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The latter half of the novel, set in the late 20th century, focuses on Cal's experiences in his hometown of Detroit and his escape to San Francisco, where he comes to terms with his modified gender identity.Entertainment Weekly, the Los Angeles Times, and The New York Times Book Review considered Middlesex one of the best books of 2002, and some scholars believed the novel should be considered for the title of Great American Novel.The novel contains many allusions to Greek mythology, including creatures such as the Minotaur, half-man and half-bull, and the Chimera, a monster composed of various animal parts.Narrator and protagonist Cal Stephanides (initially called "Callie") is an intersex man of Greek descent with 5-alpha-reductase deficiency, which causes him to have certain feminine traits.According to scholars, the novel's main themes are nature versus nurture, rebirth, and the differing experiences of what society constructs as polar opposites—such as those found between men and women.It discusses the pursuit of the American Dream and explores gender identity.Intersex people are born with sex characteristics, such as genitals, gonads and chromosome patterns that, according to the UN Office of the High Commissioner for Human Rights, "do not fit the typical definitions for male or female bodies".

The ovaries and testes may be present as separate organs, or ovarian and testicular tissue may be combined in the same organ (ovotestis).

After several years of struggling with the narrative voice, Eugenides finally seated himself at his desk and wrote Middlesex The novel starts with a narration by its protagonist, Cal (his masculine identity), also known as Calliope (feminine): He recounts how 5-alpha-reductase deficiency, a recessive condition, caused him to be born with female characteristics.

The book continues with accounts of his family's history, starting with his paternal grandparents in their home village and ending with his father's funeral.

Eugenides lived in Brooklyn when he began his first draft of the novel. He would write 50 pages in one voice, restart in a different voice with 75 pages, and then pursue a different narrative angle.

He wanted the novel to be an "intimate" portrayal of protagonist Cal's transformation, so he wrote a draft in the first-person narrative in Cal's voice.


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