No abstract

The unbound fraction of plasma testosterone (T) can freely enter tissues, whereas the bioavailability of the albumin-bound T is controversial. A clinical observation in hirsute women receiving spironolactone suggested an experimental paradigm to test the effect of albumin binding on T bioavailability. We found an increase in the non-T-estrogen-binding globulin-bound fraction of plasma T in women from 24.1 +/- 3.9% to 42.0 +/- 8.1% (+/-SEM) while they received spironolactone. Computer modeling indicated that the absolute increase in the albumin-bound T concentration would be about 22.4-fold greater than that in the unbound T concentration (the ratio of albumin-bound to free T remaining virtually constant) because of the binding of T to albumin. We reasoned that the addition of graded amounts of spironolactone and its metabolites to plasma would provide a means to increase the albumin-bound T concentration appreciably. We evaluated the biological effects of this perturbation of T transport by spironolactone and its metabolites in a bioassay system using the Oldendorf technique. Bioavailable T increased proportionately with increments in free and albumin-bound T (r = 0.85; P less than 0.01). A major portion of the albumin-bound T (i.e. 55%) entered tissues under all conditions; the amount that was bioavailable vastly exceeded the amount of T that was unbound in the injected samples. An index of the amount of bioavailable T can be determined using the ammonium sulfate precipitation technique, as the percentage of non-T-estrogen-binding globulin-bound T in vitro correlated well with T bioavailability in vitro (r = 0.86; P less than 0.01). These studies support the conclusion that albumin-bound T is biologically important.

We report an incidence of thrombosis of 17.6% in 159 patients treated with a five-drug chemotherapy regimen (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) for Stage IV breast carcinoma. Chi-squared analysis of risk factors for thrombosis (ambulatory status, obesity, family history, smoking, diabetes mellitus, hypertension, liver dysfunction, thrombocytosis, and previous endocrine therapy) showed no difference between the patients who had a thromboembolic event and those who did not.Statistical analysis revealed that a significantly higher incidence of thrombosis occurred during the chemotherapy regimen than when off this regimen (P < 0.05). Detailed coagulation studies donie prospectively on 10 patients receiving the five-drug chemotherapy regimen compared with 10 control patients showed a significantly elevated Factor VIII antigen:activity ratio in the group receiving the chemotherapy regimen compared with the control group and normals. These results implicate the chemotherapeutic regimen in the pathogenesis of the increased incidence of thrombosis. The pathophysiology of thrombosis in settings such as this awaits better in vitro tests defining the "hypercoagulable state." Cancer 54:1264-1268, 1984. N INCREASED INCIDENCE OF THROMBOSIS has longA been recognized inThe frequency of such a complication ranges from 5% to 10%4*5 compared to an incidence of 0. I% in the general population.6 The mechanisms inducing altered hemostasis in malignancy are extremely complex,' and the pathophysiology of this "hypercoagulability'" has not been well defined except in a handful of neoplasms.9-' 'We report an incidence of thrombosis of 17.6% in 159 patients treated with a five-drug chemotherapy regimen (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone [CMFW]) for Stage IV metastatic breast carcinoma. Statistical analysis implicated the chemotherapeutic regimen as cause of this increased incidence. Detailed coagulation studies showed changes that could be attributed to the regimen. Awareness of this striking association may lead to future prospective studies that could better define the pathophysiology of chemotherapy-associated hypercoagulability. Materials and MethodsA total of 189 patients with progressive metastatic breast cancer were treated with combination chemotherapy from 197 1 to 1980. Thirty patients were not evaluable because of inadequate clinical data (lost to follow-up, records incomplete). The remaining 159 patients were women with Stage IV breast cancer, none of whom had received previous chemotherapy. Thirty-three patients had received no previous therapy, whereas 128 had previously received endocrine therapy. The dominant sites of disease were bone (82 patients), liver (53), lung (48) and soft tissue (3 1). A modification of the regimen reported by Cooper was used.I3