly handover."
Asked if two resignations by Foreign Office ministers in a week was a disaster, Work and Pensions Secretary Iain Duncan Smith told the BBC: "No, it's not. People will always have different reasons for why they go."
In other ministerial changes triggered by the resignation of Lady Warsi, Lord Bourne of Aberystwyth has been appointed a whip, replacing Lord Bates who moved to the Home Office last week.
In a later interview, Mr Simmonds said his "main reason" for resigning was the absence of a support structure enabling MPs to have a family life and be normal.
Asked about the role of the expenses scandal in his decision, he replied: "I wasn't embroiled in it at all. But it is not that. In my view the pendulum has swung too far the other way. The support is not there for those with families.
"What we have got to be very careful of here is that certain sectors of society are not barred from entering or standing for Parliament which is what I believe is the case at the moment."
He added that there were other MPs in a similar position to him who were "reluctant" to talk because they feared being attacked as " greedy" or "wanting to return to a broken expenses system".
He stressed that was not what he was suggesting and added: "The previous expenses system was clearly indefensible, abused and people rightly went to prison for fraudulent behaviour.
"But there does need to be a system of allowances and support structures in place that supports MPs in their work, enables them to have a family life, enables them to be normal people, which currently I believe is not the case and that's the main reason why I have resigned.
"The sacrifice to family life has become intolerable and in my view the support for continuance of family life is not there... I think it is time that we had a mature debate about this.
"When I first became an MP, the situation and support mechanisms were very different. You were able both to have a family home in the constituency and a family home in London. That is no longer the case.
"I have no regrets about making that decision. It was absolutely the right thing for me and my family."
Asked about the rise of Ukip in his constituency, he said their gains had "nearly" made him change his mind about stepping down next year.
But he added: "I decided ultimately the decision I had made to put my family first was the right one."
He also said he believed the Conservatives would hold the seat at the election provided they selected a hardworking candidate.
In a statement following Mr Simmonds' resignation, the Independent Parliamentary Standards Authority said it was "awake to the impact on family life" for MPs who have to live in two locations - London and their constituency.
It continued: "That is exactly why we provide more support to MPs with family or caring responsibilities."
An MP with three school age children would get an uplift to their accommodation budget of £7,275 - giving a total of £27,875 a year.