Natural Progesterone for the Treatment of Recurrent Glioblastoma

Inclusion Criteria:

* Patients must have pathologic confirmation of a glioblastoma or gliosarcoma diagnosis at initial surgery or second or later surgery
* Patients may have had up to two previous salvage agents administered for treatment of recurrent GBM (may be at 1st, 2nd or 3rd recurrence)
* Patients must be \>= 18 years of age
* Patients must be able to have magnetic resonance imaging (MRI) scans for disease follow up
* Recurrent GBM must consist of a minimum of 1 cm\^3 of contrast enhancing disease on high resolution T1 post-contrast sequence as defined on pre-treatment MRI obtained within 14 days of initiating therapy
* White blood cell (WBC) \>= 3,000/uL (=\< 14 days prior to registration)
* Absolute neutrophil count (ANC) \>= 1,500/uL (=\< 14 days prior to registration)
* Platelet count of \>= 75,000/uL (=\< 14 days prior to registration)
* Hemoglobin \>= 9.0 gm/dl (=\< 14 days prior to registration) (transfusion is allowed to reach minimum level)
* Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =\< 2.0 x upper limit of normal (UNL) (=\< 14 days prior to registration)
* Bilirubin =\< 2 x UNL (=\< 14 days prior to registration)
* Creatinine =\< 1.5 mg/dL (=\< 14 days prior to registration)
* Patients must have a life expectancy of \>= 12 weeks
* Patients must have a Karnofsky Performance Status (KPS) \>= 60
* Patients who are women of childbearing potential must have a negative pregnancy test documented =\< 14 days prior to registration and agree to use adequate barrier contraceptive methods or abstinence for duration of study
* Patients must be able to understand and provide written informed consent
* Both men and women, and members of all races and ethnic groups are eligible for this trial. Subjects will be approximately representative of the demographics of the referral base for the participating institutions
* Patient must not have a known allergy to progesterone
* In females, no active vaginal bleeding
* Patients may not be enrolled on any other therapeutic trial for which they are receiving an anti-tumor therapy

Exclusion Criteria:

* Patients with pacemakers, aneurysm clips, neurostimulators, cochlear implants, metal in ocular structures, history of being a steel worker, or other incompatible implants which makes MRI safety an issue are excluded
* Patients that have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy are excluded
* Patients with a history of severe hepatic dysfunction of disease are excluded
* Patients with a history of idiopathic jaundice, severe pruritus and pemphigoid gestationis during pregnancy are excluded
* Patients with a history of breast or genital tract cancer are excluded
* Patients with a history of any other invasive cancer (except non-melanoma skin cancer and excluding carcinoma in-situ), unless in complete remission and off all therapy for that disease for \>= 3 years, are ineligible
* Patients with an active infection or serious intercurrent medical illness are ineligible
* Patients who received any other in anti-tumor agents (including investigational ones) must be off therapy for 4 weeks prior to initiating progesterone on study
* Patient receiving anti-coagulation therapy are excluded
* Patient with active or recent (within 6 months) thromboembolic disease are excluded
* Patient with current ongoing therapy with estrogen/progesterone (including hormonal contraceptives) are excluded. Would need to stop this form of birth control at least 7 days prior to initiation of therapy to be eligible